Can associations between free fatty acid levels and metabolic parameters determine insulin resistance development in obese Zucker rats?

These studies were undertaken to further characterize and explain the differences in hepatic fatty acid metabolism between lean and obese Zucker rats. It was shown that the rate of palmitate or octanoate oxidation and the inhibition of palmitate oxidation by malonyl CoA in mitochondria isolated from lean and obese Zucker rats were similar. Cytochrome oxidase activity was similar in lean and obese rat livers. It was found that the addition of cytosol from the obese rat liver inhibited palmitate oxidation by 20-30% in mitochondria isolated from lean or obese rat livers and thus reproduced the conditions observed in the intact cell. Increased concentrations of metabolites such as malonyl CoA and glycerophosphate in the liver of the obese rat are likely contributors to this inhibitory effect. These results are extrapolated to the intact cell and suggest that decreased hepatic fatty acid oxidation in the obese rat can be accounted for by cytosolic influences on the mitochondria. The decreased rate of fatty acid oxidation observed in the intact hepatocyte or perfused liver cannot be explained by a defect in the capacity of mitochondria to oxidize substrate or by a decrease in mitochondrial number in the obese rat liver.

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Plasma calcitonin gene-related peptide is increased prior to obesity, and sensory nerve desensitization by capsaicin improves oral glucose tolerance in obese Zucker rats

Acta Endocrinologica ◽

10.1530/eje.1.02046 ◽

2005 ◽

Vol 153 (6) ◽

pp. 963-969 ◽

Cited By ~ 53

Author(s):

Dorte X Gram ◽

Anker J Hansen ◽

Michael Wilken ◽

Torben Elm ◽

Ove Svendsen ◽

...

Keyword(s):

Insulin Resistance ◽

Glucose Tolerance ◽

Sensory Nerve ◽

Zucker Rats ◽

Oral Glucose ◽

Oral Glucose Tolerance ◽

Nerve Activity ◽

Calcitonin Gene ◽

Obese Rats ◽

Obese Zucker Rats

Objective: It has earlier been demonstrated that capsaicin-induced desensitization improves insulin sensitivity in normal rats. However, whether increased capsaicin-sensitive nerve activity precedes the onset of insulin resistance in diet-induced obesity – and therefore might be involved in the pathophysiology – is not known. Further, it is of relevance to investigate whether capsaicin desensitization improves glycaemic control even in obese individuals and we therefore chose the obese Zucker rats to test this. Design and methods: Plasma levels of calcitonin gene-related peptide (CGRP; a marker of sensory nerve activity) was assessed in 8-week-old Zucker rats. To investigate whether capsaicin desensitization (100 mg/kg at 9 weeks of age) would also ameliorate glycaemia in this non-diabetic model, we assessed oral glucose tolerance at 7 weeks after capsaicin. Results: It was found that plasma CGRP levels were elevated in obese Zucker rats prior to the onset of obesity (16.1±3.4 pmol/l in pre-obese Zucker rats vs 6.9±1.1 pmol/l in lean littermates; P = 0.015) despite similar body weights. Furthermore, capsaicin desensitization reduced both fasting blood glucose (4.3±0.2 mmol/l vs 5.1±0.2 mmol/l in controls; P = 0.050) as well as the mean blood glucose level during an oral glucose tolerance test (OGTT) (6.8±0.3 mmol/l vs 8.6±0.5 mmol/l in control obese rats; P = 0.024) whereas the plasma insulin levels during the OGTT were unchanged. However this did not lead to an improvement in insulin resistance or to a reduction of tissue triglyceride accumulation in muscle or liver. Conclusion: We concluded that capsaicin-induced sensory nerve desensitization improves glucose tolerance in Zucker rats. Since, in this study, plasma CGRP levels, a marker of sensory nerve activity, were increased in the pre-obese rats, our data support the hypothesis that increased activity of sensory nerves precedes the development of obesity and insulin resistance in Zucker rats.

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Different Types of Postinsulin Receptor Defects Contribute to Insulin Resistance in Hearts of Obese Zucker Rats*

Endocrinology ◽

10.1210/endo-119-3-1285 ◽

1986 ◽

Vol 119 (3) ◽

pp. 1285-1291 ◽

Cited By ~ 24

Author(s):

P. RÖSEN ◽

L. HERBERG ◽

H. REINAUER ◽

M. ADRIAN ◽

J. FEUERSTEIN ◽

...

Keyword(s):

Insulin Resistance ◽

Zucker Rats ◽

Different Types ◽

Obese Zucker Rats

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Effects of a unique conjugate of α-lipoic acid and γ-linolenic acid on insulin action in obese Zucker rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2000.278.2.r453 ◽

2000 ◽

Vol 278 (2) ◽

pp. R453-R459 ◽

Cited By ~ 17

Author(s):

J. Anthony Peth ◽

Tyson R. Kinnick ◽

Erik B. Youngblood ◽

Hans J. Tritschler ◽

Erik J. Henriksen

Keyword(s):

Fatty Acid ◽

Essential Fatty Acid ◽

Glucose Transport ◽

Lipoic Acid ◽

Insulin Action ◽

Whole Body ◽

Zucker Rats ◽

Additive Effects ◽

Insulin Resistant ◽

Obese Zucker Rats

The purpose of this study was to assess the individual and interactive effects of the antioxidant α-lipoic acid (LPA) and the n-6 essential fatty acid γ-linolenic acid (GLA) on insulin action in insulin-resistant obese Zucker rats. LPA, GLA, and a unique conjugate consisting of equimolar parts of LPA and GLA (LPA-GLA) were administered for 14 days at 10, 30, or 50 mg ⋅ kg body wt− 1 ⋅ day− 1. Whereas LPA was without effect at 10 mg/kg, at 30 and 50 mg/kg it elicited 23% reductions ( P < 0.05) in the glucose-insulin index (the product of glucose and insulin areas under the curve during an oral glucose tolerance test and an index of peripheral insulin action) that were associated with significant increases in insulin-mediated (2 mU/ml) glucose transport activity in isolated epitrochlearis (63–65%) and soleus (33–41%) muscles. GLA at 10 and 30 mg/kg caused 21–25% reductions in the glucose-insulin index and 23–35% improvements in insulin-mediated glucose transport in epitrochlearis muscle. The beneficial effects of GLA disappeared at 50 mg/kg. At 10 and 30 mg/kg, the LPA-GLA conjugate elicited 29 and 38% reductions in the glucose-insulin index. These LPA-GLA-induced improvements in whole body insulin action were accompanied by 28–63 and 38–57% increases in insulin-mediated glucose transport in epitrochlearis and soleus muscles and resulted from the additive effects of LPA and GLA. At 50 mg/kg, the metabolic improvements due to LPA-GLA were substantially reduced. In summary, these results indicate that the conjugate of the antioxidant LPA and the n-6 essential fatty acid GLA elicits significant dose-dependent improvements in whole body and skeletal muscle insulin action on glucose disposal in insulin-resistant obese Zucker rats. Moreover, these actions of LPA-GLA are due to the additive effects of its individual components.

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Acute effect of electroacupuncture at the Zusanli acupoints on decreasing insulin resistance as shown by lowering plasma free fatty acid levels in steroid-background male rats

BMC Complementary and Alternative Medicine ◽

10.1186/1472-6882-9-26 ◽

2009 ◽

Vol 9 (1) ◽

Cited By ~ 44

Author(s):

Rong-Tsung Lin ◽

Chung-Yuh Tzeng ◽

Yu-Chen Lee ◽

Wai-Jane Ho ◽

Juei-Tang Cheng ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acid ◽

Free Fatty Acid ◽

Plasma Free Fatty Acid ◽

Acute Effect ◽

Male Rats

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Effects of an adenosine-receptor antagonist on insulin-resistance in soleus muscle from obese Zucker rats

Biochemical Journal ◽

10.1042/bj2210915 ◽

1984 ◽

Vol 221 (3) ◽

pp. 915-917 ◽

Cited By ~ 38

Author(s):

R A Challis ◽

L Budohoski ◽

B McManus ◽

E A Newsholme

Keyword(s):

Insulin Resistance ◽

Receptor Antagonist ◽

Adenosine Receptor ◽

Adenosine Receptors ◽

Glucose Utilization ◽

Glycogen Synthesis ◽

Zucker Rats ◽

Adenosine Receptor Antagonist ◽

Obese Rats ◽

Obese Zucker Rats

The decreased sensitivity of glycolysis to insulin seen in isolated soleus muscles from genetically obese Zucker rats was abolished by addition of the adenosine-receptor antagonist 8-phenyltheophylline to the incubation medium; 8-phenyltheophylline had no effect on the sensitivity of glycogen synthesis to insulin. These findings suggest that changes in the sensitivity of glucose utilization by muscles of genetically obese rats may be explained, in part, by a modification in either the concentration of adenosine or the affinity of adenosine receptors in skeletal muscle.

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Hypoglycemic effects and mechanisms of electroacupuncture on insulin resistance

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00465.2013 ◽

2014 ◽

Vol 307 (3) ◽

pp. R332-R339 ◽

Cited By ~ 8

Author(s):

Jieyun Yin ◽

Jian Kuang ◽

Manisha Chandalia ◽

Demidmaa Tuvdendorj ◽

Batbayar Tumurbaatar ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acid ◽

Blood Glucose ◽

Insulin Sensitivity ◽

Free Fatty Acid ◽

Glucose Tolerance ◽

High Fat Diet ◽

Postprandial Glucose ◽

Tolerance Test ◽

High Fat

The aim of this study was to investigate effects and mechanisms of electroacupuncture (EA) on blood glucose and insulin sensitivity in mice fed a high-fat diet. Both wild-type (WT) and adipose ectonucleotide pyrophosphate phosphodiesterase (ENPP1) transgenic (TG) mice were fed a high-fat diet for 12 wk; for each mouse, an intraperitoneal glucose tolerance test (IPGTT) and insulin tolerance test (ITT) were performed with or without EA at abdomen or auricular areas. A high-fat diet-induced insulin resistance in both WT and TG mice. In the WT mice, EA at 3 Hz and 15 Hz, but not at 1 Hz or 100 Hz, via CV4+CV12 significantly reduced postprandial glucose levels; EA at 3 Hz was most potent. The glucose level was reduced by 61.7% at 60 min and 74.5% at 120 min with EA at 3 Hz (all P < 0.001 vs. control). Similar hypoglycemic effect was noted in the TG mice. On the contrary, EA at auricular points increased postprandial glucose level ( P < 0.03). 4). EA at 3 Hz via CV4+CV12 significantly enhanced the decrease of blood glucose after insulin injection, suggesting improvement of insulin sensitivity. Plasma free fatty acid was significantly suppressed by 42.5% at 15 min and 50.8% at 30 min with EA ( P < 0.01) in both WT and TG mice. EA improves glucose tolerance in both WT and TG mice fed a high-fat diet, and the effect is associated with stimulation parameters and acupoints and is probably attributed to the reduction of free fatty acid.

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Variants in the Calpain-10 Gene Predispose to Insulin Resistance and Elevated Free Fatty Acid Levels

Diabetes ◽

10.2337/diabetes.51.8.2658 ◽

2002 ◽

Vol 51 (8) ◽

pp. 2658-2664 ◽

Cited By ~ 84

Author(s):

M. Orho-Melander ◽

M. Klannemark ◽

M. K. Svensson ◽

M. Ridderstrale ◽

C. M. Lindgren ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acid ◽

Free Fatty Acid ◽

Calpain 10

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Article Commentary: A Role for IR-β in the Free Fatty Acid Mediated Development of Hepatic Insulin Resistance?

Biochemistry Insights ◽

10.4137/bci.s2996 ◽

2009 ◽

Vol 2 ◽

pp. BCI.S2996

Author(s):

Samit Shah ◽

Arthur G. Cox

Keyword(s):

Insulin Resistance ◽

Fatty Acids ◽

Fatty Acid ◽

Free Fatty Acid ◽

Free Fatty Acids ◽

Pi3k Pathway ◽

Hepatic Insulin Resistance ◽

Hamster Model ◽

High Concentrations ◽

Nfκb Pathway

Several studies have been conducted to elucidate the role of free fatty acids (FFAs) in the pathogenesis of type 2 diabetes, but the exact molecular mechanism by which FFAs alter glucose metabolism in the liver is still not completely understood. 1 – 4 In a recent publication, Ragheb and coworkers have examined the effect of free fatty acid (FFA) treatment on insulin signaling and insulin resistance by using immunoprecipitation and immunoblotting to study the effect of high concentrations of insulin and FFAs on insulin receptor-beta (IR-β) and downstream elements in the PI3K pathway using the fructose-fed hamster model. 5 Their results clearly show that free fatty acids have an insignificant effect on IR-β and supports previous findings that FFAs lead to insulin resistance in the liver via the PKC-NFκB pathway. 2 , 3

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