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Time-Dependent Effects of Free Fatty Acids on Glucose Effectiveness in Type 2 Diabetes

Division of Endocrinology and Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York

Address correspondence and reprint requests to Preeti Kishore, MD, Department of Medicine, Division of Endocrinology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. E-mail: pkishore{at}aecom.yu.edu

Abbreviations: EGP, endogenous glucose production, FFA, free fatty acid

Impaired effectiveness of glucose to suppress endogenous glucose production (EGP) is an important cause of worsening hyperglycemia in type 2 diabetes. Elevated free fatty acids (FFAs) may impair glucose effectiveness via several mechanisms, including rapid changes in metabolic fluxes and/or more gradual changes in gene expression of key enzymes or other proteins. Thus, we examined the magnitude and time course of effects of FFAs on glucose effectiveness in type 2 diabetes and whether glucose effectiveness can be restored by lowering FFAs. Glucose fluxes ([3-³H]-glucose) were measured during 6-h pancreatic clamp studies, at euglycemia (5 mmol/l glucose, t = 0–240 min), and hyperglycemia (10 mmol/l, t = 240–360 min). We studied 19 poorly controlled subjects with type 2 diabetes (HbA_1c 10.9 ± 0.4%, age 50 ± 3 years, BMI 30 ± 2 kg/m²) on at least two occasions with saline (NA– group) or nicotinic acid (NA group) infusions for 3, 6, or 16 h (NA3h, NA6h, and NA16h groups, respectively) to lower FFAs to nondiabetic levels. As a reference group, glucose effectiveness was also assessed in 15 nondiabetic subjects. There was rapid improvement in hepatic glucose effectiveness following only 3 h of NA infusion (NA3h = 31 ± 6% suppression of EGP with hyperglycemia vs. NA– = 8 ± 7%; P < 0.01) and complete restoration of glucose effectiveness after 6 h of NA (NA6h = 41 ± 8% suppression of EGP; P = NS vs. nondiabetic subjects). Importantly, the loss of hepatic glucose effectiveness in type 2 diabetes is completely reversible upon correcting the increased FFA concentrations. A longer duration of FFA lowering may be required to overcome the chronic effects of increased FFAs on hepatic glucose effectiveness.

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