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

TY - JOUR

T1 - Examining the effects of hyperglycemia on pancreatic endocrine function in humans

T2 - evidence for in vivo glucotoxicity

AU - Solomon, Thomas P J

AU - Knudsen, Sine H

AU - Karstoft, Kristian

AU - Winding, Kamilla

AU - Holst, Jens Juul

AU - Pedersen, Bente K

PY - 2012/12

Y1 - 2012/12

N2 - 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.

AB - 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.

KW - Blood Glucose

KW - Cross-Over Studies

KW - Diabetes Mellitus, Type 2

KW - Female

KW - Glucagon

KW - Glucose

KW - Glucose Clamp Technique

KW - Humans

KW - Hyperglycemia

KW - Insulin

KW - Islets of Langerhans

KW - Male

KW - Middle Aged

KW - Pancreatic Hormones

U2 - 10.1210/jc.2012-2097

DO - 10.1210/jc.2012-2097

M3 - Journal article

C2 - 23043193

SN - 0021-972X

VL - 97

SP - 4682

EP - 4691

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 12

ER -