Diabetes Metab 1996 Feb;22(1):43-50
Is Metformin safe enough for ageing type 2 diabetic patients?
Gregorio F, Ambrosi F, Filipponi P, Manfrini S, Testa I.
Anti-Diabetic Unit, E. Profili General Hospital, Fabriano (AN), Italy.

We assessed the effect of adding low doses of Metformin to sulfonylurea therapy in 76 elderly Type 2 diabetic patients by monitoring glycaemic control and blood lactate for one year. Metformin markedly improved glycaemic control. Fasting lactate concentrations were not affected and post-meal lactate peaks were minimally increased. Additional benefits included an improvement in some lipid parameters, a reduction in serum uric acid and a significant weight loss in overweight patients. Metformin was clinically well-tolerated. Instead of advanced age alone, renal function and/or any other age-related factor likely to contribute to lactate overproduction should be the basis for deciding on Metformin therapy. No evidence indicated that Metformin should be denied "a priori" to ageing Type 2 diabetic patients.

J Clin Endocrinol Metab 2003 Mar;88(3):1323-32
Metformin rapidly increases insulin receptor activation in human liver and signals preferentially through insulin-receptor substrate-2.
Gunton JE, Delhanty PJ, Takahashi S, Baxter RC.
Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St. Leonards, Sydney, New South Wales 2065 Australia.

Metformin decreases endogenous glucose production by the liver. Few studies have examined the effect of Metformin on the insulin-signaling pathway in liver models, and none have presented data on the effect in normal human liver. Huh7 human hepatoma cells and primary human hepatocytes were used. Insulin receptor (IR) and IR substrates (IRS)-1 and -2 were assessed by immunoprecipitation and immunoblot. Normal human liver was used to assay IR kinase activity (IR-KA). Tyrphostin AG1024 was used to inhibit IR-KA and examine effects on deoxyglucose uptake. Metformin (1 micro g/ml) increased IR tyrosine phosphorylation by 78% (P = 0.0007) in 30 min in human hepatocytes and Huh7 cells and increased IRS-2 but not IRS-1 activation, and the downstream increase in deoxyglucose uptake was mediated via increased translocation of GLUT-1 to the plasma membrane. Metformin did not augment maximal or submaximal insulin-stimulated IR activation. Metformin increased basal IR-KA by 150% (P = 0.0001). AG1024 inhibited Metformin-induced IR-beta phosphorylation in a concentration-dependent manner and abolished Metformin-induced 2-deoxyglucose uptake. This study demonstrates that the mechanism of action of Metformin in liver involves IR activation, followed by selective IRS-2 activation, and increased glucose uptake via increased GLUT-1 translocation. The effect of Metformin was completely blocked by an IR inhibitor.

J Clin Endocrinol Metab 1991 Dec;73(6):1294-301
Mechanism of Metformin action in obese and lean noninsulin-dependent diabetic subjects.
DeFronzo RA, Barzilai N, Simonson DC.
Department of Medicine, University of Texas Health Science Center, San Antonio 78284-7877.

The effect of Metformin on glucose metabolism was examined in eight obese (percent ideal body weight, 151 +/- 9%) and six lean (percent ideal body weight, 104 +/- 4%) noninsulin-dependent diabetic (NIDD) subjects before and after 3 months of Metformin treatment (2.5 g/day). Fasting plasma glucose (11.5-8.8 mmol/L), hemoglobin-A1c (9.8-7.7%), oral glucose tolerance test response (20.0-17.0 mmol/L; peak glucose), total cholesterol (5.67-4.71 mmol/L), and triglycerides (2.77-1.52 mmol/L) uniformly decreased (P less than 0.05-0.001) after Metformin treatment; fasting plasma lactate increased slightly from baseline (1.4 to 1.7 mmol/L; P = NS). Body weight decreased by 5 kg in obese NIDD subjects, but remained constant in lean NIDD. Basal hepatic glucose production declined in all diabetics from 83 to 61 mg/m2.min (P less than 0.01), and the decrease correlated (r = 0.80; P less than 0.01) closely with the fall in fasting glucose concentration. Fasting insulin (115 to 79 pmol/L) declined (P less than 0.05) after Metformin. During a 6.9 mmol/L hyperglycemic clamp, glucose uptake increased in every NIDD subject (113 +/- 15 to 141 +/- 12 mg/m2.min; P less than 0.001) without a change in the plasma insulin response. During a euglycemic insulin clamp, total glucose uptake rose in obese NIDD subjects (121 +/- 10 to 146 +/- 9 mmol/m2.min; P less than 0.05), but decreased slightly in lean NIDD (121 +/- 10 to 146 +/- 0.5; P = NS). Hepatic glucose production was suppressed by more than 80-90% in all insulin clamp studies before and after Metformin treatment. In conclusion, Metformin lowers the fasting plasma glucose and insulin concentrations, improves oral glucose tolerance, and decreases plasma lipid levels independent of changes in body weight. The improvement in fasting glucose results from a reduction in basal hepatic glucose production. Metformin per se does not enhance tissue sensitivity to insulin in NIDD subjects. The improvement in glucose metabolism under hyperglycemic, but not euglycemic, conditions suggests that Metformin augments glucose-mediated glucose uptake. Metformin has no stimulatory effect on insulin secretion.