Prevention of inhibitory effect of free fatty acids on insulin binding and action in isolated rat hepatocytes by etomoxir

Svedberg, J.; Bjorntorp, P.; Lonnroth, P.; Smith, U.

doi:10.2337/diabetes.40.6.783

Cited by 16 publications

(16 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The inhibitory effect was counteracted by prevention offatty acid oxidation by a carnitine-acylCoA transferase inhibitor (16). It seems likely that the inhibitory effect of FFA on hepatic insulin clearance shown in the present work, is explained by these mechanisms, viz., that insulin binding is diminished by fatty acids, and their subsequent oxidation, presumably an effect of insulin receptor internalization/recycling, in agreement with an independent recent report (27).…”

Section: Discussionmentioning

confidence: 68%

“…The applicability of the findings in isolated hepatocytes (15)(16)(17)27) and in the perfused liver, reported here, to the situation in vivo must, however, still be regarded with caution, because no direct data are available to address this problem. Although several reports have suggested a decrease of hepatic insulin clearance in obesity in animals (30) and man (31)(32)(33) particularly when localized to abdominal regions (6), the methods used in these reports have not always been adequate (34).…”

Section: Discussionmentioning

confidence: 94%

“…We recently reported that fatty acids in physiological concentrations inhibit insulin binding, degradation, and function in isolated rat hepatocytes (15), apparently dependent on the oxidation of the fatty acids (15,16).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Fatty acids in the portal vein of the rat regulate hepatic insulin clearance.

Svedberg¹,

Strömblad²,

Wirth³

et al. 1991

J. Clin. Invest.

112

View full text Add to dashboard Cite

The effects of FFA on hepatic insulin clearance were studied in the in situ perfused rat liver. Clearance decreased with increasing body weight (age) of the rats. When FFA were added to the perfusate a 40% reduction of hepatic removal of insulin was found over the normal, physiological range (< 1,000 ,umol/ liter), less pronounced in heavier rats. When perfusion was started with high concentrations of FFA, inhibition was rapidly reversible, a phenomen again blunted in heavier rats. In contrast to FFA, different glucose concentrations in the perfusate did not affect the hepatic insulin uptake in the presence of FFA within physiological concentrations.Thus, hepatic clearance of insulin is proportional to rat weight (age) and portal FFA concentrations. Other studies have recently shown that fatty acids inhibit insulin binding, degradation, and function in isolated rat hepatocytes, and that hepatic clearance is inversely dependent on hepatic triglyceride concentrations, both inhibitions reversible by prevention of fatty acid oxidation. It is suggested that the diminished hepatic clearance of insulin in heavier (older) rats is at least partly due to their relative obesity and increased hepatic triglyceride contents. This effect as well as that of portal FFA is probably mediated via fatty acid oxidation in the liver. This mechanism may have implications for the regulation of hepatic metabolism, and peripheral insulin concentrations. (J. Clin. Invest.

show abstract

Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 94%

See 1 more Smart Citation

Fatty acids in the portal vein of the rat regulate hepatic insulin clearance.

Svedberg¹,

Strömblad²,

Wirth³

et al. 1991

J. Clin. Invest.

112

View full text Add to dashboard Cite

show abstract

“…Studies in isolated rat hepatocytes showed a concentration-dependent FFA -m e d iated decrease in binding and degradation of insulin (43). This effect was also shown ex vivo in rat liver (43)(44)(45)(46). We have recently shown that heparin-Intralipid infusion in dogs reduces hepatic insulin extraction in vivo (47).…”

Section: Discussionmentioning

confidence: 86%

Prolonged elevation of plasma free fatty acids impairs pancreatic beta-cell function in obese nondiabetic humans but not in individuals with type 2 diabetes.

et al. 2000

View full text Add to dashboard Cite

Our recent in vivo observations in healthy nonobese humans have demonstrated that prolonged elevation of plasma free fatty acids (FFAs) results in diminished glucose-stimulated insulin secretion (GSIS) when the F FA-mediated decrease in insulin sensitivity is taken into account. In the present study, we investigated whether obese individuals and patients with type 2 diabetes are more sensitive than healthy control subjects to the inhibitory effect of prolonged elevation of plasma FFAs on GSIS. In seven patients with type 2 diabetes and seven healthy nondiabetic obese individuals, we assessed GSIS with a programmed graded intravenous glucose infusion on two occasions, 6-8 weeks apart, with and without a prior 48-h infusion of heparin and Intralipid, which was designed to raise plasma FFA concentration approximately twofold over basal. The nondiabetic obese subjects had a significant 21% decrease in GSIS (P = 0.0008) with the heparin and Intralipid infusion, associated with a decrease in whole body insulin clearance. The impairment in GSIS was evident at low (<11 mmol/l) but not at higher plasma glucose concentrations. In contrast, the patients with t y p e 2 diabetes had a slight increase in GSIS (P = 0.027) and no change in insulin clearance, although there was marked interindividual variability in response. Plasma proinsulin concentrations measured in a subset of subjects were not altered in either group by the infusion of heparin and Intralipid. In summary, 1) obese nondiabetic individuals are susceptible to a desensitization of GSIS with heparin and Intralipid infusion, and 2) patients with type 2 diabetes do not demonstrate such susceptibility when FFAs are elevated approximately twofold above basal with heparin and Intralipid. Our results suggest that FFAs could play an important role in the development of -cell failure in obese individuals who are at risk for developing t y p e 2 diabetes. They do not, however, seem to further deteriorate the -cell function of patients who already have established type 2 diabetes and may even result in a slight increase in GSIS in this latter group. D i a b e t e s 4 9 :3 9 9-408, 2000 I t is well accepted that type 2 diabetes is characterized by defects in both insulin action and insulin secretion (1,2), with a specific defect in glucose-stimulated insulin secretion (GSIS) early in the evolution of this disease (3,4). Over the past decade, several investigators have focused their attention on the possible role of free fatty acids (FFAs), which are often elevated in states of insulin resistance, in selectively desensitizing the -cell to glucose (5-9). The concept of FFA-induced -cell desensitization has received support from prospective epidemiological studies, which show that elevated plasma FFA levels are a risk marker for the long-term development of glucose intolerance and progression toward type 2 diabetes both in Caucasians (10) and in Pima Indians (11).The acute stimulating effect of FFAs on GSIS has been well described both in vitro (12,13) and in vivo (14-16), and...

show abstract

“…In humans, the hepatic TG content has been shown to correlate to the visceral AT volume ( 5 ) as well as to measures of insulin resistance (14). The decreased insulin clearance can be prevented by drugs which reduce the mitochondrial FFA oxidation (42).…”

Section: Discussionmentioning

confidence: 99%

Are Elevated Aminotransferases and Decreased Bilirubin Additional Characteristics of the Metabolic Syndrome?

et al. 1997

View full text Add to dashboard Cite

Abnormal liver tests, as well as morphological changes in the liver, are frequent among obese patients. Other frequent disturbances are visceral fat accumulation, insulin resistance, non-insulin-dependent diabetes mellitus (NIDDM), hypertriglyceridemia, and hypertension; these are a set of aberrations known as the metabolic syndrome. In order to investigate a possible relationship between the metabolic syndrome and impaired liver status we examined associations between liver tests, metabolic variables (insulin, glucose, and triglycerids), body composition and nutrition in 1083 men (BMI 28.8-63.8 kg/m2) and 1367 women (BMI 26.7-68.0 kg/m2) in the ongoing intervention study of Swedish Obese Subjects (SOS). Standard biochemical techniques were used to assess liver status and metabolic variables. Lean body mass (LBM) and masses of visceral and subcutaneous adipose tissue (AT) were estimated by means of computed tomography (CT) calibrated anthropometric equations. In both genders aspartate aminotransferase and alanine aminotransferase were, or tended to be, positively correlated to fasting serum insulin, visceral AT (women), and alcohol intake. In women, the aminotransferases were also correlated with fasting blood glucose. In both genders alkaline phosphatase was, or 1997;5:105-114. tended to be, positively associated with visceral AT, insulin (women), and glucose. Bilirubin was negatively correlated to insulin and visceral AT in men and women. Additional multivariate analyses indicated that alcohol had less explanatory power than serum insulin for the examined liver tests, especially among women. These results suggest that pathological liver tests in the obese may represent an expression of the metabolic syndrome.

show abstract

Prevention of inhibitory effect of free fatty acids on insulin binding and action in isolated rat hepatocytes by etomoxir

Cited by 16 publications

References 0 publications

Fatty acids in the portal vein of the rat regulate hepatic insulin clearance.

Fatty acids in the portal vein of the rat regulate hepatic insulin clearance.

Prolonged elevation of plasma free fatty acids impairs pancreatic beta-cell function in obese nondiabetic humans but not in individuals with type 2 diabetes.

Are Elevated Aminotransferases and Decreased Bilirubin Additional Characteristics of the Metabolic Syndrome?

Contact Info

Product

Resources

About