title: Ketosis-prone type 2 diabetes: effect of hyperglycemia on beta-cell function and skeletal muscle insulin signaling.
abstract: OBJECTIVE
  To determine the underlying mechanism for the severe and transient beta-cell dysfunction and impaired insulin action in obese African American patients with ketosis-prone diabetes.
  
  
  METHODS
  The effect of sustained hyperglycemia (glucotoxicity) and increased free fatty acids (lipotoxicity) on beta-cell function was assessed by changes in insulin secretion during a 20-hour glucose (200 mg/m2 per minute) and a 48-hour Intralipid (40 mL/h) infusion, respectively. Insulin-activated signaling pathways and pattern of Akt-1 and Akt-2 expression and insulin-stimulated phosphorylation were analyzed in skeletal muscle biopsy specimens. Studies were performed in an obese African American woman within 48 hours after resolution of diabetic ketoacidosis and 1 week after discontinuation of insulin treatment.
  
  
  RESULTS
  Dextrose infusion rapidly increased C-peptide levels from a baseline of 3.2 ng/mL to a mean of 7.1 +/- 0.5 ng/mL during the first 8 hours of infusion; thereafter, C-peptide levels progressively declined. Lipid infusion was not associated with any deleterious effect on insulin and C-peptide secretion. Initial in vitro stimulation of muscle tissue with insulin resulted in a substantial and selectively decreased Akt-2 expression and insulin-stimulated phosphorylation on the serine residue. Improved metabolic control resulted in 70% greater Akt expression at near-normoglycemic remission in comparison with the period of hyperglycemia.
  
  
  CONCLUSIONS
  Hyperglycemia, but not increased free fatty acid levels, led to progressive beta-cell dysfunction and impaired insulin secretion. Hyperglycemia was also associated with diminished skeletal muscle Akt expression and phosphorylation in an African American woman with ketosis-prone diabetes, and this defect improved notably with aggressive insulin therapy. These results indicate the importance of glucose toxicity in the pathogenesis of ketosis-prone diabetes in obese African American patients.
authors.affiliation: Department of Medicine, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Guillermo E
authors.initials: GE
authors.lastname: Umpierrez
authors.forename: Dawn
authors.initials: D
authors.lastname: Smiley
authors.forename: Aidar
authors.initials: A
authors.lastname: Gosmanov
authors.forename: Donald
authors.initials: D
authors.lastname: Thomason
mesh_terms: D001741:Black or African American; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D016883:Diabetic Ketoacidosis / Q000503:physiopathology*; D005217:Fat Emulsions, Intravenous / Q000008:administration & dosage; D005260:Female; D005947:Glucose / Q000008:administration & dosage; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology; D007328:Insulin / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects*; D009765:Obesity / Q000150:complications
chemical_list: D005217:Fat Emulsions, Intravenous; D007328:Insulin; D005947:Glucose