Mechanisms of hyperinsulinaemia in apparently healthy non-obese young adults: role of insulin secretion, clearance and action and associations with plasma amino acids

Steven Hamley, Danielle Kloosterman, Tamara Duthie, Chiara Dalla Man, Roberto Visentin, Shaun A Mason, Teddy Ang, Ahrathy Selathurai, Gunveen Kaur, Maria G Morales-Scholz, Kirsten F Howlett, Greg M Kowalski, Christopher S Shaw, Clinton R Bruce, Steven Hamley, Danielle Kloosterman, Tamara Duthie, Chiara Dalla Man, Roberto Visentin, Shaun A Mason, Teddy Ang, Ahrathy Selathurai, Gunveen Kaur, Maria G Morales-Scholz, Kirsten F Howlett, Greg M Kowalski, Christopher S Shaw, Clinton R Bruce

Abstract

Aims/hypothesis: This study aimed to examine the metabolic health of young apparently healthy non-obese adults to better understand mechanisms of hyperinsulinaemia.

Methods: Non-obese (BMI < 30 kg/m2) adults aged 18-35 years (N = 254) underwent a stable isotope-labelled OGTT. Insulin sensitivity, glucose effectiveness and beta cell function were determined using oral minimal models. Individuals were stratified into quartiles based on their insulin response during the OGTT, with quartile 1 having the lowest and quartile 4 the highest responses.

Results: Thirteen per cent of individuals had impaired fasting glucose (IFG; n = 14) or impaired glucose tolerance (IGT; n = 19), allowing comparisons across the continuum of insulin responses within the spectrum of normoglycaemia and prediabetes. BMI (~24 kg/m2) was similar across insulin quartiles and in those with IFG and IGT. Despite similar glycaemic excursions, fasting insulin, triacylglycerols and cholesterol were elevated in quartile 4. Insulin sensitivity was lowest in quartile 4, and accompanied by increased insulin secretion and reduced insulin clearance. Individuals with IFG had similar insulin sensitivity and beta cell function to those in quartiles 2 and 3, but were more insulin sensitive than individuals in quartile 4. While individuals with IGT had a similar degree of insulin resistance to quartile 4, they exhibited a more severe defect in beta cell function. Plasma branched-chain amino acids were not elevated in quartile 4, IFG or IGT.

Conclusions/interpretation: Hyperinsulinaemia within normoglycaemic young, non-obese adults manifests due to increased insulin secretion and reduced insulin clearance. Individual phenotypic characterisation revealed that the most hyperinsulinaemic were more similar to individuals with IGT than IFG, suggesting that hyperinsulinaemic individuals may be on the continuum toward IGT. Furthermore, plasma branched-chain amino acids may not be an effective biomarker in identifying hyperinsulinaemia and insulin resistance in young non-obese adults.

Keywords: Hyperinsulinaemia; Insulin secretion; Insulin sensitivity; Minimal model; Plasma amino acids; Prediabetes.

Figures

Fig. 1
Fig. 1
Plasma metabolite and hormone concentrations during the OGTT, which began at time 0 min. (a) Plasma glucose concentrations. (b) The AAB for the glucose response. (c) Plasma insulin concentrations. (d) The AAB for the insulin response. (e) Plasma C-peptide concentrations. (f) The AAB for the C-peptide response. (g) ISR. (h) The AAB for the ISR response. (i) Plasma NEFA concentrations. (j) The area below basal (ABB) for the NEFA response. (k) Plasma triacylglycerol concentrations. (l) The ABB for the triacylglycerol response. Pink circles, Q1; blue squares, Q2; black triangles, Q3; red triangles, Q4; grey diamonds, IFG; purple circles, IGT. Data are median and interquartile range. *p< 0.05 vs IGT; †p< 0.05 vs Q1; ‡p< 0.05 vs Q2; §p< 0.05 vs Q3; ¶p< 0.05 vs IFG
Fig. 2
Fig. 2
Metabolic responses during the OGTT in women vs men. The OGTT began at time 0 min. (a) Plasma glucose concentrations. (b) The AAB for the glucose response. (c) Plasma insulin concentrations. (d) The AAB for the insulin response. (e) Plasma C-peptide concentrations. (f) The AAB for the C-peptide response. (g) ISR. (h) The AAB for the ISR response. (i) Plasma NEFA concentrations. (j) The area below basal (ABB) for the NEFA response. Red circles, women; blue squares, men. Data are median and interquartile range. *p< 0.001 vs women
Fig. 3
Fig. 3
Sex-specific plasma metabolite and hormone concentrations in normoglycaemic women (a, d, g, j, m) and men (b, e, h, k, n) during the OGTT. The OGTT began at time 0 min. (a, b) Plasma glucose concentrations. (c) The AAB for the glucose response. (d, e) Plasma insulin concentrations. (f) The AAB for the insulin response. (g, h) Plasma C-peptide concentrations. (i) The AAB for the C-peptide response. (j, k) ISR. (l) The AAB for the ISR response. (m, n) Plasma NEFA concentrations. (o) The area below basal (ABB) for the NEFA response. Pink circles, Q1; blue squares, Q2; black triangles, Q3; red triangles, Q4. Data are median and interquartile range. *p< 0.05 vs Q1; †p< 0.05 vs Q2; ‡p< 0.05 vs Q3

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