The Effects of Metformin on Adipocyte Insulin Action and Metabolic Control in Obese Subjects with Type 2 Diabetes

Abstract

To investigate the mechanisms of action of metformin, insulin receptor binding and the activity of several insulin-controlled metabolic pathways were measured in adipocytes taken from 10 obese Type 2 diabetic patients treated for 4 weeks with either metformin (0.5 g x 3 daily) or matching placebo using a double-blind crossover design. Metformin therapy was associated with a significant fall in serum fructosamine levels (3.1 +/- 0.4 vs 2.8 +/- 0.4 mmol l-1, p less than 0.02) as well as fasting (10.8 +/- 2.4 vs 9.4 +/- 2.1 mmol l-1) and daytime (11.5 +/- 2.4 vs 10.0 +/- 2.2 mmol l-1) plasma glucose concentrations (p less than 0.05). Fasting and postprandial plasma levels of C-peptide and insulin were unchanged. While fasting plasma lactate concentrations remained unaltered after metformin, a rise was noted in response to meals (from 1.4 +/- 0.1 to 1.8 +/- 0.2 mmol l-1, p less than 0.05). Adipocyte insulin receptor binding was unaffected by drug treatment. Moreover, no insulin-like effects or post-binding potentiation of insulin action could be found on adipocyte glucose transport, glucose oxidation, lipogenesis, glycolysis or antilipolysis. A complementary in vitro study using adipocytes from non-obese healthy volunteers failed to show any direct effect of metformin on adipocyte insulin binding or glucose transport and metabolism, at media drug concentrations corresponding to therapeutic plasma levels.

Metformin inhibits catecholamine‐stimulated lipolysis in obese, hyperinsulinemic, hypertensive subjects in subcutaneous adipose tissue: an in situ microdialysis study

“…These observations are in accordance with previous investigations that have demonstrated the inhibitory effect of this biguanide on b-stimulated lipolysis in vitro [10]. The results, however, stand in contrast to observations that showed either no change [11,22] or an increase in basal lipolysis [10]. Such differences might derive from different methodology, including whether the studies were performed in vitro or in vivo [23], and the different means of administering metformin.…”

“…Metformin induced a lower glycerol out¯ow, an index for lipolysis rate [12]. The results, however, stand in contrast to observations that showed either no change [11,22] or an increase in basal lipolysis [10]. The results, however, stand in contrast to observations that showed either no change [11,22] or an increase in basal lipolysis [10].…”

Cellular Mechanism of Action of Metformin

“…Furthermore, other studies reported that metformin was without effect (28,30) or even decreased insulin binding in monocytes from NIDDM patients (29). Adipocytes from metform in-treated diabetic patients also showed no increase in insulin binding, and the drug did not increase hormone binding to isolated human adipocytes in vitro (21). In animal models, the results have been equally inconsistent.…”

“…Effects in both adipocytes and muscle cells have been described, and some of these studies have suggested that the main effect of metformin in obese NIDDM patients is not in fat but rather in muscle (21).…”

Metformin inhibits leptin secretion via a mitogen-activated protein kinase signalling pathway in brown adipocytes

“…By contrast to liver and muscle, relatively little is known about direct metformin actions in adipocytes. In rat adipose tissue glucose uptake has been found to be enhanced (Matthaei et al 1991(Matthaei et al , 1993 whereas in human adipocytes no change has been described by metformin treatment (Pedersen et al 1989, Ciaraldi et al 2002. Recently, there has been a growing appreciation of adipose tissue as an endocrine organ that is pivotal for the systemic regulation of insulin action and energy homeostasis (Rajala & Scherer 2003).…”