Effects of free fatty acids on hepatic glycogenolysis and gluconeogenesis in conscious dogs

Abstract

.-The aim of this study was to determine the effect of high levels of free fatty acids (FFA) and/or hyperglycemia on hepatic glycogenolysis and gluconeogenesis. Intralipid was infused peripherally in 18-h-fasted conscious dogs maintained on a pancreatic clamp in the presence (FFA ϩ HG) or absence (FFA ϩ EuG) of hyperglycemia. In the control studies, Intralipid was not infused, and euglycemia (EuG) or hyperglycemia (HG) was maintained. Insulin and glucagon were clamped at basal levels in all four groups. The arterial blood glucose level increased by 50% in the HG and FFA ϩ HG groups. It did not change in the EuG and FFA ϩ EuG groups. Arterial plasma FFA increased by ϳ140% in the FFA ϩ EuG and FFA ϩ HG groups but did not change significantly either in the EuG or HG groups. Arterial glycerol levels increased by ϳ150% in both groups. Overall (3-h) net hepatic glycogenolysis was 196 Ϯ 26 mg/kg in the EuG group. It decreased by 96 Ϯ 20, 82 Ϯ 16, and 177 Ϯ 22 mg/kg in the HG, FFA ϩ EuG, and FFA ϩ HG groups, respectively. Overall (3-h) hepatic gluconeogenic flux was 128 Ϯ 22 mg/kg in the EuG group, but it was suppressed by 30 Ϯ 9 mg/kg in response to hyperglycemia. It was increased by 59 Ϯ 12 and 56 Ϯ 10 mg/kg in the FFA ϩ EuG and FFA ϩ HG groups, respectively. In conclusion, an increase in plasma FFA and glycerol significantly inhibited hepatic glycogenolysis and markedly stimulated hepatic gluconeogenesis.free fatty acid; hyperglycemia; glycogenolysis; gluconeogenesis AN INCREASE IN FREE FATTY ACIDS (FFA) stimulates hepatic gluconeogenesis (10,14,37). In vitro studies have shown that perfusion of rat liver with lipid increases gluconeogenesis (36,37) and that an increase in FFA oxidation stimulates the activities of key enzymes in the gluconeogenic pathway (3,26). In accord with this, Boden and Jadali (5) reported that a rise in plasma FFA increased hepatic glucose production (HGP) in normal human subjects. In addition, Saloranta et al. (30) showed that an increase in FFA and glycerol availability, brought about by Intralipid infusion, increased gluconeogenesis and glucose production in type 2 diabetic patients. In contrast, in a recent study, Roden et al. (27) did not detect a change in HGP in response to an increase in FFA in normal humans. Likewise, Johnston et al. (18) reported that an acute increase in the plasma FFA level did not change HGP in type 2 diabetic subjects. In agreement with the latter, Puhakainen and colleagues (24,25) showed that a decrease in plasma FFA, although it reduced gluconeogenesis, did not change HGP in patients with type 2 diabetes. Most recently, Boden et al. (4) showed in both normal and type 2 diabetic subjects that increasing and decreasing plasma FFA stimulated and inhibited gluconeogenesis, respectively, but did not alter glucose production. In another recent study, Stingl et al. (35) showed that in normal humans HGP and glycogenolysis both decreased in response to an increase in plasma FFA level. It is obvious from the above discordance that the effect of an increase in FFA av...

Obesity and Type 2 Diabetes Impair Insulin-Induced Suppression of Glycogenolysis as Well as Gluconeogenesis

“…This finding is in agreement with the report of Gastaldelli et al (9) and the well-established stimulatory effect of FFAs on gluconeogenesis (9,28,29). Boden et al (30) have shown that an increase in plasma FFAs produced by means of an intralipid heparin infusion impairs insulin-induced suppression of glycogenolysis in nondiabetic subjects.…”

“…Boden et al (30) have shown that an increase in plasma FFAs produced by means of an intralipid heparin infusion impairs insulin-induced suppression of glycogenolysis in nondiabetic subjects. In contrast, Chu et al (28) have reported that elevated FFAs in the presence of hyperglycemia enhance, rather than impair, suppression of glycogenolysis. The observation that plasma FFAs were positively correlated with glycogenolysis during the clamp in the current study suggests that endogenous FFAs also modulate the ability of insulin to suppress glycogenolysis in obese nondiabetic and diabetic humans.…”

Metformin Prevents the Development of Acute Lipid-Induced Insulin Resistance in the Rat Through Altered Hepatic Signaling Mechanisms

“…To our knowledge, metformin-induced enhancement of insulin signaling in the liver has not previously been identified in any in vivo model of insulin resistance. Previous studies of lipid-induced insulin resistance in a few species have demonstrated that accelerated gluconeogenesis is primarily responsible for the increased HGO observed (4,7,9,20,21); however, not all studies have detected a net effect on HGO, because a concurrent effect of lipid to suppress glycogenolysis has been observed (4,9). In this study, we quantified the expression of two key gluconeogenic enzymes (FBP and PEPCK) in the liver after lipid infusion but did not detect differences in expression of either enzyme as a result of lipid infusion or metformin.…”

“…Hyperlipidemia is an important component of this syndrome; in particular, elevation of circulating free fatty acid (FFA) concentrations has been associated with insulin resistance in many clinical studies (2,3). Furthermore, artificial elevation of systemic FFA in normal humans or animals by means of triacylglycerol-heparin infusion (4 -10) or increasing dietary fat content (11,12) results in insulin resistance, usually involving a substantial impairment in the ability of insulin to suppress hepatic glucose output (HGO) (4,7,9). Several groups have identified changes in expression or activation of molecules linked to the insulinsignaling cascade as a result of increased supply of FFAs to the liver.…”

Orchestration of Glucose Homeostasis

“…The former slowed increasing glucose disposal, and the latter slowed suppression of FFA, hence slowing the suppression of glucose output. There is still debate regarding what precise fraction of suppression of glucose output is secondary to suppression of FFA (85). However, there is consensus that FFA suppression accounts for at least part of the reduction in gluconeogenesis and glycogenolysis that accompanies nutrient intake.…”