Impaired beta-cell sensitivity to glucose and maximal insulin secretory capacity in adolescents with type 2 diabetes

Abstract

Background: Adults with type 2 diabetes mellitus (T2DM) have broad impairments in beta-cell function, including severe attenuation of the first-phase insulin response to glucose, and reduced beta-cell mass. In adolescents with T2DM, there is some evidence that beta-cell dysfunction may be less severe. Our objective was to determine beta-cell sensitivity to glucose and maximal insulin secretory capacity (AIR(max)) in teenagers with T2DM.

Methods: Fifteen adolescents with T2DM [11 F/4 M, age 18.4 +/- 0.3 yr, body mass index (BMI) 39.8 +/- 2.2 kg/m(2)] and 10 non-diabetic control subjects (7 F/3 M, age 17.4 +/- 0.5 yr, BMI 41.5 +/- 2.2 kg/m(2)) were studied. T2DM subjects had a mean duration of diabetes of 48.8 +/- 6.4 months, were treated with conventional therapies, and had good metabolic control [hemoglobin A1c (HbA1c) 6.7 +/- 1.2%]. Insulin and C-peptide were determined before and after a graded glucose infusion and after intravenous arginine at a whole blood glucose level of >or=22 mM.

Results: The insulin response to increasing plasma glucose concentrations was blunted in the diabetic compared with control subjects (34.8 +/- 11.9 vs. 280.5 +/- 57.8 pmol/mmol; p < 0.0001), and AIR(max) was also significantly reduced in the diabetic group (1868 +/- 330 vs. 4445 +/- 606; p = 0.0005).

Conclusion: Even adolescents with well-controlled T2DM have severe impairments of insulin secretion. These data support beta-cell dysfunction as central in the pathogenesis of T2DM in young people, and indicate that these abnormalities can develop over a period of just several years.

Fig. 1

Glycemic and hormone responses to graded glucose infusion. Mean ± standard error of the mean (SEM) presented for each time point. (A) Circulating glucose, (B) insulin, and (C) C-peptide. Symbols used within figures: black triangles represent controls and black circles represent subjects with type 2 diabetes mellitus (T2DM).

Fig. 2

A) Insulin response to circulating glucose. Predicted slopes and 95% confidence limits presented from longitudinal mixed model. Black triangles represent controls and black circles represent subjects with type 2 diabetes mellitus (T2DM). Inset: estimates of the slope [±standard error (SE)] between insulin and circulating glucose. B) C-peptide response to circulating glucose. Predicted slopes and 95% confidence limits presented from longitudinal mixed model. Black triangles represent controls and black circles represent subjects with T2DM. Inset: estimates of the slope (±SE) between C-peptide and circulating glucose.

Fig. 3

AIR_max in diabetic and control subjects. A) Insulin response to arginine. Mean ± standard error of the mean (SEM) presented for each time point. Black triangles represent controls and black circles represent subjects with type 2 diabetes mellitus (T2DM). B) AIR_max by subject group.