Insulin, effects
The insulin receptor consists of two entirely extracellular alpha units which are the insulin binding domain. These two alpha units are interconnected, and connected to two beta units by disulfide bonds. Beta units are transmembrane and intracellular. The insulin receptor is a receptor-enzyme: its activation by insulin directly induces phosphorylation of intracytoplasmic protein like IRS-1 (insulin receptor substrate) which, itself, acts on other proteins such as phosphatidylinositol-3 kinase (PI 3-K) which plays an essential part in the translocation of glucose transporters to the cell surface.
Many of the effects of insulin are the consequence of its indirectly acting nuclear effects: it modulates gene transcription leading to regulation of synthesis of enzymes implicated in particular in the metabolism of carbohydrates. There is, for example, increase of biosynthesis of glucokinase and glycogen synthase, and decrease of biosynthesis of phosphoenolpyruvate carboxykinase which is involved in the gluconeogenesis.
There exists, moreover, differences of structure and function between insulin receptors of various tissues.
Insulin acts on the metabolism of carbohydrates, proteins, lipids and potassium.
Hypoglycemic action
The hypoglycemic action results from two principal effects which are the consequence of modifications of the transcription of genes controlling enzyme synthesis:
- increase of the uptake of glucose by some tissues, in particular skeletal muscles and adipose tissue into which its penetration is insulin-dependant. Insulin induces migration of glucose transporters from intracytoplasmic localization to plasma membrane in which they are incorporated to ensure the penetration of glucose. Insulin could moreover activate the carriers already inserted in the membrane. These carriers are channels which, open, ensure a passive glucose entry into the cells according to a concentration gradient.
Regulation of glycemia
- decrease of the release of glucose by the liver.
Insulin does not modify the penetration of glucose in hepatocytes which are normally permeable to it , but decreases its release.
By its enzymatic effects, it induces the storage of glucose in the form of glycogen and inhibits the transformation of glycogen into glucose. It increases the transformation of glucose into glycogen by increasing the activity of the enzymes glucokinase and glycogen-synthase.
Action on proteins
Insulin increases uptake of amino acids by tissues, which leads to a decrease of their plasma concentration except for two of them: alanine, because of its formation starting from pyruvate, and tryptophan whose relative concentration rises, because, being more bound to plasma albumin, its concentration drops less than that of the other amino acids.
Insulin inhibits gluconeogenesis, i.e. the transformation of amino acids into carbohydrates.
Lipid metabolism
Insulin induces lipogenesis and inhibits lipolysis in the liver, adipose tissue and striated muscles. In insulin absence, fatty acid catabolism by ß-oxidationn increases, which induces excessive production of acetyl-CoA at the origin of ketogenesis, i.e. of the production of acetone and ß-hydroxybutyrate.
Insulin induces the release of leptin by adipocytes. Leptin, by acting at the hypothalamic level, reduces appetite and increases thermogenesis.
Potassium transport
Insulin, by increasing potassium uptake by cells tends to induce hypokalemia. A potassium deficiency decreases the hypoglycemic action of insulin. . It has the same effect on magnesium
Central effects
By activating cerebral receptors, insulin modulates food behavior. An insulin deficiency elicits neuropeptide Y release, responsible of the increase in appetite and a decrease of the release by adipocytes of leptine which, by acting on the hypothalamus, reduces appetite and increase thermogenesis.
Notice
C peptide which was regarded for a long time as inactive could play a protective role against the vascular damages observed in diabetic patients.
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