Contribution of muscle and liver to glucose-fatty acid cycle in humans

Abstract

To examine the influence of elevated free fatty acid (FFA) levels on hepatic glucose production (HGP) and oxidative and nonoxidative pathways of glucose metabolism, 12 healthy subjects participated in two euglycemic insulin-clamp studies performed with and without infusion of Intralipid plus heparin. To elucidate the role of skeletal muscle in this putative interaction, we performed muscle biopsies for the measurement of activities of glycogen synthase (GS), pyruvate dehydrogenase (PDH), and carnitine palmitoyltransferase (CPT). Infusion of Intralipid plus heparin caused an increase in plasma FFA concentrations and rate of lipid oxidation (measured by indirect calorimetry) that was not inhibited by insulin. Suppression of HGP by insulin was impaired by elevated plasma FFA levels. Furthermore, the increase in plasma FFA was associated with a 20% reduction in total glucose metabolism (P < 0.01), which was completely accounted for by a reduction in the rate of glucose oxidation. Although the fractional activity of GS was increased by insulin, elevation of plasma FFA had no influence on this key enzyme of glycogen synthesis. In addition, the activities of PDH and CPT were uninfluenced by the elevation of FFA, suggesting that oxidative processes in skeletal muscle were not a major target for the operative glucose-fatty acid cycle under the current conditions. Taken together, the data indicate that the interaction between FFA and glucose metabolism also involves impaired suppression of HGP by insulin.

Induction of Hepatic Glucose-6-Phosphatase Gene Expression by Lipid Infusion

“…It is suggested that prolonged hyperlipidemia may contribute to the increased production of glucose via increased expression of this protein. Taken together with numerous other reports on the impact of lipids on carbohydrate metabolism in skeletal muscle (7)(8)(9), liver (8)(9)(10)12,13), and pancreatic (3-cells (11,38,39), our finding provides experimental support for the role of hyperlipidemia in the pathogenesis of NIDDM (40,41).…”

“…It also suggests that the mechanism(s) by which a sustained increase in the availability of lipids might affect hepatic glucose output involves more than the short-term increase in the rate of gluconeogenesis (15). Indeed, increased hepatic glucose production is an early (~1 week) consequence of high-fat feeding in rodents (34), and the plasma FFA levels are closely related to the rate of endogenous glucose production in humans (8)(9)(10)12,13). Furthermore, most patients with NIDDM display increased concentrations of plasma FFA throughout the day (14).…”

“…In particular, numerous studies have shown that the rate of endogenous glucose production is closely related to the circulating plasma FFA concentrations ER, endoplasmic reticulum; FFA, free fatty acid; PMSF, phenylmethylsulfonyl fluoride; SSC, sodium chloride-sodium citrate. (9,10,12,13) and that the majority of individuals with NIDDM have increased 24-h plasma FFA profiles (14). While the acute effects of an increase in plasma FFA availability are likely to be largely caused by its known stimulatory effect on gluconeogenesis (15), much less is known regarding the long-term consequences of increased hepatic availability of FFAs.…”

The biochemical basis of increased hepatic glucose production in a mouse model of type 2 (non-insulin-dependent) diabetes mellitus

“…As such, abnormalities in hepatic insulin receptor level and function have been sought in a variety of animal models of Type 2 diabetes (NIDDM) [10][11][12]. On the other hand, it has also been shown that hepatic insulin resis-tance can be produced by acute elevation of nonesterified fatty acids (NEFA) [13][14][15]. Excess lipid levels have been shown to stimulate gluconeogenesis, but the enzymatic mechanism responsible is not fully understood [16].…”

High Plasma Free Fatty Acids Decrease Splanchnic Glucose Uptake in Patients with Non-Insulin-Dependent Diabetes Mellitus.

“…Among them, high free fatty acid (FFA) levels could partially account for insulin resistance in NIDDM patients [8]. It has recently been reported that healthy subjects increased plasma FFA levels induced by lipid-heparin administration impair insulin-mediated increase in peripheral glucose uptake [9][10][11][12][13] and suppression of HGP under euglycemic hyperinsulinemic conditions [13,14]. In patients with NIDDM, circulating plasma FFA concentrations are increased in postabsorptive and postprandial states [15].…”