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 Haugaard
AU - Karstoft, Kristian
AU - Winding, Kamilla
AU - Holst, Jens Juul
AU - Pedersen, Bente K
PY - 2012
Y1 - 2012
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-(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 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-(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 β-cell function but did not acutely impair α-cell glucagon secretion in normal glucose-tolerant subjects.
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 -