title: Examining the effects of hyperglycemia on pancreatic endocrine function in humans: evidence for in vivo glucotoxicity.
abstract: BACKGROUND
  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.
  
  
  METHODS
  A randomized, crossover in healthy controls, compared with type 2 diabetic patients.
  
  
  METHODS
  The study was conducted at a university hospital.
  
  
  METHODS
  Normal glucose-tolerant subjects (n = 10) and patients with type 2 diabetes (n = 10), individually matched by age, sex, and body mass index.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
authors.affiliation: The Centre of Inflammation and Metabolism, Department of Infectious Diseases, Rigshospitalet, Copenhagen 2100, Denmark. thomas.solomon@inflammation-metabolism.dk
authors.forename: Thomas P J
authors.initials: TP
authors.lastname: Solomon
authors.forename: Sine H
authors.initials: SH
authors.lastname: Knudsen
authors.forename: Kristian
authors.initials: K
authors.lastname: Karstoft
authors.forename: Kamilla
authors.initials: K
authors.lastname: Winding
authors.forename: Jens J
authors.initials: JJ
authors.lastname: Holst
authors.forename: Bente K
authors.initials: BK
authors.lastname: Pedersen
mesh_terms: D001786:Blood Glucose / Q000187:drug effects; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000503:physiopathology; D005260:Female; D005934:Glucagon / Q000097:blood / Q000378:metabolism; D005947:Glucose / Q000633:toxicity*; D015309:Glucose Clamp Technique / Q000379:methods; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism / Q000503:physiopathology*; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D010187:Pancreatic Hormones / Q000378:metabolism / Q000502:physiology*
chemical_list: D001786:Blood Glucose; D007328:Insulin; D010187:Pancreatic Hormones; D005934:Glucagon; D005947:Glucose