Examining the effects of hyperglycemia on pancreatic endocrine function in humans: Evidence for in vivo glucotoxicity

Abstract

Context: Investigating the impact of hyperglycemia on pancreatic endocrine function promotes our understanding of the pathophysiology of hyperglycemia-related disease. Objective: The objective of the study was to test the hypothesis that experimental hyperglycemia impairs insulin and glucagon secretion. Design: A randomized, crossover in healthy controls, compared with type 2 diabetic patients. Setting: The study was conducted at a university hospital. Participants: Normal glucose-tolerant subjects (n = 10) and patients with type 2 diabetes (n = 10), individually matched by age, sex, and body mass index. Interventions: Normal glucose-tolerant subjects underwent 24 h of experimental hyperglycemia (+5.4 mM above basal). Subjects with type 2 diabetes did not undergo an intervention. Main Outcome Measures: Insulin secretion, glucagon secretion, insulin sensitivity, disposition index, and endogenous glucose production (via [6,6-2H2]glucose infusion) were measured during hyperglycemic clamps combined with infusion of glucagon-like peptide (GLP)-17-36 (0.5 pmol/kg·min) and injection of arginine (5 g). Results: Insulin secretion was correlated with glucagon suppression in subjects with normal glucose tolerance only. Individuals with type 2 diabetes had lower insulin sensitivity (-33 ± 11%) and insulin secretory responses to glucose, GLP-1, and arginine (-40 ± 11, -58 ± 7, and -36 ± 13%, respectively) and higher plasma glucagon and endogenous glucose production compared with normal glucose-tolerant subjects (all P < 0.05). After 24 h of experimental hyperglycemia, insulin sensitivity (-29 ± 10%), disposition index (-24 ± 16%), and GLP-1- (-19 ± 7%) and arginine-stimulated (-15 ± 10%) insulin secretion were decreased in normal glucose-tolerant subjects (all P < 0.05). However, plasma glucagon responses were not affected. Furthermore, experimental hyperglycemia abolished the correlation between insulin secretion and glucagon suppression. Conclusions: Experimental hyperglycemia impaired pancreatic β-cell function but did not acutely impair α-cell glucagon secretion in normal glucose-tolerant subjects. Copyright © 2012 by The Endocrine Society.