Examining the Effects of Hyperglycemia on Pancreatic Endocrine Function in Humans: Evidence for in Vivo Glucotoxicity

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-H-2(2)] glucose infusion) were measured during hyperglycemic clamps combined with infusion of glucagon-like peptide (GLP)-1(7-36) (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 beta-cell function but did not acutely impair alpha-cell glucagon secretion in normal glucose-tolerant subjects. (J Clin Endocrinol Metab 97: 4682-4691, 2012)