Hyperglycemic clamp-derived disposition index is negatively associated with metabolic syndrome severity in obese subjects

Abstract

Objective: Metabolic syndrome is associated with insulin resistance and increased future risk of type 2 diabetes. This study investigates the relationship between insulin secretion, insulin resistance and individual metabolic syndrome components in subjects without a prior diagnosis of diabetes.

Research design and methods: We assessed insulin secretion during hyperglycemic clamps by infusing dextrose to maintain hyperglycemia (200mg/dL), followed by L-arginine administration. Studies in 98 individuals (mean age 45.3±1.2years, 56% female, 22% African-American, 49% with metabolic syndrome) were analyzed. We tested the association between the number of metabolic syndrome components and individual outcome variables using linear mixed-effects models to adjust for potential confounding effects of age, sex, and race.

Results: Insulin sensitivity index was reduced in the presence of 1 or more metabolic syndrome components. Insulin sensitivity was independently associated with age, waist circumference, male gender and decreased HDL cholesterol. The acute insulin response was greater with two or more metabolic syndrome components, and late glucose-stimulated and L-arginine-stimulated insulin responses exhibited a similar trend. In contrast, the disposition index, a measure of beta cell compensation for insulin resistance, was linearly lower with the number of metabolic syndrome components, and was negatively associated with age, Caucasian race, waist circumference, fasting glucose, and decreased HDL cholesterol.

Conclusions: The insulin secretory response in metabolic syndrome is inadequate for the worsening insulin sensitivity, as demonstrated by a decline in disposition index. A dysfunctional insulin secretory response is evident in non-diabetic individuals and worsens with accumulation of metabolic syndrome components.

Keywords: Disposition Index; Insulin secretion; Insulin sensitivity; Metabolic syndrome.

Figure 1. Hyperglycemic clamp measures stratified by number of metabolic syndrome components

A, Insulin sensitivity index (ISI, in mg/kg/min per μU/mL•100). B, Acute insulin response (AUC for insulin during first 10 minutes of hyperglycemic clamp, μU/mL•min). C, Disposition index (product of ISI and acute insulin response), D, Late-phase insulin response (ΔInsulin_90-120). E, L-arginine-stimulated insulin response. F, Maximal disposition index calculated using the L-arginine insulin response. Data are presented as least square mean±SEM adjusted for age, sex, and race. *P<0.05 vs 0, †P<0.05 vs 1, and ‡P<0.05 vs 2 components. Two symbols indicate P<0.01 and 3 indicates P<0.001.

Figure 2. Relationship between insulin secretion and insulin sensitivity

A, Individual data points for insulin secretion (AUC for insulin during first 10 minutes of hyperglycemic clamp) plotted again insulin sensitivity index in subjects with and without metabolic syndrome. B, Data are presented as least square mean±SEM adjusted for age, sex, and race for insulin sensitivity index versus insulin secretion. Numbers adjacent to each data point indicate the number of metabolic syndrome components.