Global health context and background

        In Europe, 52 million people are living with diabetes, with more than 90% of them having type 2 diabetes (T2D), a multifactorial disease associated with obesity and sedentary lifestyle. Association of obesity with high blood pressure, insulin resistance and/or high circulating fats is a leading cause of type 2 diabetes and cardiovascular diseases. This cluster of risk factors, defined as the “metabolic syndrome”, is now considered a health epidemic and economic burden of unmanageable proportions.
        Insulin resistance is a central problem in the metabolic syndrome and I and others have demonstrated that it can be induced in vitro by either the damaging effects of saturated fatty acids, oxidants or inflammatory cytokines; however, the situation in vivo is far more complex and needs further investigation, as no efficient therapeutic strategies are currently available for the treatment of type 2 diabetes.
        In this context, I am focused on understanding how insulin action can be impaired by excess fatty acids, oxidative stress and inflammation, from both cell biology and more global physiological perspectives.

- Metabolic diseases, Diabetes, Obesity
- Inflammation
- Insulin, signal transduction
- Skeletal muscle

Skeletal muscle inflammation: ambivalent roles in exercise and diabetes

    Skeletal muscle inflammation is emerging as a potential contributor to T2D. Inflammation occurs during exercise and repair and is a hallmark of myopathies, suggesting that it plays crucial roles in skeletal muscle homeostasis. Despite the fact that exercise is associated with inflammation, physical activity has beneficial effects on T2D, which highlights the ambivalent role of muscle inflammation in controlling glucose homeostasis. 
Epigenetic processes are potential molecular links between diseases and environmental factors such as diet and exercise. Abnormal promoter methylation of inflammatory genes was recently suggested in adipose tissue during obesity, but little is currently known about epigenetic regulations in muscle during exercise and diabetes. Surprisingly, it is unknown whether there is any parallel between local inflammation of muscle and T2D and no therapeutic strategies currently target skeletal muscle for T2D treatment.

    The overall aim of this study is to determine the interaction between inflammation and the metabolic response to exercise and T2D to define potent interventional strategies that can improve insulin sensitivity.

    It will identify what type of inflammatory response induces the greatest metabolic effect on signal transduction and expression of genes through profiling DNA methylation, chromatin structure and small RNAs. It will use primary cell cultures from human biopsies to obtain proof of principle that the beneficial effect of exercise on metabolism is dependent on inflammation, and translate these discoveries into innovative exercise and anti-inflammatory intervention strategies to improve insulin sensitivity.

Current funding:
- Individual Fellowship. Marie Skłodowska-Curie Actions, European Union.
- Research project grant. Lars Hiertas Minne Foundation, Sweden.
- Research project grant.Sigurd och Elsa Goljes Minne Foundation, Sweden.

Metabolic regulation of skeletal muscle internal clock

    Circadian rhythms occur in all species and modulate fundamental physiological processes. Day-night cycles align the phase of circadian rhythms to earth rotation, but most cells of the body follow an endogenous circadian clock independent of light exposure. Disruption of circadian cycles is associated with metabolic imbalance, and leads to increased risk of type 2 diabetes in individuals working night shifts. This suggests that alterations in circadian rhythms could contribute to the worldwide epidemic of metabolic syndrome, but the pathophysiological mechanisms are poorly understood. Skeletal muscle is engaged in locomotor activity, and glucose uptake and metabolism in this tissue are exquisitely regulated by insulin-independent contractile activity. Skeletal muscle is indeed the major determinant of post-prandial glycaemia and whole-body insulin sensitivity. But surprisingly little is known about the cross-talk between glucose/lipid metabolism and the internal clock in skeletal muscle and subsequent impact on whole body insulin sensitivity.

    The aim of this study is to determine if and how metabolic challenges impair the skeletal muscle internal clock leading to disturbances in glucose and fatty acid metabolism.

    It will identify if and how fatty acids discretely affect elements of the core clock in skeletal muscle and the interactions between insulin resistance and clock impairments to decipher the cause-consequence relationship between these two events. Identification of pathways linking metabolic and clock disturbances could lead to new pharmacological targets to target fatty acid-induced insulin resistance.