Actos scientific update |
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Metabolism. 2009 Sep 28.
Iwanishi M, Ebihara K, Kusakabe T, Chen W, Ito J, Masuzaki H, Hosoda K, Nakao K.
Diabetes and Endocrine Division, Kusatsu General Hospital 1660 Yabase, Kusatsu, Shiga 525-8585, Japan.
Clinical characteristics and efficacy of pioglitazone in a Japanese diabetic patient with an unusual type of familial partial lipodystrophy.
This report describes a 46-year-old Japanese diabetic woman with an unusual type of familial partial lipodystrophy. She has marked loss of subcutaneous fat in her lower limbs and buttocks, with sparing of the face, neck, upper limbs, and trunk. This distribution of fat atrophy appears to be rare in comparison with previous reports. Sequencing of candidate genes LMNA, PPARG, AKT2, caveolin-1, as well as the PPARG4 promoter gene, which are known to be associated with familial partial lipodystrophy, revealed no genetic abnormalities, suggesting that this case may involve a novel gene. Pioglitazone was markedly effective in glycemic control in this case. Her diabetes remained uncontrolled despite a total daily dose of insulin of 30 U and combined treatment with 10 mg of glibenclamide and 0.6 mg of voglibose. We therefore attempted combined treatment with 30 mg of pioglitazone and 30 U/d insulin injection. The hemoglobin A(1c) level was reduced from 11.2% to 6.1% after 6 months of treatment and has since remained stable. Her body weight increased from 62.0 to 71.0 kg after 12 months of treatment, suggesting that weight gain may result from synergism between thiazolidinediones and insulin-promoting adipogenesis. Pioglitazone increased the fat mass in the upper limbs and trunk, while inducing less increase in the lower limbs, where fat atrophy exists in this patient. Pioglitazone may thus have improved the glycemic control in this case through adipocyte differentiation from progenitor cells mainly in the upper limbs and trunk.
Am J Physiol Endocrinol Metab. 2009 Oct 27.
Tao H, Aakula S, Abumrad NN, Hajri T.
1Vanderbilt University.
Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) regulates the expression and Function of very low density lipoprotein receptor.
Very low density lipoprotein receptor is a member of the low density receptor family, highly expressed in adipose tissue, heart and skeletal muscle. It binds apolipoprotein-E (apo-E)-TG-rich lipoproteins and plays a significant role in triglyceride metabolism. PPARgamma is a primary regulator of lipid metabolism in adipocyte and controls the expression of an array of genes involved in lipid trafficking in adipocytes. However, it is not known whether VLDLR is also under the control of PPARgamma. In this study, we have investigated the role of PPARgamma in the regulation of VLDLR expression and function in vivo and in vitro. During the differentiation of 3T3-L1 preadipocytes, the levels of VLDLR protein and mRNA increased in parallel to the induction of PPARgamma expression, and reached a maximum in mature adipocyte. Treatment of differentiated adipocytes with PPARgamma agonist pioglitazone upregulated VLDLR expression in dose- and time-dependent manners. In contrast, specific inhibition of PPARgamma significantly downregulated the protein level of VLDLR. Induction of VLDLR is also demonstrated in vivo in adipose tissue of wild type (WT) mice treated with pioglitazone. In addition, pioglitazone increased plasma TG-rich lipoprotein clearance and increased epididymal fat mass in WT mice, but failed to induce similar effects in vldlr(-/-) mice. These results were further corroborated by the finding that pioglitazone treatment enhanced adipogenesis and lipid deposition in preadipocytes of WT mice, while its effect in VLDLR null preadipocytes was significantly blunted. These findings provide direct evidence that VLDLR expression is regulated by PPARgamma and contributes in lipid uptake and adipogenesis.
Nephrol Dial Transplant. 2009 Oct 28.
Han SJ, Hur KY, Kim YS, Kang ES, Kim SI, Kim MS, Kwak JY, Kim DJ, Choi SH, Cha BS, Lee HC.
1Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon 443-721, Korea.
Effects of pioglitazone on subclinical atherosclerosis and insulin resistance in nondiabetic renal allograft recipients.
BACKGROUND: The aim of this study was to evaluate the effect of pioglitazone treatment on the progression of subclinical atherosclerosis and insulin resistance in renal allograft recipients with no preoperative history of diabetes. METHODS: Eighty-three patients without diabetes were randomly assigned to either the pioglitazone group or the control group. Carotid intima-media thickness (IMT), serum adiponectin level and lipid profile were assessed before transplantation and at 12 months after transplantation. Insulin secretory function and insulin resistance were evaluated by the oral glucose tolerance test. RESULTS: The pioglitazone group showed a significant reduction in the mean and maximum carotid IMT compared with the control group after 12 months (mean carotid IMT, 0.05 +/- 0.04 vs -0.03 +/- 0.07 mm, P < 0.001; maximum carotid IMT, 0.08 +/- 0.05 vs -0.05 +/- 0.09 mm, P < 0.001). Pioglitazone increased the adiponectin level, and the change in adiponectin was negatively correlated with carotid IMT changes. Pioglitazone treatment increased the insulin sensitivity index compared with the control group (-0.8 +/- 3.1x10(-)(2) vs +1.1 +/- 3.7x10(-)(2), P = 0.036). CONCLUSIONS: These results suggest that pioglitazone treatment reduces the progression of carotid IMT and improves insulin resistance in renal allograft recipients without a history of diabetes.
J Diabetes Sci Technol. 2008 Mar;2(2):244-9.
Schöndorf T, Pfützner A, Lübben G, Karagiannis E, Roth W, Forst T.
Institute for Clinical Research and Development , Mainz, Germany.
Pioglitazone Improves Metabolic Markers in Patients with Type 2 Diabetes Independently from Physical Activities: Results from the IRIS III Study.
AIM: Pioglitazone is an established peroxisome proliferator-activated receptor gamma agonist for the treatment of insulin resistance in patients with type 2 diabetes mellitus. This analysis of the observational IRIS III study was performed to evaluate the effects of pioglitazone treatment in relation to the degree of physical exercise activities in a large patient population under daily life conditions. METHODS: A total of 1298 patients out of 2092 enrolled into the IRIS III study who had provided information about their exercise level could be included in the final analysis (622 female, 676 male; age: 63.1 +/- 10.4 years, diabetes duration: 6.6 +/- 5.0 years, mean +/- SD). All patients were glitazone naïve prior to study entry. They received pioglitazone in addition to their previous oral antidiabetic treatment. The patients were stratified according to their physical activity level (never, sometimes, and regularly). Data were evaluated at baseline and after 20 +/- 2 weeks of treatment. Observation parameters were fasting blood glucose, lipids, and blood pressure. Hemoglobin A1c (HbA1c) was determined in a central laboratory, and insulin sensitivity was assessed by the IRIS II score. RESULTS: Glycemic control, blood pressure, and the lipid profile improved independently from the degree of physical activity (e.g., no exercise vs frequent exercise: DeltaHbA1c: -0.89 +/- 1.2% vs -0.72 +/- 1.1%, not significant). A positive impact of exercise on insulin resistance could be observed at baseline, which, however, was further decreased by pioglitazone treatment [IRIS II score (baseline/end point): no exercise vs frequent exercise: 74.0 +/- 15.9/62.5 +/- 20.2 vs 66.7 +/- 19.0/58.0 +/- 21.8, p < 0.001/not significant]. CONCLUSIONS: These observational results, obtained from a nonselected patient population under daily routine conditions, confirm that the benefits of pioglitazone treatment on glycemic control, lipid metabolism, and blood pressure are independent from physical activity. Exercise has a positive influence on insulin sensitivity, but pioglitazone shows additional favorable effects and is, therefore, recommended for use independently from the activity level of the patients.
Diabetes Obes Metab. 2009 Nov 2.
Mudaliar S, Chang AR, Aroda VR, Chao E, Burke P, Baxi S, Griver KA, O'Connor DT, Henry RR.
VA San Diego Healthcare System, San Diego, CA, USA.
Effects of intensive insulin therapy alone and with added pioglitazone on renal salt/water balance and fluid compartment shifts in type 2 diabetes.
Objective: To evaluate the effects of intensive insulin therapy alone or with added pioglitazone on renal salt/water balance and body fluid compartment shifts in type 2 diabetes. Methods: A total of 25 insulin-treated, obese patients with type 2 diabetes were randomized to pioglitazone 45 mg (n = 12) or placebo (n = 13) and treated intensively for 12-16 weeks to achieve equivalent glycaemic control. We measured total body water (TBW) and extracellular/intracellular fluid by bioimpedance analysis; plasma/RBC volume with I(131)albumin; sodium handling by fractional excretion of sodium/lithium (FeNa/FeLi) and other renal/hormonal parameters. Results: Intensification of insulin therapy and the addition of pioglitazone significantly improved glycaemia (HbA1C 7.8-7.2% and 7.6-7.1%) and increased body weight (1.7 and 4.9 kg) respectively. TBW increased 1.7 l with insulin alone (65% intracellular) and 1.6 l with added pioglitazone (75% extracellular) (p = 0.06 and 0.09 respectively). Plasma volume increased 0.2 +/- 0.1 l with insulin alone (p = 0.05) and 0.4 +/- 0.1 l with added pioglitazone (p < 0.05). Extravascular, extracellular (interstitial) fluid increased significantly and more with added pioglitazone (0.8 +/- 0.2 l, p < 0.01) than with insulin alone (0.4 +/- 0.2 l, p = ns ). At steady-state, FeLi (marker of proximal-tubular sodium delivery to the distal nephron) increased significantly with added pioglitazone (12.4 +/- 1.3 to 18.0 +/- 3.2%) vs. no significant change with insulin alone (15.4 +/- 1.2 to 14.5 +/- 2.3%). There were no significant changes in the other parameters. Conclusion: In intensively insulin-treated obese type 2 diabetic patients, at equivalent glycaemic control, the addition of pioglitazone causes greater weight gain, but a similar increase in body water that is mainly extracellular and interstitial compared with intracellular increase with insulin therapy alone. Pioglitazone also increases the filtered load of sodium reabsorbed at the distal nephron with no net change in FeNa.
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Drug category:Antidiabetic agents
 Actos scientific update
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