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Diabetes mellitus and antidiabetic drugs

An insufficient production of insulin by the pancreas or an insufficient receptivity of tissues to insulin characterizes diabetes mellitus whose main sign is an abnormal rise of glycemia.

When the beta cells of the pancreas are altered, most probably by immunological reactions, and diabetes mellitus known as insulin-dependant and now as type I diabetes appears. It needs an insulin treatment. This type of diabetes appears in children and teenagers and touches less than 10% of the diabetics.

When hyperglycemia results from a resistance of tissues to the action of insulin, secreted in normal or even in high levels at the beginning of the disease, diabetes mellitus is known as non-insulin-dependant, now called type II. It occurs usually in adults of more than forty years. It is also called fatty diabetes because the affected patients are generally obese and concerns more than 90% of the diabetics. The prevalence of type II diabetes mellitus is estimated at 2,2% of the population.

Diabetes mellitus is the consequence of a dysregulation of glycemia. Glucose, food essential for the cells, is supplied in the diet discontinuously, and consumed by tissues in an irregular way. The periods of allowance of glucose, i.e. the meals, do not coincide with the periods of raised requirements, i.e. physical activity. Mechanisms of regulation of glycemia, in particular via insulin, are necessary because a decrease or an excessive increase in glycemia has harmful effects. The principal regulator is the liver which stores glucose excess in the form of glycogen from which it releases it according to requirements. The striated muscle can also store glucose.

Glucose, polar molecule, does not penetrate into the cell through the lipid bilayer but by protein structures called carriers. One distinguishes two types from them:

  • insulin-dependant carriers, present in striated muscles and in adipocytes and which are primarily of Glut4 type.
  • noninsulin-dependant carriers, present in liver, pancreas, kidney, intestine, erythrocytes, placenta.

Among the noninsulin-dependant carriers, one distinguishes the Co-carriers glucose/Na+ which ensure the digestive absorption of glucose and its reabsorption in the renal tubule, and carriers less well known, present in the neuron and the lens for example.

Insulin absence induces a glucose deficiency in striated muscles and adipose tissues and, because of hyperglycemia, an excess in cells where it penetrates freely without insulin.

Glucose deficiency in adipose tissue induces metabolic compensations leading to the hydrolysis of triglycerides and release of fatty acids which are then oxidized by the liver and are transformed into ketonic derivatives.

Glucose excess has harmful consequences:

  • osmotic diuresis: when glycemia is higher than 1,8 G/L, it exceeds the capacities of renal reabsorption and induces an osmotic diuresis with loss of water, amino acids and electrolytes.
  • excessive glycosylation: in excess, glucose interacts by its aldehyde function with the amine function of the amino acids of proteins to form bases of Schiff. The most known example of this glycosylation or glycation is the formation of glycosylated hemoglobin.
  • sorbitol accumulation: glucose is transformed under the influence of aldose reductase into sorbitol whose transformation into fructose is carried out with difficulty. Sorbitol and fructose accumulate in tissues, creating a deficiency in inositol, sugar with six carbon atoms, and a modification of reduction potential of the cell in the reducing direction.

Insulin excess itself, in the event of resistance to its hypoglycemic action as in certain noninsulin-dependant diabetics, can have harmful effects over the long term.

These various disorders take part in the genesis of microangiopathies (retinopathy, nephropathy), of macroangiopathies (angina pectoris, infarction, arteritis) and of peripheral neuropathies.

Besides insulin, other hormones, glucagon known for a long time, adiponectin, leptin, resistin, ghrelin of more recent knowledge, are involved in the modulation of the effects of insulin and in the regulation of appetite.

Insulin remains the essential drug for diabetes mellitus.  Other drugs stimulate insulin secretion (sulfonylureas, repaglinide), enhance its effects (metformin, thiazolidinediones) or reduce insulin resistance which appears in many diabetics. Other drugs touch the metabolism of glucose directly. Lastly, more recently, a certain number of hormones acting on glycemia and especially on food behavior were discovered. We will consider these various aspects successively.

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