Mechanisms of Insulin Resistance After Insulin-Induced Hypoglycemia in Humans: The Role of Lipolysis

OBJECTIVE-Changes in glucose metabolism occurring during counterregulation are, in part, mediated by increased plasma free fatty acids (FFAs), as a result of hypoglycemia-activated lipolysis. However, it is not known whether FFA plays a role in the development of posthypoglycemic insulin resistance as well. RESEARCH DESIGN AND METHODS-We conducted a series of studies in eight healthy volunteers using acipimox, an inhibitor of lipolysis. Insulin action was measured during a 2-h hyperinsulinemic-euglycemic clamp (plasma glucose [PG] 5.1 mmo/l) from 5:00 P.M. to 7:00 P.M. or after a 3-h morning hyperinsulinemic-glucose clamp (from 10 A.m. to 1:00 P.M.), either euglycemic (study 1) or hypoglycemic (PG 3.2 mmol/l, studies 2-4), during which FFA levels were allowed to increase (study 2), were suppressed by acipimox (study 3), or were replaced by infusing lipids (study 4). [6,6-H-2(2)]-Glucose was infused to measure glucose fluxes. RESULTS-Plasma adrenaline, norepinephrine, growth hormone, and cortisol levels were unchanged (P > 0.2). Glucose infusion rates (GIRs) during the euglycemic clamp were reduced by morning hypoglycemia in study 2 versus study 1(16.8 +/- 2.3 vs. 34.1 +/- 2.2 mu mol/kg/min, respectively, P < 0.001). The effect was largely removed by blockade of lipolysis during hypoglycemia in study 3 (28.9 +/- 2.6 mu mol/kg/min, P>0.2 vs. study 1) and largely reproduced by replacement of FFA in study 4 (22.3 +/- 2.8 mu mol/kg/min, P < 0.03 vs. study 1). Compared with study 2, blockade of lipolysis in study 3 decreased endogenous glucose production (2 +/- 0.3 vs. 0.85 +/- 0.1 mu mol/kg/min, P < 0.05) and increased glucose utilization (16.9 +/- 1.85 vs. 28.5 +/- 2.7 mu mol/kg/min, P < 0.05). In study 4, GIR fell by similar to 23% (22.3 +/- 2.8 mu mol/kg/min, vs. study 3, P = 0.058), indicating a role of acipimox per se on insulin action. CONCLUSION-Lipolysis induced by hypoglycemia counterregulation largely mediates posthypoglycemic insulin resistance in healthy subjects, with an estimated overall contribution of similar to 39%. Diabetes 59:1349-1357, 2010