Membrane physiology as a basis for the cellular effects of metformin in insulin resistance and diabetes.
Many recent data provide new, original insights into the mechanisms of action of the antidiabetic Metformin. Careful selection of most relevant data in terms of dosage prompted this original review, largely devoted to the drug action at the cell level and whose hypotheses/conclusions are tentatively interpreted according to corresponding basic scientific knowledge. Metformin interferes with several processes linked to HGP (gluconeogenesis, glycogenolysis and their regulatory mechanisms), lowering glucose production and resensitizing the liver to insulin. The hepatic drug effect is largely favoured by prevailing glycemia. In peripheral tissues, metformin potentiates the effects of both hyperglycemia and hyperinsulinemia. Increase in glucose-mediated glucose transport is mainly mediated by an improvement in the glucose transporter's intrinsic activity. Potentiation of the hormone effect relates to an increase in insulin receptor tyrosine kinase activity. Both mechanisms (insulin signalling and glucose transport) result in the activation of glycogen synthase, a limiting enzyme in the causal defects of NIDDM. Exciting findings show that, conversely, priming cells with very low insulin concentrations also leads to full expression of metformin's antidiabetic activity. Specific investigations confirm a working hypothesis defining the site of action as the cell membrane level. Indeed metformin corrects membrane fluidity and protein configuration disturbed by the diabetic state and which interfere with normal protein-protein or protein-lipid interactions required for proper functioning of the processes regulating glucose transport/metabolism. It is proposed that membrane changes largely represent a common denominator explaining metformin effects on various systems involved in receptor signalling and related functions.
Wiernsperger
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International Pharmacological Support, LIPHA S.A., Lyon, France.
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D007333:Insulin Resistance; D008687:Metformin / Q000493:pharmacokinetics / Q000494:pharmacology*; D011972:Receptor, Insulin / Q000187:drug effects
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D008687:Metformin; D011972:Receptor, Insulin