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BRAME, LORI A., ROBERT V. CONSIDINE, MIKAKO YAMAUCHI, ALAIN D. BARON, AND KIEREN J. MATHER. Insulin and endothelin in the acute regulation of adiponectin in vivo in humans. Obes Res. 2005;13:582-588. Objective: In vitro, insulin and endothelin (ET) both modulate adiponectin secretion from adipocyte cell lines. The current studies were performed to assess whether endogenous ET contributes to the acute action of insulin infusions on adiponectin levels in vivo in humans. Research Methods and Procedures:We studied 17 lean and 20 obese subjects (BMI 21.8 Ϯ 2.2 and 34.0 Ϯ 5.0 kg/m 2 , respectively). Hyperinsulinemic euglycemic clamp studies were performed using insulin infusion rates of 10, 30, or 300 mU/m 2 per minute alone or with concurrent infusion of BQ123, an antagonist of type A ET receptors. Circulating adiponectin levels were assessed at baseline and after achievement of steady-state glucose with the insulin infusion. Results: Adiponectin levels were lower in obese than lean subjects (6.76 Ϯ 3.66 vs. 8.37 Ϯ 2.79 g/mL, p ϭ 0.0148 adjusted for differences across gender). Insulin infusions suppressed adiponectin by a mean of 7.8% (p Ͻ 0.0001). In a subset of 13 lean and 14 obese subjects for whom data with and without BQ123 were available, there was no evident effect of BQ123 to modulate clamp-associated suppression of adiponectin (p ϭ 0.16). Surprisingly, there was no evident relationship between steady-state insulin concentrations and adiponectin suppression (r ϭ 0.14, p ϭ 0.30), and again no effect of BQ123 to modify this relationship was seen.Discussion: Despite baseline differences in adiponectin levels, we observed equal suppression of adiponectin with insulin infusions in lean and obese subjects. ET receptor antagonism with BQ123 did not modulate this effect, suggesting that endogenous ET does not have a role in modifying the acute effects of insulin on adiponectin production and/or disposition.

Endothelial dysfunction is a feature of a variety of clinical states of insulin resistance, and increasingly it is recognized that pre-diabetic states of insulin resistance are associated not only with insulin resistance but with increased cardiovascular risk. The metabolic syndrome which typically accompanies insulin resistance brings aberrations in a number of classical cardiovascular risk factors, but it appears that insulin resistance itself represents an additional, non-classical risk factor. Therefore, the approach to treating the endothelium in patients with the metabolic syndrome might include therapies targeting insulin resistance. In this review, we provide a detailed overview of the current state of knowledge regarding the biguanide metformin and its effects on the endothelium. Its mode of action is reviewed, along with the available data from laboratory and experimental studies related to vascular function in animals and in humans. Metformin has beneficial effects on endothelial function which appear to be mediated through its effects to improve insulin resistance. Therapeutically targeting insulin resistance appears to be a viable route to improving endothelial function in clinical states of insulin resistance.

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