Identification, pathophysiology, and clinical implications of primary insulin hypersecretion in nondiabetic adults and adolescents

Abstract

Background: Excessive insulin secretion may lead to glucose dysregulation. Our aim was to identify primary (independent of insulin resistance) insulin hypersecretion in subjects with normal glucose tolerance and its role in the progression of dysglycemia.

Methods: In 1,168 adults, insulin secretion rate (ISR) and β cell function were estimated by C-peptide modeling during an oral glucose tolerance test (OGTT) and an i.v. glucose tolerance test. Whole-body insulin sensitivity was measured by a hyperinsulinemic-euglycemic clamp. After regressing ISR on insulin sensitivity, subjects in the upper tertile of the distribution of residuals were defined as primary hypersecretors. This approach was applied to a biethnic cohort of 182 obese adolescents, who received an OGTT, a hyperglycemic, and a euglycemic clamp.

Results: Adult hypersecretors showed older age, more familial diabetes, sedentary lifestyle, increased fat mass, and worse lipid profile compared with the rest of the cohort, despite virtually identical BMI and insulin sensitivity. Insulin secretion was increased by 53% due to enhanced (+23%) β cell glucose sensitivity. Despite the resulting hyperinsulinemia, glucose tolerance was worse in hypersecretors among both adults and adolescents, coupled with higher indices of liver insulin resistance and increased availability of gluconeogenic substrates. At the 3-year follow-up, adult hypersecretors had increased incidence of impaired glucose tolerance/type 2 diabetes.

Conclusion: Primary insulin hypersecretion, independent of insulin resistance, is associated with a worse clinical and metabolic phenotype in adults and adolescents and predicts deterioration of glucose control over time.

Funding: The relationship between insulin sensitivity and cardiovascular disease (RISC) Study was partly supported by EU grant QLG1-CT-2001-01252.

Keywords: Beta cells; Diabetes; Endocrinology; Insulin signaling; Metabolism.

Figure 1. Identification of primary insulin hypersecretion.

(A) Relationship between total insulin secretion during a 75-g OGTT (ISR_OGTT) and insulin sensitivity (M/I) and in the RISC study cohort (n = 1,168). (B) Relationship between M/I and acute insulin response during an i.v. glucose tolerance test (AIR_IVGTT) in the same cohort. Primary insulin hypersecretion was defined as either the ISR_OGTT or AIR_IVGTT values in the upper tertile of the distribution of the residuals from the regression of log-linear data (ISR_OGTT = 99 – 12 ln[M/I], r = 0.43, P < 0.0001, and AIR_IVGTT = 10 – 14 ln[M/I], r = 0.35, P < 0.0001, respectively). Using this cutoff, subjects were classified as hypersecretors (HyperS, red triangles; n = 389) or normosecretors (NormS, blue circles; n = 779).

Figure 2. Dose-response of insulin secretion in adults and adolescents.

(A) Dose-response of insulin secretion rate during a 75-g OGTT in hypersecretors (HyperS, red line, n = 389) and normosecretors (NormS, blue line, n = 779) in the RISC study cohort. (B) Dose-response of insulin secretion rate during a 75-g OGTT in HyperS (n = 61) and NormS (n = 121) in the adolescent group. Note the steeper slopes of adolescents vs. adults.

Figure 3. Plasma glucose and insulin concentrations during a 75-g OGTT in adults and adolescents.

Insulin hypersecretors (HyperS) are shown as red triangles (n = 389 in adults and n = 61 in adolescents), while normosecretors (NormS) are shown as blue circles (n = 779 in adults and n = 121 in adolescents). Repeated-measure ANOVA was performed including group (HyperS vs. NormS), time, and group × time interaction as factors, followed by post hoc pairwise comparisons using Tukey HSD tests. Plots are mean ± SD. Asterisks denote values that are significantly (*P ≤ 0.05) different between HyperS and NormS.

Figure 4. Insulin secretion rates during a hyperglycemic clamp in obese adolescents.

Insulin hypersecretors (HyperS) are shown in red (n = 61), and normosecretors (NormS) are shown in blue (n = 121). Plots are mean ± SEM.

Figure 5. Glucose tolerance at follow-up in the adult cohort.

(A) Plasma glucose concentrations during a 75-g OGTT at baseline (dotted lines) and follow-up (full lines) in insulin hypersecretors (HyperS, n = 313) and normosecretors (NormS, n = 640) in the RISC study cohort. Follow-up plasma glucose levels were analyzed by repeated-measure ANOVA including group (HyperS vs. NormS), time, and group × time interaction as factors, followed by post hoc pairwise comparisons using Tukey HSD tests. Plots are mean ± SD. (B) Incidence of dysglycemia at follow-up (progressors) in HyperS and NormS in the RISC study cohort. Asterisks denote values that are significantly (*P ≤ 0.05) different between HyperS and NormS.

Figure 6. Schematic summary of the insulin/glucose system in primary insulin hypersecretors and normosecretors.

Green arrows indicate stimulation, and red arrows denote inhibition. Dotted arrows indicate speculative mechanisms.