Effect of fatty acids on glucose production and utilization in man.

Abstract

A B S T R A C T Since the initial proposal of the glucose fatty acid cycle, considerable controversy has arisen concerning its physiologic significance in vivo. In the present study, we examined the effect of acute, physiologic elevations of FFA concentrations on glucose production and uptake in normal subjects under three controlled experimental conditions. In group A, plasma insulin levels were raised and maintained at -100 uU/ ml above base line by an insulin infusion, while holding plasma glucose at the fasting level by a variable glucose infusion. In group B, plasma glucose concentration was raised by 125 mg/100 ml and plasma insulin was clamped at -50 ,U/ml by a combined infusion of somatostatin and insulin. In group C, plasma glucose was raised by 200 mg/100 ml above the fasting level, while insulin secretion was inhibited with somatostatin and peripheral glucagon levels were replaced with a glucagon infusion (1 ng/min* kg). Each protocol was repeated in the same subject in combination with a lipid-heparin infusion designed to raise plasma FFA levels by 1.5-2.0 Mmol/ml.With euglycemic hyperinsulinemia (study A), lipid infusion caused a significant inhibition of total glucose uptake (6.3±1.3 vs. 7.4±0.6 mg/min.kg, P < 0.02).Endogenous glucose production (estimated by the [3-3H]glucose technique) was completely suppressed both with and without lipid infusion. With hyperglycemic hyperinsulinemia (study B), lipid infusion also induced a marked impairment in glucose utilization (6.2±1.1 vs. 9.8±1.9 mg/min kg, P < 0.05); endogenous glucose production was again completely inhibited despite the increase in FFA concentrations. Under both conditions (A and B), the percentage inhibition of glucose uptake by FFA was positively correlated with the total rate of Address all correspondence to Dr. Ferrannini. Received for publication 16 July 1982 and in revised form 1I July 1983. glucose uptake (r = 0.69, P < 0.01). In contrast, when hyperglycemia was associated with relative insulinopenia and hyperglucagonemia (study C), thus simulating a diabetic state, lipid infusion had no effect on glucose uptake (2.9±0.2 vs. 2.6±0.2 mg/min kg) but markedly stimulated endogenous glucose production (1.4±0.5 vs. 0.5±0.4 mg/min-kg, P < 0.005). Under the same conditions as study C, a glycerol infusion producing plasma glycerol levels similar to those achieved with lipid-heparin, enhanced endogenous glucose production (1.5±0.5 vs. 0.7±0.6 mg/min kg, P < 0.05).We conclude that, in the well-insulinized state raised FFA levels effectively compete with glucose for uptake by peripheral tissues, regardless of the presence of hyperglycemia. When insulin is deficient, on the other hand, elevated rates of lipolysis may contribute to hyperglycemia not by competition for fuel utilization, but through an enhancement of endogenous glucose output.

Reduction of insulin resistance by combined kidney-pancreas transplantation in Type 1 (insulin-dependent) diabetic patients

“…The cause of insulin resistance is multifactorial and has been related to hormonal and metabolic abnormalities [13,[31][32][33][34][35][36][37][38][39][40][41][43][44][45][46][47][48][49][50][51]. In contrast with Type 1 diabetes, in chronic renal failure high polypeptide hormone levels, are not necessarily the result of hypersecretion, but can be due to clearance defects.…”

Substrate cycling between de novo lipogenesis and lipid oxidation: a thermogenic mechanism against skeletal muscle lipotoxicity and glucolipotoxicity

“…24,25 In particular, it has been demonstrated in humans that under in vivo conditions when fatty acid concentrations are elevated (eg, in response to infusion of lipid emulsions together with heparin) whole body and skeletal muscle glucose utilizations are impaired. [26][27][28] The mechanisms put forward to explain how fatty acids limit insulin-stimulated glucose utilization fall into two main categories, both of which were first proposed by Randle following the original studies which formed the basis of the glucose-fatty acid cycle, [20][21][22][23] namely: (a) via fatty acidinduced desensitization of insulin-mediated glucose transport and (b) via inhibitory effects of fatty acid oxidation. According to the Randle hypothesis for the latter mechanism, 22,24 an increase in lipid oxidation in muscle will decrease glucose oxidation by suppression of the mitochondrial pyruvate dehydrogenase complex, with the consequential reduction of glycolytic flux resulting in an increase in glucose-6-phosphate, inhibition of hexokinase activity, and ultimately leading to decreased glucose uptake.…”

Interaction between specific fatty acids, GLP-1 and insulin secretion in humans

“…Increased plasma NEFA concentrations can have adverse effects on various tissues. Excess plasma NEFA concentrations can lead to a reduced skeletal muscle glucose uptake and oxidation [4,5,6], increased hepatic glucose output [7] and a decrease in hepatic insulin clearance [8,9]. These mechanisms could lead to glucose intolerance and insulin resistance leading to Type II diabetes.…”