The Restoring Insulin Secretion (RISE) Study found that compared to adults (A), youth (Y) with early DM (33 Y, 104 A) or IGT (53 Y, 250 A) have higher insulin and C-peptide responses, even after adjusting for differences in insulin sensitivity. To better understand these differences, we compared mathematical modeling data from OGTTs to those from a hyperglycemic clamp within the RISE Study. Modeled measures were the dose-response relationship between glucose and insulin secretion (glucose sensitivity [GS], rate sensitivity [RS]) and the oral glucose insulin sensitivity index (OGIS). Clamp measures were insulin sensitivity (steady state glucose infusion rate/insulin [M/I]), acute (0-10 minutes) C-peptide (ACPRg) and insulin (AIRg) responses to glucose, steady-state C-peptide (SSCP) at plasma glucose of 11.1 mmol/L, and arginine-stimulated maximum C-peptide (ACPRmax) response at glucose >25 mmol/L. Linear regression models were fit to assess relationships between OGTT model and clamp measures by age group. GS (r2 = 0.29, p<0.01) and RS (r2 = 0.22, p<0.01) were inversely correlated with M/I. GS was directly correlated with ACPRg (r2 = 0.55, p<0.01), AIRg (r2 = 0.52, p<0.01), SSCP (r2 = 0.46, p<0.01) and ACPRmax (r2 = 0.33, p<0.01), with a steeper slope in Y vs. A for AIRg and ACPRg vs. GS (p’s < 0.01), and in IGT vs. DM for ACPRg vs. GS (p=0.03). RS was directly correlated with ACPRg (slope r2 = 0.55, p<0.01), with a steeper slope in Y vs. A (P < 0.01) and in IGT vs. DM (p=0.04). M/I was directly correlated with OGIS (r2 = 0.34, p<0.01). The inverse correlation of GS with M/I in both Y and A suggests that differences in insulin sensitivity should be accounted for when comparing GS across groups. The fact that relationships between acute insulin and C-peptide responses from the clamp and GS and RS from OGTTs differed between Y and A, while these relationships were similar for SSCP and ACPRmax, suggest fundamental differences exist in the early-phase response between Y and A with IGT or early DM.
K. Utzschneider: Consultant; Self; Novo Nordisk Inc. A. Mari: Consultant; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim International GmbH. M. Tripputi: None. K.J. Mather: Advisory Panel; Self; Roche Diabetes Care. Research Support; Self; Abbott, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. K.J. Nadeau: None. S. Edelstein: None. T.S. Hannon: Advisory Panel; Self; Eli Lilly and Company. S.A. Arslanian: None. M. Cree-Green: None. T.A. Buchanan: Research Support; Self; Allergan, Apollo EndoSurgery. S. Caprio: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. Consultant; Self; Neurimmune. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. R. Consortium: None.
American Diabetes Association (1-14-RISE-01 to S.E.K.); National Institute of Diabetes and Digestive and Kidney Diseases