Impaired First-Phase Insulin Secretion Predicts the Development of Hyperglycemia in a Human Model of Acute Beta-Cell Mass Reduction

β-cell functional defects temporally anticipate (and eventually cause) the subsequent development of hyperglycemia, whereas a significant reduction (∼50%) of beta-cell mass is observed at diagnosis of T2D. To further investigate the relative role of beta-cell mass reduction/dysfunction in the development of T2D, we performed, pre- and post-surgery, oral glucose tolerance tests (OGTT) and hyperglycemic clamps (HC), followed by arginine stimulation and mixed meal test (MMT), in 39 patients undergoing pancreatoduodenectomy (PD), as model of acute mass reduction. Based on post-surgery OGTT, subjects were divided into 3 groups depending on glucose tolerance: normal (NGT, n=11), impaired (IGT, n=10) or diabetic (DM, n=18) (23 F/16 M, 63±13.7 yrs, BMI 23.9±4.5 kg/m2). To evaluate β-cell function, β-cell glucose sensitivity (GS) was calculated during HC, MMT e OGTT as the ratio of insulin secretion (IS) and glucose increments. Comparison among the 3 groups revealed that PD had a significantly different effect on time-dependent change of glucose and insulin levels during all tests (P<0.01 for the interaction between PD, time and glucose tolerance). Before surgery, Arginine-stimulated Insulin Secretion rates (AIS) and GS were similar across groups, whereas incremental 1st phase IS were significantly lower in IGT and DM as compared with NGT subjects (p=0.01). Following PD, the reduction of GS during HC e OGTT was greater in IGT and DM compared to NGT (p=0.01 per HC and OGTT). A similarly reduction was observed in ΔAIS and 2nd phase of IS (p<0.01), but not in ΔIS1 (p=0.33). In this study the acute beta-cell mass reduction had a different impact on insulin secretory capacity, despite comparable functional mass at baseline, according to pre-surgery IS characteristics. This suggests that underlying impairment in β-cell dysfunction anticipates the decline of beta-cell responses, being the pivotal mechanism for the development of hyperglycemia. Disclosure T. Mezza: None. P. Ferraro: None. G. Di Giuseppe: None. C. Cefalo: None. S. Moffa: None. G. Quero: None. F. Cinti: None. F. Impronta: None. U. Capece: None. S. Alfieri: None. A. Mari: Consultant; Self; Lilly Diabetes. Research Support; Self; Boehringer Ingelheim International GmbH. A. Giaccari: Speaker’s Bureau; Self; Amgen, AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi-Aventis.