Kurzgesagt – In a Nutshell 

Sources – Fat

We thank the following experts for their critical reading of the script and scientific input:

• Prof. Jörg Heeren
  The Department of Biochemistry and Molecular Cell Biology, Universitätsklinikum Hamburg-Eppendorf | UKE

• Dr. Laura den Hartigh
  Division of Metabolism, Endocrinology and Nutrition, University of Washington Medicine Diabetes Institute

• Prof. Peter Tontonoz
  Professor of Pathology and Laboratory Medicine and of Biological Chemistry, UCLA

• Prof. Shingo Kajimura
  Department of Medicine, Harvard Medical School

 – Fat is your most dangerous organ. Yes, organ. While it is often falsely described as a mere expression of laziness or gluttony, fat is essential for health, controlling and guiding crucial processes in your body. But if you have too much fat, it starts to disrupt your metabolism becoming one of the most deadly things that can happen to your body.

#Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab. 2004
https://pubmed.ncbi.nlm.nih.gov/15181022/
Quote: “The traditional view of adipose tissue as a passive reservoir for energy storage is no longer valid. As early as 1987, adipose tissue was identified as a major site for metabolism of sex steroids (1) and production of adipsin, an endocrine factor that is markedly down-regulated in rodent obesity (2). The subsequent identification and characterization of leptin in 1994 firmly established adipose tissue as an endocrine organ (3). Adipose tissue is now known to express and secrete a variety of bioactive peptides, known as adipokines, which act at both the local (autocrine/paracrine) and systemic (endocrine) level (Table 1). In addition to these efferent signals, adipose tissue expresses numerous receptors that allow it to respond to afferent signals from traditional hormone systems as well as the central nervous system (CNS) (Table 2). Thus, besides the biological repertoire necessary for storing and releasing energy, adipose tissue contains the metabolic machinery to permit communication with distant organs including the CNS. Through this interactive network, adipose tissue is integrally involved in coordinating a variety of biological processes including energy metabolism, neuroendocrine function, and immune function.”

– Today more people are obese than starving, which is a huge victory.

#WHO. Obesity and overweight. March 2024
https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight
Quote: “Key facts
– In 2022, 1 in 8 people in the world were living with obesity.
– Worldwide adult obesity has more than doubled since 1990, and adolescent obesity has quadrupled.
– In 2022, 2.5 billion adults (18 years and older) were overweight. Of these, 890 million were living with obesity.
– In 2022, 43% of adults aged 18 years and over were overweight and 16% were living with obesity.
– In 2022, 37 million children under the age of 5 were overweight.
– Over 390 million children and adolescents aged 5–19 years were overweight in 2022, including 160 million who were living with obesity.”

#Fu et al. World Bank Blogs. Five alarming statistics on global hunger. 2025.
https://blogs.worldbank.org/en/opendata/five-alarming-statistics-on-global-hunger
Quote: “The same report concluded that rising food prices and income inequality have led to 2.8 billion people being unable to afford a healthy diet in 2022, contributing to what is termed as "hidden hunger." Rising food prices disproportionately affect poorer households which spend a greater proportion of their incomes on food.

 3. Food prices driving extreme poverty

World food prices have declined from their 2022 peaks, but price dynamics will remain a key determinant of food security in 2025. During the sharp price rises in 2022, World Bank estimations found that a mere 1% rise in global food prices pushes an additional 10 million people into extreme poverty. This underscores the vulnerability of low-income populations to even seemingly minor market fluctuations.”

#WHO. Hunger numbers stubbornly high for three consecutive years as global crises deepen: UN report. July 2024.
https://www.who.int/news/item/24-07-2024-hunger-numbers-stubbornly-high-for-three-consecutive-years-as-global-crises-deepen--un-report
Quote: “Around 733 million people faced hunger in 2023, equivalent to one in eleven people globally and one in five in Africa, according to the latest State of Food Security and Nutrition in the World (SOFI) report published today by five United Nations specialized agencies.

The annual report, launched this year in the context of the G20 Global Alliance against Hunger and Poverty Task Force Ministerial Meeting in Brazil, warns that the world is falling significantly short of achieving Sustainable Development Goal (SDG) 2, Zero Hunger, by 2030.  The report shows that the world has been set back 15 years, with levels of undernourishment comparable to those in 2008-2009.

Despite some progress in specific areas such as stunting and exclusive breastfeeding, an alarming number of people continue to face food insecurity and malnutrition as global hunger levels have plateaued for three consecutive years, with between 713 and 757 million people undernourished in 2023—approximately 152 million more than in 2019 when considering the mid-range (733 million).”


– There are all sorts of ideas about the cause of the obesity epidemic but it really comes down to one thing: For millions of years, humans had to expend a lot of effort to get food and often faced hunger. Our bodies evolved to hold on to every bit of energy.

#Blüher, Matthias. “Obesity: global epidemiology and pathogenesis.” Nature reviews. Endocrinology vol. 15,5 (2019)
https://pubmed.ncbi.nlm.nih.gov/30814686/
Quote: “The fundamental cause of obesity is a long-term energy imbalance between too many calories consumed and too few calories expended (Fig. 1). Evolutionarily, humans and their predecessors had to survive periods of undernutrition; therefore, selection pressure most likely contributed to a genotype that favours overeating, low energy expenditure and physical inactivity. Humans who could stand longer periods of famine and who could store and mobilize energy more efficiently might have reproduced more than those without these adaptations, subsequently leading to the overrepresentation of genetic variants that promote the ability to eat more rapidly, to resorb calories to a higher degree and to expand energy stores in adipose tissue more efficiently11. Only in the past few years has overnutrition emerged as a bigger health threat than the consequences of undernutrition (that is, more people are now dying from overweight and obesity than underweight)7.”

#WHO. Obesity and overweight. May 2025.
https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight
Quote: “Overweight and obesity result from an imbalance of energy intake (diet) and energy expenditure (physical activity).
In most cases obesity is a multifactorial disease due to obesogenic environments, psycho-social factors and genetic variants. In a subgroup of patients, single major etiological factors can be identified (medications, diseases, immobilization, iatrogenic procedures, monogenic disease/genetic syndrome).

The obesogenic environment exacerbating the likelihood of obesity in individuals, populations and in different settings is related to structural factors limiting the availability of healthy sustainable food at locally affordable prices, lack of safe and easy physical mobility into the daily life of all people, and absence of adequate legal and regulatory environment.
At the same time, the lack of an effective health system response to identify excess weight gain and fat deposition in their early stages is aggravating the progression to obesity.”


#NHS-UK. Overview-Obesity. Retrieved May 2025.
https://www.nhs.uk/conditions/obesity/
Quote: “Obesity is a complex issue with many causes. Obesity and overweight is caused when extra calories, particularly those from foods high in fat and sugar, are stored in the body as fat.
Obesity is an increasingly common problem because the environment we live in makes it difficult for many people to eat healthily and do enough physical activity.
Genetics can also be a cause of obesity for some people. Your genes can affect how your body uses food and stores fat.
There are also some underlying health conditions that can occasionally contribute to weight gain, such as an underactive thyroid gland (hypothyroidism), although these types of conditions do not usually cause weight problems if they're effectively controlled with medicines.
Some medicines can also make people more likely to put on weight, including steroids and some medicines for high blood pressure, diabetes or mental health conditions.”


– Body fat is also often unfairly villainized – but it is crucially important for your health and if you don't have enough, you can suffer problems from infertility to a weak immune system, fatigue, mental health issues and osteoporosis. 

#Childs GV, Odle AK, MacNicol MC, MacNicol AM. The Importance of Leptin to Reproduction. Endocrinology. 2021
https://pmc.ncbi.nlm.nih.gov/articles/PMC7749705/
Quote: “Nutritional deficiency results in reduced pituitary luteinizing hormone (LH) release in response to decreased hypothalamic gonadotropin-releasing hormone (GnRH) stimulation (7-10). When reproduction occurs in spite of nutritional deprivation, the initial outcomes are a reduction in the number and/or the size of the young (2, 3). Severe nutritional deficiency inhibits reproduction altogether as the immediate survival of the animal takes priority over its reproduction (2, 3).

In order to respond to nutritional challenges, metabolic signals relay information on energy status to the hypothalamic–pituitary–gonadal (HPG) axis. One of the most powerful signals is leptin, the 167 amino acid product of the Lep (formerly ob) gene. Leptin has the distinction of being the only known biomarker of adiposity, as its circulating levels are in linear proportion to fat mass (11, 12).”

#Scott Flynn, Jonathan Howard, Lisa Jellum, and Althea Moser. 6.3: How Much Fat is Needed? Georgia Highlands College via GALILEO Open Learning Materials. May 2025.
https://med.libretexts.org/Bookshelves/Health_and_Fitness/Concepts_of_Fitness_and_Wellness_3e_(Flynn_et_al.)/06%3A_Body_Composition/6.03%3A_How_Much_Fat_is_Needed
Quote: ”Fat storage in the body consists of two types of fat: essential and nonessential fat.Essential fat is the minimal amount of fat necessary for normal physiological function. For males and females, essential fat values are typically considered to be 3% and 12%, respectively. Fat above the minimal amount is referred to as nonessential fat. It is generally accepted that an overall range of 10-22 percent for men and 20-32 percent for women is considered satisfactory for good health. A body composition within the recommended range suggests a person has less risk of developing obesity-related diseases, such as diabetes, high blood pressure, and even some cancers.”

#Open Oregon Educational Resources. Risks of Too Little and Too Much Body Fat. Retrieved May 2025.
https://openoregon.pressbooks.pub/nutritionscience2e/chapter/__unknown__-3/
Quote: “Being underweight has been shown to be associated with an increased risk of several health conditions:11-16
Osteoporosis and low bone mineral density
Increased risk of infection, delayed wound healing, and greater post-surgical complications
Cardiovascular disease, including stroke, heart attack, and coronary heart disease
Some cancers, plus poorer response to treatment and survival rates after diagnosis
Irregular menstrual cycles, decreased fertility, and poorer pregnancy outcomes
Depression in women
Decreased semen quality in men
Stunted growth in children”


#NHS. Symptoms -Malnutrition. Retrieved May 2025.
https://www.nhs.uk/conditions/malnutrition/symptoms/
Quote: “Other symptoms of malnutrition include:
reduced appetite
lack of interest in food and drink
feeling tired all the time
feeling weaker
getting ill often and taking a long time to recover
wounds taking a long time to heal
poor concentration
feeling cold most of the time
low mood, sadness and depression”

#Yale Medicine. Lipodystrophy. Retrieved May 2025.
https://www.yalemedicine.org/conditions/lipodystrophy
Quote: “Lipodystrophy syndromes are rare disorders marked by a lack of body fat just beneath the skin’s surface. Which type a person has is determined by the patterns of fat loss on the body and whether the disease is acquired or genetic. Due to the body’s inability to process fat, lipodystrophy leads to severe metabolic, hormonal, cardiovascular and fat storage disorders. Because the disease affects an individual’s outward appearance, it can also have deep psychological effects that may need to be addressed by a mental health care professional.

People who have lipodystrophy can end up with extra fat deposits in their legs, on the face, the back of the neck, or abdomen, and within the liver (called non-alcoholic fatty liver disease). This happens because the body is unable to maintain a layer of fat beneath the skin’s surface, so the fat he or she consumes concentrates elsewhere in the body.” 

– If you consume more energy than you burn you store it as triglycerides, an organic battery bustling with energy. Collected in a large drop of fat inside a white fat cell. Gain weight and white fat cells expand with fat, lose weight and they shrink.

#Coelho M, Oliveira T, Fernandes R. Biochemistry of adipose tissue: an endocrine organ. Arch Med Sci. 2013
https://pmc.ncbi.nlm.nih.gov/articles/PMC3648822/
Quote: “During periods of calorie surplus, WAT mass expands by increasing both the size (hypertrophy) and the number of adipocytes (hyperplasia). However, chronic activation of this process becomes detrimental, leading to obesity. In obesity, excessive WAT expansion is accompanied by structural and cellular changes in the tissue, including adipocyte hypertrophy and fibrosis10, local inflammation, infiltration of immune cells, polarization of macrophages from an anti-inflammatory to a pro-inflammatory phenotype (Fig. 2), altered lipid handling in macrophages, decreased response of adipocytes to insulin (insulin resistance) and a disturbed metabolism11–14.”

#Liu, Fangcen et al. “Adipose Morphology: a Critical Factor in Regulation of Human Metabolic Diseases and Adipose Tissue Dysfunction.” Obesity surgery (2020).
https://link.springer.com/article/10.1007/s11695-020-04983-6
Quote: “In the past few decades, fat mass content has been regarded as a key factor that influences the severity of metabolic disturbances. In recent years, numerous researches have focused on how the excessive energy is stored (hypertrophy or hyperplasia) in adipose tissue (AT) rather than the total fat mass content [5,6,7]. Physiologically, adipocytes expand or proliferate in order to store more energy as triglyceride. However, in morbid obesity, adipocytes tend to expand to the greatest extent, which is termed as “adipocyte hypertrophy”. Even within the same WAT depot, cell diameter of different adipocytes varies dramatically, ranging from less than 20 to 300 μm [8]. Accordingly, alteration in adipocyte size as well as the proportions of small or large adipocytes could manifest the development of T2D and non-alcoholic fatty liver disease (NAFLD) [9,10,11,12]. Importantly, enlargement of adipocytes triggers low-grade chronic inflammation, insufficient angiogenesis, and excessive collagen deposition, which further lead to abnormal adipokine release and impaired glucose metabolism [13].”

#Chait A, den Hartigh LJ. Adipose Tissue Distribution, Inflammation and Its Metabolic Consequences, Including Diabetes and Cardiovascular Disease. Front Cardiovasc Med. 2020
https://pmc.ncbi.nlm.nih.gov/articles/PMC7052117/
Quote: “Adipose tissue is an essential organ for the regulation of energy homeostasis. Primarily tasked with storing excess energy as triglycerides, adipocytes undergo hyperplasia to increase the number of adipocytes and hypertrophy to increase the size of each adipocyte, allowing adipose tissue to expand in times of nutrient excess. As needed, i.e., during fasting and exercise, triglycerides stored in adipose tissue are mobilized to provide fatty acids for energy utilization by the rest of the body. Stored triglycerides are therefore in a constant state of flux, whereby energy storage and energy mobilization are determined largely by hormonal fluctuations. Thus, adipose tissue functions as an energy balance “hub” that integrates and services the energy requirements of diverse organ systems, such as the liver, skeletal and heart muscle, pancreas, and brain (64).

In healthy lean individuals, the majority of adipose tissue resides in subcutaneous depots, where it serves a thermoregulatory function, and from which stored triglycerides can be readily mobilized when needed (65). Conditions that favor adipose tissue expansion, if endured chronically, will eventually exceed the storage capacity of defined adipose tissue depots, leading to the ectopic deposition of triglycerides in other tissues, including intra-abdominal depots (discussed in more detail in later sections).”

#Choe SS, Huh JY, Hwang IJ, Kim JI and Kim JB (2016) Adipose Tissue Remodeling: Its Role in Energy Metabolism and Metabolic Disorders. Front. Endocrinol.
https://www.researchgate.net/figure/Characteristics-of-hypertrophic-and-hyperplasic-adipocytes-In-obesity-adipose-tissue_fig2_301280725

– Only in the last few decades have we learned fats' most important job: Fat is an endocrine organ, part of the system that makes and regulates your hormones: chemical signals for your brain, liver, muscles, digestive tract and immune system, making them work correctly together. Unfortunately if you become overweight and obese, your fat organ and the many hormones it releases turn insane.

#Coelho M, Oliveira T, Fernandes R. Biochemistry of adipose tissue: an endocrine organ. Arch Med Sci. 2013 Apr 20;9(2):191-200.
https://pmc.ncbi.nlm.nih.gov/articles/PMC3648822/
Quote: “Adipose tissue is no longer considered to be an inert tissue that stores fat. This tissue is capable of expanding to accommodate increased lipids through hypertrophy of existing adipocytes and by initiating differentiation of pre-adipocytes. Adipose tissue metabolism exerts an impact on whole-body metabolism. As an endocrine organ, adipose tissue is responsible for the synthesis and secretion of several hormones. These are active in a range of processes, such as control of nutritional intake (leptin, angiotensin), control of sensitivity to insulin and inflammatory process mediators (tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), resistin, visfatin, adiponectin, among others) and pathways (plasminogen activator inhibitor 1 (PAI-1) and acylation stimulating protein (ASP) for example). ”

#Scheja, Ludger, and Joerg Heeren. “The endocrine function of adipose tissues in health and cardiometabolic disease.” Nature reviews. Endocrinology vol. 15,9 (2019).
https://pubmed.ncbi.nlm.nih.gov/31296970/

– In adults fat comes in two types of white fat depots – most of it is subcutaneous fat, the gooey soft stuff under your skin that insulates against the cold and serves as energy storage. The other one is visceral fat nestled between your organs providing a soft cushion for your sensitive insides. But it also happens to be more dangerous. 

#Subcutaneous Fat. Cleveland Clinic. 2022.
https://my.clevelandclinic.org/health/diseases/23968-subcutaneous-fat
Quote: “Subcutaneous fat is a type of fat that’s stored just beneath your skin. Your skin is made up of three layers – the epidermis, dermis and subcutaneous fat. Subcutaneous fat is the deepest layer of your skin. It serves many functions. Subcutaneous fat:

– Pads your muscles and bones to protect you from bumps and falls.
– Helps your blood vessels and nerves get from your skin to your muscles.
– Controls your body temperature, making sure you don’t get too warm or too cold.
– Attaches your middle layer of skin (dermis) to your muscles and bones with special connective tissue.

Visceral fat is fat that lies deep within your abdominal organs and can’t be seen from the outside. It surrounds your stomach, liver, intestines and other important organs. Subcutaneous fat is different. Subcutaneous fat is the fat just under your skin. It’s the kind that you can grab and pinch between your fingers. Subcutaneous fat collects mainly around your hips, butt, thighs and belly.”

#Ibrahim, M Mohsen. “Subcutaneous and visceral adipose tissue: structural and functional differences.” Obesity reviews : an official journal of the International Association for the Study of Obesity vol. 11,1 (2010)
https://pubmed.ncbi.nlm.nih.gov/19656312/
Quote: ”The main areas for subcutaneous fat deposition are the femerogluteal regions, back and anterior abdominal wall. About 80% of all body fat is in the subcutaneous area (7,8). The abdominal fat is present in two main depots: subcutaneous and intra-abdominal. Intra-abdominal fat: Visceral fat accounts for up to 10–20% of total fat in men and 5–8% in women (7). The amount of visceral fat increases with age in both genders (7).”

#Chait A, den Hartigh LJ. Adipose Tissue Distribution, Inflammation and Its Metabolic Consequences, Including Diabetes and Cardiovascular Disease. Front Cardiovasc Med. 2020
https://pmc.ncbi.nlm.nih.gov/articles/PMC7052117/
Quote: “Primarily localized to upper and lower body depots in humans, subcutaneous WAT is the most prominent WAT depot in lean, healthy subjects, making up ~80% of all adipose tissue (13). Thus, more than any other depot, subcutaneous WAT represents a physiological buffer for excess energy intake during times of limited energy expenditure. Subcutaneous WAT acts as a metabolic “sink” for excess lipid storage (14). When this storage capacity is exceeded, either due to an inability to generate sufficient new adipocytes (limited hyperplasia) or an inability to further expand existing adipocytes (limited hypertrophy), fat begins to accumulate ectopically in areas outside the subcutaneous WAT (see sections on Ectopic and Visceral Fat below). Additionally, subcutaneous WAT functions as an insulator to prevent heat loss, as a barrier against dermal infection, and as a protective cushion against physical external stress (15).”

#Abate N, Garg A, Peshock RM, Stray-Gundersen J, Grundy SM. Relationships of generalized and regional adiposity to insulin sensitivity in men. J Clin Invest. 1995
https://pubmed.ncbi.nlm.nih.gov/7615840/
Quote: “39 healthy middle-aged men with a wide range of adiposity were studied. Overall, the intraperitoneal and retroperitoneal fat constituted only 11 and 7% of the total body fat. Glucose disposal rate (Rd) and residual hepatic glucose output (rHGO) values during the 40 mU/m2.min insulin infusion correlated significantly with total body fat (r = -0.61 and 0.50, respectively), subcutaneous abdominal fat (r = -0.62 and 0.50, respectively), sum of truncal skinfold thickness (r = -0.72 and 0.57, respectively), and intraperitoneal fat (r = -0.51 and 0.44, respectively) but not to retroperitoneal fat. After adjusting for total body fat, the Rd and rHGO values showed the highest correlation with the sum of truncal skinfold thickness (partial r = -0.40 and 0.33, respectively). We conclude that subcutaneous truncal fat plays a major role in obesity-related insulin resistance in men, whereas intraperitoneal fat and retroperitoneal fat have a lesser role.”

#Liu, Fangcen et al. “Adipose Morphology: a Critical Factor in Regulation of Human Metabolic Diseases and Adipose Tissue Dysfunction.” Obesity surgery (2020).
https://link.springer.com/article/10.1007/s11695-020-04983-6
Quote: “AT is commonly classified as visceral AT (VAT) and subcutaneous AT (SAT). Anatomically, VAT is located primarily in the mesentery and omentum while SAT is presented mainly in gluteofemoral, back, and anterior abdominal region. Metabolically, SAT is suggested to have a protective role of metabolic risk [15, 16], while excessive VAT accumulation is an independent risk factor for obesity-induced metabolic disorders [17].

Specifically, VAT contains fewer preadipocytes and more large adipocytes. On the contrary, SAT tended to contain more small adipocytes [18]. One study measured adipocyte size in both SAT and VAT in 11 morbidly obese women with normal glucose level. Mean adipocyte volume was larger in VAT than that in SAT, but these two depots did not differ in the proportion of small adipocytes [14]. Also, expressions of cell differentiation markers were greater in SAT, whereas VAT displayed greater expression of inflammatory genes [19]. These results suggest that VAT tends to be less involved in triglyceride deposition but relates more to adipose inflammation, compared with SAT.”

#Chait A, den Hartigh LJ. Adipose Tissue Distribution, Inflammation and Its Metabolic Consequences, Including Diabetes and Cardiovascular Disease. Front Cardiovasc Med. 2020
https://pmc.ncbi.nlm.nih.gov/articles/PMC7052117/
Quote: “Fat localized within the visceral compartment has been classified as omental, mesenteric, and retroperitoneal. Lean, healthy individuals do not have large amounts of visceral fat, which largely falls into the category of ectopic fat. Visceral fat is highly metabolically active and is constantly releasing free fatty acids (FFA) into the portal circulation. As such, visceral fat content contributes to various features of the metabolic syndrome, such as hyperinsulinemia, systemic inflammation, dyslipidemia, and atherosclerosis (25), to be discussed in more detail in later sections pertaining to obesity.”

[...]
Other obese individuals tend to accumulate fat mainly intra-abdominally in visceral depots, which is also known as central obesity. Visceral adiposity is associated with insulin resistance, a predisposition to diabetes, local and systemic inflammation, dyslipidemia [characterized by hypertriglyceridemia, a preponderance of small, dense low-density lipoprotein (LDL) particles and reduced high-density lipoprotein (HDL)-cholesterol levels], insulin resistance, dysglycemia [a broad term that refers to an abnormality in blood sugar stability], adipose tissue and systemic inflammation, hypertension, a thrombogenic profile and non-alcoholic fatty liver disease (NAFLD) (194). This constellation of CVD risk factors associated with visceral obesity is widely known as the metabolic syndrome and is a hallmark of MUHO, illustrated in Figure 1. Visceral obesity and the metabolic syndrome are associated with an increased risk of developing CVD, which is exacerbated when overt diabetes develops as a result of insulin secretion failing to adequately compensate for insulin resistance. Interestingly, even normal weight individuals who accumulate fat intra-abdominally have these metabolic abnormalities (195, 196), including an increased risk of CVD.”

– These fat cells are super sensitive to stress hormones like cortisol or adrenaline. When they pick up a surge of stress, they release fatty acids directly into your blood and are picked up by your liver, as a rapid source of energy. On top of that your visceral fat is very metabolically active, in a constant hormonal dialog with the rest of your body.

#Shively CA, Register TC, Clarkson TB. Social stress, visceral obesity, and coronary artery atherosclerosis: product of a primate adaptation. Am J Primatol. 2009 Sep;71(9):742-51. doi: 10.1002/ajp.20706. PMID: 19452515; PMCID: PMC3970187.
https://pmc.ncbi.nlm.nih.gov/articles/PMC3970187
Quote: “Unremitting stress may result in chronic hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis, and sustained glucocorticoid production. The long-term effects of glucocorticoids on adipocyte metabolic processes are thought to promote visceral obesity. Visceral fat has some unique properties which distinguish it from subcutaneous fat and make it more sensitive to glucocorticoids [Black, 2006]. Visceral fat is highly innervated by blood vessels and nerves and has a high concentration of glucocorticoid receptors. When bound, the glucocorticoid-receptor complex promotes lipoprotein lipase (LPL) gene expression and activates LPL on the cell surface. LPL promotes fatty acid uptake and storage as triglycerides in fat, promoting visceral fat accumulation. The stromal cells in visceral fat contain relatively high levels of the enzyme 11β-hydroxysteroid dehydrogenase type 1, which converts cortisone to the active form of cortisol [Lundgren et al., 2008]. Thus, the downstream effects of glucocorticoids may be enhanced, again promoting visceral fat accumulation. More recently, obesity, particularly visceral obesity, has been recognized as a systemic low-grade inflammatory state. The proinflammatory cytokines secreted from visceral fat promote a hypersecretory HPA axis, which in turn promotes visceral fat accumulation. Thus, the relationship between stress and visceral obesity may be bidirectional and self-sustaining [Beasley et al., 2009; Black, 2006; Kyrou & Tsigos, 2007].
Autonomic nervous system responses to stress also play an important role. Visceral fat has an abundance of β-adrenergic receptors, is relatively less responsive to α-adrenergic agonists, and is less responsive to the antilipolytic effects of insulin [Bolinder et al., 1983]. Under stress-induced sympathetic arousal, these characteristics promote lipolysis. Visceral adipocyte lipolysis results in increased delivery of free fatty acids to the portal vein which may promote glucose intolerance, hyperinsulinemia, and dyslipidemia by influencing hepatic function [Arner, 1997]. Recently, Kuo et al. [2007] observed in rats that chronic stress, combined with a high-fat/high-sugar diet, increased release of sympathetic neurotransmitter neuropeptide Y and the expression of neuropeptide Y-Y2 receptors in visceral fat, promoting preadipocyte proliferation, differentiation, and lipid-filling, thus increasing visceral obesity and the metabolic syndrome. Thus, several characteristics of visceral fat may contribute to the tendency for it to accumulate in response to stress [Kyrou & Tsigos, 2007].”

#Ibrahim, M Mohsen. “Subcutaneous and visceral adipose tissue: structural and functional differences.” Obesity reviews : an official journal of the International Association for the Study of Obesity vol. 11,1 (2010)
https://pubmed.ncbi.nlm.nih.gov/19656312/
Quote: “Adipocytes constitute the main cellular component of adipose tissue and are the chief storage depots of the energy in form of TG droplets. New smaller adipocytes act as a sink or powerful buffers, which avidly absorb FFAs and TGs in the postprandial period. As adipocytes grow larger, they become dysfunctional. Large adipocytes are insulin resistant, hyperlipolytic and resistant to anti-lipolytic effect of insulin. VAT contains greater number of large adipocytes in contrast to SCAT, which contains the small adipocytes. Small adipocytes are more insulin-sensitive and have high avidity for FFAs and TGs uptake, preventing their deposition in non-adipose tissue (10,11).”

#Imbeault, P et al. “Reduced alpha(2)-adrenergic sensitivity of subcutaneous abdominal adipocytes as a modulator of fasting and postprandial triglyceride levels in men.” Journal of lipid research 2000
https://pubmed.ncbi.nlm.nih.gov/10974043/
Quote: “Alterations in plasma lipid and lipoprotein levels are prominent features of obesity, especially abdominal obesity (1, 2, 3). Indeed, individuals displaying a substantial accumulation of abdominal adipose tissue show greater plasma triglycerides (TG), very low density lipoprotein (VLDL), and apolipoprotein B (apoB) concentrations than nonobese persons. These metabolic alterations probably result from an increased free fatty acid (FFA) flux to the liver and a major culprit seems to be visceral adipose tissue, because it is characterized by a high lipolytic activity and a low antilipolytic response to insulin (4, 5).

As α2-adrenoceptors inhibit and β-adrenoceptors stimulate adipose tissue lipolysis (6, 7), the fact that subcutaneous adipocytes possess more α2- and fewer β-adrenoceptors than visceral fat cells explains in part their lower lipolytic capacity (8, 9). Moreover, subcutaneous adipocytes do not display the same potential as visceral adipose cells to deliver FFA into the portal circulation because of their anatomic location. However, some in vitro studies have already emphasized that subcutaneous fat cell lipolysis may also contribute to the development of metabolic perturbations in abdominally obese patients. In this regard, Arner et al. (10) have previously reported that low β2-adrenoceptor sensitivity in subcutaneous abdominal fat cells was related to high plasma VLDL-TG and apoB levels. Furthermore, we have demonstrated that men with high femoral fat cell lipolysis (i.e., a low α2-adrenergic component) were characterized by increased fasting plasma insulin, low density lipoprotein (LDL)-cholesterol (C), and LDL-apoB levels (11), suggesting that high femoral adipose tissue lipolysis may be associated with an enhanced cardiovascular disease (CVD) risk profile in men.”

– This is also why the health of two people with the same weight and amount of fat can be totally different. If you are pear shaped and your fat is mostly in your hips or limbs you are much less at risk than someone apple shaped with a lot of fat in their torso. 

#Jayedi, Ahmad et al. “Central fatness and risk of all cause mortality: systematic review and dose-response meta-analysis of 72 prospective cohort studies.” BMJ 2020.
https://www.bmj.com/content/370/bmj.m3324.long
Quote: “Results Of 98 745 studies screened, 1950 full texts were fully reviewed for eligibility. The final analyses consisted of 72 prospective cohort studies with 2 528 297 participants. The summary hazard ratios were as follows: waist circumference (10 cm, 3.94 inch increase): 1.11 (95% confidence interval 1.08 to 1.13, I2=88%, n=50); hip circumference (10 cm, 3.94 inch increase): 0.90 (0.81 to 0.99, I2=95%, n=9); thigh circumference (5 cm, 1.97 inch increase): 0.82 (0.75 to 0.89, I2=54%, n=3); waist-to-hip ratio (0.1 unit increase): 1.20 (1.15 to 1.25, I2=90%, n=31); waist-to-height ratio (0.1 unit increase): 1.24 (1.12 to 1.36, I2=94%, n=11); waist-to-thigh ratio (0.1 unit increase): 1.21 (1.03 to 1.39, I2=97%, n=2); body adiposity index (10% increase): 1.17 (1.00 to 1.33, I2=75%, n=4); and A body shape index (0.005 unit increase): 1.15 (1.10 to 1.20, I2=87%, n=9). Positive associations persisted after accounting for body mass index. A nearly J shaped association was found between waist circumference and waist-to-height ratio and the risk of all cause mortality in men and women. A positive monotonic association was observed for waist-to-hip ratio and A body shape index. The association was U shaped for body adiposity index.

Conclusions Indices of central fatness including waist circumference, waist-to-hip ratio, waist-to-height ratio, waist-to-thigh ratio, body adiposity index, and A body shape index, independent of overall adiposity, were positively and significantly associated with a higher all cause mortality risk. Larger hip circumference and thigh circumference were associated with a lower risk. The results suggest that measures of central adiposity could be used with body mass index as a supplementary approach to determine the risk of premature death.”

– As you gain unhealthy weight, excess visceral fat triggers a cascade of negative changes all at once. Fat cells bloat up to their limit until they outgrow their blood supply and get starved of oxygen. They become critically stressed or even die. 

#Mirabelli, Maria et al. “Hypoxia in Human Obesity: New Insights from Inflammation towards Insulin Resistance-A Narrative Review.” International journal of molecular sciences 2024.
https://pubmed.ncbi.nlm.nih.gov/39337290/
Quote: “Indeed, a key mechanism implicated in VAT dysfunction and abnormal release of biologically active adipose-derived products is hypoxia. As VAT expands in obesity, the distance between adipocytes and the vasculature increases, reducing oxygen tension and leading to hypoxia. Oxygen deprivation below physiological levels contributes to the aberrant secretion of pro-inflammatory cytokines and adipokines by hypertrophic adipocytes [34]. Hypertrophic adipocytes can grow to diameters of 150–200 μm, exceeding the typical oxygen diffusion limit of 100–200 μm. Landmark studies using validated genetic obesity models, in which oxygen levels were directly measured in visceral fat using a needle-type oxygen microsensor, demonstrated a significant difference in interstitial oxygen levels. In obese mice, epididymal fat depots exhibited oxygen levels of 15.2 mmHg (~2% O2), compared to 47.9 mmHg (~7% O2) in their lean counterparts. This represents a 70% reduction in oxygen tension within the visceral fat of obese mice, which is attributed not to systemic hypoxia, but rather to inadequate local blood flow and vascular support [35]. Corresponding human studies, although focused on oxygen levels in abdominal subcutaneous fat, have similarly documented lower oxygen levels in obese individuals’ adipose tissue. This reduction correlates with a decrease in capillary density, paralleling findings in obese mice [36]. This hypoxic environment induces oxidative stress, ER stress, and the activation of the unfolded protein response (UPR), collectively contributing to cell dysfunction. The ER is essential for the proper folding, maturation, and assembly of proteins, as well as for maintaining cellular calcium homeostasis. Hypoxia can alter these processes by causing protein misfolding, as the formation of disulfide bonds, which require oxygen, becomes compromised. This leads to ER stress and triggers the UPR [37]. This cascade of events aims to manage the accumulation of unfolded and misfolded proteins in the ER lumen, thereby alleviating cellular stress and restoring homeostasis. A key aspect of the UPR involves the activation of mTORC1, a critical regulator of protein synthesis and cell growth that functions downstream of the PI3K/Akt signaling pathway (Figure 1). Additionally, ER stress can reciprocally influence mTORC1 and the PI3K/Akt pathway, resulting in suppressed insulin signaling and reduced Akt phosphorylation [38]. While the UPR initially serves a protective role, prolonged ER stress can lead to cell death [39]. Hypoxia also targets mitochondria, where it induces overproduction of reactive oxygen species and calcium overload, impairing ATP generation through oxidative phosphorylation and resulting in an energy deficit [40]. ”

#Chait A, den Hartigh LJ. Adipose Tissue Distribution, Inflammation and Its Metabolic Consequences, Including Diabetes and Cardiovascular Disease. Front Cardiovasc Med. 2020
https://pmc.ncbi.nlm.nih.gov/articles/PMC7052117/#s4
Quote: “Obesity results when energy intake chronically exceeds energy expenditure. Many factors are involved, including genetic, epigenetic, hormonal, and lifestyle factors that are beyond the scope of this review. Adipocyte number is believed to be tightly regulated and determined during childhood (167). However, during the development of obesity, adipose tissue can expand by either hypertrophy (an increase in adipocyte size) or hyperplasia (an increase in adipocyte number due to the recruitment of new adipocytes). Obesity is characterized by dysfunctional adipose tissue, in which adipocytes initially become hypertrophic during periods of caloric excess and secrete adipokines that result in the recruitment of additional pre-adipocytes, which differentiate into mature adipocytes as compensatory protection against some of the adverse metabolic consequences of obesity (168). This concept is supported by observations in AdipoChaser mice, a model for tracking adipogenesis (169). AdipoChaser mice fed a high fat diet display evidence of hypertrophy of visceral WAT within 1 month, while hyperplasia occurs after 2 months. Importantly, subcutaneous WAT does not undergo hyperplasia, and hypertrophy lags behind the visceral compartment, with evidence of subcutaneous WAT hypertrophy after 2 months of high fat feeding (170). However, when the capacity for adipocyte recruitment and hypertrophy is overwhelmed, fat accumulates in ectopic sites such as visceral depots, the liver, skeletal muscle, and pancreatic beta cells. These changes are accompanied by inflammation, insulin resistance and other features of the metabolic syndrome, and have been termed metabolically unhealthy obesity (MUHO) (171, 172). In contrast to MUHO, some people accumulate fat mainly in subcutaneous depots, a condition that has been termed metabolically healthy obesity (MHO). MHO is not accompanied to any great extent by insulin resistance, adipose tissue and systemic inflammation, and other features of the metabolic syndrome such as dyslipidemia and hypertension (173–176). Thus, the distribution of fat accumulation is a major determinant of metabolic complications associated with obesity, which can increase the risk of CVD. Various features that contribute to dysfunctional WAT in obesity will be discussed in the sections that follow.”

– This is bad. If you are overweight or obese your fat is basically a wounded organ leaking stress and poison into your system. Especially your visceral fat, even more triggered by the extra stress hormones, makes your blood more fatty. This overfeeds your organs like your liver or your muscles, who can’t keep up anymore and begin to take damage. 

#Girard, J, and M Lafontan. “Impact of visceral adipose tissue on liver metabolism and insulin resistance. Part I: Visceral adipose tissue production and liver metabolism.” Diabetes & metabolism 2008.
https://pubmed.ncbi.nlm.nih.gov/18550411/
Quote: “Obesity is a risk factor for numerous diseases such as type 2 diabetes (T2D), hypertension and cardiovascular events, including myocardial infarction and stroke. The anatomical distribution of fat deposition has a marked impact on the level of risk. Abdominal, or male, obesity, in particular, sharply raises the risk of insulin resistance, T2D, and further risk factors of metabolic and cardiovascular diseases [1]. Patients with abdominal obesity due to adipose tissue (AT) accumulation in the upper part of the body have more extensive visceral AT (VAT) [1]. The insulin resistance, or metabolic syndrome, that precedes T2D onset is usually associated with dyslipidaemia. Patients with excess VAT are characterized by anomalies of blood-glucose homoeostasis, elevated plasma triglycerides (TG) and low levels of high-density lipoprotein (HDL) cholesterol. These disorders are often associated with a prothrombotic and proinflammatory state that further contributes to the later appearance of cardiovascular syndromes [1,2]. It has been shown that VAT releases a large amount of free fatty acids (FFA) and hormones/cytokines in the portal vein that are then directly delivered to the liver. The anatomy of the liver also provides a mechanism by which the portal and arterial circulations can interact with both the parenchyma (hepatocytes) and immune-system cells that are also located within the liver.”

– The cellular stress and dead fat cells are emergency signals that call your immune system to a fight. Armies of macrophages invade your fat tissue, creating clusters, trying to eliminate the cause of the stress but can’t. So they stay and call for more help. In a lean person’s fat, immune cells make up about 5% of cells – in an obese person's fat, up to 40%! 

#Mirabelli, Maria et al. “Hypoxia in Human Obesity: New Insights from Inflammation towards Insulin Resistance-A Narrative Review.” International journal of molecular sciences vol. 25,18 9802. 11 Sep. 2024, doi:10.3390/ijms25189802
https://pubmed.ncbi.nlm.nih.gov/39337290/
Quote: “In obesity, the metabolic and endocrine functions of adipose tissue shift towards a pro-inflammatory and pro-fibrotic state. Hypoxia-induced stress or death of VAT adipocytes triggers macrophage infiltration and activation, forming crown-like structures around apoptotic adipocytes. This macrophagic infiltration is characterized by both increased recruitment and decreased egress of macrophages, mediated by chemokines like the monocyte chemoattractant protein-1 (MCP-1), which attracts macrophages, and the macrophage migration inhibitory factor (MIF), which prevents their departure [56]. Another hallmark of immune alterations in obesity is the transition of macrophages from an M2 to an M1 phenotype, further remodeling the adipose tissue microenvironment and contributing to the complex pro-inflammatory network [57,58]. Activation of HIF-1α is implicated in the shift of M2 macrophages towards the pro-inflammatory M1 phenotype. M2 macrophages release anti-inflammatory cytokines such as IL-1 receptor antagonist, IL-4, IL-10, and TGF-β, and activate arginase 1 (Arg1) to inhibit inducible nitric oxide synthase (iNOS) activity. In contrast, M1 macrophages secrete pro-inflammatory cytokines such as IL-1β, IL-6, IL-12, TNF-α, and MCP-1, along with reactive oxygen species generated by iNOS [59]. This increases the risk of cardiovascular diseases and atherosclerosis [60]. Additionally, hypoxia, mediated by HIF-1, alongside insulin signaling through Akt and inflammatory cytokines, also influences the expression and/or activity of endothelial nitric oxide synthase (eNOS), a key regulator of endothelial and vascular homeostasis [61]. M1 macrophages also release VEGF, which is associated with angiogenic and tumorigenic processes [62]. This inflammatory milieu contributes to the link between obesity and cancer, now the leading cause of death in obese patients, surpassing cardiovascular disease mortality rates [63]. Other immune cells also contribute to local inflammation. Neutrophils, abundant in circulation, migrate to specific sites and exacerbate chronic inflammation by promoting macrophage recruitment and secreting proteases like elastase, myeloperoxidase, and calprotectin. Neutrophils from obese individuals show increased superoxide secretion compared to their lean counterparts, promoting cell apoptosis and macrophage activation, thus amplifying the pro-inflammatory response [64]. ”

#Boutens, L., Stienstra, R. Adipose tissue macrophages: going off track during obesity. Diabetologia 59, 879–894 (2016). 
https://link.springer.com/article/10.1007/s00125-016-3904-9
Quote: "Macrophages are immune cells that have gained much attention as important contributors to adipose tissue functioning. Whereas macrophages in lean mice and humans make up around 5% of the cells in adipose tissue, during obesity they constitute up to 50% of all adipose tissue cells [5]. As well as increasing in number, adipose tissue macrophages (ATMs) change their localisation and inflammatory features during obesity. Contrary to the lean state, in which ATMs are distributed throughout the adipose tissue exposing limited inflammatory properties, ATMs in obese adipose tissue are located around dead adipocytes and form so-called crown-like structures (CLSs) while displaying profound proinflammatory features [6–8]. Macrophage presence in CLSs within obese adipose tissue has been directly linked with insulin resistance [9, 10]. Notably, however, the importance of macrophage-mediated inflammation in determining insulin resistance is related to long-term exposure to a high-fat diet (HFD) whereas the initial stage of insulin resistance is independent of macrophage action [11]."

#Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003 https://pmc.ncbi.nlm.nih.gov/articles/PMC296995/
Quote: “We estimate that the percentage of macrophages in adipose tissue ranges from under 10% in lean mice and humans to over 50% in extremely obese, leptin-deficient mice and nearly 40% in obese humans.”

#Rohm TV, Meier DT, Olefsky JM, Donath MY. Inflammation in obesity, diabetes, and related disorders. Immunity. 2022
https://pmc.ncbi.nlm.nih.gov/articles/PMC8773457/
Quote: “Following the initial reports of increased numbers of adipose tissue macrophages (ATMs) in both mouse and human obesity (Weisberg et al., 2003; Xu et al., 2003), additional studies showed that these cells contribute to the insulin resistant state (Bigornia et al., 2012; Lackey and Olefsky, 2016; Xu et al., 2003). Indeed, prevention of ATM accumulation or pro-inflammatory macrophage signaling, protects obese mice from glucose intolerance and IR (Desai et al., 2017; Dror et al., 2017; Lee and Olefsky, 2021; Takikawa et al., 2016). In addition to macrophages, there are other immune cell types which participate in adipose tissue inflammation during obesity. However, while certain T and B cell subsets play important regulatory roles, it is generally thought that macrophages are the major effector cells leading to decreased insulin signaling (Chawla et al., 2011; McLaughlin et al., 2017). In lean mice and humans, ATMs make up 10% to 15% of the stromovascular cells and largely display an M2-like polarization state (Weisberg et al., 2003; Xu et al., 2003) (Figure 1, lean AT). In obesity, the number of ATMs increases and can comprise up to 40% of all adipose tissue cells (Lumeng et al., 2007). Most of these obesity-induced ATMs are pro-inflammatory (M1-like) (Lumeng et al., 2007; Nguyen et al., 2007) (Figure 1, Obese AT) and similar findings have been shown in human ATMs (Fuchs et al., 2021; Wentworth et al., 2010). The phenotype of these macrophages is not fixed and can be modified by SFAs acting through a TLR-4 mechanism which stimulates the M1-like polarization state (Shi et al., 2006). Omega-3 fatty acids (fish oils) inhibit this inflammatory state by binding to the cell surface receptor GPR120 (Oh et al., 2010).”

#Chait A, den Hartigh LJ. Adipose Tissue Distribution, Inflammation and Its Metabolic Consequences, Including Diabetes and Cardiovascular Disease. Front Cardiovasc Med. 2020
https://pmc.ncbi.nlm.nih.gov/articles/PMC7052117/
Quote: “Adipose tissue expansion in obesity is accompanied by inflammatory changes within adipose tissue, contributing to chronic low-grade systemic inflammation that is characterized as mildly elevated levels of circulating cytokines, chemokines, and acute phase reactants. In mice fed a high fat diet, obesity is associated with the induction of a large number of inflammatory pathways, constituting as many as 59% of total pathways that are differentially regulated (212). Expansion of adipose tissue depots during weight gain is accompanied by an infiltration of new inflammatory cells, the major one initially being macrophages. Reported to represent ~5–10% of total cells within lean adipose tissue, macrophages in obese adipose tissue represent up to 60% of all cells present (213). These pro-inflammatory cells are recruited in response to chemokines such as monocyte chemotactic protein-1 (MCP-1) produced by hypertrophic adipocytes (213, 214). Studies in mice have demonstrated that most macrophages in obese adipose tissue are derived from circulating monocytes (213), although a small percentage appear to derive from proliferation of resident tissue macrophages (215). Resident macrophages that are present in normal adipose tissue express markers of “alternatively activated,” or M2 macrophages such as the mannose receptor (CD206), macrophage galactose type C-type Lectin/CD301a/CLEC10A (MGL1), and arginase-1 (ARG1). These anti-inflammatory macrophages are believed to be responsible for maintaining tissue homeostasis (216). It remains unclear whether the derivation of adipose tissue macrophages is the same in human obesity.”

#Bigornia, S., Farb, M., Mott, M. et al. Relation of depot-specific adipose inflammation to insulin resistance in human obesity. Nutr & Diabetes 2, e30 (2012).
https://www.nature.com/articles/nutd20123#Fig1

– The inflammation molecules and fatty acids rip countless tiny wounds into the insides of your blood vessels, which leads to plaques that desperately try to close them.

Rocha, Viviane Z, and Peter Libby. “Obesity, inflammation, and atherosclerosis.” Nature reviews. Cardiology. 2009.
https://pubmed.ncbi.nlm.nih.gov/19399028/
Quote: “Understanding of the pathophysiology of atherogenesis has evolved substantially during the last few decades. Atherosclerosis was once identified as a lipid-storage disease, but is now recognized as a subacute inflammatory condition of the vessel wall, characterized by infiltration of macrophages and T cells, which interact with one another and with cells of the arterial wall. The pathological mechanisms of obesity recapitulate many features of the inflammatory processes at work in atherosclerosis. Our current appreciation of the similarities between obesity and atherosclerosis has already fostered innovations for the diagnosis, prognosis, and prevention of these two conditions.”

– This narrows your blood vessels and reduces the flow of oxygen-rich blood. Inflammation also causes your blood pressure to rise, so your heart has to work harder and your risk of heart attacks or strokes increases massively.

#Leggio, M., Lombardi, M., Caldarone, E. et al. The relationship between obesity and hypertension: an updated comprehensive overview on vicious twins. Hypertens Res 40, 947–963 (2017).
https://doi.org/10.1038/hr.2017.75
Quote: “There is a clearly established link between obesity and hypertension.28,29,56,57 The accumulation of excess adipose tissue initiates a cascade of events that give rise to an elevated blood pressure; obesity-induced hypertension is a common pathway in both children and adults.29,58,59 Pathogenetic factors and pathophysiological mechanisms linking obesity to hypertension (Figure 1) are described and reviewed herein as they provide the basis for a rational therapeutic strategy.
[...]
Hypertension is a complex phenotype that arises from numerous genetic, environmental (including air pollution26), behavioral and even social origins, and obesity is one of the most prevalent risk factors for its development. Regardless of its etiology, however, hypertension is a highly prevalent and highly significant risk factor for the development of all manifestations of cardiovascular disease, including coronary heart disease, stroke, heart failure, aortic and peripheral arterial disease, and valvular heart disease. The association of hypertension with cardiovascular risk in the short and long term is unequivocally established. The association of obesity with short-term cardiovascular disease event rates (for example, in the next 10 years) is more difficult to establish, largely because the major effects of obesity appear to act through more proximal risk factors, such as diabetes, dyslipidemia and hypertension. However, longer-term studies of obesity and cardiovascular disease do indicate risk for cardiovascular disease associated with obesity independent of these other risk factors.”

#Parvanova, Aneliya et al. “Mechanisms and treatment of obesity-related hypertension-Part 1: Mechanisms.” Clinical kidney journal 2023.
https://pubmed.ncbi.nlm.nih.gov/38186879/
Quote: “Obesity, especially when associated with increased visceral and ectopic fat expansion, is a major cause of hypertension and related cardiovascular and kidney injury. Obesity-related hypertension is initiated by increased renal sodium reabsorption and plasma volume expansion due to renal compression by perirenal/sinus fat and moderate increases in systemic/renal SNS and RAAS activity sustained by a complex interplay among hyperleptinemia, AngII, intermedin, adrenomedullin, and impaired baroreceptor and chemoreceptor reflexes. This manuscript overviews a series of pathophysiological mechanisms involved in the pathogenesis of obesity-related hypertension—such as leptin resistance, impaired baroreceptor and chemoreceptor reflexes, increased renal sympathetic nervous activity, mitochondrial dysfunction, the regulatory role of intermedin, adrenomedullin and sPRR—that could be the target of specific and selective therapeutic interventions in the innovative context of precision medicine.”
"Figure 1. Putative mechanisms of obesity-related hypertension. BAT, baroreceptor activation therapy; CV, cardiovascular; MSNA, muscle sympathetic nerve activity; NP, natriuretic peptide; POMC-MC3/4R, pro-opiomelanocortin-melanocortin receptors; RDN, renal denervation; ROS, reactive oxygen species; RSNA, renal sympathetic nerve activity."

– Like leptin, the satiety hormone. With a healthy amount of fat, leptin tells your brain when you have enough energy storage, can eat less and spend more energy. But if you have too much fat, instead of becoming less hungry, your brain becomes resistant against the constant flood of leptin. This breaks your internal food thermostat. 

#Gruzdeva O, Borodkina D, Uchasova E, Dyleva Y, Barbarash O. Leptin resistance: underlying mechanisms and diagnosis. Diabetes Metab Syndr Obes. 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC6354688/

Quote: “Leptin is an adipocyte-secreted hormone that regulates the appetite and represents a key factor in the development of obesity, a serious medical, social, and economic problem in modern society.1,2 More than 20 years ago, leptin and its receptors were identified as key regulators of body weight and energy homeostasis. A minor increase in leptin concentration reduces the appetite and leads to a decrease in body weight;3 however, in obesity, despite increased leptin concentration, the efficacy of the anorexic effect of leptin is decreased,1,3 with leptin resistance developing due to a defect in intracellular signaling associated with the leptin receptor or decreases in leptin transport across the blood–brain barrier (BBB).4”

#Scheja, Ludger, and Joerg Heeren. “The endocrine function of adipose tissues in health and cardiometabolic disease.” Nature reviews. Endocrinology vol. 15,9 (2019)
https://pubmed.ncbi.nlm.nih.gov/31296970/

Quote: “In healthy conditions in humans and rodents, circulating leptin levels correlate positively with adipose tissue mass and leptin levels decrease sharply during prolonged fasting34, but do not substantially change between meals35. Thus, low plasma leptin levels can be regarded as an endocrine signal reflecting depleted adipose tissue energy stores and high energy demand. In line with this notion, low plasma leptin concentration not only fosters

increased energy intake but is also causally involved in starvation-associated alterations such as increased corticosterone and decreased thyroid hormone levels, gonadal hypoactivity and suppression of the immune system36.

Leptin is expressed in all types of adipose tissues, with a preference for subcutaneous WAT in humans37, and is predominantly regulated at the transcriptional level38. In the fasted state, the sympathetic nervous system acting on adipocyte β-adrenergic receptors is the principal leptin-lowering mechanism39–41. By this mechanism, the secretion of leptin is tightly coupled to nutritional state and thus can mediate physiological adaptations.”

– Which is one of the reasons why many people who are overweight feel intense hunger. Their fat is screaming at their brain that they have enough but the brain is not hearing the message anymore.

#Cleveland Clinic. Leptin. Retrieved May 2025.
https://my.clevelandclinic.org/health/body/22446-leptin
Quote: “What is leptin resistance?

If you have leptin resistance, your brain doesn’t respond as it normally would to leptin. Since leptin constantly stimulates your brain, you don’t get the sensation of feeling full. This causes you to eat more even though your body has enough fat stores.

The seeming lack of leptin also causes your body to enter starvation mode. To save energy, your brain decreases your energy levels and makes you use fewer calories at rest. In other words, it lowers your basal metabolic rate (BMR).

So, leptin resistance makes weight gain worse by making you feel hungry and lowering your BMR.”

#Friedman, Jeffrey M. “Leptin and the endocrine control of energy balance.” Nature metabolism vol. 1,8 (2019)
https://pubmed.ncbi.nlm.nih.gov/32694767/
Quote: “The precise mechanism through which hyperleptinaemia leads to leptin resistance is not known. However, induction of PTP1b and/ or SOCS3 in cells expressing the leptin receptor, perhaps secondarily to hyperleptinaemia, is likely to contribute44,45. The causes of leptin resistance appear to be heterogeneous and, as mentioned, also include constitutive defects in the neural circuit downstream of leptin, such as in mice lacking the leptin receptor or mice with defects in melanocortin signalling, such as Ay  or melanocortin 4 receptor–knockout mice22,31. Indeed, to date, all genes identified as Mendelian causes of obesity in humans are expressed in the central nervous system, and most are components of the neural circuit modulated by leptin. Decreased transport of leptin across the blood–brain barrier has also been suggested to contribute to leptin resistance both in DIO mice and in New Zealand obese mice, which lose weight after intracerebroventricular but not subcutaneous administration of the hormone31,76. These findings suggest the possibility that decreased transport across the blood–brain barrier, or a lowered Vmax, could cause obesity, although definitive evidence supporting this possibility is lacking. Thus, the aetiology of leptin resistance is known in some individuals, including humans and animals with mutations in the neural circuit that responds to leptin to regulate feeding, whereas in other cases the aetiology is less clear.”

#Izquierdo AG, Crujeiras AB, Casanueva FF, Carreira MC. Leptin, Obesity, and Leptin Resistance: Where Are We 25 Years Later? Nutrients. 2019 https://pmc.ncbi.nlm.nih.gov/articles/PMC6893721/
Quote: “Leptin is an adipokine that reflects, at the level of the brain, the degree of adiposity of an organism. To exert this action, it must pass through the BBB through a specific and saturable transporter. Right from early studies, it was postulated that as adiposity increases, serum leptin levels also increase, which can lead to the development of resistance at the level of the BBB transporter [10]. This implies that a lesser amount of leptin will reach the brain, thereby leading to reduced activation of the signaling pathway for body weight regulation. Several studies have shown that obese mice are sensitive to intracerebro-ventricular (ICV), but not subcutaneous or intraperitoneal (IP), or the administration of leptin [15,16], indicating that the lack of leptin activity is due to 35% decrease in BBB permeability [10]. Moreover, the cerebrospinal fluid/serum leptin ratio in obese humans is 4–5 times lower [17,18]. These data suggest that reduced brain access is the source of leptin resistance in obesity and further increase in body weight. Until now, it has been unclear which mechanism allows leptin access to the central nervous system to further exert its effects. With a size of 16-kDa, leptin does not appear likely to use a passive diffusion mechanism, although direct access to the neurons in the mediobasal hypothalamus (MBH) region, which are not protected by the BBB, has been observed [19]. The entry of leptin into the brain is partially saturable [20], which indicates the involvement of a protein transporter. Moreover, leptin transport by tanycytes in the MHB requires the presence of the leptin receptor (OBR) [21] as well as the short isoforms of the receptor (OBRa and OBRc) [22,23,24,25,26], which are highly expressed in the BBB. The loss of OBR isoforms reduces the amount of leptin in the brain of mice [26]. Interestingly, the decrease in the passage of leptin through the BBB does not appear to be due to the loss of leptin transporters [27,28]. The molecular mechanism involved in this effect is unknown. Considering that leptin is transported through the BBB by the leptin receptor, which is, therefore, subject to the regulatory mechanisms of the membrane receptors, it is expected that the high levels of circulating leptin could activate the mechanisms of desensitization and downregulation, causing the degradation of these receptors. Leptin resistance at the BBB has been attributed to receptor saturation effects exerted by excess leptin or reversible inhibition caused by circulating factors such as triglycerides [9]. It has been described that at the physiological concentrations of circulating leptin, this transporter works at 50% saturation [29], which suggests that leptin plays its role as a regulator of body weight within very defined and narrow concentration ranges. In addition, with progressing obesity, a phenomenon of double-level resistance is observed in the BBB and in the leptin receptor in the arcuate nucleus [10,16,30].”

– Your sex hormones are also getting out of whack, testosterone is lowered while estrogen is over produced.

#Mintziori, Gesthimani et al. “The effect of excess body fat on female and male reproduction.” Metabolism: clinical and experimental vol. 107 (2020)
https://pubmed.ncbi.nlm.nih.gov/32119876/
Quote: “Obese men present with a dysregulation of the HPG axis [62], such as a decreased testosterone-to-estradiol (T/E2) ratio [64]. This can be explained by the fact that aromatase expression in the WAT is significantly high. This causes an increase in estrogen (estrone and E2) concentration, which in turn negatively affects spermatogenesis, and the concentration of gonadotropins and T, which initiates a negativefeedback mechanism [65]. Evidence that aromatase inhibitors normalize the hormonal profile of obese men further supports this mechanism [66], even though no consensus has been reached [67]. Furthermore, decreased sex hormone-binding globulin (SHBG) concentration, caused by hyperinsulinemia, as a result of insulin resistance prevalent in obese individuals, contributes to a decrease in T concentration [49,62]. Insulin resistance might also exert central effects by targeting hypothalamic neurons, and thus GnRH secretion [58]. Dysfunctional Sertoli cell function has also been suggested in obese individuals, given that inhibin B concentrations of obese young adults are lower than those of normalweight controls [49]. Interestingly, not all obese males present with hypogonadotropic hypogonadism [68].”

#Ahmed, Fozia et al. “Altered expression of aromatase and estrogen receptors in adipose tissue from men with obesity or type 2 diabetes.” The Journal of clinical endocrinology and metabolism, dgaf038. 21 Jan. 2025.
https://pubmed.ncbi.nlm.nih.gov/39833659
Quote: “Sex differences in body fat distribution have been associated with differences in estrogen levels (5). While estrogen is crucial for regulating fat distribution in women, it also plays a pivotal role in regulating fat distribution in men (6, 7). In women, the main estrogen, estradiol (E2), promotes a gynoid fat distribution, but, in contrast, hyperestrogenemia in men is associated with increased visceral fat mass and obesity (7), highlighting sex-specific effects of estrogen on body fat distribution. In men, approximately 15% of circulating estrogens are derived from testicular production, whereas the remainder is produced in peripheral tissues through conversion of androgens by the enzyme aromatase (ARO) (8), encoded by the CYP19A1 (or ARO) gene. Adipose tissue is a major source of estrogen production in men, and it is hypothesized that increased aromatase activity in adipose tissue contributes to lower testosterone and hyperestrogenemia in men with obesity (8, 9).”

#Stárka L, Hill M, Pospíšilová H, Dušková M. Estradiol, obesity and hypogonadism. Physiol Res. 2020
https://pmc.ncbi.nlm.nih.gov/articles/PMC8603736/
Quote: “The hypothesis that reduced testosterone levels in obese men are the result of higher estrogen production and effects on the hypothalamic-pituitary-testicular axis was based on the fact that slightly higher estrogen levels have been found in obese men compared to those of normal BMI. For instance, Aggerholm et al. (2008) found that total testosterone serum concentrations were 25–32 % lower in obese men in comparison with normal-weight men, whereas estradiol concentrations were 6 % higher (Aggerholm et al. 2008). In another study (Ramlau-Hansen et al. 2010), men with high adulthood BMI had 14 % lower testosterone, 9 % lower inhibin B, 31 % lower SHBG, and 20 % higher estradiol than men with low adulthood BMI. Pauli et al. (2008) found that BMI was positively correlated with estradiol (R=0.34, P=0.001), though for men with BMI in the range 20–30 this correlation was insignificant. Chavarro et al. (2010) found a total testosterone decrease with increasing BMI, though estradiol concentrations did not differ between lean (estradiol, 29.5 [22.5–38.0] pg/ml) and overweight men (29.0 [21.5–35.0] pg/ml), and only a small increase was observed in obese men (33.5 [23.0–38.0] pg/ml).

We found similar relative changes in estradiol levels, with higher levels in obese men by 10.3 % and lower levels in overweight men by 9.2 % compared to men with BMI from 18–25. However, these differences were not significant. Other studies have also found no correlation between estradiol and body mass (e.g. Pasquali et al. 1991, Wang et al. 2014, Dhindsa et al. 2018). Similarly, in women with polycystic ovarian disease, no significant correlation was found between estradiol levels and body mass, though estrone levels did significantly increase with increased mass (Lazúrová et al. 2019). The study of Pasquali et al. (1991) found similar results for estrone in men.

In all these studies, estradiol levels were within reference ranges. Even though in cases of extreme obesity there is a demonstrable increase in estradiol, this does not explain the quantitatively deep declines of testosterone in obese men with hypogonadism.”

– In women this increases the risk of breast cancer significantly.

#Glassman I, Le N, Asif A, Goulding A, Alcantara CA, Vu A, Chorbajian A, Mirhosseini M, Singh M, Venketaraman V. The Role of Obesity in Breast Cancer Pathogenesis. Cells. 2023
https://www.mdpi.com/2073-4409/12/16/2061
Quote: “Of importance is a study by Iyengar et al. that specifically investigates the utility of BMI as a measurement for risk assessment of breast cancer [63]. Using the WHI clinical trial data, this study examined postmenopausal women with normal BMI (18.5–24.9). It found that despite normal BMI, high body fat levels were associated with an elevated risk of invasive breast cancer [63]. Women with normal BMIs were found to have a 56% increase in breast cancer risk for every 5 kg increase in trunk fat. Specifically, these women were found to have an increase in ER-positive breast cancer. From this study, the authors conclude that, despite the utility of BMI in assessing risk of breast cancer in overweight and obese women, BMI categorization may be a poor metric for assessing risk in postmenopausal women who have a normal BMI. In The Cancer Prevention Study II (CPS II), waist circumference was also estimated as a risk for postmenopausal breast cancer. Although it did correlate with increased risk, it was not improved over BMI. Interestingly, a meta-analysis of studies reported for adjusting BMI found that waist circumference may be specifically associated with breast cancer risk in premenopausal women [64]. This association may also contribute to the possibility that elevated BMI in premenopausal women correlates with a lower risk of developing breast cancer, not due to adiposity, but rather due to increased muscle mass.
It has been established that increased BMI, whether classified as overweight or obese, is a modifiable risk factor for the development of breast cancer in postmenopausal women. Specifically, it has been reported by the American Cancer Society that 26,780 cases of breast cancer annually are attributable to excess body weight [65]. A study by Neuhouser et al. used data from the Women’s Health Initiative (WHI) clinical trials, which included 67,142 postmenopausal women enrolled over a period of five years [66]. The results from this study demonstrated that overweight and obese women had an increased risk of invasive breast cancer compared to their normal-weight counterparts. This study also demonstrated the relationship of increasing BMI with breast cancer, as women with BMI > 35 kg/m2 had the greatest risk of breast cancer development, with features of advanced disease and increased tumor size [66]. The results from the WHI clinical trials differ slightly from those of another large study in the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (NSABP P-1) and the Study of Tamoxifen and Raloxifene (STAR). These studies only found a nonsignificant increase in breast cancer in postmenopausal women with BMI > 30 kg/m2 compared to women with BMI < 25 kg/m2 [66,67]. Other studies that had similar findings of increased risk of breast cancer with increased BMI found that this risk typically manifests in “younger” postmenopausal women (mid–late 50s) [14,68]. NSABP P-1 and STAR found that elevated HRs were seen in premenopausal women for both ER-positive and ER-negative breast cancer; however, only ER-positive showed a statistically significant trend. Among postmenopausal women, there was a nonsignificant positive association between BMI and ER-positive breast cancer and no association between BMI and ER-negative breast cancer [67]. It is worth mentioning that these results differ from other studies which demonstrate a direct association between abdominal adiposity and ER-negative breast cancer only [69].”

Quote#2: “In contrast to postmenopausal women, the relationship between increased BMI and breast cancer risk appears to be inverse in premenopausal women [14,15,16]. Schoemaker et al. found a linear association between decreased breast cancer risk and increased BMI in premenopausal women with an estimated risk reduction of 23% for every five-unit difference for BMI at ages 18–24 years old and 12% for BMI at 45–54 years old [16]. Other studies have reported similar reductions in risk but to a lesser degree of 5–9% in risk reduction [73]. Additionally, the study by Hopper et al. found that greater BMI at young age is associated with a decreased risk of breast cancer, although this negative association does not have a substantial influence on absolute risk of breast cancer [14]. Theories behind this association are not well established. There is reason to think it may be estrogen-related, as those with higher BMIs have longer and more irregular menstrual cycles with more frequent anovulation and hence decreased estrogen and progesterone levels. This theory, however, is contraindicated by the protective effects of BMI persisting in women with no history of infertility due to ovulatory disorders [15]. Another theory proposes that increased estrogen, because of childhood adiposity, leads to increased expression of tumor-suppressing genes and earlier breast differentiation [16].”


#Devericks, Emily N et al. “The obesity-breast cancer link: a multidisciplinary perspective.” Cancer metastasis reviews vol. 41,3. 2022.
https://pubmed.ncbi.nlm.nih.gov/35752704/
Quote: “Estrogen could be the missing link in regard to the hormonal unbalance between lean and obese women. After menopause, the ovaries stop producing estrogen and the adipose tissue is the main systemic provider of estrogen. A higher degree of adipose tissue means a higher systemic production of estrogen, and the post-menopausal exposure to this sex hormone leads to BC installment [105,106]. Some researchers stated that the increased burden of converting androgen precursors in estradiol might be a cause of obesity-related BC in post-menopausal women [107]. For instance, a study done in 1991 wanted to counteract the menopause effects by giving estrogen replacement therapy to post-menopausal women, however, the treatment had a detrimental effect on women’s health, causing among others, a higher incidence of BC [108]. Continuous rise in oxidative stress, as well as estradiol (E2) stimulation, leads to NRF2 accumulation by means of P13K–AKT signaling pathway activation. Gorrini C. et al. were able to demonstrate the interplay between P13K signaling, and the NRF2 antioxidant involvement in BRCA1-mediated tumorigenesis [109].”
The distribution of fat in the obese body influences the susceptibility of BC. A higher visceral adiposity leads to a greater risk of BC due to the systemic, as well as local imbalance at hormonal, inflammatory and non-coding RNA profile. The adiponectin-leptin-estrogen axis is altered, resulting in a decreased level of adiponectin, while leptin and estrogen levels are increased. The NFκB, JAK, STAT3, AKT signaling pathways are activated, as a consequence of this unbalance. The oxidative stress is greater in the case of obese people, because the adipose tissue secretes a greater quantity of pro-inflammatory cytokines, such as IL-1β, IL-6, IL-8, and TNFα, and exhibits the formation of inflammasome NLRP3 and NLRP4. The visceral fat in the case of obesity also releases an increased quantity of the BC oncomiRs - miR-23, and miR-155, miR-10b, miR-140, miR-302f, and a decreased quantity of the tumor suppressor miR-148b. Furtherin vitro studies of co-cultures of visceral adipocytes and breast cancer cells or in vivo studies of adipose tissue co-transplanted with breast cancer cells are needed. In addition, the epidemiological data related strictly to central obesity is still scarce and further analysis in this regard would also offer more valuable information. All of these will ultimately result in a more complete and informed understanding of the health risks associated with obesity in the general population.”

– Most people are not aware how much the risk of cancer rises with excess fat. In the US almost 10% of all cancers are directly related to being overweight or obese. And to top this off, obese cancer patients have much worse outcomes, succumbing to the disease more often and sooner.

Numbers vary between studies, from 4% to 20%. We looked into a few of the most recent papers, and also countries other than the USA.


#Islami, Farhad et al. “Proportion and number of cancer cases and deaths attributable to potentially modifiable risk factors in the United States, 2019.” CA: a cancer journal for clinicians vol. 74,5 (2024)
https://pubmed.ncbi.nlm.nih.gov/38990124/
Quote: “In 2019, an estimated 40.0% (713,340 of 1,781,649) of all incident cancers (excluding nonmelanoma skin cancers) and 44.0% (262,120 of 595,737) of all cancer deaths in adults aged 30 years and older in the United States were attributable to the evaluated risk factors. Cigarette smoking was the leading risk factor contributing to cancer cases and deaths overall (19.3% and 28.5%, respectively), followed by excess body weight (7.6% and 7.3%, respectively), and alcohol consumption (5.4% and 4.1%, respectively). For 19 of 30 evaluated cancer types, more than one half of the cancer cases and deaths were attributable to the potentially modifiable risk factors considered in this study. Lung cancer had the highest number of cancer cases (201,660) and deaths (122,740) attributable to evaluated risk factors, followed by female breast cancer (83,840 cases), skin melanoma (82,710), and colorectal cancer (78,440) for attributable cases and by colorectal (25,800 deaths), liver (14,720), and esophageal (13,600) cancer for attributable deaths. Large numbers of cancer cases and deaths in the United States are attributable to potentially modifiable risk factors, underscoring the potential to substantially reduce the cancer burden through broad and equitable implementation of preventive initiatives.”

#Pati, Sukanya, Wadeed Irfan, Ahmad Jameel, Shahid Ahmed, and Rabia K. Shahid. 2023. "Obesity and Cancer: A Current Overview of Epidemiology, Pathogenesis, Outcomes, and Management" Cancers 15, no. 2: 485.
https://doi.org/10.3390/cancers15020485
Quote: “Background: Obesity or excess body fat is a major global health challenge that has not only been associated with diabetes mellitus and cardiovascular disease but is also a major risk factor for the development of and mortality related to a subgroup of cancer. This review focuses on epidemiology, the relationship between obesity and the risk associated with the development and recurrence of cancer and the management of obesity. Methods: A literature search using PubMed and Google Scholar was performed and the keywords ‘obesity’ and cancer’ were used. The search was limited to research papers published in English prior to September 2022 and focused on studies that investigated epidemiology, the pathogenesis of cancer, cancer incidence and the risk of recurrence, and the management of obesity. Results: About 4–8% of all cancers are attributed to obesity. Obesity is a risk factor for several major cancers, including post-menopausal breast, colorectal, endometrial, kidney, esophageal, pancreatic, liver, and gallbladder cancer. Excess body fat results in an approximately 17% increased risk of cancer-specific mortality. The relationship between obesity and the risk associated with the development of cancer and its recurrence is not fully understood and involves altered fatty acid metabolism, extracellular matrix remodeling, the secretion of adipokines and anabolic and sex hormones, immune dysregulation, and chronic inflammation. Obesity may also increase treatment-related adverse effects and influence treatment decisions regarding specific types of cancer therapy. Structured exercise in combination with dietary support and behavior therapy are effective interventions. Treatment with glucagon-like peptide-1 analogues and bariatric surgery result in more rapid weight loss and can be considered in selected cancer survivors. Conclusions: Obesity increases cancer risk and mortality. Weight-reducing strategies in obesity-associated cancers are important interventions as a key component of cancer care. Future studies are warranted to further elucidate the complex relationship between obesity and cancer with the identification of targets for effective interventions.”

#NIH, National Cancer Institute. Obesity and Cancer. January 28, 2025
https://www.cancer.gov/about-cancer/causes-prevention/risk/obesity/obesity-fact-sheet
Quote: “A 2024 study examined whether the increasing incidence of early-onset cancers over the period 2000 to 2012 worldwide could be explained by increasing rates of obesity among young adults over this period (46). Six of nine obesity-related cancers increased in incidence among young adults during this period, and for four of these cancers (colon, rectal, pancreatic, and kidney), this rise was associated with increases in body weight. This finding suggests a possible link between the obesity epidemic and the rising incidence in these early-onset cancers worldwide (46). Obesity has also been linked to increased risks of early-onset breast cancer in Black women (47, 48).” 

#Steele CB, Thomas CC, Henley SJ, et al. Vital Signs: Trends in Incidence of Cancers Associated with Overweight and Obesity — United States, 2005–2014. MMWR Morb Mortal Wkly Rep 2017
https://www.cdc.gov/mmwr/volumes/66/wr/mm6639e1.htm
Quote: “Results: In 2014, approximately 631,000 persons in the United States received a diagnosis of a cancer associated with overweight and obesity, representing 40% of all cancers diagnosed. Overweight- and obesity-related cancer incidence rates were higher among older persons (ages ≥50 years) than younger persons; higher among females than males; and higher among non-Hispanic black and non-Hispanic white adults compared with other groups. Incidence rates for overweight- and obesity-related cancers during 2005–2014 varied by age, cancer site, and state. Excluding colorectal cancer, incidence rates increased significantly among persons aged 20–74 years; decreased among those aged ≥75 years; increased in 32 states; and were stable in 16 states and the District of Columbia.”

#Pati S, Irfan W, Jameel A, Ahmed S, Shahid RK. Obesity and Cancer: A Current Overview of Epidemiology, Pathogenesis, Outcomes, and Management. Cancers (Basel). 2023
https://pmc.ncbi.nlm.nih.gov/articles/PMC9857053/
Quote: “Results: About 4–8% of all cancers are attributed to obesity. Obesity is a risk factor for several major cancers, including post-menopausal breast, colorectal, endometrial, kidney, esophageal, pancreatic, liver, and gallbladder cancer. Excess body fat results in an approximately 17% increased risk of cancer-specific mortality. The relationship between obesity and the risk associated with the development of cancer and its recurrence is not fully understood and involves altered fatty acid metabolism, extracellular matrix remodeling, the secretion of adipokines and anabolic and sex hormones, immune dysregulation, and chronic inflammation.”

#Sun, Ming et al. “Body mass index and risk of over 100 cancer forms and subtypes in 4.1 million individuals in Sweden: the Obesity and Disease Development Sweden (ODDS) pooled cohort study.” The Lancet regional health. Europe vol. 45 101034. 20 Aug. 2024.
https://pubmed.ncbi.nlm.nih.gov/39253735/
Quote: “The findings of this study have important public health implications. Established obesity-related cancers accounted for 25% of all cancer cases in this study, and the proportion increased to 40% when potential obesity-related cancers were added. Therefore, a substantial proportion of cancers could potentially be prevented by implementing public health measures enabling and advocating a healthy lifestyle to keep a normal weight, or to reduce weight with the same measures or by obesity treatment. Cancer risk has been shown to reduce after bariatric surgery of individuals with obesity, which could be an effect of the resulting weight loss.35 Nevertheless, our findings, particularly of rarer cancers, should be verified in future studies and in updated systematic reports weighing the total epidemiological and biological mechanistic evidence to conclude which cancers are likely to be caused by obesity.”

#Safizadeh F, Mandic M, Hoffmeister M, Brenner H. Reevaluating the fraction of cancer attributable to excess weight: overcoming the hidden impact of prediagnostic weight loss. Eur J Epidemiol. 2024
https://link.springer.com/article/10.1007/s10654-024-01146-0
Quote: “A study evaluating the proportion of cancer cases attributable to modifiable riskfactors in the United States estimated that 7.8% (men: 4.8%, women:10.9%) of cancer cases in 2014 were attributable to excess weight [11]. The higher PAF estimates compared to the study of Brown et al. for the UK for 2015 may primarily reflect the much higher prevalence of obesity in the United States. This prevalence have further increased in recent years, with 30.7% and 42.4% of adults being overweight and obese in the US in 2017–2018 [35], and 37.9% and 25.9% of adults being overweight and obese in the UK in 2021 [36], respectively. It is plausible to assume that due consideration of prediagnostic weight loss would likewise have led to higher PAF estimates for the US in 2014, and that these PAFs further increased in the meantime due to the ongoing obesity epidemic in the past decades.”

#Avgerinos, Konstantinos I et al. “Obesity and cancer risk: Emerging biological mechanisms and perspectives.” Metabolism: clinical and experimental vol. 92 (2019)
https://pubmed.ncbi.nlm.nih.gov/30445141/
Quote: “Continuously rising trends in obesity-related malignancies render this disease spectrum a public health priority. Worldwide, the burden of cancer attributable to obesity, expressed as population attributable fraction, is 11.9% in men and 13.1% in women. There is convincing evidence that excess body weight is associated with an increased risk for cancer of at least 13 anatomic sites, including endometrial, esophageal, renal and pancreatic adenocarcinomas; hepatocellular carcinoma; gastric cardia cancer; meningioma; multiple myeloma; colorectal, postmenopausal breast, ovarian, gallbladder and thyroid cancers. We first synopsize current epidemiologic evidence; the obesity paradox in cancer risk and mortality; the role of weight gain and weight loss in the modulation of cancer risk; reliable somatometric indicators for obesity and cancer research; and gender differences in obesity related cancers. We critically summarize emerging biological mechanisms linking obesity to cancer encompassing insulin resistance and abnormalities of the IGF-I system and signaling; sex hormones biosynthesis and pathway; subclinical chronic low-grade inflammation and oxidative stress; alterations in adipokine pathophysiology; factors deriving from ectopic fat deposition; microenvironment and cellular perturbations including vascular perturbations, epithelial-mesenchymal transition, endoplasmic reticulum stress and migrating adipose progenitor cells; disruption of circadian rhythms; dietary nutrients; factors with potential significance such as the altered intestinal microbiome; and mechanic factors in obesity and cancer. Future perspectives regarding prevention, diagnosis and therapeutics are discussed. The aim of this review is to investigate how the interplay of these main potential mechanisms and risk factors, exerts their effects on target tissues provoking them to acquire a cancerous phenotype.”

– Insulin is a hormone produced by your pancreas that tells your cells to open their tiny mouths and eat up glucose from your blood. It is your body’s way of screaming “dinner time”.

#Cleveland Clinic. Insulin. Retrieved May 2025.
https://my.clevelandclinic.org/health/body/22601-insulin
Quote: “Insulin moves glucose from your blood into cells all over your body. Glucose comes from both the food and drinks you consume and your body’s natural release of stored glucose (glycogen). Glucose is your body’s main — and preferred — source of energy.
All of your body’s cells need energy. Think of insulin as the key that opens the doors of the cells in your body. Once insulin opens your cell doors, glucose can leave your bloodstream and move into your cells where you use it for energy.
Without enough insulin, glucose can’t get into your cells and instead builds up in your blood. This leads to high blood sugar and diabetes. A total lack of insulin for a prolonged time leads to a life-threatening complication called diabetes-related ketoacidosis (DKA).”


#Thota S, Akbar A. Insulin. [Updated 2023 Jul 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025
https://www.ncbi.nlm.nih.gov/books/NBK560688/
Quote: “Insulin is a peptide hormone secreted in the body by beta cells of islets of Langerhans of the pancreas and regulates blood glucose levels. Medical treatment with insulin is indicated when there is inadequate production or increased insulin demands in the body.[1]
[...]
Insulin acts by directly binding to its receptors on the plasma membranes of the cells. These receptors are present on all the cells, but their density depends on the type of cells, with the maximum density being on the hepatic cells and adipocytes.

The insulin receptor is a heterotetrameric glycoprotein consisting of two subunits, the alpha and the beta subunits. The extracellular alpha subunits have insulin binding sites. The beta subunits, which are transmembranous, have tyrosine kinase activity.[16] When insulin binds to the alpha subunits, it activates the tyrosine kinase activity in the beta subunit, which causes the translocation of glucose transporters from the cytoplasm to the cell's surface.[17] These glucose transporters allow the influx of glucose from the blood into the cell, thus reducing blood glucose levels.[18]

Insulin causes the following effects in the cells[19]:

Hepatic cells: Promotes glycogenesis, inhibits gluconeogenesis

Adipocytes: Promotes lipogenesis, inhibits lipolysis

Muscle cells: Promotes glycogenesis and protein synthesis. Inhibits protein catabolism

Pancreatic beta cells: Inhibits glucagon release

Brain cells: Involved in appetite regulation”

– Disastrously bombarded by the stress from your excess fat, cells all over your body become insulin resistant – worse at eating glucose and taking up energy. Your body tries to compensate by pumping out more insulin, screaming louder.

#Chait A, den Hartigh LJ. Adipose Tissue Distribution, Inflammation and Its Metabolic Consequences, Including Diabetes and Cardiovascular Disease. Front Cardiovasc Med. 2020
https://pmc.ncbi.nlm.nih.gov/articles/PMC7052117/#s6
Quote: “Abundant evidence indicates that adiposity and adipose tissue inflammation are associated with insulin resistance, which refers to a reduced response to binding of insulin to its receptor in peripheral tissues such as adipose tissue and skeletal muscle. This differs from glucose effectiveness, which is uptake of glucose by peripheral tissues in an insulin-independent manner. Insulin inhibits hepatic glucose output and stimulates lipogenesis in the liver, both of which are reduced in the presence of insulin resistance. Such desensitization of insulin signaling pathways also inhibits glucose uptake in peripheral tissues and stimulates lipolysis in adipose tissue. To compensate for reduced insulin sensitivity, insulin secretion is increased in order to maintain euglycemia. If the pancreatic beta cells are unable to secrete sufficient insulin to compensate for the reduced insulin sensitivity (termed beta cell dysfunction), hyperglycemia will ensue, leading to glucose intolerance and eventually T2DM (366). While the precise mechanisms that lead to beta cell dysfunction are not completely understood, ectopic fat accumulation may contribute, as discussed earlier. Nonetheless, ample evidence suggests that excess adiposity and adipose tissue inflammation contribute to insulin resistance [reviewed in (64, 367)]. Many studies have demonstrated that excess adiposity is correlated with insulin resistance in humans. Cross-sectional studies in men of European, Asian Indian, and American descent have shown that total, visceral, and subcutaneous adiposity, BMI, and waist circumference are all negatively associated with insulin sensitivity (368, 369). As noted earlier, adiposity, especially visceral adiposity, is characterized by adipose tissue inflammation.”

#Miao, Zong et al. “The causal effect of obesity on prediabetes and insulin resistance reveals the important role of adipose tissue in insulin resistance.” PLoS genetics vol. 16,9 e1009018. 14 Sep. 2020, doi:10.1371/journal.pgen.1009018
https://pubmed.ncbi.nlm.nih.gov/32925908/
Quote: “Even though the previous MR studies have shown that obesity has a causal effect on T2D [50,51], MR evidence showing that obesity is causally linked with prediabetes or insulin resistance among non-diabetic individuals is missing. Noteworthy, the annualized conversion rate of prediabetes to diabetes is estimated to be 5%–10% [9] and thus, some prediabetes patients do not develop T2D. Thus, the causal effect between obesity and prediabetes cannot be simply deduced by the causal role of obesity on T2D. In the present study, we utilized the extensive UK Biobank cohort [20] and carefully phenotyped Finnish METSIM cohort [21] to investigate whether obesity causes prediabetes and causally increases insulin resistance in the non-diabetic population using the MR analysis. Our MR result sheds new light on the long-standing reverse causality question between obesity and insulin resistance by establishing its directionality. Stancakova et al. have showed earlier that the Matsuda index is the best index of insulin sensitivity when compared to other surrogate indexes of insulin resistance using an M value from the euglycemic hyperinsulinemic clamp as the gold standard [52]. Therefore, the Matsuda index is largely a measure of systemic rather than adipose-based insulin resistance. However, when we examined the role of adipose cell-type heterogeneity, adipose MT gene expression, and BMI in systemic insulin resistance, we discovered that even when excluding BMI from the calculation, the estimated adipose cell-type proportions and adipose MT gene expression together still explain a substantial amount (R2 = 35.42%) of the variance in the Matsuda index. When we included BMI into this analysis, all three factors are independently associated with insulin resistance (p<0.05 for each) and the R2 increased to 44.39% which is higher than using any trait alone (R2< = 30.89%). This surprisingly high proportion of variance explained by adipose tissue (i.e. adipose cell types and MT gene expression) and BMI suggests that adipose tissue has an important role in the systemic insulin resistance. Based on this novel finding, we built a prediction model using adipose cell-types, adipose MT gene expression, and BMI that accurately predicted insulin resistance across multiple cohorts.”

– This can go on silently for many years and progress to prediabetes – with no or only subtle symptoms like fatigue or hunger. But as the damage accumulates, eventually your body just can’t keep up anymore.  Something breaks and you get Type 2 diabetes.

#Prediabetes – Your Chance to Prevent Type 2 Diabetes. Retrieved May 2025.
https://www.cdc.gov/diabetes/prevention-type-2/prediabetes-prevent-type-2.html
Quote: “Insulin is a hormone that acts like a key to let blood sugar into cells for use as energy. If you have prediabetes, the cells in your body don’t respond normally to insulin. Your pancreas makes more insulin to try to get cells to respond. Eventually your pancreas can’t keep up, and your blood sugar rises. This sets the stage for prediabetes—and type 2 diabetes down the road.

Signs and symptoms
You can have prediabetes for years but have no clear symptoms. It often goes undetected until serious health problems such as type 2 diabetes show up. Talk to your doctor about getting your blood sugar tested if you have any risk factors for prediabetes, such as:
Being overweight
Being 45 years or older
Having a parent, brother, or sister with type 2 diabetes
Being physically active less than 3 times a week
Ever having gestational diabetes (diabetes during pregnancy)
Giving birth to a baby who weighed more than 9 pounds
Having polycystic ovary syndrome”

#Prediabetes symptoms and risk reduction. Retrieved May 2025.
https://www.diabetes.org.uk/about-diabetes/type-2-diabetes/prediabetes
Quote: “Prediabetes symptoms
Prediabetes doesn’t have any symptoms. If you start to have any of the symptoms of type 2 diabetes it means you have probably already developed it.
So it’s important to know the risk factors and what support is available that could help you prevent or delay type 2 diabetes.
A lot of people don’t get any symptoms when it comes to type 2 diabetes, or don’t notice them. But you may notice:
going for a wee more often, especially at night
feeling more tired, because your body can't get enough glucose in to your cells for energy
losing weight without trying
genital itching or thrush
cuts and wounds taking longer to heal
blurred vision
feeling extremely thirsty.”

#Kathy Katella. Yale Medicine. Prediabetes Is on the Rise—But It Can Be Reversed. 2023
https://www.yalemedicine.org/news/prediabetes
Quote: “Type 2 diabetes, in which the body doesn’t use insulin properly, is on the rise in the United States. There are more than 35 million people with the condition, and many are diagnosed when they are young, even in adolescence. Perhaps more astonishing—and worrying—is that prediabetes, the condition that leads to type 2 diabetes, now affects 98 million people. That’s one in three of us.

Prediabetes can be seen as a warning sign—it’s the body’s way of saying that your insulin levels are rising. You can still prevent or delay type 2 diabetes by losing weight—even a modest amount—with the help of dietary changes, stress reduction, and physical activity. Taking medication can also help.

And reversing the process is key because type 2 diabetes can be a devastating disease. The condition usually begins with insulin resistance, in which the fat, liver, and muscle cells do not use insulin properly. Eventually, the body needs more insulin than it can produce, causing blood glucose to rise. Those elevated levels can lead to serious health issues if they are not managed properly.

You may not even know you have prediabetes or diabetes—you can be symptom-free for years. But once the complications of diabetes start to occur, nearly every aspect of your health can be affected. That’s because the excessive sugar in your blood damages blood vessels and nerves throughout your body.”

#Tabák AG, Herder C, Rathmann W, Brunner EJ, Kivimäki M. Prediabetes: a high-risk state for diabetes development. Lancet. 2012 https://pmc.ncbi.nlm.nih.gov/articles/PMC3891203/#S5
Quote: “As evidenced by studies with repeat measures of glucose levels, insulin sensitivity and insulin secretion, the development of diabetes from NGT is a continuous process.35,36,40,41 Recently we described trajectories of fasting and postload glucose in addition to trajectories of HOMA insulin sensitivity and insulin secretion (β-cell function) preceding the development of type 2 diabetes in the British Whitehall II study (figure 2).36 In people who developed diabetes, increased glucose values were observed already at the beginning of the follow-up, 13 years before diagnosis, although glucose values seemed to be tightly regulated within the normal range until 2–6 years before diagnosis when an abrupt increase was found. This pattern of glycaemic changes was confirmed by others.35,40,41”

#Janez, Andrej et al. “Modern Management of Cardiometabolic Continuum: From Overweight/Obesity to Prediabetes/Type 2 Diabetes Mellitus. Recommendations from the Eastern and Southern Europe Diabetes and Obesity Expert Group.” Diabetes therapy: research, treatment and education of diabetes and related disorders vol. 15,9 (2024) https://pubmed.ncbi.nlm.nih.gov/38990471/
Quote: “A vast body of evidence confirms that appropriate management of obesity can postpone the progression from prediabetes to T2D and improve hyperglycaemia in patients with T2D [32,33,34]. Modest and maintained weight reduction in patients with T2D who are overweight or obese was associated with decreased need for glucose-lowering medications [21, 32]. The analysis of the effect of BW loss on selected variables in a 0.5 million population from the UK Clinical Practice Research Datalink (CPRD) GOLD database revealed that a median 13% BW loss corresponded with 41% reduced risk of T2D [35]. Moreover, clinical data indicate that weight loss of ≥ 15% can reverse metabolic abnormalities in T2D as well as ameliorate glucose control and improve quality of life [36]. Interesting results concerning the significance of lifestyle modification were obtained from the DiRECT clinical trial. In this trial, an average BW loss of about 10 kg resulting from a low-calorie diet and intense lifestyle modifications was associated with T2D remission in about 46% of patients within 1 year and in approximately 36% of individuals after 2 years [37, 38]. Comparable rates of T2D remission after 1 year were reported in the DIADEM-I trial in which diabetes remission was observed in 61% of participants and normoglycaemia in 33% of participants [39]. The results of the Look AHEAD (Action for Health in Diabetes) study have shown that either a 10% BW loss or a considerable escalation in fitness translates into approximately a 20% reduction in CVD risk [40].”

– The cells responsible for insulin production are so overworked that they stop functioning properly and eventually give in. Your insulin crashes drastically and your body can’t compensate, while the blood is now saturated with glucose – yet you are starving and feel exhausted and unwell.

#Tabák, Adam G et al. “Prediabetes: a high-risk state for diabetes development.” Lancet (London, England) vol. 379,9833 (2012)
https://pmc.ncbi.nlm.nih.gov/articles/PMC3891203/
Quote: “Prediabetes (or “intermediate hyperglycaemia”), based on glycaemic parameters above normal but below diabetes thresholds is a high risk state for diabetes with an annualized conversion rate of 5%–10%; with similar proportion converting back to normoglycaemia. The prevalence of prediabetes is increasing worldwide and it is projected that >470 million people will have prediabetes in 2030. Prediabetes is associated with the simultaneous presence of insulin resistance and β-cell dysfunction, abnormalities that start before glucose changes are detectable. Observational evidence shows associations of prediabetes with early forms of nephropathy, chronic kidney disease, small fibre neuropathy, diabetic retinopathy, and increased risk of macrovascular disease. Multifactorial risk scores could optimize the estimation of diabetes risk using non-invasive parameters and blood-based metabolic traits in addition to glycaemic values. For prediabetic individuals, lifestyle modification is the cornerstone of diabetes prevention with evidence of a 40%–70% relative risk reduction. Accumulating data also suggests potential benefits from pharmacotherapy.”

#American Diabetes Association. How Type 2 Diabetes Progresses. Retrieved May 2025.
https://diabetes.org/living-with-diabetes/type-2/how-type-2-diabetes-progresses
Quote: “Type 2 diabetes is a progressive condition, meaning initial management strategies may become less effective over time. Understanding the type 2 diabetes complications timeline can help you prepare for adjustments in your treatment plan.
Scientists understand the basics of type 2 well, including how the body makes and uses insulin. When beta cells in the pancreas can’t produce enough insulin to keep your blood sugar (blood glucose) from raising too high, the result is diabetes.
First, your body stops making enough insulin or using insulin it does make properly. When your body doesn’t use insulin properly, it’s called insulin resistance. 
Your beta cells increase the amount of insulin they produce to make up for the insulin resistance. Over time, the body works even harder to make more insulin and eventually it can’t keep up.
Unlike people with type 1 diabetes, people with type 2 still have functioning beta cells. They usually have no idea there is a problem until a doctor tests their blood sugar levels. Because symptoms can be minimal and go unnoticed, many people can have type 2 diabetes for a long time before it’s diagnosed. “

#Society for Endocrinology. Retrieved May 2025.
https://www.endocrinology.org/media/2917/the-endocrinologist-129-fig-p13.jpg

#Klein S, Gastaldelli A, Yki-Järvinen H, Scherer PE. Why does obesity cause diabetes? Cell Metab. 2022
https://pmc.ncbi.nlm.nih.gov/articles/PMC8740746/
Quote: “Pancreatic β-cell function is a critical determinant of whether people with obesity develop type 2 diabetes. Plasma insulin concentrations and the rate of insulin secretion during basal conditions and after glucose ingestion is typically greater in people with obesity who do not have type 2 diabetes than people who are lean (van Vliet et al., 2020). This increase in insulin secretion rate and plasma insulin concentration is often able to overcome the resistance to insulin action, so that fasting blood glucose concentration and oral glucose tolerance are normal. However, a progressive decline in β-cell function causes a progressive decline in glycemic control, resulting in prediabetes and ultimately type 2 diabetes (Gastaldelli et al., 2004; Weyer et al., 1999).

It is likely that the number of pancreatic β-cells, per se, influences the secretion of insulin during both basal and postprandial conditions. Pancreatic β-cell mass, often expressed as the relative volume (ratio of the β-cell area to exocrine area assessed at autopsy), is about 50% greater in people with obesity than in people who are lean. However the relative β-cell volume in those with impaired fasting glucose or type 2 diabetes is about 50% lower than the relative volume in lean people because of β-cell apoptosis (Butler et al., 2003). It is unlikely that the increase in β-cell mass associated with obesity is simply caused by insulin resistance, because weight gain in mice fed a high-fat diet is associated with an increased proliferation in β-cell mass before the development of insulin resistance (Mosser et al., 2015) and both basal and postprandial insulin secretion rates are greater in people with obesity than in lean people when both groups are matched on insulin sensitivity (van Vliet et al., 2020). The mechanism(s) responsible for β-cell hyperplasia in people with obesity is not known, but could be related to stimulation by specific nutrients, insulin, incretins and growth factors associated with high-calorie diet consumption and obesity (Linnemann et al., 2014).”

#Christensen, Ashley A, and Maureen Gannon. “The Beta Cell in Type 2 Diabetes.” Current diabetes reports. 2019.
https://pubmed.ncbi.nlm.nih.gov/31399863/

#Klein S, Gastaldelli A, Yki-Järvinen H, Scherer PE. Why does obesity cause diabetes? Cell Metab. 2022
https://pmc.ncbi.nlm.nih.gov/articles/PMC8740746/
Quote: “Obesity, particularly when associated with increased abdominal and intra-abdominal fat distribution and increased intrahepatic and intramuscular triglyceride content, is a major risk factor for prediabetes and type 2 diabetes because it causes both insulin resistance and β-cell dysfunction. Accordingly, the worldwide increase in the prevalence of obesity has led to the concomitant increase in the prevalence of type 2 diabetes. A better understanding of the mechanisms responsible for the adverse effects of excess body fat on the factors involved in the pathogenesis of type 2 diabetes can lead to novel therapeutic interventions to prevent and treat this debilitating disease. A series of studies conducted in mouse models and in people have demonstrated alterations in adipose tissue biology that link obesity with insulin resistance and β-cell dysfunction. These alterations include adipose tissue fibrosis (increased rates of fibrogenesis and expression of genes involved in extracellular matrix formation), inflammation (increased proinflammatory macrophage and T cell content and the production of PAI-1), and the production of exosomes that can induce insulin resistance. However, none of these factors can influence systemic metabolic function without a mechanism for adipose tissue communication with other organs. It is possible that several adipose tissue secretory products that are released into the bloodstream, including PAI-1, adiponectin, FFAs and exosomes, are involved in this signaling process, but additional research is needed to fully assess their clinical importance. In addition, it is also likely that cross-talk among adipose tissue, the liver, muscle and pancreatic islets contribute to insulin resistance and hepatic steatosis (Figure 3). Decreasing body fat mass by inducing a negative energy balance, not by surgical removal, can ameliorate or normalize obesity-induced metabolic dysfunction and can even achieve diabetes remission if there is adequate restoration of β-cell function.”

– The kidneys are overwhelmed, making you pee way more, your vision gets blurry, your immune system is severely weakened, wounds heal slower, dying nerves lead to numbness and pain. You may experience shortness of breath, chest discomfort, erectile dysfunction and high blood pressure, problems with your memory, focus, mood and even depression. Your risk of developing just about every possible deadly disease goes through the roof.

#Symptoms of type 2 diabetes and how it's diagnosed. NHS. Retrieved May 2025.
https://www.nhs.uk/conditions/type-2-diabetes/symptoms/
Quote: “Symptoms of type 2 diabetes
The most common symptoms of type 2 diabetes are:
feeling very tired
peeing more than usual
feeling thirsty all the time
losing weight without trying to

Other symptoms can include:
blurred vision
cuts or wounds taking longer to heal
itching around your penis or vagina, or you keep getting thrush

These symptoms are the same for both adults and children. If you get symptoms (not everyone gets them), they may develop gradually. The symptoms can be similar to type 1 diabetes, but type 1 diabetes usually develops more quickly and is more common in younger people.”

#Diabetes UK. Diabetic neuropathy (nerve damage). Retrieved May 2025.
https://www.diabetes.org.uk/about-diabetes/looking-after-diabetes/complications/nerves-neuropathy
Quote: “Diabetic neuropathy is when diabetes causes damage to your nerves. It can affect different types of nerves in your body, including in your feet, organs and muscles. 
Nerves carry messages between the brain and every part of our bodies so that we can see, hear, feel and move. They also carry signals to parts of the body such as the heart, making it beat at different speeds, and the lungs, so we can breathe.
Damage to the nerves can cause serious problems in different parts of the body for people with type 1, type 2 or other types of diabetes.”

#CDC: Diabetes and Mental Health. May 2024.
https://www.cdc.gov/diabetes/living-with/mental-health.html
Quote: “People with diabetes are 2 to 3 times more likely to have depression than people without diabetes. Only 25% to 50% of people with diabetes who have depression get diagnosed and treated. But treatment—therapy, medicine, or both—is usually very effective. And without treatment, depression often gets worse, not better.”

#Defeudis G, Mazzilli R, Tenuta M, Rossini G, Zamponi V, Olana S, Faggiano A, Pozzilli P, Isidori AM, Gianfrilli D. Erectile dysfunction and diabetes: A melting pot of circumstances and treatments. Diabetes Metab Res Rev. 2022
https://pmc.ncbi.nlm.nih.gov/articles/PMC9286480/
Quote: “Diabetes mellitus (DM), a chronic metabolic disease characterised by elevated levels of blood glucose, is among the most common chronic diseases. The incidence and prevalence of DM have been increasing over the years. The complications of DM represent a serious health problem. The long‐term complications include macroangiopathy, microangiopathy and neuropathy as well as sexual dysfunction (SD) in both men and women. Erectile dysfunction (ED) has been considered the most important SD in men with DM. The prevalence of ED is approximately 3.5‐fold higher in men with DM than in those without DM. Common risk factors for the development of DM and its complications include sedentary lifestyle, overweight/obesity and increased caloric consumption. Although lifestyle changes may help improve sexual function, specific treatments are often needed. This study aims to review the definition and prevalence of ED in DM, the impact of DM complications and DM treatment on ED and, finally, the current and emerging therapies for ED in patients with DM.”

#Moheet A, Mangia S, Seaquist ER. Impact of diabetes on cognitive function and brain structure. Ann N Y Acad Sci. 2015
https://pmc.ncbi.nlm.nih.gov/articles/PMC4837888/
Quote: “Diabetes mellitus is associated with decrements in cognitive function and changes in brain structure. People with both type 1 and type 2 diabetes have been shown to have mild to moderate reductions in cognitive function as measured by neuropsychological testing compared to non-diabetic controls. Type 2 diabetes (T2DM) has also been associated with 50% increased risk of dementia.1 Whether such an association is true for people with type 1 diabetes(T1DM) is not yet known.”

#Dal Canto, Elisa et al. “Diabetes as a cardiovascular risk factor: An overview of global trends of macro and micro vascular complications.” European journal of preventive cardiology 2019
https://academic.oup.com/eurjpc/article/26/2_suppl/25/5925419
Quote: “The global prevalence of diabetes is predicted to increase dramatically in the coming decades as the population grows and ages, in parallel with the rising burden of overweight and obesity, in both developed and developing countries. Cardiovascular disease represents the principal cause of death and morbidity among people with diabetes, especially in those with type 2 diabetes mellitus. Adults with diabetes have 2–4 times increased cardiovascular risk compared with adults without diabetes, and the risk rises with worsening glycaemic control. Diabetes has been associated with 75% increase in mortality rate in adults, and cardiovascular disease accounts for a large part of the excess mortality. Diabetes-related macrovascular and microvascular complications, including coronary heart disease, cerebrovascular disease, heart failure, peripheral vascular disease, chronic renal disease, diabetic retinopathy and cardiovascular autonomic neuropathy are responsible for the impaired quality of life, disability and premature death associated with diabetes. Given the substantial clinical impact of diabetes as a cardiovascular risk factor, there has been a growing focus on diabetes-related complications. While some population-based studies suggest that the epidemiology of such complications is changing and that rates of all-cause and cardiovascular mortality among individuals with diabetes are decreasing in high-income countries, the economic and social burden of diabetes is expected to rise due to changing demographics and lifestyle especially in middle- and low-income countries. In this review we outline data from population-based studies on recent and long-term trends in diabetes-related complications.”

#Harding, Jessica L et al. “Global trends in diabetes complications: a review of current evidence.” Diabetologia vol. 62,1 (2019)
https://pubmed.ncbi.nlm.nih.gov/30171279/
Quote: “In recent decades, large increases in diabetes prevalence have been demonstrated in virtually all regions of the world, with 415 million people worldwide now living with diabetes [1]. This is most concerning because an increase in diabetes prevalence will increase the number of chronic and acute diseases in the general population, with profound effects on quality of life, demand on health services and economic costs. Macrovascular complications of diabetes, including coronary heart disease, stroke and peripheral vascular disease, and microvascular complications, such as end-stage renal disease (ESRD), retinopathy and neuropathy, along with lower-extremity amputations (LEA), are responsible for much of the burden associated with diabetes. There is also growing recognition of a diversifying set of causally-linked conditions, including cancers, ageing-related outcomes (e.g. dementia), infections and liver disease. Since current data suggests that rates of all-cause and cardiovascular disease (CVD) mortality are decreasing in individuals with diabetes [2], trends in other complications of diabetes may become proportionately more prominent in the future.”

– On average Type 2 diabetes shaves 10 years off your life and reduces your health span massively –  arguably as much as smoking.

#Emerging Risk Factors Collaboration. “Life expectancy is associated with different ages at diagnosis of type 2 diabetes in high-income countries: 23 million person-years of observation.” The Lancet. 2023.
https://www.sciencedirect.com/science/article/pii/S2213858723002231
Quote: “For participants with diabetes, we observed a linear dose–response association between earlier age at diagnosis and higher risk of all-cause mortality compared with participants without diabetes. HRs were 2·69 (95% CI 2·43–2·97) when diagnosed at 30–39 years, 2·26 (2·08–2·45) at 40–49 years, 1·84 (1·72–1·97) at 50–59 years, 1·57 (1·47–1·67) at 60–69 years, and 1·39 (1·29–1·51) at 70 years and older. HRs per decade of earlier diagnosis were similar for men and women. Using death rates from the USA, a 50-year-old individual with diabetes died on average 14 years earlier when diagnosed aged 30 years, 10 years earlier when diagnosed aged 40 years, or 6 years earlier when diagnosed aged 50 years than an individual without diabetes. Using EU death rates, the corresponding estimates were 13, 9, or 5 years earlier.”

#Type 2 diabetes diagnosis at age 30 can reduce life expectancy by up to 14 years. Retrieved May 2025.
https://www.cam.ac.uk/research/news/type-2-diabetes-diagnosis-at-age-30-can-reduce-life-expectancy-by-up-to-14-years
Quote: “Using data from US population it was estimated that, individuals with type 2 diabetes diagnosed at ages 30, 40, and 50 years died on average about 14, 10, and 6 years earlier, respectively, than individuals without the condition. These estimates were slightly higher in women (16, 11, and 7 years, respectively) than they were in men (14, 9, and 5 years, respectively).

The findings were broadly similar in analyses using EU data, with corresponding estimates being about 13, 9, or 5 years earlier death on average.

Professor Emanuele Di Angelantonio from the Victor Phillip Dahdaleh Heart and Lung Research Institute (VPD-HLRI), University of Cambridge, said: “Type 2 diabetes used to be seen as a disease that affected older adults, but we’re increasingly seeing people diagnosed earlier in life. As we’ve shown, this means they are at risk of a much shorter life expectancy than they would otherwise have.””

#CDC Archive. Tobacco-Related Mortality. Retrieved May 2025.
https://archive.cdc.gov/www_cdc_gov/tobacco/data_statistics/fact_sheets/health_effects/tobacco_related_mortality/index.htm
Quote: “Cigarette smoking causes premature death:
Life expectancy for smokers is at least 10 years shorter than for nonsmokers.1,2
Quitting smoking before the age of 40 reduces the risk of dying from smoking-related disease by about 90%.2”

– If current obesity trends continue up to  1 in 3 Americans will have diabetes by 2050.

#Boyle, James P et al. “Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence.” Population health metrics 2010
https://pubmed.ncbi.nlm.nih.gov/20969750/
Quote: “The authors project that annual diagnosed diabetes incidence (new cases) will increase from about 8 cases per 1,000 in 2008 to about 15 in 2050. Assuming low incidence and relatively high diabetes mortality, total diabetes prevalence (diagnosed and undiagnosed cases) is projected to increase from 14% in 2010 to 21% of the US adult population by 2050. However, if recent increases in diabetes incidence continue and diabetes mortality is relatively low, prevalence will increase to 33% by 2050. A middle-ground scenario projects a prevalence of 25% to 28% by 2050. Intervention can reduce, but not eliminate, increases in diabetes prevalence.”

Figure Caption: “Figure 2 Projections of total diabetes prevalence as a percentage of the total US adult population for four scenarios: low incidence projections and r1 = 1.77, r2 = 2.11; low incidence projections and r1 = 1.00, r2 = 4.08; middle incidence projections and r1 = 1.77, r2 = 2.11; middle incidence projections and r1 = 1.00, r2 = 4.08.”

It was estimated that 15% of adults in the USA had diabetes in 2021.

#CDC. National Diabetes Statistics Report. May 2024.
https://www.cdc.gov/diabetes/php/data-research/index.html
Quote: “Among the U.S. population overall, crude estimates for 2021 were:

38.4 million people of all ages—or 11.6% of the U.S. population—had diabetes.

38.1 million adults aged 18 years or older—or 14.7% of all U.S. adults—had diabetes (Table 1a; Table 1b).

8.7 million adults aged 18 years or older who met laboratory criteria for diabetes were not aware of or did not report having diabetes (undiagnosed diabetes, Table 1b). This number represents 3.4% of all U.S. adults (Table 1a) and 22.8% of all U.S. adults with diabetes.

The percentage of adults with diabetes increased with age, reaching 29.2% among those aged 65 years or older (Table 1a).”

– There is no nice way to put this: Excessive fat strains nearly every organ system in your body, ages you much quicker and often leads to multisystem damage and dysfunction. And yet, fat is still mostly discussed through the lens of aesthetics first and health second.

#Salvestrini V, Sell C, Lorenzini A. Obesity May Accelerate the Aging Process. Front Endocrinol (Lausanne). 2019
https://pmc.ncbi.nlm.nih.gov/articles/PMC6509231/
Quote: “We have reviewed and organized the literature with the intent of showing the existing parallels between excessive fat accumulation and the aging process. We have categorized these reports following what have been proposed to be the nine hallmarks of aging (21) (Figure 1). Based on the evidence, two distinct hypotheses can be proposed. One is that the cellular responses provoked by an excess of nutrients cause obesity, and that obesity is responsible for accelerating the pace of aging. Supporting this hypothesis are the observations that knocking out the fat-specific insulin receptor, to produce extremely lean mice (180), and removal of visceral fat in rats (181) increased life span; additionally, CR on lean strains of rats, had only a minor effects on lifespan (182, 183). The alternative possibility is that the cellular responses provoked by an excess of nutrients are responsible for increasing the pace of aging. This common soil shared by both aging and obesity has been named “adipaging” (184), and there is some evidence of commonalities: hyperglycaemia, for example, induces senescence and the SASP in endothelial cells and macrophages (185) while glucose reduction prevents replicative senescence in human mesenchymal stem cells (186). The more abundant macronutrients (by weight and by calories) in the diet are usually carbohydrates and lipids, and specific reviews are available that focus on the possible toxic effects of their respective excess: carbotoxicity (187) and lipotoxicity (188). In this second scenario, obesity represents only a side effect of the excess nutrient status and the fulcrum are the cellular nutrient sensing pathways; see for example the possible central role of mTOR (189, 190). Whether adipose tissue hyper-function/dysfunction is causative of aging functional decline or whether it represents simply a marker of the advancing aging process will become clearer with future studies. In addition, not all fat depots are equal in their impact to health (191) and it could also turn out that both hypotheses are concurrently true (192).”

Figure Caption: “Effect of obesity or nutrient excess on the hallmarks of aging. The size of the arrows indicate how solid are the evidences, see “take home summaries” in the text. The double-headed arrow for cellular senescence indicate that detrimental influences can feedback from senescence to obesity.”

– Which is kind of baffling considering that most if not all of the toxic effects of your excess fat basically go away as soon as you lose it and start eating a healthy-ish diet. Once your fat cells contract again they stop being stressed and your immune system calms down. The excess blood fat and sugar drops to normal levels and your body recovers.

#Bianchi, Vittorio Emanuele. “Weight loss is a critical factor to reduce inflammation.” Clinical nutrition ESPEN vol. 28 (2018): 21-35. doi:10.1016/j.clnesp.2018.08.007
https://pubmed.ncbi.nlm.nih.gov/30390883/
Quote: “Caloric restricted diets result in a negative energy balance causing body fat loss [143] and the activation of lipolysis [144] necessary to provide energy substrates [145]. The reduced caloric intake is the most critical factor to improve cellular metabolism and mitochondrial function compared to exercise and gastric bypass to induce weight loss over the term [146]. Weight loss induced by calorie restriction diet represents the most effective treatment for patients with metabolic disorders [147] reducing the visceral adiposity, and the incidence of type-2 diabetes, and inflammation [147,148]. Weight loss reduces the adipocytes size and the adipokines synthesis and release [149], with consequent improvement in insulin resistance and in the inflammatory process [150] (Fig. 2).

A modest weight loss of 10% [148] is capable of reducing the serum level of inflammatory markers more than double, reducing the cardiovascular risk factor and increasing serum adiponectin level [76,151]. Weight loss assessed a reduction in insulin level of 25%, MCP-1 of 20% and leptin by 24% strengthening the hypothesis that weight loss is beneficial by reducing the low-grade inflammation [152], and is an activator of insulin sensitivity [31,153e155], particularly the CRP level [156,157]. Low carbohydrates diet is more efficient on metabolic improvement compared to conventional weight loss diet, also after adjustment for weight loss differences [158]. The Mediterranean diet determined a significant reduction in pro-inflammatory cytokine thought a modest weight loss was found (about 2 kg) [38].”


#Włodarczyk, Marta, and Grażyna Nowicka. “Obesity, DNA Damage, and Development of Obesity-Related Diseases.” International journal of molecular sciences vol. 20,5 1146. 6 Mar. 2019, doi:10.3390/ijms20051146
https://pubmed.ncbi.nlm.nih.gov/30845725/
Quote: “Obesity has been recognized to increase the risk of such diseases as cardiovascular diseases, diabetes, and cancer. It indicates that obesity can impact genome stability. Oxidative stress and inflammation, commonly occurring in obesity, can induce DNA damage and inhibit DNA repair mechanisms. Accumulation of DNA damage can lead to an enhanced mutation rate and can alter gene expression resulting in disturbances in cell metabolism. Obesity-associated DNA damage can promote cancer growth by favoring cancer cell proliferation and migration, and resistance to apoptosis. Estimation of the DNA damage and/or disturbances in DNA repair could be potentially useful in the risk assessment and prevention of obesity-associated metabolic disorders as well as cancers. DNA damage in people with obesity appears to be reversible and both weight loss and improvement of dietary habits and diet composition can affect genome stability.”

#Heymsfield, Steven B, and Thomas A Wadden. “Mechanisms, Pathophysiology, and Management of Obesity.” The New England journal of medicine. 2017.
https://pubmed.ncbi.nlm.nih.gov/28099824/
Quote: “Moderate weight loss, defined as a 5 to 10% reduction in baseline weight, is associated with clinically meaningful improvements in obesity-related metabolic risk factors and coexisting disorders.9,38,39 A 5% weight loss improves pancreatic β-cell function and the sensitivity of liver and skeletal muscle to insulin; a larger relative weight loss leads to graded improvements in key adipose-tissue disturbances.40 These salutary effects were observed clinically in overweight and obese patients with type 2 diabetes who were treated with an intensive lifestyle intervention in the Look AHEAD (Action for Health in Diabetes) study.41 At 1 year, patients had a mean weight loss of 8.6% of baseline weight, which was accompanied by significant reductions in systolic and diastolic blood pressure (of 6.8 and 3.0 mm Hg, respectively) and levels of triglycerides (of 30.3 mg per deciliter [0.34 mmol per liter]) and glycosylated hemoglobin (of 0.64%). A graded response was observed for these weight-sensitive measures, with larger weight losses accompanied by greater improvements.42

Moderate weight loss can translate to disease prevention in high-risk persons. Patients with overweight or obesity and impaired glucose tolerance who received an intensive lifestyle intervention in the Diabetes Prevention Program had a mean weight loss of 5.6 kg at 2.8 years and a 58% relative reduction in the risk of type 2 diabetes.43 The incidence of type 2 diabetes remained 34% below the incidence in the control group at 10 years of follow-up, even though the participants in the intervention group had, on average, returned to close to their baseline weight.44

Mean losses of 16 to 32% of baseline weight produced by bariatric surgery in patients with severe obesity may lead to disease remission, including remission of type 2 diabetes in patients who undergo bariatric surgery, particularly Roux-en-Y gastric bypass.45–50 Significant reductions in all-cause mortality have also been shown in observational studies of surgically treated patients.51,52

Although weight loss is an effective, broad-acting therapeutic measure, not all risk factors and chronic disease states respond equally well.38,39,42 Severe obstructive sleep apnea, for example, improves but rarely fully remits in response to weight-loss treatments, including bariatric surgery.26 Moreover, the beneficial clinical effects of moderate weight loss achieved with intensive lifestyle intervention did not reduce morbidity and mortality associated with cardiovascular disease after 9.6 years in the Look AHEAD study.53 Well-established medical therapies must be used with weight loss to achieve good control of obesity-related coexisting conditions. Similarly, symptoms of some psychiatric disorders may improve with weight loss,33,54 but adjunctive psychiatric care is critical, particularly in persons with moderate or severe disorders. For example, adjunctive care has been shown to be of value for improving mental health and eating behaviors such as binge eating.34”

#Bosch-Sierra, Neus et al. “The Impact of Weight Loss on Inflammation, Oxidative Stress, and Mitochondrial Function in Subjects with Obesity.” Antioxidants (Basel, Switzerland) 2024
https://www.mdpi.com/2076-3921/13/7/870
Quote: “Inflammation, oxidative stress, and mitochondrial function are implicated in the development of obesity and its comorbidities. The purpose of this study was to assess the impact of weight loss through calorie restriction on the metabolic profile, inflammatory and oxidative stress parameters, and mitochondrial respiration in an obese population. A total of 109 subjects underwent two cycles of a very low-calorie diet alternated with a low-calorie diet (24 weeks). We analyzed biochemical and inflammatory parameters in serum, as well as oxidative stress markers, mRNA antioxidant gene expression, and mitochondrial respiration in peripheral blood mononuclear cells (PBMCs). After the intervention, there was an improvement in both insulin resistance and lipid profiles, including cholesterol subfractions. Weight loss produced a significant reduction in mitochondrial ROSs content and an increase in glutathione levels, coupled with an enhancement in the mRNA expression of antioxidant systems (SOD1, GSR, and CAT). In addition, a significant improvement in basal oxygen consumption, maximal respiration, and ATP production was observed. These findings demonstrate that moderate weight loss can improve insulin resistance, lipid profiles and subfractions, inflammatory and oxidative stress parameters, and mitochondrial respiration. Therefore, we can affirm that dietary intervention can simultaneously achieve significant weight loss and improve metabolic profile and mitochondrial function in obesity.”

#Forsythe, L Kirsty et al. “Obesity and inflammation: the effects of weight loss.” Nutrition research reviews vol. 21,2 (2008
https://pubmed.ncbi.nlm.nih.gov/19087366/
Quote: “Overall, the present review indicates that during a period of weight loss, the unfavourable inflammatory profile associated with increased adiposity can be improved, thus providing further evidence for the beneficial effects of weight loss in overweight and obesity in terms of reducing the risk of co-morbidities. However, it is likely that the improvements observed are mainly due to a negative energy balance in the short term, rather than decreasing adiposity. More randomised, controlled intervention studies are required to accurately determine the time needed, in which a reduced weight is maintained, in order to benefit from improved inflammatory status long-term. Furthermore, it is recommended that these studies include younger adults, with equal numbers of both men and women, and contain measures of body composition appropriately adjusted for body size.”

 
– Even if you already have full blown diabetes type 2, by losing weight you can reverse many of the negative effects and drastically improve your health and lifespan.

#Taylor, Roy et al. “Understanding the mechanisms of reversal of type 2 diabetes.” The lancet. Diabetes & endocrinology. 2019
https://www.thelancet.com/journals/landia/article/PIIS2213-8587(19)30076-2/abstract
Quote: “Clinical and pathophysiological studies have shown type 2 diabetes to be a condition mainly caused by excess, yet reversible, fat accumulation in the liver and pancreas. Within the liver, excess fat worsens hepatic responsiveness to insulin, leading to increased glucose production. Within the pancreas, the β cell seems to enter a survival mode and fails to function because of the fat-induced metabolic stress. Removal of excess fat from these organs via substantial weight loss can normalise hepatic insulin responsiveness and, in the early years post-diagnosis, is associated with β-cell recovery of acute insulin secretion in many individuals, possibly by redifferentiation. Collectively, these changes can normalise blood glucose levels. Importantly, the primary care-based Diabetes Remission Clinical Trial (DiRECT) showed that 46% of people with type 2 diabetes could achieve remission at 12 months, and 36% at 24 months, mediated by weight loss. This major change in our understanding of the underlying mechanisms of disease permits a reassessment of advice for people with type 2 diabetes.”

#Petersen, Kitt Falk et al. “Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes.” Diabetes 2005
https://pubmed.ncbi.nlm.nih.gov/15734833/
Quote: “All of the type 2 diabetic patients manifested severe hepatic and peripheral insulin resistance associated with hepatic steatosis and increased IMCL. A moderate weight loss of ~8 kg, or ~8% of their body weight, normalized fasting plasma glucose concentrations and was associated with an ~10% decrease in plasma cholesterol concentrations. This improved glycemic control could be attributed to a marked improvement in their insulin responsiveness, as reflected by an approximately fourfold increase in the glucose infusion rate required to maintain euglycemia during the hyperinsulinemic-euglycemic clamp. To ascertain the mechanism for the improved insulin responsiveness, we also assessed rates of hepatic and peripheral glucose metabolism using deuterated glucose and found that the weight reduction normalized insulin suppression of hepatic glucose production but had no effects on peripheral insulin sensitivity. This improvement in hepatic insulin sensitivity was associated with an ~80% reduction of hepatic triglyceride content. In contrast, there was no change in IMCL content with weight reduction. Previous studies by our group (3,4,9,10) and others (11–13) have demonstrated a strong relationship between hepatic triglyceride content and hepatic insulin resistance. The mechanism by which hepatic steatosis causes hepatic insulin resistance is unknown but may be related to activation of a serine kinase cascade by accumulation of intracellular fatty acid metabolites that in turn inhibit insulin signaling at the level of the insulin receptor and insulin receptor substrates (IRS) 1 and 2 (IRS-1 and IRS-2) (14). Studies in transgenic mice with hepatic steatosis as a result of liver-specific overexpression of lipoprotein lipase (9) or mice with lipodystrophy and hepatic steatosis (15) have shown that intracellular accumulation of fatty acid–derived metabolites, such as long-chain fatty acyl CoAs, results in reduced insulin activation of IRS-2–associated phosphatidylinositol 3-kinase activity (9,16). More recent studies that have examined this question have shown that 3 days of high-fat feeding in rats resulted in hepatic steatosis–associated and liver-specific insulin resistance. These changes were associated with increases in hepatic fatty acyl CoAs, reduced insulin activation of IRS-1– and IRS-2–associated phosphatidylinositol 3-kinase, activation of protein kinase Cε, and increased gluconeogenesis (10). Furthermore, all of these changes, including the hepatic steatosis, were reversed by treating the rats with a low dose of the mitochondrial uncoupling agent 2,4 dinitrophenol (10).”

#Daryl Austin. It’s possible to reverse diabetes—and even faster than you think. February 21, 2025
https://www.nationalgeographic.com/science/article/type-2-diabetes-reversible-diet-exercise
Quote: “"Type 2 diabetes is like having termites in your home in that it doesn't show many symptoms at first, but can cause significant internal damage over time," says Osama Hamdy, senior staff physician at the Joslin Diabetes Center in Massachusetts. "The good news is, we have learned that if we catch the disease and intervene early, we can reverse it or induce remission." “