Inverse relationship between peripheral insulin removal and action: studies with metformin

The interaction of insulin with metformin on muscle glucose metabolism was examined in the perfused rat hindquarter. Glucose, lactate, and insulin wer e measured at the inflow to and outflow from the hindquarter, which was per fused with human erythrocytes suspended in a Kreb's-Ringer albumin buffer f or 120 min. Perfusions were performed with no additions (I) and with insuli n infusions targeted to concentrations of 175 (II) and 350 pmol/l (III) as well as infusions targeted to levels of 0 (IV), 70 (V), and 175 pmol/l (VI) but in the presence of metformin (90 mug/ml). In the presence of metformin , identical infusion rates of insulin yielded higher insulin concentrations , namely 283 +/- 19 vs. 202 +/- 31 pmol/l for VI and II, respectively (P < 0.05). Glucose uptake (GU) increased correspondingly to 79.8 +/- 0.8 in VI from 60.8 +/- 2.1 for IV and 50.1 +/- 1.3 for II and 46.1 +/- 2.7 mg/120 mi n for I (P, 0.05). This enhanced GU was matched by increasing insulin level s using only a higher rate of its infusion (III): GU of 70.2 +/- 2.4 mg/120 min with insulin of 334 +/- 26 pmol/l (P > 0.05). The simple concurrent pr esence of metformin and insulin [matching insulin concentrations in II rath er than infusion rates (IV)] demonstrated no additional effect on GU above that of metformin. The synergistic effects of metformin and insulin could t hus be explained by a metformin-mediated decrease in the extraction of insu lin by the hindquarter (4.8 +/- 0.4% vs. 8.6 +/- 0.9%, P < 0.05). This incr eases interstitial insulin (and, in a closed system, perfusate insulin), wh ich acts on cell surface receptors to increase glucose uptake. The results demonstrate that the extracellular insulin concentration, rather than insul in internalization and degradation, is the primary determinant of insulin a ction on GU in muscle and that changes in tissue insulin extraction may alt er local concentrations and, therefore, systemic insulin sensitivity. This provides both a physiological mechanism and a possible therapeutic target f or improving insulin sensitivity.