Thiazolidinedione Treatment Prevents Free Fatty Acid–Induced Insulin Resistance in Male Wistar Rats

Hevener, Andrea L.; Reichart, Donna; Olefsky, Jerrold M.

doi:10.2337/diabetes.50.10.2316

Cited by 73 publications

(59 citation statements)

References 51 publications

(33 reference statements)

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“…The results confirm recent studies [13,27] that in normal rats pretreated with a TZD, the ability to clear systemic fatty acids is substantially augmented (by ~62%) in the face of an elevation in fatty acids produced by triglyceride/heparin infusion. The current study goes on to show that enhancement of whole-body fatty acid uptake by TZD pre-treatment is associated with a substantial increase (~2-fold) in the flux of circulating fatty acids into adipose tissue, with decreased uptake into liver and muscle.…”

Section: Discussionsupporting

confidence: 91%

Direct demonstration of lipid sequestration as a mechanism by which rosiglitazone prevents fatty-acid-induced insulin resistance in the rat: comparison with metformin

et al. 2004

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Aims/hypothesis. Thiazolidinediones can enhance clearance of whole-body non-esterified fatty acids and protect against the insulin resistance that develops during an acute lipid load. The present study used [ 3 H]-R-bromopalmitate to compare the effects of the thiazolidinedione, rosiglitazone, and the biguanide, metformin, on insulin action and the tissue-specific fate of non-esterified fatty acids in rats during lipid infusion. Methods. Normal rats were treated with rosiglitazone or metformin for 7 days. Triglyceride/heparin (to elevate non-esterified fatty acids) or glycerol (control) were then infused for 5 h, with a hyperinsulinaemic clamp being performed between the 3rd and 5th hours. Results. Rosiglitazone and metformin prevented fattyacid-induced insulin resistance (reduced clamp glucose infusion rate). Both drugs improved insulinmediated suppression of hepatic glucose output but only rosiglitazone enhanced systemic non-esterified fatty acid clearance (plateau plasma non-esterified fatty acids reduced by 40%). Despite this decrease in plateau plasma non-esterified fatty acids, rosiglitazone increased fatty acid uptake (two-fold) into adipose tissue and reduced fatty acid uptake into liver (by 40%) and muscle (by 30%), as well as reducing liver longchain fatty acyl CoA accumulation (by 30%). Both rosiglitazone and metformin increased liver AMPactivated protein kinase activity, a possible mediator of the protective effects on insulin action, but in contrast to rosiglitazone, metformin had no significant effect on non-esterified fatty acid kinetics or relative tissue fatty acid uptake. Conclusions/interpretation. These results directly demonstrate the "lipid steal" mechanism, by which thiazolidinediones help prevent fatty-acid-induced insulin resistance. The contrasting mechanisms of action of rosiglitazone and metformin could be beneficial when both drugs are used in combination to treat insulin resistance.

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Section: Discussionsupporting

confidence: 91%

Direct demonstration of lipid sequestration as a mechanism by which rosiglitazone prevents fatty-acid-induced insulin resistance in the rat: comparison with metformin

et al. 2004

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“…An increase in circulating insulin, such as observed in obese Zucker rats, does not alter skeletal muscle fatty acid transporter expression (35). A recent report has shown that increasing circulating fatty acids, 6-fold in excess of the normal physiological range, reduces total FAT/CD36 expression (36). But, in studies in our laboratory we do not observe a relationship between circulating fatty acids and FAT/CD36 or FABPpm expression.…”

Section: Discussioncontrasting

confidence: 54%

Chronic Leptin Administration Decreases Fatty Acid Uptake and Fatty Acid Transporters in Rat Skeletal Muscle

Steinberg¹,

Dyck²,

Calles-Escandon³

et al. 2002

Journal of Biological Chemistry

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Chronic leptin administration reduces triacylglycerol content in skeletal muscle. We hypothesized that chronic leptin treatment, within physiologic limits, would reduce the fatty acid uptake capacity of red and white skeletal muscle due to a reduction in transport protein expression (fatty acid translocase (FAT/CD36) and plasma membrane-associated fatty acid-binding protein (FABPpm)) at the plasma membrane. Female Sprague-Dawley rats were infused for 2 weeks with leptin (0.5 mg/kg/day) using subcutaneously implanted miniosmotic pumps. Control and pair-fed animals received saline-filled implants. Leptin levels were significantly elevated (ϳ4-fold; p < 0.001) in treated animals, whereas pair-fed treated animals had reduced serum leptin levels (approximately ؊2-fold; p < 0.01) relative to controls. Palmitate transport rates into giant sarcolemmal vesicles were reduced following leptin treatment in both red (؊45%) and white (؊84%) skeletal muscle compared with control and pair-fed animals (p < 0.05). Leptin treatment reduced FAT mRNA (red, ؊70%, p < 0.001; white, ؊48%, p < 0.01) and FAT/CD36 protein expression (red, ؊32%; p < 0.05) in whole muscle homogenates, whereas FABPpm mRNA and protein expression were unaltered. However, in leptin-treated animals plasma membrane fractions of both FAT/CD36 and FABPpm protein expression were significantly reduced in red (؊28 and ؊34%, respectively) and white (؊44 and ؊56%, respectively) muscles (p < 0.05). Across all experimental treatments and muscles, palmitate uptake by giant sarcolemmal vesicles was highly correlated with the plasma membrane FAT/CD36 protein (r ‫؍‬ 0.88, p < 0.01) and plasma membrane FABPpm protein (r ‫؍‬ 0.94, p < 0.01). These studies provide the first evidence that proteinmediated long chain fatty acid transport is subject to long term regulation by leptin.

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“…We have found no previous reports that pioglitazone increases NEFA clearance in humans, although increased NEFA clearance was seen during lipid emulsion infusion into thiazolidinedione-treated animals [35]. Previous studies suggested that thiazolidinediones lower NEFA concentrations in type 2 diabetes via improved insulin suppression of lipolysis [17][18][19][20].…”

Section: Discussionmentioning

confidence: 45%

Pioglitazone increases non-esterified fatty acid clearance in upper body obesity

Shadid

Jensen

2005

Diabetologia

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Aims/hypothesis: Plasma NEFA concentrations are largely determined by adipose tissue lipolysis. Insulin suppression of lipolysis is commonly impaired with insulin resistance and improves with thiazolidinedione treatment of type 2 diabetes. The present studies were designed to assess the effects of thiazolidinedione on NEFA (oleate) metabolism that are independent of improved glycaemic control. Materials and methods: We measured plasma oleate concentration and flux ([ H 2 ] glucose) and substrate oxidation (indirect calorimetry) before and after pioglitazone (30 mg/day for ∼20 weeks) in 20 non-diabetic adults with upper body obesity. To assess the effects of improved insulin sensitivity per se we performed the same measurements in a matched group of volunteers treated with diet/exercise. Half of the two groups underwent these measurements during a hyperinsulinaemic-euglycaemic clamp, and the other half had their measurements taken during a (control) saline infusion before and after the intervention. Results: Both interventions increased insulinstimulated glucose disposal and reduced plasma oleate concentrations during the insulin clamp. After diet/exercise, oleate flux decreased (p=0.03) during the insulin clamp and oleate clearance remained unchanged (p=0.55), whereas in the pioglitazone group, oleate flux during the clamp was unchanged (p=0.97) and oleate clearance increased (p=0.003). Oleate clearance in the saline control condition was increased in the pioglitazone group compared with the diet/exercise group (p=0.02).Conclusions/ interpretation: In insulin-resistant, non-diabetic adults, pioglitazone increases NEFA clearance during physiological hyperinsulinaemia, whereas improved insulin sensitivity achieved by diet/exercise does not alter NEFA clearance but enhances insulin suppression of NEFA release. This action of pioglitazone may contribute to improved glucose metabolism in type 2 diabetes.

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Thiazolidinedione Treatment Prevents Free Fatty Acid–Induced Insulin Resistance in Male Wistar Rats

Cited by 73 publications

References 51 publications

Direct demonstration of lipid sequestration as a mechanism by which rosiglitazone prevents fatty-acid-induced insulin resistance in the rat: comparison with metformin

Direct demonstration of lipid sequestration as a mechanism by which rosiglitazone prevents fatty-acid-induced insulin resistance in the rat: comparison with metformin

Chronic Leptin Administration Decreases Fatty Acid Uptake and Fatty Acid Transporters in Rat Skeletal Muscle

Pioglitazone increases non-esterified fatty acid clearance in upper body obesity

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