In Insulin-Resistant Subjects, Islet Functional Changes Might Represent an Attempt to Increase the Incretin Effect

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Nondiabetic insulin-resistant subjects (InsRes) display an increased α-cell mass, suggesting a key role of α-cells in the compensatory mechanisms to cope with insulin resistance states. The mechanism contributing to greater GLP-1 secretion detected in healthy patients following pancreatoduodenectomy (PD), is not fully understood and suggests other potential sources of the incretin hormone, such as α-cells. To investigate the dynamic changes of in-vivo GLP-1 secretion, insulin secretion (IS), and incretin effect (IE), 16 nondiabetic patients (10 F/6 M, 51±15 years.) scheduled for PD underwent a mixed meal test (MMT), a 2-h hyperglycemic clamp (HC), and a hyperinsulinemic euglycemic clamp (HEC) before and after surgery. β-cell glucose sensitivity (GS) was calculated as the ratio of IS and glucose increments, both during HC and MMT. The IE was estimated as the ratio of GS during the HC and MMT. InsRes displayed a reduction in the 1st IS at baseline (p=0.04), which did not decrease following PD. Both groups experienced a reduction of 2nd phase ISR (p<0.for both groups) and arginine-induced IS (p<0.for both groups) after surgery, with no difference observed in the reduction delta; while a significant reduction in basal ISR and GS was observed only in InsRes after surgery (respectively p=0.03 and p=0.06). Following PD, GLP-1 secretion significantly increased in both groups (P=0.and P=0.02 respectively), but the percentage of increase was greater in InsRes compared to insulin-sensitive subjects (InsSen) (respectively 54.4% vs. 36.2%). Further, the IE was significantly decreased in the InsSen (p=0.05), whereas no changes were observed in InsRes. Our data suggest that acute islet mass reduction leads to different functional effects in InsRes compared to InsSen. Impaired β-cell GS and reduced 1stIS are relatively compensated by preserved IE following PD in InsRes. This may be driven by an increased α-mass in InsRes, that might be the source of the increased GLP-1 secretion. Disclosure T. Mezza: None. S. Moffa: None. G. Sorice: None. C. Cefalo: None. F. Cinti: None. A. Mari: None. A. Giaccari: Advisory Panel; Self; Sanofi-Aventis. Speaker's Bureau; Self; AstraZeneca, Merck Sharp & Dohme Corp., Amgen Inc..