TY - JOUR
T1 - Pancreaticoduodenectomy model demonstrates a fundamental role of dysfunctional β cells in predicting diabetes
AU - Mezza, Teresa
AU - Ferraro, Pietro Manuel
AU - Giuseppe, Gianfranco Di
AU - Moffa, Simona
AU - Cefalo, Chiara M.A.
AU - Cinti, Francesca
AU - Impronta, Flavia
AU - Capece, Umberto
AU - Quero, Giuseppe
AU - Pontecorvi, Alfredo
AU - Mari, Andrea
AU - Alfieri, Sergio
AU - Giaccari, Andrea
N1 - Funding Information:
We thank Stefano Del Prato for having inspired us to use this model to explain the pathogenesis of T2DM. We thank Serena Rotun-no (Università Cattolica del Sacro Cuore) for assistance with the editing. This study was supported by grants from the Università Cattolica del Sacro Cuore (FondiAteneo Linea D.3.2, Fondi Ateneo Linea D.1, anno 2019, and Fondi Ateneo Linea D.1, anno 2020); the Italian Ministry of Education, University and Research (GR-2018-12365577) (to TM); a European Foundation for the Study of Diabetes Rising Star and Lilly and Astra Zeneca Awards (to TM); and the European Foundation for the Study of Diabetes Lilly and Astra Zeneca Awards (to FC). CMAC is the recipient of a fellowship prize from Associazione Medici Diabetologi (AMD).
Publisher Copyright:
Copyright: © 2021, American Society for Clinical Investigation.
PY - 2021/6
Y1 - 2021/6
N2 - BACKGROUND. The appearance of hyperglycemia is due to insulin resistance, functional deficits in the secretion of insulin, and a reduction of β cell mass. There is a long-standing debate as to the relative contribution of these factors to clinically manifesting β cell dysfunction. The aim of this study was to verify the acute effect of one of these factors, the reduction of β cell mass, on the subsequent development of hyperglycemia. METHODS. To pursue this aim, nondiabetic patients, scheduled for identical pancreaticoduodenectomy surgery, underwent oral glucose tolerance tests (OGTT) and hyperglycemic clamp (HC) procedures, followed by arginine stimulation before and after surgery. Based on postsurgery OGTT, subjects were divided into 3 groups depending on glucose tolerance: normal glucose tolerance (post-NGT), impaired glucose tolerance (post-IGT), or having diabetes mellitus (post-DM). RESULTS. At baseline, the 3 groups showed similar fasting glucose and insulin levels; however, examining the various parameters, we found that reduced first-phase insulin secretion, reduced glucose sensitivity, and rate sensitivity were predictors of eventual postsurgery development of IGT and diabetes. CONCLUSION. Despite comparable functional mass and fasting glucose and insulin levels at baseline and the very same 50% mass reduction, only reduced first-phase insulin secretion and glucose sensitivity predicted the appearance of hyperglycemia. These functional alterations could be pivotal to the pathogenesis of type 2 diabetes (T2DM).
AB - BACKGROUND. The appearance of hyperglycemia is due to insulin resistance, functional deficits in the secretion of insulin, and a reduction of β cell mass. There is a long-standing debate as to the relative contribution of these factors to clinically manifesting β cell dysfunction. The aim of this study was to verify the acute effect of one of these factors, the reduction of β cell mass, on the subsequent development of hyperglycemia. METHODS. To pursue this aim, nondiabetic patients, scheduled for identical pancreaticoduodenectomy surgery, underwent oral glucose tolerance tests (OGTT) and hyperglycemic clamp (HC) procedures, followed by arginine stimulation before and after surgery. Based on postsurgery OGTT, subjects were divided into 3 groups depending on glucose tolerance: normal glucose tolerance (post-NGT), impaired glucose tolerance (post-IGT), or having diabetes mellitus (post-DM). RESULTS. At baseline, the 3 groups showed similar fasting glucose and insulin levels; however, examining the various parameters, we found that reduced first-phase insulin secretion, reduced glucose sensitivity, and rate sensitivity were predictors of eventual postsurgery development of IGT and diabetes. CONCLUSION. Despite comparable functional mass and fasting glucose and insulin levels at baseline and the very same 50% mass reduction, only reduced first-phase insulin secretion and glucose sensitivity predicted the appearance of hyperglycemia. These functional alterations could be pivotal to the pathogenesis of type 2 diabetes (T2DM).
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U2 - 10.1172/JCI146788
DO - 10.1172/JCI146788
M3 - Article
C2 - 33905373
AN - SCOPUS:85108150388
VL - 131
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 12
M1 - e146788
ER -