Inhibiting gluconeogenesis prevents fatty acid-induced increases in endogenous glucose production.
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 > or =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 approximately 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.
Kehlenbrink
Sylvia
S
Division of Endocrinology and Diabetes Research and Training Center, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA.
Tonelli
Julia
J
Koppaka
Sudha
S
Chandramouli
Visvanathan
V
Hawkins
Meredith
M
Kishore
Preeti
P
D000328:Adult; D015536:Down-Regulation / Q000187:drug effects; D004526:Efficiency / Q000187:drug effects; D000431:Ethanol / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D005260:Female; D005943:Gluconeogenesis / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique / Q000379:methods; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D013997:Time Factors
D005230:Fatty Acids, Nonesterified; D000431:Ethanol; D005947:Glucose