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Endocr Pract. 2007 May-Jun;13(3):283-90.

Ketosis-prone type 2 diabetes: effect of hyperglycemia on beta-cell function and skeletal muscle insulin signaling.

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1
Department of Medicine, Emory University School of Medicine, Atlanta, Georgia.

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.

CONCLUSION:

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.

PMID:
17599861
DOI:
10.4158/EP.13.3.283
[Indexed for MEDLINE]
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