Increased Lipolysis, Diminished Adipose Tissue Insulin Sensitivity, and Impaired β-Cell Function Relative to Adipose Tissue Insulin Sensitivity in Obese Youth With Impaired Glucose Tolerance

Abstract

Despite evidence of insulin resistance and β-cell dysfunction in glucose metabolism in youth with prediabetes, the relationship between adipose tissue insulin sensitivity (ATIS) and β-cell function remains unknown. We investigated whole-body lipolysis, ATIS, and β-cell function relative to ATIS (adipose disposition index [DI]) in obese youth with impaired glucose tolerance (IGT) versus normal glucose tolerance (NGT). Whole-body lipolysis (glycerol appearance rate [GlyRa], [²H₅]glycerol at baseline and during a hyperinsulinemic-euglycemic clamp), lipid oxidation (indirect calorimetry), insulin secretion (2-h hyperglycemic clamp), and body composition (dual-energy X-ray absorptiometry) were examined. Adipose DI was calculated as ATIS: (1/GlyRa × fasting insulin) × first-phase insulin secretion. Despite similar percent body fat, youth with IGT versus NGT had higher GlyRa, lower ATIS at baseline and during hyperinsulinemia, and higher lipid oxidation. Adipose DI was ∼43% lower in youth with IGT and correlated positively with glucose DI. The lower ATIS and diminished adipose DI in IGT versus NGT is in line with the compromised glucose metabolism reflected in impaired β-cell function relative to peripheral insulin resistance. We conclude that youth with IGT manifest a global decline in insulin sensitivity, including impaired insulin action in suppressing lipolysis and lipid oxidation, accompanied by β-cell dysfunction in fat and glucose metabolism, enhancing their risk of type 2 diabetes.

Figure 1

A: Whole-body lipolysis, fasting and during the last 30 min of the hyperinsulinemic-euglycemic clamp. B: ATIS, fasting and during the hyperinsulinemic-euglycemic clamp. C: Lipid oxidation, fasting and during the hyperinsulinemic-euglycemic clamp in youth with IGT vs. NGT.

Figure 2

A: Adipose DI, i.e., β-cell function relative to ATIS. B: Hyperbolic relationship between ATIS and first-phase insulin concentration during the hyperglycemic clamp. C: Glucose DI, i.e., β-cell function relative to peripheral IS. D: Hyperbolic relationship between peripheral IS and first-phase insulin concentration during the hyperglycemic clamp in youth with IGT vs. NGT.