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Insulin resistance, the antechamber of diabetes mellitus

  1. Gastroepato
  2. Diabetology
  3. Insulin resistance
  4. Insulin resistance and hepatic steatosis
  5. Diabetes, α cells and pancreatic β cells
  6.  Type 1 or type 2 diabetes mellitus
  7. Diabetes. What are we talking about?

notes by dr Claudio Italiano

Are you obese, do you have a tummy like me?
Did your father or mother be diabetic?
Beware, think about diabetes or you are about to become diabetic. Before becoming diabetic, you become intolerant to carbohydrates, which means that in the morning your blood sugar levels will be around 120-125 and you have much insulin in your blood, this may be excessive, even when you are fasting.
This condition forces you to eat continuously and dream of sweets, chips and donuts. Often, after a few hours of breakfast, if you do not eat, you feel sweating, you are anxious, your legs shake and you have to eat something, otherwise you feel dizzy.
Talk to your doctor, ask for glycemic control, glycated hemoglobin, fasting insulin dosage and start doing sports regularly, leave your car in the garage, eat without sweets, without fat, without fried food.
Insulin resistance refers to the low sensitivity of the peripheral cells to the action of insulin, which can lead to excessive production of insulin, exhaustion of the beta cell and, finally, to type 2 diabetes mellitus; for this reason, that is, for the problem of peripheral insulin resistance, a pancreas is forced to produce large amounts of insulin to be able to provide an adequate insulin signal in the periphery. To give a practical example it is as if a patient were deaf and that to allow him to listen to the words another person used a megaphone. The causes can be hormonal (the most common), genetic, or pharmacological.

Hormonal causes

Insulin is a polypeptide hormone that is essential for glucose uptake within cells, it binds to a protein receptor located in the cell membrane, this binding causes in turn a whole series of metabolic events (a signal transduction pathway) which ultimately, through IRS proteins, causes glucose to enter the cell and accumulate in the liver. This is the organ of glucose storage, which in the early hours of fasting, ie from 4-5 ° hour from meal, replaces glucose requirements and keeps blood glucose levels high, thanks to the action of gluoconeogenesis. In the patient, diabetic, however, as explained below, the liver continues to dispose of glucose also in the post-prandium, contributing to the dangerous glycemic spurs of diabetes.

It is important to underline that the relationships between diabetes and liver are complex and, as already mentioned, different depending on the time of onset of diabetes compared to hepatopathy. If there is a common element it is the onset of insulin resistance, which can then be associated, in so-called "hepatogenous" diabetes, with other factors such as the altered response of the insular beta cells and the reduced hepatic clearance of insulin. It must be said that many hormones (cortisol and glucocorticoids, but also GH, glucagon, adrenaline), antagonize the insulin action, because if this was not limited there would be an excessive cellular absorption of glucose, resulting in hypoglycemia and death (as happens for example in the most severe cases of Addison's syndrome). These hormones antagonize insulin action in various ways, for example glucocorticoids decrease the affinity of insulin receptors with insulin itself, thereby lowering the binding capacity of insulin with its receptor, further inhibiting IRS-I protein synthesis, GH decreases the number of insulin receptors. Of course, the balance of these substances is essential for proper insulin action, however when the hormones that antagonize insulin are in excess (as in the case of endocrine diseases such as Cushing's syndrome, acromegaly, glucagonoma, pheochromocytoma) is established insulin resistance.

Metabolic effects of insulin resistance

It is important to underline that the relationships between diabetes and liver are complex and, as already mentioned, different depending on the time of onset of diabetes compared to hepatopathy. If there is a common element it is the onset of insulin resistance, which can then be associated, in so-called "hepatogenous" diabetes, with other factors such as the altered response of the insular beta cells and the reduced hepatic clearance of insulin.

Metabolic syndrome and type 2 diabetes

These pathologies, due to their epidemiological relevance, are the most important studied pathogenetic models. In these clinical conditions, the onset of insulin resistance is able to generate a chain of events leading to liver injury. Nosulino-resistance is a metabolic condition with a poly-factorial genesis resulting from an altered balance between genetic and environmental factors. In the metabolic syndrome and in type 2 diabetes mellitus, the crucial phenotypic moment is represented by the increase in adipose mass and the alteration of the gene expression of the adipocytes, with consequent triggering of insulin resistance.

This induces an increased adipocyte lipolysis with an increase in circulating free fatty acids (FFA) and their influx to the liver, resulting in increased hepatic glucose production and reduced glucose uptake in skeletal muscle (cf. glucose metabolism). Moreover, in the patient with type 2 diabetes mellitus, the suppressive effect of hyperinsulinemia on hepatic gluconeogenesis and glycogenolysis is lost, with the result that instead of reducing glucose production, this is even achieved in the post-prandium (see the dangerous post-glycemia). prandial). Finally, hyperinsulinemia induces a hepatic hyperproduction of VLDL (Very Low Density Lipoprotein) and apolipoprotein B with consequent hypertriglyceridemia (cf. lipid metabolism). This is frequently accompanied by a reduced level of HDL (High density lipoprotein). The complex neuro-hormonal regulatory mechanism of lipid homeostasis at the adipocyte level includes, in addition to regulatory hormones, also adipocyte cytokines, adipokines, such as leptin, adiponectin and resistin, neurotransmitters (noradrenaline and angiotensin II) and immunomodulatory cytokines, such as TNFα and IL6.


This biochemical milieu, under conditions of insulin resistance, is unbalanced in favor of TNFα, which has pro-inflammatory action. The result is a cascade of inflammatory reactions represented by:
• Endothelial dysfunction
• Hypercoagulability
• Inflammation
• Heterogenesis
• Fibrogenesis
• Cell growth

Diabetology