Ketosis-prone type 2 diabetes

Effect of hyperglycemia on β-cell function and skeletal muscle insulin signaling

Guillermo E. Umpierrez, Dawn Smiley, Aidar Gosmanov, Donald Thomason

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Objective: To determine the underlying mechanism for the severe and transient β-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 β-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. Conclusion: Hyperglycemia, but not increased free fatty acid levels, led to progressive β-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.

Original languageEnglish (US)
Pages (from-to)283-290
Number of pages8
JournalEndocrine Practice
Volume13
Issue number3
DOIs
StatePublished - Jan 1 2007

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Ketosis
Hyperglycemia
Type 2 Diabetes Mellitus
Skeletal Muscle
Insulin
African Americans
C-Peptide
Phosphorylation
Nonesterified Fatty Acids
Glucose
Diabetic Ketoacidosis
Serine
Lipids
Biopsy
Muscles

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Ketosis-prone type 2 diabetes : Effect of hyperglycemia on β-cell function and skeletal muscle insulin signaling. / Umpierrez, Guillermo E.; Smiley, Dawn; Gosmanov, Aidar; Thomason, Donald.

In: Endocrine Practice, Vol. 13, No. 3, 01.01.2007, p. 283-290.

Research output: Contribution to journalArticle

Umpierrez, Guillermo E. ; Smiley, Dawn ; Gosmanov, Aidar ; Thomason, Donald. / Ketosis-prone type 2 diabetes : Effect of hyperglycemia on β-cell function and skeletal muscle insulin signaling. In: Endocrine Practice. 2007 ; Vol. 13, No. 3. pp. 283-290.
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