Pancreaticoduodenectomy model demonstrates a fundamental role of dysfunctional β cells in predicting diabetes

Abstract

BACKGROUNDThe 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.METHODSTo 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).RESULTSAt 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.CONCLUSIONDespite 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).TRIAL REGISTRATIONClinicalTrials.gov NCT02175459.FUNDINGUniversità Cattolica del Sacro Cuore; Italian Ministry of Education, University and Research; European Foundation for the Study of Diabetes.

Keywords: Beta cells; Diabetes; Endocrinology; Insulin; Metabolism.

Conflict of interest statement

Conflict of interest: The authors have declared that no conflict of interest exists.

Figures

Figure 1. Flow diagram of study participants.

Figure 2. Identical hemipancreatectomies show different results after surgery.

Glucose (A), insulin (B), and C-peptide (C) levels during OGTT before (solid lines) and after (dotted lines) partial pancreatectomy in post-NGT (first column, green circles), post-IGT (second column, orange triangles), and post-DM (third column, red diamonds) patients. P < 0.05 was considered statistically significant for glucose, insulin, and C-peptide levels for third-level interactions and included a product term of time × pancreatectomy × glucose tolerance in the model.

Figure 3. Functional defects predict diabetes occurrence after hemipancreatectomy.

OGTT-derived glucose sensitivity (A) and rate sensitivity (B) before and after partial pancreatectomy in post-NGT (green box), post-IGT (orange box), and post-DM subjects (red box). The relationship between variables was derived by linear regression analysis. Variables were regressed against glucose tolerance status by using (a) prepancreatectomy values, (b) postpancreatectomy values, and (c) postpancreatectomy values adjusted for prepancreatectomy values. *P < 0.05 before surgery; #P < 0.05 after surgery; §P < 0.05 before surgery adjusted for after surgery. Box plots indicate median and interquartile range; whiskers indicate 2.5th to 97.5th percentile ± mean value.

Figure 4. Impaired first-phase insulin secretion, rather than reduced β cell mass, predicts diabetes appearance.

Clamp-derived first-phase insulin secretion (A), second-phase insulin secretion (B), and arginine-stimulated insulin secretion (C) before and after partial pancreatectomy in post-NGT (green box), post-IGT (orange box), and post-DM subjects (red box). INC, incremental. The relationship between variables was derived by linear regression analysis. Variables were regressed against glucose tolerance status by using (a) prepancreatectomy values, (b) postpancreatectomy values, and (c) postpancreatectomy values adjusted for prepancreatectomy values. *P < 0.05 before surgery; #P < 0.05 after surgery; §P < 0.05 before surgery adjusted for after surgery. Box plots indicate median and interquartile range, and whiskers indicate 2.5th–97.5th percentile ± mean value.