Metabolic effects of troglitazone on fat-induced insulin resistance in the rat

Khoursheed, Mousa; Miles, P. D. G.; Gao, Keming; Lee, Moon-Kyu; Moossa, A. R.; Olefsky, Jerrold M.

doi:10.1016/0026-0495(95)90151-5

Cited by 46 publications

(23 citation statements)

References 31 publications

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“…The ability of troglitazone to increase whole-body glucose uptake has been demonstrated in a number of insulin-resistant animal models (43,44) as well as in subjects with type 2 diabetes (17,45). This response is observed in the absence or presence of sulfonylureas, although, just as we found, thiazolidinedione treatment augments glycemic control over that seen with sulfonylurea monotherapy (46,47).…”

Section: Discussionsupporting

confidence: 60%

Regulation of Glucose Transport and Insulin Signaling by Troglitazone or Metformin in Adipose Tissue of Type 2 Diabetic Subjects

et al. 2002

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Type 2 diabetic subjects failing glyburide therapy were randomized to receive additional therapy with either metformin (2,550 mg/day) or troglitazone (600 mg/day) for 3-4 months. Biopsies of subcutaneous abdominal adipose tissue were obtained before and after therapy. Glycemic control was similar with both treatments. Metformin treatment increased insulin-stimulated whole-body glucose disposal rates by 20% (P < 0.05); the response to troglitazone was greater (44% increase, P < 0.01 vs. baseline, P < 0.05 vs. metformin). Troglitazone-treated subjects displayed a tendency toward weight gain (5 ؎ 2 kg, P < 0.05), increased adipocyte size, and increased serum leptin levels. Metformintreated subjects were weight-stable, with unchanged leptin levels and reduced adipocyte size (to 84 ؎ 4% of control, P < 0.005). Glucose transport in isolated adipocytes from metformin-treated subjects was unaltered from pretreatment. Glucose transport in both the absence (321 ؎ 134% of pre-Rx, P < 0.05) and presence of insulin (418 ؎ 161%, P < 0.05) was elevated after troglitazone treatment. Metformin treatment had no effect on adipocyte content of GLUT1 or GLUT4 proteins. After troglitazone treatment, GLUT4 protein expression was increased twofold (202 ؎ 42%, P < 0.05). Insulin-stimulated serine phosphorylation of Akt was augmented after troglitazone (170 ؎ 34% of pre-Rx response, P < 0.05) treatment and unchanged by metformin. We conclude that the ability of troglitazone to upregulate adipocyte glucose transport, GLUT4 expression, and insulin signaling can contribute to its greater effect on whole-body glucose disposal. Diabetes 51: 30 -36, 2002

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Section: Discussionsupporting

confidence: 60%

Regulation of Glucose Transport and Insulin Signaling by Troglitazone or Metformin in Adipose Tissue of Type 2 Diabetic Subjects

et al. 2002

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“…Other investigations have demonstrated enhanced skeletal muscle and whole-body insulin sensitivity after short-term (4 days [7] or 2 weeks [24]) rosiglitazone treatment in high-fat-fed rats. We are not the first, however, to report a failure of TZDs to improve insulin resistance induced by high-fat feeding in rodents (25,26). Our observation of increased muscle FAT/CD36 expression and lipid storage provides a potential mechanism for an absence of rosiglitazone-induced muscle insulin sensitization.…”

Section: Discussionmentioning

confidence: 71%

Tissue-Specific Effects of Rosiglitazone and Exercise in the Treatment of Lipid-Induced Insulin Resistance

et al. 2007

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Both pharmacological intervention (i.e., thiazolidinediones [TZDs]) and lifestyle modification (i.e., exercise training) are clinically effective treatments for improving whole-body insulin sensitivity. However, the mechanism(s) by which these therapies reverse lipid-induced insulin resistance in skeletal muscle is unclear. We determined the effects of 4 weeks of rosiglitazone treatment and exercise training and their combined actions (rosiglitazone treatment and exercise training) on lipid and glucose metabolism in high-fat-fed rats. High-fat feeding resulted in decreased muscle insulin sensitivity, which was associated with increased rates of palmitate uptake and the accumulation of the fatty acid metabolites ceramide and diacylglycerol. Impairments in lipid metabolism were accompanied by defects in the Akt/AS160 signaling pathway. Exercise training, but not rosiglitazone treatment, reversed these impairments, resulting in improved insulinstimulated glucose transport and increased rates of fatty acid oxidation in skeletal muscle. The improvements to glucose and lipid metabolism observed with exercise training were associated with increased AMP-activated protein kinase ␣1 activity; increased expression of Akt1, peroxisome proliferator-activated receptor ␥ coactivator 1, and GLUT4; and a decrease in AS160 expression. In contrast, rosiglitazone treatment exacerbated lipid accumulation and decreased insulin-stimulated glucose transport in skeletal muscle. However, rosiglitazone, but not exercise training, increased adipose tissue GLUT4 and acetyl CoA carboxylase expression. Both exercise training and rosiglitazone decreased liver triacylglycerol content. Although both interventions can improve whole-body insulin sensitivity, our results show that they produce divergent effects on protein expression and triglyceride storage in different tissues. Accordingly, exercise training and rosiglitazone may act as complementary therapies for the treatment of insulin resistance.

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“…The second result was the observation of marked and early onset IR in mice fed a standard, moderately high-fat, Western diet (42% of calories as fat). Diets with much higher fat content (55% to 65% of calories) have been used previously to induce IR in other animal models, [27][28][29][30]46 and Surwit et al 31,32 have shown that high-fat diets also induce IR in mice. Our study documents that Western-type diets also cause IR in LDLR Ϫ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, we hypothesized that it should be possible to study the effect of IR on atherosclerosis in mice with similar plasma cholesterol levels. Because diets with a very high fat content can induce IR in rats [27][28][29][30] and some strains of mice, 31,32 it was conceivable that a Western diet moderately rich in fat could also induce some degree of IR in the control mice. Even though the potential occurrence of IR in LDLR Ϫ/Ϫ mice fed a Western diet could complicate the interpretation of this study, we thought such an observation would be of importance because of the common use of Western diets in murine atherosclerosis studies.…”

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confidence: 99%

Western-Type Diets Induce Insulin Resistance and Hyperinsulinemia in LDL Receptor-Deficient Mice But Do Not Increase Aortic Atherosclerosis Compared With Normoinsulinemic Mice in Which Similar Plasma Cholesterol Levels Are Achieved by a Fructose-Rich Diet

Merat

Casanada

Sutphin

et al. 1999

ATVB

142

105

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Abstract-The role of insulin resistance (IR) in atherogenesis is poorly understood, in part because of a lack of appropriate animal models. We assumed that fructose-fed LDL receptor-deficient (LDLR Ϫ/Ϫ ) mice might be a model of IR and atherosclerosis because (1) fructose feeding induces hyperinsulinemia and IR in rats; (2) a preliminary experiment showed that fructose feeding markedly increases plasma cholesterol levels in LDLR Ϫ/Ϫ mice; and (3) hypercholesterolemic LDLR Ϫ/Ϫ mice develop extensive atherosclerosis. To test whether IR could be induced in LDLR Ϫ/Ϫ mice, 3 groups of male mice were fed a fructose-rich diet (60% of total calories; nϭ16), a fat-enriched (Western) diet intended to yield the same plasma cholesterol levels (nϭ18), or regular chow (nϭ7) for approximately 5.5 months. The average cholesterol levels of both hypercholesterolemic groups were similar (849Ϯ268 versus 964Ϯ234 mg/dL) and much higher than in the chow-fed group (249Ϯ21 mg/dL). Final body weights in the Western diet group were higher (39Ϯ6.2 g) than in the fructose-(27.8Ϯ2.7 g) or chow-fed (26.7Ϯ3.8 g) groups. Contrary to expectation, IR was induced in mice fed the Western diet, but not in fructose-fed mice. The Western diet group had higher average glucose levels (187Ϯ16 versus 159Ϯ12 mg/dL) and 4.5-fold higher plasma insulin levels. Surprisingly, the non-insulin-resistant, fructose-fed mice had significantly more atherosclerosis than the insulin-resistant mice fed Western diet (11.8Ϯ2.9% versus 7.8Ϯ2.5% of aortic surface; PϽ0.01). These results suggest that (1) Key Words: arteriosclerosis Ⅲ diabetes Ⅲ fructose Ⅲ hypercholesterolemia Ⅲ lipoproteins I ndividuals with underlying insulin resistance (IR) and resulting impaired glucose tolerance (IGT) and noninsulin-dependent diabetes mellitus (NIDDM) have an increased prevalence of atherosclerosis and increased rates of coronary heart disease (CHD), 1-5 but the mechanisms responsible are poorly understood. Hyperglycemia has been hypothesized to enhance atherosclerosis in NIDDM, but the specific contribution of hyperglycemia has been difficult to demonstrate in either population studies or animal models. [5][6][7][8] Moreover, hyperglycemia per se is unlikely to play a role in the development of atherosclerosis in individuals with IGT who usually demonstrate only modest postprandial hyperglycemia. Insulin resistance is frequently associated with a number of metabolic abnormalities such as obesity, hypertriglyceridemia, low HDL, and hypertension. These risk factors explain some, but not all, of the increased risk for CHD. 9,10 Thus, additional factors associated with IR are likely to contribute to the accelerated development of atherosclerosis. Hyperinsulinemia is frequently present in both IGT and NIDDM, and several lines of evidence suggest that hyperinsulinemia itself may be proatherogenic. 11,12 For example, insulin has been shown to increase smooth muscle cell proliferation in vitro 11,13 and to enhance accumulation of cholesterol ester in aortas of rats. 14 Although several mechani...

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Metabolic effects of troglitazone on fat-induced insulin resistance in the rat

Cited by 46 publications

References 31 publications

Regulation of Glucose Transport and Insulin Signaling by Troglitazone or Metformin in Adipose Tissue of Type 2 Diabetic Subjects

Regulation of Glucose Transport and Insulin Signaling by Troglitazone or Metformin in Adipose Tissue of Type 2 Diabetic Subjects

Tissue-Specific Effects of Rosiglitazone and Exercise in the Treatment of Lipid-Induced Insulin Resistance

Western-Type Diets Induce Insulin Resistance and Hyperinsulinemia in LDL Receptor-Deficient Mice But Do Not Increase Aortic Atherosclerosis Compared With Normoinsulinemic Mice in Which Similar Plasma Cholesterol Levels Are Achieved by a Fructose-Rich Diet

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