14.01.3 Insulin Replacement Therapy

The logical treatment for low insulin secretion or low sensitivity to insulin is to replace the insulin. The insulin for replacement is made my recombinant DNA techniques. Insulin replacement therapy is indicated for all subjects with Type 1 diabetes. Many subjects with Type 2 diabetes also end up by producing very little insulin and becoming very insensitive to the insulin they produce, and need to use insulin replacement therapy. However, before that changes in diet and oral hypoglycemics (drugs that are active after oral administration, and increase the levels of insulin) are initial treatment for Type 2 diabetes. Insulin is not active after oral administration, as it is digested in the gut. Insulin can be administered in a variety of ways: intravenously, intramuscularly, subcutaneously, and by inhalation, but not by oral administration, and this is the major drawback to using insulin.

When insulin replacement therapy is used, the goal is to mimic what the endogenous insulin would do, if it was there. Endogenous insulin produced by the beta cells of the pancreas is injected into the portal vein, which takes in straight to the liver. Thus, the highest concentrations with endogenous insulin will be in the liver, which is very convenient as this is the major site of action of insulin. However, insulin replacement therapy does not mimic this. With all the routes used for insulin (i.v. i.m. s.c. and inhalation), the highest concentrations will be at the site of administration, which is not the liver. Endogenous insulin levels are determined by glucose levels, insulin replacement therapy levels is not sensitive to plasma levels of glucose. Thus, insulin replacement therapy is not a perfect match for endogenous insulin.

With insulin replacement therapy, we try and match the kinetics of endogenous insulin, by using combinations of normal and long-acting preparations of insulin. Endogenous insulin has quite low fasting levels, but when there is a meal, the glucose stimulates insulin secretion and there are increased level of insulin. Pre-breakfast and pre-supper (dinner) injection of normal insulin preparations mimics the meal’s effect on the insulin by increasing the insulin concentrations (Figure 14.2). Long-acting preparations of insulin mimic the fasting levels of endogenous insulin by maintaining low levels of insulin (Figure 14.2).

Figure 14.2 Effect of different preparations of insulin on levels (Copyright QUT, Sheila Doggrell)

The meal can be mimicked by insulin injection, which is short acting. An alternative is to use isophane insulin, which is an intermediate acting preparation of insulin. The fasting levels of insulin can be mimicked by insulin glargine, which is a long acting preparation of insulin. Commonly two forms of insulin are combined, so that one injection can be used to mimic the fasting and meal levels of insulin. For instance, insulin injection and isophane insulin in various proportions can be used.

The main adverse effect of insulin replacement therapy is hypoglycaemia (low plasma levels of glucose). Hypoglycaemia is characterised by sweating, hunger, palpitations, tremor, anxiety, convulsions, and coma. To prevent hypoglycaemia, regular monitoring of glucose levels is used. The treatment of mild hypoglycemia is to ingest some glucose that is being carried. After a few incidents of hypoglycaemia, diabetics are able to recognise the start, and ingest glucose. If the hypoglycemia is severe, and occurs regularly, it is advisable to have an identification card saying you are diabetic or a bracelet that provides the information. Thus, at the convulsions/coma state, it will be known to use intravenous glucose or glucagon to overcome the hypoglycemia.

There are quite a lot of drug interactions with insulin replacement therapy. Things that can lead to hypoglycemia in combination with insulin replacement therapy include ethanol (ie alcohol). Ethanol inhibits gluconeogenesis, which is the conversion of amino acids to glucose, and thus ethanol decreases the levels of glucose. If a fixed dose of insulin is being taken, and ethanol is also taken, there may be excessive reductions in the levels of glucose, which may result in hypoglycemia. Aspirin increases the sensitivity of the pancreas to glucose, thereby increasing the secretion of any remaining insulin to reduce levels of glucose. Thus, in type 2 diabetes, where there is still some endogenous insulin, the combination of aspirin and insulin replacement therapy may lead to hypoglycemia.

A group of drugs that may cause hypoglycemia in combination with insulin replacement therapy are the β-adrenoceptor antagonists. Adrenaline is secreted from the adrenal medulla and stimulates β₂-adrenoceptors that promote gluconeogenesis, the conversion of amino acid to glucose, and glycogenolysis, which is the conversion of glycogen to glucose (Figure 14.3). The β-adrenoceptor antagonists prevent these effects of adrenaline, and therefore reduce the levels of glucose (Figure 14.3). The reduced levels of glucose in combination with insulin replacement therapy can lead to hypoglycemia.

Figure 14.3 β2-adrenoceptors and glucose levels (Copyright QUT, Sheila Doggrell)

Conversely, when the levels of adrenaline are high, as in the fight and flight response, there will be increased levels of glucose, and the replacement therapy may not be sufficient to decrease the levels of glucose, leading to hyperglycemia (high levels of glucose). Glucocorticoids do a lot of things, besides being anti-inflammatory. For instance, they have a permissive action to increase the ability of adrenaline to generate glucose. Thus, the glucocorticoids may lead to hyperglycemia in combination with insulin replacement therapy.

For type 2 diabetes, a number of drugs may be used prior to insulin replacement therapy. These include metformin, acarbose, sulfonylureas, glitazones, exenatide and dipeptidyl peptidase-4 inhibitors.