Differential Effects of Rosiglitazone and Metformin on Adipose Tissue Distribution and Glucose Uptake in Type 2 Diabetic Subjects

Virtanen, Kirsi A.; Hällsten, Kirsti; Parkkola, Riitta; Janatuinen, Tuula; Lönnqvist, Fredrik; Viljanen, Tapio; Rönnemaa, Tapani; Knuuti, Juhani; Huupponen, Risto; Lönnroth, Peter; Nuutila, Pirjo

doi:10.2337/diabetes.52.2.283

Cited by 145 publications

(109 citation statements)

References 53 publications

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“…One adipose tissue depot that may behave differently is visceral adipose tissue. A reduction in postprandial NEFA generation from this depot in response to rosiglitazone could account for the observed lowering of postprandial NEFA concentrations and would be consistent with the reduction of visceral adipose tissue mass with rosiglitazone found by other authors [52,53].…”

Section: Discussionsupporting

confidence: 89%

The effects of rosiglitazone on fatty acid and triglyceride metabolism in type 2 diabetes

et al. 2004

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Aims/hypothesis: We investigated the effects of rosiglitazone on NEFA and triglyceride metabolism in type 2 diabetes. Methods: In a double-blind, placebo-controlled, cross-over study of rosiglitazone in diet-treated type 2 diabetic subjects, we measured arteriovenous differences and tissue blood flow in forearm muscle and subcutaneous abdominal adipose tissue, used stable isotope techniques, and analysed gene expression. Responses to a mixed meal containing [1,1,1-13 C]tripalmitin were assessed. Results: Rosiglitazone induced insulin sensitisation without altering fasting NEFA concentrations (−6.6%, p=0.16). Postprandial NEFA concentrations were lowered by rosiglitazone compared with placebo (−21%, p=0.04). Adipose tissue NEFA release was not decreased in the fasting state by rosiglitazone treatment (+24%, p=0.17) and was associated with an increased fasting hormone-sensitive lipase rate of action (+118%, p=0.01). Postprandial triglyceride concentrations were decreased by rosiglitazone treatment (−26%, p<0.01) despite unchanged fasting concentrations. Rosiglitazone did not change concentrations of triglyceride-rich lipoprotein remnants. Adipose tissue blood flow increased with rosiglitazone (+32%, p=0.03).

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Section: Discussionsupporting

confidence: 89%

The effects of rosiglitazone on fatty acid and triglyceride metabolism in type 2 diabetes

et al. 2004

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“…This is the capacity for muscle to shift reliance between glucose and lipids in response to insulin, which is impaired in individuals with large subcutaneous fat cells [32]. In quantitative terms, more glucose is taken up by subcu-taneous adipose tissue than by visceral adipose tissue following insulin infusion and this regional difference is enhanced following treatment with insulin sensitisers (biguanides or glitazones) [33,34]. With regard to plasma lipids, visceral adipose tissue is drained by the portal vein directly into the liver where the production of circulating lipids and lipoprotein takes place.…”

Section: Discussionmentioning

confidence: 99%

Regional impact of adipose tissue morphology on the metabolic profile in morbid obesity

et al. 2010

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Aims/hypothesis The aim of this study was to determine whether the mean size of fat cells in either visceral or subcutaneous adipose tissue has an impact on the metabolic and inflammatory profiles in morbid obesity. Methods In 80 morbidly obese women, mean visceral (omental) and subcutaneous fat cell sizes were related to in vivo markers of inflammation, glucose metabolism and lipid metabolism. Results Visceral, but not subcutaneous, adipocyte size was significantly associated with plasma apolipoprotein B, total cholesterol, LDL-cholesterol and triacylglycerols (p ranging from 0.002 to 0.015, partial r ranging from 0.3 to 0.4). Subcutaneous, but not visceral, adipocyte size was significantly associated with plasma insulin and glucose, insulininduced glucose disposal and insulin sensitivity (p ranging from 0.002 to 0.005, partial r ranging from −0.34 to 0.35). The associations were independent of age, BMI, body fat mass or body fat distribution. Adipose tissue hyperplasia (i.e. many small adipocytes) in both regions was significantly associated with better glucose, insulin and lipid profiles compared with adipose hypertrophy (i.e. few large adipocytes) in any or both regions (p ranging from <0.0001 to 0.04). Circulating inflammatory markers were not associated with fat cell size or corresponding gene expression in the fat cell regions examined. Conclusions/interpretation In morbidly obese women region-specific variations in mean adipocyte size are associated with metabolic complications but not systemic or adipose inflammation. Large fat cells in the visceral region are linked to dyslipidaemia, whereas large subcutaneous adipocytes are important for glucose and insulin abnormalities. Hyperplasia (many small adipocytes) in both adipose regions may be protective against lipid as well as glucose/insulin abnormalities in obesity.

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“…Given that AMPK activation (5-aminoimidazole-4-carboxamide ribonucleoside) with AICAR has been recently shown to inhibit glucose uptake and lipogenesis in adipocytes (49), our results are consistent with increased adipose tissue glucose uptake and lipid storage. In support of this contention, Virtanen et al (50) demonstrated that enhanced glucose uptake into adipose tissue makes a significant contribution to rosiglitazoneinduced insulin sensitization in patients with newly diagnosed type 2 diabetes. Our observations of increased adipose tissue mass combined with elevated adipose GLUT4 content and reduced AMPK activation provide a potential mechanism for increased adipose tissue glucose uptake after rosiglitazone treatment.…”

Section: Fig 3 Skeletal Muscle Ampk Activity and Protein Expressionmentioning

confidence: 92%

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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Differential Effects of Rosiglitazone and Metformin on Adipose Tissue Distribution and Glucose Uptake in Type 2 Diabetic Subjects

Cited by 145 publications

References 53 publications

The effects of rosiglitazone on fatty acid and triglyceride metabolism in type 2 diabetes

The effects of rosiglitazone on fatty acid and triglyceride metabolism in type 2 diabetes

Regional impact of adipose tissue morphology on the metabolic profile in morbid obesity

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

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