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44Examining the effects of hyperglycemia on pancreatic endocrine function in humans: evidence for in vivo glucotoxicity.
Solomon TP; Knudsen SH; Karstoft K; Winding K; Holst JJ; Pedersen BK
J Clin Endocrinol Metab 2012; 97(12): 4682-91
PubMed ID: 23043193

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-(2)H(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. Solomon, Thomas P J

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