Effects of troglitazone on fat distribution in the treatment of male type 2 diabetes

Kawai, Takeshi; Takei, Izumi; Oguma, Yuko; Ohashi, Norimi; Tokui, Mikiya; Oguchi, Shuji; Katsukawa, Fuminori; Hara, Hiroshi; Shimada, Akira; Watanabe, Kazuhiro; Saruta, Takao

doi:10.1016/s0026-0495(99)90122-1

Cited by 88 publications

(57 citation statements)

References 35 publications

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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%

“…Similar to the change in the V:S ratio induced by diet and exercise interventions, variations in the extent of the reduction in the V:S ratio that accompanies improvements in systemic metabolism are also observed in TZD trials PCOS polycystic ovary syndrome. Kawai et al [33] Mori et al [34] Nakamura et al [35] Shadid and Jensen [36] Smith et al [39] Kelly et al [54.3] 108.1 [53.5] 155 (13) 166 (14) 154 (15) performed by different research groups in different ethnic populations (Table 3). For example, treatment with troglitazone or pioglitazone, either alone or in combination with a diet or exercise programme or with a sulfonylurea, reduced the V:S ratio of the subjects by ∼1.5-32% of the values before the treatment (Table 3), which was associated with improved lipid profile and insulin sensitivity.…”

Section: What Do We Learn From Body Fat Distribution?mentioning

confidence: 99%

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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%

Section: What Do We Learn From Body Fat Distribution?mentioning

confidence: 99%

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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“…Glucocorticoids are known to increase leptin levels (36,54), which has led to speculation that glucocorticoids produce leptin resistance (55). In contrast, troglitazone has been reported to decrease leptin in rats (38,56); however, the current and previous data (57,58) demonstrate the absence of an effect in humans. The interaction between glucocorticoids and thiazolidinediones is a novel observation with respect to leptin and is analogous to effects of insulin and IGF-1 to antagonize glucocorticoid-induced increments in leptin secretion in cultured rat adipose tissue (59).…”

Section: Discussionmentioning

confidence: 67%

Troglitazone Antagonizes Metabolic Effects of Glucocorticoids in Humans

et al. 2002

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Glucocorticoids induce insulin resistance in humans, whereas thiazolidinediones enhance insulin sensitivity. Although the effects of glucocorticoids and thiazolidinediones have been assessed in isolation, interaction between these drugs, which both act as ligands for nuclear receptors, has been less well studied. Therefore, we examined the metabolic effects of dexamethasone and troglitazone, alone and in combination, for the first time in humans. A total of 10 healthy individuals with normal glucose tolerance (age 40 ؎ 11 years, BMI 31 ؎ 6.1 kg/m 2) were sequentially studied at baseline, after 4 days of dexamethasone (4 mg/day), after 4 -6 weeks on troglitazone alone (400 mg/day), and again after 4 days of dexamethasone added to troglitazone. Key metabolic variables included glucose tolerance assessed by blood glucose and insulin responses to an oral glucose tolerance test (OGTT), insulin sensitivity evaluated via hyperinsulinemic-euglycemic clamp, free fatty acids (FFAs) and FFA suppressibility by insulin during the clamp study, and fasting serum leptin. Dexamethasone drastically impaired glucose tolerance, with fasting and 2-h OGTT insulin values increasing by 2.3-fold (P < 0.001) and 4.4-fold (P < 0.001) over baseline values, respectively. The glucocorticoid also induced a profound state of insulin resistance, with a 34% reduction in maximal glucose disposal rates (GDRs; P < 0.001). Troglitazone alone increased GDRs by 20% over baseline (P ‫؍‬ 0.007) and completely prevented the deleterious effects of dexamethasone on glucose tolerance and insulin sensitivity, as illustrated by a return of OGTT glucose and insulin values and maximal GDR to near-baseline levels. Insulin-mediated FFA suppressibility (FFA decline at 30 min during clamp/FFA at time 0) was also markedly reduced by dexamethasone (P ‫؍‬ 0.002). Troglitazone had no effect per se, but it was able to normalize FFA suppressibility in subjects coadministered dexamethasone. Futhermore, the magnitudes of response of FFA suppressibility and GDR to dexamethasone were proportionate. The same was true for the reversal of dexamethasone-induced insulin resistance by troglitazone, but not in response to troglitazone alone. Leptin levels were increased 2.2-fold above baseline by dexamethasone. Again, troglitazone had no effect per se but blocked the dexamethasone-induced increase in leptin. Subjects experienced a 1.7-kg weight gain while taking troglitazone but no other untoward effects. We conclude that in healthy humans, thiazolidinediones antagonize the action of dexamethasone with respect to multiple metabolic effects. Specifically, troglitazone reverses both glucocorticoid-induced insulin resistance and impairment of glucose tolerance, prevents dexamethasone from impairing the antilipolytic action of insulin, and blocks the increase in leptin levels induced by dexamethasone. Even though changes in FFA suppressibility were correlated with dexamethasone-induced insulin resistance and its reversal by troglitazone, a cause-and-effect relationship cannot be establ...

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“…Peroxisome proliferator-activated receptor-γ agonists are known to increase body weight [27][28][29][30] and total fat mass [31][32][33] based on studies with both animals and diabetic humans. It has been suggested that PPARγ agonists promote differentiation of preadipocytes in subcutaneous fat tissue but not in visceral fat tissue.…”

mentioning

confidence: 99%

Fat redistribution preferentially reflects the anti-inflammatory benefits of pioglitazone treatment

Moon

Kim

et al. 2011

Metabolism

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Effects of troglitazone on fat distribution in the treatment of male type 2 diabetes

Cited by 88 publications

References 35 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?

Troglitazone Antagonizes Metabolic Effects of Glucocorticoids in Humans

Fat redistribution preferentially reflects the anti-inflammatory benefits of pioglitazone treatment

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