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

Abstract

OBJECTIVEChanges 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 METHODSWe 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). [6,6-2H2]-Glucose was infused to measure glucose fluxes.RESULTSPlasma 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 μmol/kg/min, respectively, P < 0.001). The effect was largely removed by blockade of lipolysis during hypoglycemia in study 3 (28.9 ± 2.6 μmol/kg/min, P > 0.2 vs. study 1) and largely reproduced by replacement of FFA in study 4 (22.3 ± 2.8 μmol/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 μmol/kg/min, P < 0.05) and increased glucose utilization (16.9 ± 1.85 vs. 28.5 ± 2.7 μmol/kg/min, P < 0.05). In study 4, GIR fell by ∼23% (22.3 ± 2.8 μmol/kg/min, vs. study 3, P = 0.058), indicating a role of acipimox per se on insulin action.CONCLUSIONLipolysis induced by hypoglycemia counterregulation largely mediates posthypoglycemic insulin resistance in healthy subjects, with an estimated overall contribution of ∼39%.

Increased plasma β-hydroxybutyrate levels during the fasting test in patients with endogenous hyperinsulinaemic hypoglycaemia

“…An escape of ketogenesis from inhibition by insulin during hypoglycaemia has been shown in pancreatectomised dogs undergoing a hyperinsulinaemic clamp with euglycaemia or hypoglycaemia (10). Moreover, similar results were observed during hyperinsulinaemic hypoglycaemia in humans (11). Lipolysis can escape the inhibitory effect of insulin during the rise in counter-regulatory hormone levels.…”

Hypoglycemia: A Possible Link between Insulin Resistance, Metabolic Dyslipidemia, and Heart and Kidney Disease (the Cardiorenal Syndrome)

“…Recent research supports the notion that obese individuals have a higher baseline lipolytic rate and an increased release of NEFA during starvation than lean individuals [19] . Further, studies on insulin-induced hypoglycemia reinforce the concept that NEFA levels decrease initially, reaching a nadir at 30 min that lasts about 90 min, and then increase parallel to enhanced catecholamine release [20][21][22][23][24] . It appears that blood glucose levels that elicit counter-regulatory hormone release are slightly higher in obese than lean persons.…”

Mechanisms for greater insulin-stimulated glucose uptake in normal and insulin-resistant skeletal muscle after acute exercise

“…However, research on humans has provided information about the effects of sequential in vivo exposure of muscle to elevated circulating insulin concentration on glucose metabolism. Studying humans undergoing two sequential euglycemic hyperinsulinemic clamps that were 15 h apart, Lucidi et al (73) found no enhancement of glucose disposal during the second clamp compared with the first clamp. Jovanovic et al (60) studied the second-meal phenomenon, which refers to the well-documented observation that postmeal glycemia is lower after the second of two similar meals that are spaced several hours apart.…”

“…The greater glycogen accumulation after the breakfast-plus-lunch trial vs. the lunch-only trial was characterized by similar insulinemia, lower glycemia, and lower nonesterified fatty acids. The results of these studies using nonexercised rats or humans are interesting (41,60,73), but it is unclear whether these experiments are truly relevant to the postexercise increase in insulin sensitivity.…”