Metformin increases insulin sensitivity and basal glucose clearance in Type 2 (non‐insulin dependent) diabetes mellitus

Abstract

The effects of metformin on glycaemia, insulin and c-peptide levels, hepatic glucose production and insulin sensitivity (using the euglycaemic, hyperinsulinaemic clamp) were evaluated at fortnightly intervals in 9 Type 2 diabetic patients using a stepwise dosing protocol: Stage 1--no metformin for four weeks; stage 2--metformin 500mg mane; stage 3--metformin 500mg thrice daily; stage 4--metformin 1000mg thrice daily. Results are expressed as Mean +/- SEM. Fasting blood glucose decreased from basal values (9.7 +/- 1.0 mmol/L) by 13% at stage 2, 34% at stage 3 and 41% at stage 4 (p less than 0.02 vs basal for all stages; p less than 0.02 stage 2 vs stage 3). Post-prandial glycaemia was significantly improved only with metformin 3000mg/day (p less than 0.05). Fasting, meal-stimulated and total insulin and c-peptide levels showed no change. Hepatic glucose output did not change significantly with metformin. Insulin sensitivity, measured as total glucose utilisation during hyperinsulinaemia, increased from stage 1 (10.3 +/- 2.1 mumoL/kg/min) by 23% at stage 3 (p less than 0.05) and by 29% at stage 4 (p less than 0.02). Basal metabolic clearance of glucose increased compared to stage 1 (1.69 +/- 0.16 mL/kg/min) by 30% at stage 2, 53% at stage 3 and 44% at stage 4 (all p less than 0.02). This study demonstrates that improved efficiency of glucose utilisation, both basally and under conditions of euglycaemic hyperinsulinaemia, is the basis of metformin's antihyperglycaemic action.

Metformin Rapidly Increases Insulin Receptor Activation in Human Liver and Signals Preferentially through Insulin-Receptor Substrate-2

“…The lack of effect of metformin in the presence of insulin is consistent with the negative results of many of the hyperinsulinemic euglycemic clamp studies (18 -22, 45). However, many studies have shown significant improvements in insulin-mediated glucose disposal with metformin (3,7,10,13,14,16,17,20,23,45). Metformin activates AMPactivated protein kinase (7), increases hepatic expression of glucokinase and liver-type pyruvate kinase, and decreases expression of glucose-6-phosphatase, phosphoenolpyruvate carboxykinase, carnitine palmitoyltransferase-I, and mito-FIG.…”

Metformin improves atypical protein kinase C activation by insulin and phosphatidylinositol-3,4,5-(PO4)3 in muscle of diabetic subjects

“…However, particularly with long-term therapy, metformin provokes increases in insulin-stimulated glucose disposal [6][7][8][9][10], presumably at least partly by increasing glucose utilisation in muscle. Moreover, in vivo treatment of rats with metformin provokes increases in insulin-stimulated glucose transport, as measured in isolated skeletal muscle preparations [11,12], and metformin itself increases 2-deoxyglucose uptake in cultured myocytes [13,14].…”

Bioequivalence evaluation of two brands of metformin 500 mg tablets (Dialon® & Glucophage®) – in healthy human volunteers

“…Metformin acts to reverse two of the above defects via three mechanisms: (1) reduction in hepatic glucose production, (2) reduction in intestinal glucose absorption, and (3) increased insulin sensitivity [7][8][9][10].…”