Disproportionately increased proinsulin (PI) relative to C-peptide (CP) is a marker of inefficient β cell PI processing. To determine whether PI processing differs between youth (Y) and adults (A) with impaired glucose tolerance (IGT) and drug naïve T2D, we measured PI and CP in 58 Y (81% IGT, 69% female, 26% white, 22% black, 40% Hispanic, BMI=37±6 kg/m2) and 322 A (71% IGT, 52% female, 47% white, 28% black, 19% Hispanic, BMI=35±5 kg/m2) in the Restoring Insulin Secretion (RISE) Study. We assessed fasting PI, CP, PI/CP, and acute PI (API) and CP (ACP) responses to glucose (Rg) (APIRg, ACPRg, APIRg/ACPRg) and arginine at maximal (Rmax) glycemic potentiation (APIRmax, ACPRmax, APIRmax/ACPRmax) during a hyperglycemic clamp. Fasting PI, CP, and PI/CP were higher in Y vs. A, suggesting PI processing in the fasted state is lower in Y (Table) . APIRg and APCPg were higher in Y, and APIRg/ACPRg was similar. APIRmax, but not ACPRmax, was lower in Y. Thus, APIRmax/ACPmax was lower in Y, suggesting PI processing at maximal β cell stimulation is greater in Y. These results suggest that increased fasting β-cell secretory demand in Y may decrease the time available for PI processing and cause the release of more immature granules during fasting. Y may utilize a larger pool of granules in which PI processing is more complete when secretory demand is maximal.


T.S.Hannon: Advisory Panel; Eli Lilly and Company. S.E.Kahn: Advisory Panel; Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc. T.Consortium: None. S.Sam: None. A.H.Tjaden: None. S.Edelstein: None. K.J.Nadeau: None. S.A.Arslanian: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Other Relationship; AstraZeneca, Research Support; Eli Lilly and Company, Novo Nordisk. M.Cree-green: None. D.A.Ehrmann: None. K.J.Mather: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company.


American Diabetes Association (1-20-RISE-01) ; NIDDK, Department of Veterans Affairs, and Kaiser Permanente Southern California

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