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This Article Full Text Full Text (PDF) All Versions of this Article: 297/1/E165    most recent 00001.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Kehlenbrink, S. Articles by Kishore, P. PubMed PubMed Citation Articles by Kehlenbrink, S. Articles by Kishore, P.

Inhibiting gluconeogenesis prevents fatty acid-induced increases in endogenous glucose production

¹Division of Endocrinology and Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York; and ²Division of Clinical and Molecular Endocrinology, Case Western Reserve University School of Medicine, Cleveland, Ohio

Submitted 5 January 2009 ; accepted in final form 30 April 2009

Glucose effectiveness, the ability of glucose per se to suppress endogenous glucose production (EGP), is lost in type 2 diabetes mellitus (T2DM). Free fatty acids (FFA) may contribute to this loss of glucose effectiveness in T2DM by increasing gluconeogenesis (GNG) and impairing the response to hyperglycemia. Thus, we first examined the effects of increasing plasma FFA levels for 3, 6, or 16 h on glucose effectiveness in nondiabetic subjects. Under fixed hormonal conditions, hyperglycemia suppressed EGP by 61% in nondiabetic subjects. Raising FFA levels with Liposyn infusion for 3 h reduced the normal suppressive effect of glucose by one-half. Second, we hypothesized that inhibiting GNG would prevent the negative impact of FFA on glucose effectiveness. Raising plasma FFA levels increased gluconeogenesis by 52% during euglycemia and blunted the suppression of EGP by hyperglycemia. Infusion of ethanol rapidly inhibited GNG and doubled the suppression of EGP by hyperglycemia, thereby restoring glucose effectiveness. In conclusion, elevated FFA levels rapidly increased GNG and impaired hepatic glucose effectiveness in nondiabetic subjects. Inhibiting GNG could have therapeutic potential in restoring the regulation of glucose production in type 2 diabetes mellitus.

free fatty acids; hyperglycemia; diabetes mellitus