Effects of a thiazolidinedione compound on body fat and fat distribution of patients with type 2 diabetes.

Kelly, Isabelle; Han, Thang S.; Walsh, Katie; Lean, Michael E. J.

doi:10.2337/diacare.22.2.288

Cited by 296 publications

(188 citation statements)

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“…Preadipocytes derived from subcutaneous adipose tissue express higher levels of PPARγ, C/EBPα and retinoid X receptor α (RXRα), and more readily proliferate and differentiate in vitro than cells from visceral fat depots (Table 1). In addition, these cells are more sensitive to TZD treatment in vitro, which is consistent with the selective increase in subcutaneous fat mass in patients treated with TZDs [32][33][34][35][36][37][38][39].…”

Section: Biological Differences Between Visceral and Subcutaneous Adisupporting

confidence: 78%

Adipose tissue distribution and risk of metabolic disease: does thiazolidinedione-induced adipose tissue redistribution provide a clue to the answer?

2007

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The relative effect of visceral and subcutaneous obesity on the risk of chronic metabolic disease has been a matter of long-term dispute. While ample data support either of the fat depots being causative or associative, valid argument for one depot often automatically belittles the other. Paradigms such as the visceral/portal hypothesis and the acquired lipodystrophy/ectopic fat storage and endocrine hypothesis have been proposed. Nevertheless, neither hypothesis alone explains the entire pathophysiological setting. Treatment of diabetes with thiazolidinediones selectively increases fat partitioning to the subcutaneous adipose depot but does not change visceral fat accumulation. This is in contrast to the preferential visceral fat mobilisation by diet and exercise. Surgical removal of visceral or subcutaneous adipose tissue yields relatively long-lasting metabolic improvement only when combined with procedures that ameliorate adipose tissue cell composition. These studies illustrate that human adipose tissue in different anatomic locations does not work in isolation, and that there is a best-fit relationship in terms of volume and function among different fat depots that needs to be met to maintain the systemic energy balance and to prevent the complications related to obesity.

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Section: Biological Differences Between Visceral and Subcutaneous Adisupporting

confidence: 78%

Adipose tissue distribution and risk of metabolic disease: does thiazolidinedione-induced adipose tissue redistribution provide a clue to the answer?

2007

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“…21,28,47,52,53 This seemingly paradoxical effect for a class of drugs that improves IS is due to increased peripheral rather than visceral fat and thus should not confer the metabolic and inflammatory abnormalities associated with intraabdominal fat. 54 Pioglitazone treatment for 16 weeks caused a 4% increase in body mass index, an 11% increase in total fat mass, a 14% increase in subcutaneous fat mass, but a 9% decrease in intraabdominal fat and improved hepatic and peripheral IS. 55 By promoting maturation of adipocytes in peripheral fat depots, these drugs direct fat in inert storage sites rather than allowing excess trafficking of fatty acids from metabolically active visceral stores.…”

Section: Adverse Effects Of Glitazonesmentioning

confidence: 95%

Therapeutic trials in nonalcoholic steatohepatitis: Insulin sensitizers and related methodological issues

2010

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Insulin sensitizers are attractive candidate therapies for nonalcoholic steatohepatitis mainly because of the strong association between this disease and insulin resistance. This review provides a critical overview of the mechanisms of action, clinical trial results, and safety issues of metformin and glitazones in nonalcoholic steatohepatitis. It also highlights methodological challenges for trial design and proposes endpoints for future proof of principle, registrational, and postmarketing trials. (HEPATOLOGY 2010;52:2206-2215 N onalcoholic steatohepatitis (NASH) is emerging as the next big therapeutic challenge in hepatology. 1 Currently the top cause of newly identified chronic liver diseases, NASH has potential for fibrosis, cirrhosis decompensation, and hepatocellular carcinoma. Not all individuals with metabolic risk factors will experience these adverse outcomes and identifying those at risk is critical. Prognostic markers for progression have mostly been derived from histological studies. Compared to steatosis alone or to steatosis and minimal inflammation, the coexistence of inflammation, cell injury (ballooning), and steatosis, a pathological aggregate labeled steatohepatitis, is associated with a significant increase in overall mortality and in liver-related mortality. The degree of inflammation is the best predictor of fibrosis progression, 2 a widely accepted surrogate for hard endpoints such as cirrhosis, endstage liver disease, and possibly hepatocellular carcinoma.Insulin resistance (IR) is consistently found in patients with NASH in both cross-sectional and longitudinal studies. Moreover, there is a stepwise increase in the severity of IR and its phenotypic complications (clustered as elements of the metabolic syndrome) between normal liver, isolated steatosis, and steatohepatitis that has prompted speculation that IR might contribute to liver damage. Logically, most therapeutic trials focused on insulin sensitizers (IS) as candidate therapies.The aim of this report is to critically review the results of trials of metformin and glitazones for NASH. We highlight methodological challenges for trial design and propose endpoints for future proof of principle, registrational, and postmarketing trials.

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“…11 -HSD1 -/-mice had higher adipose PPAR mRNA levels in their fat. Since PPAR ligands cause insulin sensitisation and fat M a n u s c r i p t 11 redistribution to the periphery (Kelly et al, 1999, Sewter et al, 2002, a mechanism for the beneficial fat redistribution was suggested, on the assumption that increased circulating free fatty acids during high fat feeding were acting as endogenous ligands for the PPAR receptors . In agreement with both increased PPAR and reduced glucocorticoid action, insulin sensitisation is evident in isolated primary 11 -HSD1 -/-adipocytes which showed increased basal and insulin-stimulated glucose uptake.…”

Section: -Hsd1 Deficient (-Hsd1mentioning

confidence: 99%

Obesity and corticosteroids: 11β-Hydroxysteroid type 1 as a cause and therapeutic target in metabolic disease

Morton

2010

Molecular and Cellular Endocrinology

150

159

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Effects of a thiazolidinedione compound on body fat and fat distribution of patients with type 2 diabetes.

Cited by 296 publications

References 0 publications

Adipose tissue distribution and risk of metabolic disease: does thiazolidinedione-induced adipose tissue redistribution provide a clue to the answer?

Adipose tissue distribution and risk of metabolic disease: does thiazolidinedione-induced adipose tissue redistribution provide a clue to the answer?

Therapeutic trials in nonalcoholic steatohepatitis: Insulin sensitizers and related methodological issues

Obesity and corticosteroids: 11β-Hydroxysteroid type 1 as a cause and therapeutic target in metabolic disease

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