Phenotypic type 2 diabetes in obese youth: insulin sensitivity and secretion in islet cell antibody-negative versus -positive patients

Abstract

Objective: Some obese youth with a clinical diagnosis of type 2 diabetes have evidence of islet cell autoimmunity with positive autoantibodies. In this study, we investigated the differences in insulin sensitivity and secretion between autoantibody-negative (Ab-) and -positive (Ab+) youth with clinically diagnosed type 2 diabetes in comparison with control subjects.

Research design and methods: Sixteen Ab- and 26 Ab+ clinically diagnosed type 2 diabetic patients and 39 obese control youth underwent evaluation of insulin sensitivity (3-h hyperinsulinemic-euglycemic clamp), substrate oxidation (indirect calorimetry), first- and second-phase insulin secretion (2-h hyperglycemic clamp), body composition and abdominal adiposity (dual energy X-ray absorptiometry and computed tomography scan, respectively), and glucose disposition index (first-phase insulin secretion x insulin sensitivity).

Results: Insulin-stimulated total, oxidative, and nonoxidative glucose disposal, and suppression of fat oxidation during hyperinsulinemia were significantly lower in Ab- compared with Ab+ clinically diagnosed type 2 diabetic and control subjects with no difference between the latter two. First- and second-phase insulin secretion and C-peptide were lower in Ab+ compared with Ab- type 2 diabetes. Glucose disposition index was not different between the Ab- and Ab+ clinically diagnosed type 2 diabetic patients, but both were significantly lower than that in control subjects. Systolic blood pressure and alanine aminotransferase were higher in Ab- versus Ab+ clinically diagnosed type 2 diabetic patients, whereas the frequency of ketonuria at diagnosis was higher in Ab+ versus Ab- patients.

Conclusions: Islet-cell Ab- clinically diagnosed type 2 diabetic youth are characterized by severe insulin resistance and relative insulin deficiency, whereas Ab+ youth have severe insulin deficiency and beta-cell failure. The former group has additional features of insulin resistance. These important metabolic differences could influence the natural history of hyperglycemia, insulin dependence, and clinical outcomes in these youth.

FIG. 1.

A: Insulin-stimulated total, oxidative, and nonoxidative glucose disposal during the hyperinsulinemic-euglycemic clamp in Ab⁻ (□) versus Ab⁺ (░) versus control subjects (▪). B: Fat oxidation (FOX) during the hyperinsulinemic-euglycemic clamp in the three groups. C: Percent suppression in fat oxidation during hyperinsulinemia in the three groups. P values by ANOVA. *Post hoc Bonferroni correction; P < 0.05 Ab⁻ vs. Ab⁺, Ab⁻ vs. control subjects.

FIG. 2.

A: Insulin secretion during the hyperglycemic clamp in Ab⁻ (○) versus Ab⁺ (•) versus control subjects (▴). B: First- and second-phase C-peptide levels during the hyperglycemic clamp in Ab⁻ (□) versus Ab⁺ (░) versus control subjects (▪). C: GDI in the three groups. P values by ANOVA. *Post hoc Bonferroni correction; P < 0.05 Ab⁺ vs. Ab⁻, Ab⁺ vs. control subjects.

FIG. 3.

Relationship between GDI and A1C in Ab⁻ (○) vs. Ab⁺ (•) clinically diagnosed type 2 diabetic patients.