Metabolic Contrasts Between Youth and Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes: I. Observations Using the Hyperglycemic Clamp.

Abstract

To compare insulin sensitivity (M/I) and β-cell responses in youth versus adults with impaired glucose tolerance (IGT) or drug-naïve, recently diagnosed type 2 diabetes. In 66 youth (80.3% with IGT) and 355 adults (70.7% IGT), hyperglycemic clamps were used to measure <i>1</i>) M/I, <i>2</i>) acute (0-10 min [first phase]) C-peptide (ACPR_g) and insulin (AIR_g) responses to glucose, <i>3</i>) steady-state C-peptide and insulin concentrations at plasma glucose of 11.1 mmol/L, and <i>4</i>) arginine-stimulated maximum C-peptide (ACPR_max) and insulin (AIR_max) responses at plasma glucose >25 mmol/L. The fasting C-peptide-to-insulin ratio was used as an estimate of insulin clearance. Insulin sensitivity was 46% lower in youth compared with adults (<i>P</i> < 0.001), and youth had greater acute and steady-state C-peptide (2.3- and 1.3-fold, respectively; each <i>P</i> < 0.001) and insulin responses to glucose (AIR_g 3.0-fold and steady state 2.2-fold; each <i>P</i> < 0.001). Arginine-stimulated C-peptide and insulin responses were also greater in youth (1.6- and 1.7-fold, respectively; each <i>P</i> < 0.001). After adjustment for insulin sensitivity, all β-cell responses remained significantly greater in youth. Insulin clearance was reduced in youth (<i>P</i> < 0.001). Participants with diabetes had greater insulin sensitivity (<i>P</i> = 0.026), with lesser C-peptide and insulin responses than those with IGT (all <i>P</i> < 0.001) but similar insulin clearance (<i>P</i> = 0.109). In people with IGT or recently diagnosed diabetes, youth have lower insulin sensitivity, hyperresponsive β-cells, and reduced insulin clearance compared with adults. Whether these age-related differences contribute to declining β-cell function and/or impact responses to glucose-lowering interventions remains to be determined.