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Effects of Free Fatty Acids on Gluconeogenesis and Autoregulation of Glucose Production in Type 2 Diabetes

Division of Endocrinology, Diabetes, and Metabolism; and the General Clinical Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania

Effects of endogenously derived free fatty acids (FFAs) on rates of gluconeogenesis (GNG) (determined with ²H₂O), glycogenolysis (GL), and endogenous glucose production (EGP) were studied in 18 type 2 diabetic patients and in 7 nondiabetic control subjects under three experimental conditions: 1) during an 8-h fast (from 16–24 h after the last meal), when plasma FFA levels increased slowly; 2) during 4 h (from 16–20 h) of nicotinic acid (NA) administration (fasting plus NA), when plasma FFAs decreased acutely; and 3) during 4 h (from 20–24 h) after discontinuation of NA (FFA rebound), when plasma FFAs increased acutely. During fasting, FFAs increased from 636 to 711 µmol/l in type 2 diabetic patients and from 462 to 573 µmol/l in control subjects (P < 0.04), but GNG did not change in diabetic patients (6.9 vs. 6.5 µmol · kg^–1 · min^–1, P > 0.05) or in control subjects (5.1 vs. 5.4 µmol · kg^–1 · min^–1, P > 0.05). During fasting plus NA, FFAs decreased in diabetic patients and control subjects (from 593 to 193 and from 460 to 162 µmol/l, respectively); GNG decreased (from 6.1 to 4.2 and from 4.7 to 3.5 µmol · kg^–1 · min^-1), whereas GL decreased in diabetic patients (from 5.3 to 4.4 µmol · kg^-1 · min^-1) but increased in control subjects (from 5.4 to 7.2 µmol · kg^-1 min^-1). During the FFA rebound, FFAs increased in diabetic patients and control subjects (from 193 to 1,239 and from 162 to 1,491 µmol/l, respectively); GNG increased (from 4.2 to 5.4 and from 3.4 to 5.3 µmol · kg^–1 · min^–1 respectively), and GL decreased (from 4.4 to 3.4 and from 7.3 to 4.3 µmol · kg^-1 · min^-1, respectively). In summary, during an extended overnight fast, increasing plasma FFA levels stimulated GNG, whereas decreasing FFA levels inhibited GNG in both diabetic and control subjects; 20 h after the last meal, approximately one-third of GNG in both diabetic and control subjects was dependent on FFAs; and autoregulation of EGP by GL in response to decreasing GNG was impaired in diabetic patients.

Abbreviations: EGP, endogenous glucose production; FFA, free fatty acid; GL, glycogenolysis; GNG, gluconeogenesis; HMT, hexamethylenetetramine; ISR, insulin secretory rate; NA, nicotinic acid

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