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.
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.
Authors: Abbas E Kitabchi; Guillermo E Umpierrez; Joseph N Fisher; Mary Beth Murphy; Frankie B Stentz Journal: J Clin Endocrinol Metab Date: 2008-02-12 Impact factor: 5.958
Authors: Guillermo E Umpierrez; Dawn Smiley; Gonzalo Robalino; Limin Peng; Abbas E Kitabchi; Bobby Khan; Ahn Le; Arshed Quyyumi; Virgil Brown; Lawrence S Phillips Journal: J Clin Endocrinol Metab Date: 2008-11-11 Impact factor: 5.958
Authors: Charlotte Bavuma; Diomira Sahabandu; Sanctus Musafiri; Ina Danquah; Ruth McQuillan; Sarah Wild Journal: J Glob Health Date: 2019-12 Impact factor: 4.413
Authors: Aidar R Gosmanov; Dawn Smiley; Gonzalo Robalino; Joselita M Siqueira; Limin Peng; Abbas E Kitabchi; Guillermo E Umpierrez Journal: Diabetes Care Date: 2010-01-12 Impact factor: 19.112