Acute inhibition of lipolysis does not affect postprandial suppression of endogenous glucose production

Abstract

To test the hypothesis that intrahepatic availability of fatty acid could modify the rate of suppression of endogenous glucose production (EGP), acipimox or placebo was administered before and during a test meal. We used a modified isotopic methodology to measure EGP in 11 healthy subjects, and 1 H magnetic resonance spectroscopic measurement of hepatic triglyceride stores was also undertaken. Acipimox suppressed plasma free fatty acids markedly before the meal (0.05 Ϯ 0.01 mmol/l at Ϫ10 min, P ϭ 0) and throughout the postprandial period (0.03 Ϯ 0.01 mmol/l at 150 min). Mean peak plasma glucose was significantly lower after the meal on acipimox days (8.9 Ϯ 0.4 vs. 10.1 Ϯ 0.5 mmol/l, P Ͻ 0.01), as was mean peak serum insulin (653.1 Ϯ 99.9 vs. 909 Ϯ 118 pmol/l, P Ͻ 0.01). Fasting EGP was similar (11.15 Ϯ 0.58 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 placebo vs. 11.17 Ϯ 0.89 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 acipimox). The rate of suppression of EGP after the meal was almost identical on the 2 test days (4.36 Ϯ 1.52 vs. 3.69 Ϯ 1.21 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 at 40 min). There was a significant negative correlation between the acipimoxinduced decrease in peak plasma glucose and liver triglyceride content (r ϭ Ϫ0.827, P ϭ 0.002), suggesting that, when levels of liver fat were low, inhibition of lipolysis was able to affect glucose homeostasis. Acute pharmacological sequestration of fatty acids in triglyceride stores improves postprandial glucose homeostasis without effect on the immediate postprandial suppression of EGP. intrahepatic triglyceride; acipimox; 1 H magnetic resonance spectroscopy PLASMA GLUCOSE CONCENTRATION is determined by the interaction of two processes, the rate of release of glucose into the bloodstream and the rate of uptake of glucose by cells. In the fasted state, glucose is produced by the breakdown of glycogen stores or gluconeogenesis. In the postprandial state, absorption of glucose and other substrates from the intestine exceeds the body's energy requirements. Homeostasis is maintained by a rapid increase in insulin secretion that acutely suppresses hepatic glucose production and enhances glucose storage and oxidation.We (25) have previously shown, using novel isotopic methodology, that endogenous glucose production (EGP) was almost completely suppressed within 30 min postprandially in young normal subjects. However, a subsequent study on older, more obese normal subjects showed a slower, less complete postprandial suppression of EGP (21). Given that the major metabolic difference between our two groups of normal subjects was degree of obesity, we postulated that intrahepatic availability of fatty acid could modify the rate of suppression of EGP. Such an effect could explain the slower, incomplete suppression of EGP in subjects with type 2 diabetes. Conversely, if the fatty acid supply was curtailed, it would be expected that postprandial EGP suppression would be more rapid and more complete.The present study was designed to test this hypothesis using acipimox, a nicotinic acid derivative that suppresses both peripheral tissue li...

The lowering of hepatic fatty acid uptake improves liver function and insulin sensitivity without affecting hepatic fat content in humans

“…This observation is in accord with recent findings in humans (8). Importantly, our data show a significant reduction in liver enzymes and triglyceride levels, together with an improved hepatic insulin sensitivity, as computed from fasting measurements.…”

“…By using the antilipolytic drug acipimox, Carey et al (8) showed recently that the improvement in glucose homeostasis induced by the drug was related to the content of fat in the liver, as measured before the administration of the agent. The assessment of liver fat content was not repeated after the intervention to test whether changes in this variable might be mediators of the systemic effects of the drug (8).…”

“…By using the antilipolytic drug acipimox, Carey et al (8) showed recently that the improvement in glucose homeostasis induced by the drug was related to the content of fat in the liver, as measured before the administration of the agent. The assessment of liver fat content was not repeated after the intervention to test whether changes in this variable might be mediators of the systemic effects of the drug (8). Bajaj and colleagues (2,3) have demonstrated that a sustained, 1-wk reduction in fatty acid release improves hepatic insulin sensitivity in subjects with a strong family history of diabetes and reduces skeletal muscle lipotoxicity by lowering the levels of long-chain fatty acyl-CoA compounds in patients with type 2 diabetes.…”

Postprandial Lipemia Associates with Liver Fat Content

“…In agreement, Tiikkainen et al (34) demonstrated that the hepatic fat content is more closely related to indexes of insulin resistance than degree of obesity. It is well documented that fatty liver fails to suppress glucose production in response to insulin in people both with and without diabetes (35)(36)(37). The question of whether hepatic insulin resistance is a consequence of increased liver fat or vice versa is a matter of a hectic debate (38).…”

Non-alcoholic fatty liver disease and the metabolic syndrome: An update

“…Further, numerous studies have demonstrated that obesity, type 2 diabetes, dyslipidemia, hypertension, and insulin resistance are strongly associated with NAFLD [12,[19][20][21][22] . NAFLD also is strongly associated with hepatic, adipose tissue, and whole body reductions in insulin sensitivity, increased rate of gluconeogenesis, impaired insulin response to suppress gluconeogenesis, and impaired fatty acid oxidation [23][24][25] . However, the question about whether hepatic insulin resistance is a cause or a consequence of hepatic steatosis is unresolved [26][27][28] .…”