Pioglitazone Group Research Articles

COMPARATIVE STUDY OF SITAGLIPTINAND PIOGLITAZONE AS ADDONTHERAPY OVER PLASMA GLUCOSE LEVEL IN TYPE 2 DIABETES MELLITUS PATIENTS : AN OBSERVATIONAL COHORT STUDY

Background: Type 2 diabetes mellitus (DM) is a progressive chronic disorder and sustained control of plasma glucose is essential to prevent complications. Pioglitazoneofthiazolidinedionesand sitagliptin of Dipeptidyl peptidase-4 inhibitors (DPP4I) have recently been used as add-on therapy to control type 2 DM. The aim of this study was to compare the plasma glucose and glycocelatedHb% level of both the group who had poor glycemic control with Metformin and sulfonylurea. MATERIAL AND METHODS: In this observational cohort study, 100 patients with uncontrolled type 2 DM on 2000 mg/day of Metformin and 4 mg/day of Glimepiride were enrolled. The patients were randomly allocated into two groups with fifty each. One group received two divided doses of pioglitazone (30 mg/day) and the other received two divided doses of sitagliptin (100 mg/day) as the third medication. Plasma glucose fasting and 2 hours after drug and meal along with HbA1c were assessed before and after three months of treatment. Results: Fasting plasma glucose level in the sitagliptin group was higher than the pioglitazone group; however, this difference was not statistically significant (130.30 ± 30.29 versus 124.58 ± 46.84, p=0.212). Significantdifferences were not observed in HbA1c (7.20±0.96 versus 7.43±0.99, p=0.563) and plasma glucose 2 hours after meal (194.56±66.22 versus 198.58±51.5, p=0.946) after treatment withsitagliptin and pioglitazone among the two groups. Mean weight in the sitagliptin group was lower compared to the pioglitazone group after treatment, however, this difference was not statistically significant (p=0.824). Conclusion: Both the molecule as third agent had similar efficacy in glycemic control. Sitagliptin is better choice to add-on therapy in obese overweight patients.

Effect of Pioglitazone on Perihematomal Edema in Intracerebral Hemorrhage Mouse Model by Regulating NLRP3 Expression and Energy Metabolism.

ObjectiveCerebral edema is the predominant mechanism of secondary inflammation after intracerebral hemorrhage (ICH). Pioglitazone, peroxisome proliferator-activated receptor gamma agonist has been shown to play a role in regulation of central nervous system inflammation. Here, we examined the pharmacological effects of pioglitazone in an ICH mouse model and investigated its regulation on NLRP3 inflammasome and glucose metabolism. MethodsThe ICH model was established in C57 BL/6 mice by the stereotactical inoculation of blood (30 µL) into the right frontal lobe. The treatment group was administered i.p. pioglitazone (20 mg/kg) for 1, 3, and 6 days. The control group was administered i.p. phosphate-buffered saline for 1, 3, and 6 days. We investigated brain water contents, NLRP3 expression, and changes in the metabolites in the ICH model using liquid chromatography-tandem mass spectrometry. ResultsOn day 3, brain edema in the mice treated with pioglitazone was decreased more than that in the control group. Expression levels of NLRP3 in the ICH model treated with pioglitazone were decreased more than those of the control mice on days 3 and 7. The pioglitazone group showed higher levels of glycolytic metabolites than those in the ICH mice. Lactate production was increased in the ICH mice treated with pioglitazone. ConclusionOur results demonstrated less brain swelling following ICH in mice treated with pioglitazone. Pioglitazone decreased NLRP3-related brain edema and increased anaerobic glycolysis, resulting in the production of lactate in the ICH mice model. NLRP3 might be a therapeutic target for ICH recovery.

Pioglitazone and statins lower incidence of Parkinson disease in patients with diabetes mellitus.

The pharmacologic effects of pioglitazone on the incidence of Parkinson disease (PD) are not clear. No study has examined the interaction between pioglitazone and statin treatment on prevention of PD. This study analyzed the associations between pioglitazone, statins, and the incidence of PD in patients with diabetes mellitus (DM) in Taiwan. We used the National Health Insurance database from 1996 to 2013. DM and PD were diagnosed according to the International Classification of Diseases, Ninth Revision, Clinical Modification codes. We used the propensity score-matching method to match the study groups. Cox regression analyses were employed to calculate the relative risk of the incidence of PD. There were 48828 patients matched and categorized equally into the pioglitazone group and the non-pioglitazone group. The number of PD patients in the pioglitazone group and the non-pioglitazone group was 275 (1.1%) and 417 (1.7%), respectively. The pioglitazone group had a lower incidence of PD, with an adjusted hazard ratio (aHR) of 0.66 [95% confidence interval (CI): 0.57-0.78], and this benefit was dose-dependent. Of note, as compared with either pioglitazone or statin treatment, our results first showed that the combination of pioglitazone and statins further lowered the risk of PD, with an aHR of 0.78 (95% CI: 0.64-0.94; P=0.010). Our study results suggested that pioglitazone could be a promising agent for reducing the incidence of PD in patients with DM, and works synergistically with statins.

Comparative Efficacy of Lobeglitazone Versus Pioglitazone on Albuminuria in Patients with Type 2 Diabetes Mellitus.

IntroductionThe aim of this analysis was to evaluate the efficacy of lobeglitazone on albuminuria at 24 weeks of follow-up in patients with type 2 diabetes mellitus (T2DM) compared with pioglitazone using data from a randomized, double-blinded phase III trial.MethodsIn the phase III trial, patients who were inadequately controlled with metformin received 0.5 mg of lobeglitazone or 15 mg of pioglitazone for 24 weeks. Post hoc, exploratory analysis was used to investigate mean changes from baseline in the urine albumin–creatinine ratio (UACR) between the lobeglitazone (N = 104) and pioglitazone (N = 101) treatment groups.ResultsAfter 24 weeks of treatment, UACR was slightly decreased in the lobeglitazone group (− 4.3 mg/g creatinine [Cr]) compared to baseline and slightly increased in the pioglitazone group (5.2 mg/g Cr), with no change in the estimated glomerular filtration rate in either group; this difference was not statistically significant (P = 0.476). The incidence of new-onset microalbuminuria (2.4%) and the progression of albuminuria by > 1 stage (2.9%) in the lobeglitazone group were lower than the respective values in the pioglitazone group (6.8 and 6.1%, respectively). Of the patients in the lobeglitazone group, 50% exhibited regression to normoalbuminuria, compared to 39.3% of the patients in the pioglitazone. In subjects in the lobeglitazone group with micro- and macroalbuminuria, UACR tended to be more decreased and HbA1c was more reduced compared to those with normoalbuminuria (P = 0.014).ConclusionLobeglitazone had a tendency to improve albuminuria in patients with T2DM and had comparable effects on albuminuria as pioglitazone which has demonstrated beneficial effects.Trial RegistrationClinicalTrials.gov identifier, NCT01106131.Electronic Supplementary MaterialThe online version of this article (10.1007/s13300-020-00948-1) contains supplementary material, which is available to authorized users.

Adipose depot-specific effects of 16weeks of pioglitazone on in vivo adipogenesis in women with obesity: a randomised controlled trial.

In vitro and rodent studies suggest that pioglitazone, a thiazolidinedione, can promote adipogenesis in adipose tissue (AT); however, there is a lack of in vivo studies in humans to support these findings. The objectives of this randomised, placebo-controlled, parallel-arm trial were to test if pioglitazone stimulates in vivo adipogenesis in the subcutaneous adipose tissue depots and if these measures were related to metabolic health outcomes in women with obesity. Forty-one healthy women with obesity (20 black; 21 white; 29 ± 6years; BMI 32.0 ± 1.7kg/m2; 44.0 ± 3.6% body fat) were randomised to consume 30mg/day of pioglitazone (n = 21) or placebo (n = 20) for 16weeks. SAS v9.4 was used to generate the block randomisation code sequence (stored in password-protected files) with a 1:1 allocation ratio. The participants and study staff involved in assessing and analysing data outcomes were blinded to the group assignments. The trial was conducted at Pennington Biomedical Research Center and ended in 2016. At baseline and post-intervention, subcutaneous abdominal (scABD) and femoral (scFEM) AT biopsies were collected, and in vivo cellular kinetics (primary endpoint of the trial) were assessed by an 8week labelling protocol of deuterium (2H) into the DNA of adipose cells. Body composition was measured by dual-energy x-ray absorptiometry (DXA), scABD and visceral AT (VAT) by MRI, ectopic fat by 1H-MRS, and insulin sensitivity by an OGTT. After the 16week intervention, there was a significant decrease in visceral fat (VAT:total abdominal AT [as a %]; p = 0.002) and an increase in the Matsuda index (i.e. improved insulin sensitivity; p = 0.04) in the pioglitazone group relative to the placebo group. A significant increase in the formation of new adipocytes was observed in the scFEM (Δ = 3.3 ± 1.6%; p = 0.04) but not the scABD depot (Δ = 2.0 ± 2.1%; p = 0.32) in the pioglitazone group relative to the placebo group. No serious adverse events were reported. Pioglitazone may elicit distinct differences in in vivo adipogenesis in subcutaneous adipose depots in women with obesity, with increased rates in the protective scFEM. Trial registration ClinicalTrials.gov NCT01748994 Funding This study was funded by R01DK090607, P30DK072476, and R03DK112006 from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. U54 GM104940 from the National Institute of General Medical Sciences of the National Institutes of Health. The Robert C. and Veronica Atkins Foundation. Graphical abstract.

Effects of antidiabetic drugs on psoriasis: A meta-analysis.

Psoriasis, a chronic inflammatory skin disease, poses an elevated risk of developing diabetes mellitus. To investigate the effects of antidiabetic medications on psoriasis. We conducted a systemic review and meta-analysis and searched MEDLINE, EMBASE and CENTRAL for relevant randomized controlled trials. Our outcomes included 75% improvement in the psoriasis area and severity index from baseline (PASI 75), change in the psoriasis area and severity index (PASI) score, or change in the Dermatology Life Quality Index score under antidiabetic agents. Cochrane Collaboration's tool was used to evaluate the risk of bias of included studies. Subgroup analysis of different dosages of the antidiabetic agents was also performed. We included 10 randomized controlled studies examining the effect of antidiabetic agents. Eight studies were rated high risk of bias. Pioglitazone demonstrated significant increase in PASI 75 (risk difference=0.42; 95% CI: 0.18-0.65) and decrease in mean PASI (mean difference=-3.82; 95% CI: -6.05-1.ㄍ59). In subgroup analysis, 30mg pioglitazone group demonstrated a significantly higher portion of PASI 75 than 15mg pioglitazone group (P=.003). Some biases are reported high risk in involved articles. The main limitation of the study is in the inclusion of only glitazones. The lack of effect was seen for rosiglitazone and metformin. In the case of metformin, there was only one study available, which is also an important issue. The current evidence demonstrates therapeutic efficacy of pioglitazone, which may be a treatment option in patients with psoriasis and diabetes mellitus.

The efficacy and safety of pioglitazone in psoriasis vulgaris: A meta-analysis of randomized controlled trials.

Pioglitazone may have potential benefits in the treatment of cutaneous and metabolic derangements of psoriasis, but its role in the treatment of psoriasis remains in debate. We therefore conducted a meta-analysis to evaluate the clinical efficacy and safety of pioglitazone in psoriasis vulgaris (PsV).We performed a comprehensive search in database of PubMed, Web of Science, Cochrane library, Embase and China National Knowledge Infrastructure (CNKI), and Wan fang database through March 2019 to identify eligible studies. Randomized controlled trials that have evaluated the effect and safety of pioglitazone in PsV were included. Treatment success was defined as ≥75% reduction in psoriasis area and severity index (PASI) score after treatment. Weighted mean differences (WMD), relative risks (RRs) and the corresponding 95% confidence intervals (CIs) were pooled to compare the clinical efficacy and safety between different groups.Six randomized controlled trials (n = 270) were included. Meta-analysis showed that pioglitazone was associated with a remarkable reduction in PASI score in patients with PsV (weight mean difference: 2.68, 95% CI 1.41-3.94, P < .001). The treatment success rate in the pioglitazone group was higher than in the control group (RR 3.60, 95 CI 1.61-8.01, P < .001). Compared with control group, pioglitazone was not related to a pronounced increase in total adverse events (RR 1.180, 95 CI 0.85-1.63, P = .33). Moreover, the risk of common adverse events in the 2 groups were similar, such as elevated liver enzyme, fatigue, nausea, weight gain.This meta-analysis suggested pioglitazone is an effective and safe drug in the treatment of patients with PsV.

Effect of salvianolic acid B on high-glucose induced renal tubular epithelial-mesenchymal transition in rats and its mechanism

The aim of this paper was to observe the effect of salvianolic acid B(Sal B) on high-glucose induced renal tubular epithelial-mesenchymal transition(EMT) in rats, and to explore its possible mechanisms of prevention and treatment of diabetic nephropathy. The rat renal tubular epithelial NRK-52 E cells were cultured in vitro. The cells were divided into control group, high glucose group, high glucose+10 μmol·L~(-1)Sal B group(Sal B), the above 3 groups were set at 6, 12, 24 and 48 h for dynamic observation; high glucose+Sal B different concentration(1, 5, 10 μmol·L~(-1)) groups, high glucose+5.0 μmol·L~(-1) pioglitazone group, high glucose+10 μmol·L~(-1)Sal B+5 μmol·L~(-1)GW9662 group. The protein expression levels of PPARγ, PTEN, α-SMA, E-cadherin and PI3 K/Akt signaling molecules were determined by Western blot. The mRNA expression of PPARγ and PTEN were detected by Real-time PCR. The viabi-lity of NRK52 E cells was determined by MTT assay. The results showed that as compared with control group, the mRNA and protein expression levels of PPARγ and PTEN in high glucose group gradually reduced, the protein expression levels of α-SMA and p-Akt~((Thr308))gradually increased, and the protein expression of E-cadherin gradually reduced(P&lt;0.05). As compared with high glucose group, when increases in Sal B doses, the mRNA and protein expression levels of PPARγ, PTEN in high glucose + different concentrations of Sal B groups gradually increased, the protein expression levels of α-SMA and p-Akt~((Thr308)) gradually reduced, and the protein expression of E-cadherin gradually increased(P&lt;0.05), however, the effect of 1 μmol·L~(-1)concentration of Sal B on the expression of PPARγ mRNA and protein and PTEN mRNA was not significantly different. As compared with high glucose group, the mRNA and protein expression levels of PPARγ mRNA(except 6 h) and protein(except 6 h), PTEN mRNA(except 6 h) and protein(except 6, 12 h) kept increasing, the protein expression levels of α-SMA and p-Akt~((Thr308))(except 6 h) continued to reduce, the protein expression of E-cadherin kept increasing in high glucose+10 μmol·L~(-1) Sal B dynamic observation group(P&lt;0.05). As compared with high glucose group, Sal B and the pioglitazone(PIO) can greatly enhance the expression of PPARγ, PTEN at mRNA and protein levels, enhance the expression of E-cadherin at protein levels, and reduce the expression of α-SMA, p-Akt~((Thr308))protein level(P&lt;0.05), there was no significant difference between the two groups. However, the expression levels of PPARγ and PTEN mRNA and protein, E-cadherin, α-SMA and p-Akt(Thr308) protein in the Sal B+GW9662 control group were not statistically significant compared with the high glucose group. The effect of Sal B was blocked by the PPARγ antagonist GW9662. It can be concluded that Sal B can suppress the NRK52 E cells induced by high-glucose EMT. The mechanism may be related to the activation of PPARγ with Sal B, and the up-regulation of PTEN expression, and thereby inhibiting the fibrosis effect of PI3 K/Akt signaling pathway.

Early intervention with Di-Dang Decoction prevents macrovascular fibrosis in diabetic rats by regulating the TGF-β1/Smad signalling pathway.

Macroangiopathy is a complication of Type II Diabetes Mellitus (T2DM), which is mainly caused by fibrosis of blood vessels. Using T2DM rat models, we investigated whether the traditional Chinese medicine, Di-Dang Decoction (DDD), exhibited anti-fibrotic actions on great vessels. T2DM rats were randomly divided into non-intervention group, early-, middle-, late-stage DDD intervention groups and control groups, including pioglitazone group and aminoguanidine group. After administration of DDD to T2DM rats at different times, we detected the amount of extracellular matrix (ECM) deposition in the thoracic aorta. The results showed that early-stage intervention with DDD could effectively protect great vessels from ECM deposition. Considering that TGF-β1 is the master regulator of fibrosis, we further validated at the molecular level that, compared to middle- and late-stage intervention with DDD, early-stage intervention with DDD could significantly decrease the expression levels of factors related to the activated TGF-β1/Smad signalling pathway, as well as the expression levels of downstream effectors including CTGF, MMP and TIMP family proteins, which were directly involved in ECM remodelling. Therefore, early-stage intervention with DDD can reduce macrovascular fibrosis and prevent diabetic macroangiopathy.

Effects of aerobic exercise on PPARα signaling in diabetes rats and its association with PPARγ

To investigate the improved effects of 4-week aerobic exercise on blood glucose and lipid of diabetes mellitus (DM) rats and its association with peroxisome proliferators-activated receptor (PPAR)α signaling and PPARγ. Six-week old male SD rats were fed with 8-week high-fat diet following a single intraperitoneal injection of streptozotocin to establish DM models rats. Except control group rats (fed with ordinary diet), DM model rats were randomly divided into DM group, trained DM group (TDM), TDM plus PPARγ agonist pioglitazone group (TDP), and TDM plus PPARγ inhibitor GW9662 group (TDG), 8 rats in each group. TDM, TDP and TDG rats were undertaken a medium-intensity incremental treadmill training for 4 weeks, once a day and 6 days a week (1st week: 15 m/min speed lasting for 30 min; 2nd week: 15 m /min for 60 min; 3rd week: 20 m/min for 60 min; 4th week: 20 m/min for 90 min). All the rats were fed with ordinary diet during 4-week exercise. The rats were anesthetized and blood samples were collected at 36 h after the last exercise, and liver and gastrocnemius were collected after the rats were sacrificed. Fasting blood glucose and blood lipid were detected (blood glucose, insulin and TC, TG, HDL and LDL). The protein levels of PPARα, adenosine monophosphate (AMP)-activated protein kinase (AMPK) and carnitine palmitoyl transferase 1 (CPT1) in the liver and gastrocnemius of the rats were measured by Western blot. ①Compared with control rats, the serum levels of TC, TG, LDL, and FBG (＞11.1 mmol/L) in DM rats were significantly increased, indicated the successful establishment of DM rats. ②Compared with DM rats, accompanied with the improvements of fasting blood glucose and blood lipid, the protein levels of PPARα, AMPK and CPT1 were significantly increased in the liver and gastrocnemius of TDM rats. ③Compared with TDM rats, no significant changes were found in TDG rats including the protein levels of PPARα and CPT1 (liver and gastrocnemius) as well as AMPK (liver), except for a decrease of AMPK in gastrocnemius; while the protein levels of PPARα, AMPK and CPT1 were all increased in the liver and gastrocnemius of TDP rats. Aerobic exercise-induced improvements of blood glucose and blood lipid was related to the up-regulation of AMPK-PPARα-CPT1 signaling pathway in the liver and muscle of DM rats. The exercise-induced enhancement of PPARα in DM rats was unrelated to PPARγ, but PPARγ activation could further increase the protein levels of AMPK-PPARα-CPT1 in TDM rats.

Pioglitazone for primary stroke prevention in Asian patients with type 2 diabetes and cardiovascular risk factors: a retrospective study

BackgroundStudies assessing the efficacy of pioglitazone solely for primary stroke prevention in Asian patients with type 2 diabetes mellitus (DM) and present multiple cardiovascular (CV) risk factors are rare. Thus, we aimed to assess the effect of pioglitazone on primary stroke prevention in Asian patients with type 2 DM without established CV diseases but with risk factors for CV diseases.MethodsBetween 2000 and 2012, we enrolled patients aged ≥ 18 years, who were newly diagnosed with type 2 diabetes and had at least one of the following CV risk factors: hypertension and hyperlipidemia. Patients with a history of stroke and those using insulin or glucagon-like peptide-1 agonist for more than 3 months were excluded. Patients were divided into the pioglitazone and non-pioglitazone groups based on their receipt of pioglitazone during the follow-up period. Propensity-score matching (1:1) was used to balance the distribution of the baseline characteristics and medications. Follow-up was terminated upon ischemic stroke development, withdrawal from the insurance system, or on December 31, 2013, whichever occurred first. The overall incidence of new-onset ischemic stroke in the two groups was subsequently compared. The subgroup analyses of ischemic stroke were conducted using different baseline features. Additionally, the effect of pioglitazone exposure dose on the occurrence of ischemic stroke was evaluated. Chi square test, Student’s t-test, competing risk regression models, Kaplan–Meier method, and log-rank test were some of the statistical tests conducted.ResultsA total of 13 078 patients were included in the pioglitazone and non-pioglitazone groups. Compared with patients who did not receive pioglitazone, those administered pioglitazone had a lower risk of developing ischemic stroke (adjusted hazard ratio: 0.78; 95% confidence interval: 0.62–0.95). The subgroup analyses defined by different baseline features did not reveal significant alterations in the observed effect of pioglitazone. Moreover, a significant decreasing trend in ischemic stroke risk with an increase in pioglitazone dose (p-value for trend = 0.04) was observed.ConclusionPioglitazone use decreased the risk of new-onset ischemic stroke in Asian patients with type 2 DM and CV risk factors.Trial registration number CMUH104-REC2-115-CR4

A Triple-Blind Randomized Controlled Trial on Impacts of Pioglitazone on Oxidative Stress Markers in Diabetic Kidney Transplant Recipients

Background: Oxidative stress as a major mediator of adverse outcomes in kidney transplant recipients who are prone to oxidative stress-mediated injury by pre-transplant and post-transplant conditions. Objectives: The purpose of this study was to assess the effects of Pioglitazone on oxidative stress biomarkers and blood glucose control in diabetic patients receiving insulin after kidney transplantation. Methods: In a triple-blind randomized placebo-controlled trial, sixty-two kidney transplanted diabetic patients (40 men and 24 women) were followed for 4 months after randomly assigned to the placebo group and Pioglitazone group (30 mg/d). All of the patients continued their insulin therapy irrespective of the group that they were assigned to evaluate the effects of the addition of pioglitazone on blood glucose and oxidative stress biomarkers, Malondialdehyde (MDA) and total protein carbonyls (TPC) serum levels. Results: At baseline, there were no statistically significant differences in glycemic control levels and oxidative markers between the two groups. After 4 months of intervention, a significant improvement occurred in Hemoglobin A1c (HBA1c) in the Pioglitazone group. The changes of HBA1c during 4 months of follow up in the Pioglitazone group show improvement in glucose control were as HBA1c in the placebo group increased by 0.3% (P = 0.0001). Moreover, at the end of the study, the MDA level was significantly lower in the Pioglitazone group (P &lt; 0.0001, 1.22 - 3.90). Regarding the serum level of TPC, the changes were not statistically different at baseline and also at the end of the study between two groups. Conclusions: Administration of Pioglitazone in addition to insulin in diabetic kidney transplant patients not only improved glycemic control (evidenced by HBA1c) but also significantly decreased oxidative stress markers such as MDA.

1945-P: Pioglitazone Promotes the Function of White and Brown Adipose Tissue in Diet-Induced Obese Mice

PPARγ agonist pioglitazone is an insulin sensitizer in the treatment of type 2 diabetes. Here, we investigate the effects of pioglitazone on white and brown fat in diet-induced obese mice. After 16-week diet intervention, C57BL/6 mice were divided randomly into three groups: normal chow diet group (NC group), high-fat diet group (HFD group) and high-fat diet + pioglitazone group (HFDP group). Pioglitazone (30-40mg/kg/day) was administered in drinking water for 6 weeks. After 6-week pioglitazone treatment, there was no significant difference in both body weight and fat mass between the HFDP group and the HFD group. However, fasting blood glucose, glucose tolerance and insulin sensitivity were significantly improved in HFDP group. What’s more, the weight of liver and epididymal adipose tissue (eWAT) were not reduced by pioglitazone treatment. However, the weight of brown adipose tissue (BAT) in the HFDP group was significantly higher than HFD group. Histological staining showed that the hepatic steatosis was ameliorated by pioglitazone. Quantitative real-time PCR revealed that mRNA levels of heat-producing genes (PRDM16, FGF-21, UCP1) and mitochondrial biosynthesis and functional genes (Tfam, cidea, cox7a1, Fabp4) were upregulated in eWAT by pioglitazone. Western blotting results also showed that the protein expression of UCP1 and PGC1α was upregulated by pioglitazone both in eWAT and in BAT when compared with the HFD group. To sum up, our study revealed that pioglitazone could promote the browning of WAT and activate the function of BAT with improved hepatic steatosis in diet-induced obese mice. Disclosure F. Xu: None. W. Wang: None. X. Zheng: None. W. Guo: None. Y. Shen: None.

2023-P: Effect of Combination Therapy with a ß3 Adrenergic Receptor and PPARγ Agonist on Adipose Beiging in Obese Humans

Treatment of subjects who are obese/insulin resistant with the β3AR agonist mirabegron resulted in increased beige adipose tissue, without a change in brown adipose tissue (BAT), along with an improvement in glucose tolerance, HbA1c, and an increase in type 1 fibers in skeletal muscle. Pioglitazone has been demonstrated to increase beiging, and it has been demonstrated that combination of a thiazolidinedione with a β3AR agonist further increased beige adipocyte markers in vitro. The goal of this study was to determine whether combination therapy with pioglitazone and mirabegron would further increase beiging, BAT volume or activity, or skeletal muscle fiber type switching, and improve glucose homeostasis more than each drug separately. We randomized obese and insulin-resistant (IR) research participants to mirabegron (50 mg/day), pioglitazone (30 mg/day), or combination treatment groups. Adipose and muscle tissue biopsies and PET-CT scans were performed at baseline and after 10 weeks of treatment. Mitochondrial bioenergetics were determined in purified mitochondria from adipose tissue. Although mirabegron and pioglitazone treatment significantly induced SC WAT beiging separately, the combination of the two drugs resulted in less beiging than mirabegron treatment alone, and did not increase mitochondrial uncoupling. Furthermore, neither pioglitazone nor combination therapy increased BAT or fiber-type switching to type 1 fibers. Although each drug improved glucose homeostasis, the effect of the combination was not significantly additive. Analysis of mRNA expression revealed that pioglitazone or combination treatment induced the expression of p107, which promotes white versus brown adipose gene expression, suggesting a mechanism for inhibition of mirabegron-induced beiging by pioglitazone. These results suggest that pioglitazone inhibits mirabegron-induced beiging and does not augment other beneficial effects of mirabegron treatment. Disclosure P.A. Kern: None. H. Memetimin: None. B. Zhu: None. A.L. Confides: None. Z. Johnson: None. H.J. Vekaria: None. P. Westgate: None. P.G. Sullivan: None. E.E. Dupont-Versteegden: None. B. Finlin: None. Funding National Institutes of Health (DK112282)

2148-PUB: Relationship between SGLT2 Inhibitor, ACEI/ARB, and Pioglitazone to Renal Function in Patients with Type 2 Diabetes Mellitus

Background: Despite the recent evidence of SGLT2-inhibitors (SGLT2i) in renal function protection, the treatment of ACEI/ARB and pioglitazone may also be promising to diabetic kidney disease progression. This study aims to discuss the interplay between SGLT2i, ACEI/ARB and pioglitazone to changes of renal function in patients with type 2 diabetes (T2DM). Materials and Methods: Patients with T2DM who initialized SGLT2i over six months and had at least two serum creatinine examinations were included in the present study. We categorized our participants into three groups according to their ACEI/ARB and pioglitazone status. GEE was used to analyze significant factors for subsequent EPI changes. Results: A total of 253 patients with T2DM were included in the present study. Their SGLT2i treatment duration was 23.7±9.6 months and serum creatinine was followed 4.1± 1.6 times during the study period. After SGLT2i initiation, A1C reduced 0.5%, body weight decreased 2.2 kg, systolic blood pressure dropped 6 mmHg and LDL-C lowered 7 mg/dl; however, EPI showed a J-curve improvement as treatment duration increased (P=0.021). To disclose the interaction between ACEI/ARB and pioglitazone in these SGLT2i users, we categorized our participants into three groups, and the number of patients in the ACEI/ARB(-)/pioglitazone(-), ACEI/ARB(+)/or pioglitazone(+) and ACEI/ARB(+)/pioglitazone(+) group was 83, 133 and 37, respectively. In the consideration of the effect of age, gender, body weight, A1C, albuminuria status, treatment duration, systolic and diastolic blood pressure and LDL-C, we found SGLT2i users who simultaneously under ACEI/ARB and pioglitazone therapy had a significant renal function deterioration by 5.77 mL/min/1.73m2 (P=0.011) as compared with other two group. Conclusions: Our study suggested that the encouraging renal effect brought by SGLT2i may be lessened in patients with T2DM who simultaneously under ACEI/ARB and pioglitazone treatment. Disclosure T. Lee: None.

Different Effects of Thiazolidinediones on Cardiovascular Events among Type 2 Diabetic Patients Implanted with Bare Metal Stents: A Nationwide Study

Background: This study aimed to evaluate the effect of thiazolidinediones (TZDs) on re-hospitalization rates for revascularization after bare-metal stent (BMS) implantation. Methods: Data from the National Health Insurance Research Database (NHIRD), a government-operated, population-based database, were analyzed from March, 2000 to December, 2006. Type 2 diabetes subjects treated with BMS implantations who used TZDs (either rosiglitazone or pioglitazone) were compared with subjects not on TZDs (non-TZD group) to evaluate the risk of readmission for coronary revascularization. Endpoints were acute coronary syndrome (ACS) and readmission for revascularization (percutaneous coronary intervention or coronary artery bypass graft surgery) after 3, 6, and 12 months. Results: In total, 6911 type 2 diabetes patients were hospitalized for BMS implantation (average follow-up, 294.4 ± 108.9 days). Rosiglitazone treatment in patients who received BMSs was associated with a higher risk of re-hospitalization for revascularization at 6 and 12 months (hazard ratio (HR) = 1.33; 95% CI: 1.08-1.64 and HR = 1.20 95% CI: 1.01-1.43). However, there were no significant differences between the pioglitazone and non-TZD groups. Conclusion: The use of rosiglitazone in type 2 diabetes patients after BMS implantation may increase the risk of re-hospitalization for revascularization. Our study suggests that rosiglitazone should be used cautiously in diabetes patients with BMS implantation.

Amelioration of High Fructose Diet-Induced Insulin Resistance, Hyperuricemia, and Liver Oxidative Stress by Combined Use of Selective Agonists of PPAR-α and PPAR-γ in Rats

Background: The use of high-fructose (Fr) corn sweeteners and sucrose in manufactured food has markedly increased recently. This excessive Fr intake has been proposed in the etiology of the metabolic syndrome, which shows an increasing prevalence throughout the world. Objective: In this study, we questioned whether fenofibrate (FF), a peroxisome proliferator-activated receptor (PPAR)-α agonist, and pioglitazone (PG), a PPAR-γ agonist, might be effective in ameliorating the metabolic syndrome in a rat model. Materials and Methods: The metabolic syndrome was induced by feeding rats a high-Fr (60%) diet for 10 weeks. The rats were divided into 5 groups: control group, fed a normal rat chow; Fr + vehicle group; Fr + FF group; Fr + PG group; and Fr + (FF + PG) group (treated with both drugs). Drug or vehicle treatment was given daily for 6 weeks (from weeks 5 to 10). Thereafter, blood and liver samples were obtained for biochemical studies. Results: Rats fed a high-Fr diet developed hyperglycemia, hyperinsulinemia, hyperuricemia, hypertriglyceri­demia, and hypercholesterolemia, and had increased serum alanine aminotransferase, hepatic tumor necrosis factor-α, and malondialdehyde levels but decreases in both glutathione content and superoxide dismutase activity. Rat treatment with FF and/or PG attenuated these alterations. The improvement was greater with the combined treatment than with either drug alone, and normalization of insulin sensitivity was observed only in rats treated with the combination therapy. Conclusion: Acting on the 2 main PPAR subfamilies, the combination of FF and PG provides a more efficacious therapy for modulating the changes in serum insulin, uric acid, and lipids, as well as the accompanying hepatic inflammation and oxidative stress that characterize the Fr-induced metabolic syndrome.

Effect of liraglutide therapy on serum fetuin A in patients with type 2 diabetes and non-alcoholic fatty liver disease

We aimed to compare the effectiveness of liraglutide vs. pioglitazone on hepatic fat content and serum fetuin A levels in patients with type 2 diabetes mellitus and non-alcoholic fatty liver disease. This was a single-center, open-label, prospective, and randomized trial using a parallel design and lasting 24 weeks. Sixty patients with type 2 diabetes mellitus and non-alcoholic fatty liver disease were randomly assigned to the liraglutide and pioglitazone groups on a 1:1 basis using a computer-generated sequence. Fetuin-A levels were determined using enzyme-linked immunosorbent assay. Hepatic fat content was measured using proton 1H-MRS on a 1.5T whole-body MRI scanner. All analyses were performed with SPSS version 13.0. In the liraglutide group, fetuin-A levels decreased after 24 weeks (666.1±109.4 vs. 443.7±90.5μg/mL, P<0.05). In the pioglitazone group, fetuin-A levels also decreased after 24 weeks (659.3±111.8 vs. 538.1± 101.0μg/mL, P<0.05) but not to the level of the liraglutide group. The liraglutide treatment resulted in a decrease in 1H-MRS (24.1±3.0 vs. 20.1±3.8, P<0.05). After 24 weeks, ΔFetuin-A was positively correlated with Δweight (r=0.756, P=0.035), ΔBMI (r=0.653, P=0.006), Δwaist circumference (r=0.767, P=0.010), and Δ1H-MRS (r=0.732, P=0.004) in the liraglutide group. Liraglutide treatment resulted in a decrease in hepatic fat content and fetuin-A compared with pioglitazone treatment in patients with T2DM and NAFLD. Fetuin-A is positively correlated with weight and hepatic fat content. The reduction in the hepatic fat content may be attributed to weight loss rather than reduction of glucose.

Differential Impact of Insulin Sensitizers vs. Anti-Androgen on Serum Leptin Levels in Vitamin D Replete PCOS Women: A Six Month Open Labeled Randomized Study

Women with PCOS are linked to insulin resistance, inflammation, and vitamin D (VD) deficiency. The study endeavors to comprehend the differential impact of insulin sensitizers vs. anti-androgen on serum leptin levels among women with PCOS rendered vitamin D replete with high VD oral supplement. This was open-labeled randomized study that screened 180 eligible women presenting to Endocrine clinic with oligomenorrhea or features of hyperandrogenism. Ninety-nine women who furnished written informed consent and fulfilled the Rotterdam 2003 criteria for diagnosis of PCOS were randomized into 3 drug treatment arms to receive either spironolactone (50 mg/d; n=30), metformin (1000 mg/d; n=30) or pioglitazone (30 mg/d; n=30). These women were also administered oral VD (4000 IU/day) in addition to the allocated drug for a period of 6 months. Detailed history, clinical examination, and laboratory evaluation was carried out at baseline and 6 months after intervention. Number of menstrual cycles/year increased while as Ferriman-Gallwey score, blood glucose, HOMA-IR, and plasma insulin levels significantly decreased in all the three arms with better outcomes in spironolactone and pioglitazone arms (p<0.05). Similarly, serum leptin levels superiorly improved in spironolactone and pioglitazone group. Pioglitazone group showed better efficacy in lowering serum total testosterone (p<0.05). Co-supplementation of high dosage VD with spironolactone or pioglitazone are more effective in reducing plasma leptin levels than metformin, and thus might prove to be better therapeutic strategies for women with PCOS.

Effectiveness and safety of different doses of pioglitazone in psoriasis: a meta-analysis of randomized controlled trials.

Background:Pioglitazone may be beneficial in the treatment of psoriasis. However, based on the effectiveness and safety considerations, it has not been widely used. To fully evaluate the strength of evidence supporting psoriasis treatment with pioglitazone, we conducted a meta-analysis of existing published studies.Methods:PubMed, Ovid, Cochrane Library, Google Scholar, and Web of Science databases were systematically searched before February 2019. Randomized controlled trials (RCTs) of pioglitazone administration compared with placebo, administered to patients with psoriasis for at least 10 weeks, and published in English were included. Quality of the included RCTs was identified by the modified Jadad scale. The quality of evidence for each outcome was evaluated using the GRADEpro Guideline Development Tool online software. Primary outcomes were proportion of patients showing psoriasis area and severity index (PASI) score improvement (>75%) and the mean percent change in PASI score from baseline to the end of treatment. Dichotomous data were analyzed using odds ratios (ORs) corresponding to the 95% confidence interval (CI), whereas continuous variables, expressed as mean and standard deviation, were analyzed using the mean differences (MD) with the 95% CI.Results:Six RCTs were analyzed. Meta-analysis showed that pioglitazone reduced the PASI scores in patients with psoriasis compared with the control group when administered at 30 mg per day (P < 0.001, MD = –3.82, 95% CI = –5.70, –1.93) and at 15 mg per day (P = 0.04, MD = –3.53, 95% CI = –6.86, –0.20). The PASI-75 of the pioglitazone group was significantly higher than that of the control group at 30 mg per day (P < 0.001, OR = 8.30, 95% CI = 3.99, 17.27) and at 15 mg per day (P = 0.03, OR = 2.96, 95% CI = 1.08, 8.06). No statistically significant differences in total adverse events were observed between the groups. There were no significant differences in common adverse reactions such as weight gain and elevated liver enzymes between the two pioglitazone groups.Conclusions:Use of pioglitazone in the current treatment of psoriasis is beneficial. The therapeutic effect of the daily 30 mg dose may be greater than that of the 15 mg dose per day with no significant change in the frequency of adverse reactions.