Combination Of Pioglitazone Research Articles

2082-P: Pharmacological Induction of Brown and Beige Adipose Tissue

Brown adipose tissue (BAT) is associated with improved metabolic homeostasis in humans, and studies in rodents indicate that subcutaneous white adipose tissue (SC WAT) beiging, which involves increased uncoupling protein 1 (UCP1) expression, also is associated with improved metabolism. The goal of this study was to determine the ability of mirabegron (a β3AR agonist), pioglitazone (a thiazolidinedione), or a combination of the drugs to induce brown and beige adipose tissue and to determine the effects on glucose and lipid homeostasis. We randomized obese, insulin-resistant (IR) research participants to mirabegron (50 mg/day), pioglitazone (30 mg/day), or combination therapy treatment groups. Euglycemic clamping, oral glucose tolerance tests, adipose tissue biopsies, and PET-CT scans were performed at baseline and after 10 weeks of treatment. Mirabegron improved glucose homeostasis (reduced HbA1c and improved oral glucose tolerance) to a similar extent as pioglitazone without side effects or weight gain. Although mirabegron treatment increased insulin sensitivity, the effect size was much smaller than pioglitazone, yet mirabegron treatment significantly increased the insulinogenic and disposition indexes, suggesting that a major part of the mechanism of mirabegron action involved improving β-cell function. Mirabegron treatment consistently induced SC WAT beiging as evidenced by increased UCP1 expression (2.4 fold increase; P<0.0001), but did not induce BAT, suggesting that induction of beige adipose may be part of the mechanism responsible for improved glucose homeostasis. Pioglitazone also induced beiging (1.6 fold increase in UCP1; P<0.01), but not BAT. The combination of mirabegron plus pioglitazone was not additive, with similar effects on glucose tolerance as single drug. These results suggest that mirabegron treatment has significant beneficial metabolic effects in obese, IR subjects through a distinct mechanism involving SC WAT beiging and improved pancreatic beta cell function. Disclosure B. Finlin: None. H. Memetimin: None. A.L. Confides: None. B. Zhu: None. Z.R. Johnson: None. E.E. Dupont-Versteegden: None. P.A. Kern: None. Funding National Institutes of Health (R01DK112282)

OR25-3 Toward a Circulating Marker of Hepato-Visceral Fat Excess: S100A4 in Adolescent Girls with Polycystic Ovary Syndrome

S100A4 has recently been identified as an adipokine that can serve as a marker of "pernicious" subcutaneous adipose tissue (Arner et al, Int J Ob 2018). However, S100A4 can also be released by an inflammatory subset of macrophages in the liver (Osterreicher et al, Proc Natl Acad Sci USA 2011). Development of polycystic ovary syndrome (PCOS) in adolescent girls is often driven by an early excess of fat in subcutaneous adipose tissue, accompanied by an excess of fat in ectopic locations, notably in viscera and liver (Cree-Green et al, Obesity 2016; de Zegher et al, Trends Endocrinol Metab 2018). Adolescent PCOS phenotypes are normalized more by preferential reduction of hepato-visceral adiposity with a low-dose combination of spironolactone, pioglitazone and metformin (SPIOMET) than by treatment with an oral contraceptive (OC) (Ibanez et al, J Adolesc Health 2017). Nowadays, the assessment of hepato-visceral adiposity (by magnetic resonance imaging) is rather cumbersome. In an attempt to identify a circulating marker of hepato-visceral fat excess, we studied whether S100A4 concentrations are elevated in adolescent girls with PCOS and, if so, whether they tend to normalize with OC or SPIOMET treatment. In 12 healthy controls and in 51 adolescent girls with PCOS (by International Consortium Update criteria; Ibanez et al, Horm Res Pediatr 2017), we assessed circulating S100A4 along with endocrine markers (including fasting insulin, SHBG, testosterone [by LC-MS/MS], high-molecular-weight adiponectin), body composition (by dual X-ray absorptiometry), and abdominal fat partitioning (by magnetic resonance imaging). Girls with PCOS were randomized for treatment with an OC (n=27) or SPIOMET (n=24) for 1 year, and the changes in their study endpoints were analysed. S100A4 concentrations were on average 71% (or 2.1 Z-score) higher in girls with PCOS than in controls (P<0.001), and they associated with hepato-visceral adiposity (r=0.47; p=0.001). Treatment with OC failed to lower the elevated S100A4 concentrations, whereas treatment with SPIOMET lowered circulating S100A4 toward normal (P<0.001 for within-group changes, and P<0.01 for between-group changes); on-treatment reduction of circulating S100A4 associated closely with reduction of hepato-visceral adiposity (r=0.50; p<0.0001). If the present findings are corroborated in other study cohorts with PCOS, then S100A4 is a first candidate-member of a future set of circulating markers that may simplify the diagnosis and follow-up of patients with PCOS, and perhaps also of patients with other phenotypes of central obesity.

Simvastatin exerts antidepressant-like activity in mouse forced swimming test: Role of NO-cGMP-KATP channels pathway and PPAR-gamma receptors

Simvastatin, one of the lipophilic statins, has been shown to be effective in reducing depression in rodents. The present study aimed to investigate the potential antidepressant-like activity of simvastatin and the possible involvement of NO-cGMP-KATP channels pathway and PPARγ using forced swimming test (FST) in mice. In addition, the interaction between simvastatin and fluoxetine as a reference drug was examined. After assessment of locomotor behavior in the open-field test (OFT), FST was applied for evaluation of depressive behavior in mice. Simvastatin at doses (20, 30, and 40 mg/kg, i.p.) was administrated 30 min before the OFT or FST. To evaluate the involvement of NO-cGMP-KATP channels pathway, mice were pre-treated intraperitoneally with l-arginine (a nitric oxide precursor, 750 mg/kg), L-NAME (a NOS inhibitor, 10 mg/kg), methylene blue (guanylyl cyclase inhibitor, 20 mg/kg), sildenafil (a PDE-5 inhibitor, 5 mg/kg), glibenclamide (ATP-sensitive K+ channel blocker, 1 mg/kg), and diazoxide (K+ channels opener, 10 mg/kg). Moreover, to clarify the probable involvement of PPARγ receptors, pioglitazone, a PPARγ agonist (5 mg/kg, i.p.), and GW9662, a PPARγ antagonist (2 mg/kg, i.p.), were pre-treated with simvastatin. Immobility time was significantly decreased after simvastatin injection. Administration of L-NAME, methylene blue, glibenclamide and pioglitazone in combination with the sub-effective dose of simvastatin (20 mg/kg, i.p.) reduced the immobility time in the FST compared to drugs alone, while co-administration of effective doses of simvastatin (30 mg/kg, i.p.) with l-arginine, sildenafil, diazoxide, and GW9662 prevented the antidepressant-like effect of simvastatin. In addition, simvastatin (20 mg/kg) potentiated the antidepressant-like effect of fluoxetine through the NO pathway. None of the drugs produced any significant alterations in locomotor activity using OFT. These results demonstrated that NO-cGMP-KATP channels pathway and PPARγ receptors may be involved in the antidepressant-like effect of simvastatin.

BENEFICIAL OUTCOMES AFTER COMBINED THERAPY WITH AZATHIOPRINE AND PIOGLITAZONE IN PRECLINICAL ARTHRITIC MODELS

Objectives: The present study was designed to investigate the antioxidant and anti-arthritic activities of azathioprine-pioglitazone combination therapy to check whether it has an add on benefit over monotherapy with azathioprine or pioglitazone on disease activity in rodent models.&#x0D; Methods: The antioxidant activity of test drugs and their combination was screened by H2O2 and nitric oxide scavenging assays. They were further evaluated for anti-arthritic activity using in vitro models such as protein denaturation and membrane stabilization and in vivo methods such as formaldehyde and complete Freund’s adjuvant (CFA)-induced arthritis.&#x0D; Results: The combination of test drugs showed better inhibition of free radicals in both H2O2 and nitric oxide scavenging assay than individual counterparts revealing its potential antioxidant activity. They also showed significant inhibition of protein denaturation and proliferation of the red blood cell in in vitro models. The test drugs showed significant inhibition of the paw volume in both the formaldehyde and CFA-induced arthritis along with reverting the altered biochemical parameters. These findings were corroborated by radiological and histopathological studies.&#x0D; Conclusions: Combination of azathioprine and pioglitazone exhibited better antioxidant and anti-arthritic effect than the individual drugs showing synergistic interaction between them.

Efficacy and safety of pioglitazone plus phototherapy versus phototherapy in patients with plaque type psoriasis: a Double Blinded Randomized Controlled Trial

Introduction: Thiazolidinediones have shown a good therapeutic effect in psoriasis treatment with no major adverse effects. The purpose of this study was to evaluate and compare the therapeutic effects of the combination of phototherapy and Pioglitazone with the phototherapy alone on plaque psoriasis patients.Methods and Materials: About 60 adults with plaque type psoriasis entered the study. They were randomly divided into two groups; one with pioglitazone and one with placebo and both underwent 30 sessions of phototherapy during 10 weeks. Before and after the treatment Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) were assessed. Side effects of the treatment were also investigated.Results: The average PASI of the pioglitazone group was reduced from 20.9 ± 9.8 to 1.8 ± 1.4 (p < .001) versus the placebo group in which the PASI was reduced from 22 ± 8.5 to 4.4 ± 4. In other words, PASI was reduced in the pioglitazone and placebo group by 83.5% and 56.7% respectively (p < .05). The two groups didn’t have a significant difference in reducing the DLQI (p = .315).Conclusion: Pioglitazone can vastly enhance the effectiveness of phototherapy in plaque psoriasis patients without causing any important adverse effect and with no success in improving the score of DLQI.

Pioglitazone prevents the increase in plasma ketone concentration associated with dapagliflozin in insulin-treated T2DM patients: Results from the Qatar Study.

Because of the unique mechanism of action of sodium-glucose co-transport inhibitors (SGLT2i), which is independent of insulin secretion and insulin action, members of this class of drugs effectively lower plasma glucose concentration when used in combination with all other antidiabetic agents, including insulin. Increased plasma ketone concentration has been reported in association with SGLT2i initiation, which, under certain clinical conditions, has developed into diabetic ketoacidosis. The daily insulin dose often is reduced at the time of initiating SGLT2i therapy in insulin-treated patients to avoid hypoglycaemia. However, reduction of insulin dose can increase the risk of ketoacidosis. In the present study, we examined the effect of the addition of dapagliflozin plus pioglitazone on plasma ketone concentration in insulin-treated T2DM patients and compared the results to the effect of dapagliflozin alone. A total of 18 poorly controlled, insulin-treated T2DM participants in the Qatar Study received dapagliflozin (10 mg) plus pioglitazone (30 mg), and 10 poorly controlled non-insulin-treated T2DM patients received dapagliflozin (10 mg) alone for 4 months. Dapagliflozin plus pioglitazone produced a robust decrease in HbA1c (-1.4%) and resulted in a 50% reduction in daily insulin dose, from 133 to 66 units, while dapagliflozin alone caused a 0.8% reduction in HbA1c. Dapagliflozin caused a four-fold increase in fasting plasma ketone concentration, while the combination of pioglitazone plus dapagliflozin was not associated with a significant increase (0.13 vs 0.15 mM) in plasma ketone concentration or in risk of hypoglycaemia. These results demonstrate that the addition of pioglitazone to dapagliflozin prevents the increase in plasma ketone concentration associated with SGLT2i therapy.

PDB69 - COST-EFFECTIVENESS ANALYSIS OF ADDING PIOGLITAZONE TO INSULIN REGIMEN IN TYPE2 DIABETES IN IRAN

To evaluate the costs and health outcomes of using Pioglitazone in combination with insulin compared to insulin mono-therapy in treating patients with Type 2 Diabetes Mellitus (T2DM) in Iran. A model-based economic evaluation was performed. A systematic review and meta-analysis was conducted in order to evaluate the clinical effectiveness of the comparators. Relative randomized controlled trials, based on the inclusion criteria, were included. Treatment effect data including change in glycozilated hemoglobin (HbA1c), insulin daily dose, serum lipids, and Body Mass Index BMI) were taken from included trials. Costs were calculated from payer perspective. Quality-adjusted life years (QALYs) and life years gained (LY) were measured to evaluate the effectiveness of alternatives. The price list of pioglitazone and varied forms of insulin were extracted from Iran Food and Drug Administration website. One-way sensitivity analysis was performed for assessing the robustness of the model. The 7618 studies were found in the first phase of searching through databases. After eliminating duplicate studies and studies incompatible with the inclusion and exclusion criteria of our study, 12 study were selected. In meta-analysis, the mean reduction in HbA1c, for combination therapy of insulin with pioglitazone, was 0.64%, which was statistically significant (95% CI: -0.86, -0.41, p<0.00001). The combination therapy of Pioglitazone (15 and 30 mg dosage forms) plus insulin, was associated with an incremental cost-effectiveness ratio of 408.6 $ USD per QALY versus insulin mono-therapy. Our results suggest that the addition of pioglitazone to insulin regimen would be highly cost-effective treatment approach in Iranian T2DM patients.

Combining SGLT2 Inhibition With a Thiazolidinedione Additively Attenuate the Very Early Phase of Diabetic Nephropathy Progression in Type 2 Diabetes Mellitus.

Although both sodium glucose co-transporter 2 inhibition by dapagliflozin and thiazolidinedione, pioglitazone have glucose-lowering and anti-inflammatory effects, the therapeutic efficacy of their combination on diabetic nephropathy has not been investigated. 9-week-old male db/db mice were randomly assigned to 4 groups and administrated with (1) vehicle, (2) dapagliflozin, (3) pioglitazone, or (4) dapagliflozin and pioglitazone combination. Human proximal tubule (HK-2) cells were treated with glucose or palmitate acid in the presence of medium, dapagliflozin, pioglitazone, or both. Glomerular tuft area and mesangial expansion of the kidney more reduced in the combination group compared to control and single therapy groups. Podocyte foot process width and glomerular basement membrane thickness decreased regardless of treatment, while the combination group showed the slowest renal hypertrophy progression (P < 0.05). The combination treatment decreased MCP-1, type I and IV collagen expression in the renal cortex. Only the combination treatment decreased the expression of angiotensinogen, IL-6, and TGF-β while it enhanced HK-2 cell survival (all P < 0.05). In conclusion, dapagliflozin and pioglitazone preserved renal function, and combination therapy showed the greatest benefit. These findings suggest that the combination therapy of dapagliflozin with pioglitazone is more effective than the single therapy for preventing the progression of nephropathy in patients with type 2 diabetes.

Low-Dose Spironolactone-Pioglitazone-Metformin Normalizes Circulating Fetuin-A Concentrations in Adolescent Girls with Polycystic Ovary Syndrome.

Background Fetuin-A is a glycoprotein produced in the liver and related to metabolic syndrome; fetuin-A secretion is divergently regulated in different pathological conditions. In girls with polycystic ovary syndrome (PCOS), insulin sensitization results in a more favorable endocrine-metabolic outcome than oral contraception; we assessed whether those differences are underscored by changes in circulating fetuin-A. Methods Fetuin-A concentration endocrine-metabolic markers and hepatovisceral fat were measured longitudinally in 35 PCOS girls [age, 16 yr; body mass index (BMI), 23 kg/m2] randomized to receive either oral contraception [ethinylestradiol-levonorgestrel (n = 18)] or a low-dose combination of spironolactone, pioglitazone, and metformin (SPIOMET, n = 17) over 12 months. Healthy adolescent girls (age- and BMI-matched) were used as controls (n = 25). Results Pretreatment fetuin-A serum levels in PCOS girls were lower than those in controls. After 12 months on treatment, fetuin-A raised to control levels only in the SPIOMET subgroup (P = 0.009, versus oral contraception); this increase was paralleled by a healthier metabolic profile with less hepatic fat (by MRI); baseline serum fetuin-A as well as the changes over 12 months was inversely related to hepatic adiposity. Conclusions A low-dose combination of insulin sensitizers and an antiandrogen—but not oral contraception—normalizes fetuin-A levels in adolescent girls with PCOS. This trial is registered with ISRCTN29234515.

Treatment with combination of pioglitazone and glimepiride decreases levels of chemerin and asymmetric dimethylarginine (ADMA) in obese type 2 diabetic patients

Chemerin is an adipokine that plays a crucial role in adipocyte differentiation and development, as well as in glucose and lipid metabolism. High levels of asymmetric dimethylarginine (ADMA), a naturally occurring product of metabolism, inhibit nitric oxide (NO) synthesis and are related to endothelial dysfunction. The aim of this study was to investigate the effect of vildagliptin therapy and the combination of pioglitazone and glimepiride on the levels of NO, ADMA, and chemerin in diabetic patients. The study was conducted on 140 subjects, including 40 apparently healthy subjects, and 100 type 2 diabetic obese patients; 50 of them were treated with vildagliptin, and the other 50 patients revived combination of pioglitazone and glimepiride, both groups were treated for 12 months. For all participants, the levels of fasting blood glucose (FBG), fructosamine, HbA1c, lipid profile, ADMA, NO, and chemerin were determined. The levels of those parameters were compared before and after treatment. In both treated groups, levels of FBG, fructosamine, HbA1c, TC, and LDL-C decreased after treatment. Levels of chemerin and ADMA decreased significantly after treatment, whereas the levels of NO increased compared to the baseline values. Additionally, levels of chemerin and ADMA in the group treated with combination of pioglitazone and glimepiride were significantly lower compared to the group treated with vildagliptin. In conclusion, treatment with combination of pioglitazone and glimepiride had a favorable effect on chemerin and ADMA levels in obese type 2 diabetic patients.

Abstract 1250: Evaluation of the prevention by pioglitazone/metformin of ER-positive and ER-negative mammary cancers occurring in rodents on a high-fat diet

Abstract Both metformin and pioglitazone have demonstrated cancer chemopreventive properties. Actoplus/Met, a combination of the two agents, is currently used in the clinic with an additive effect on improving insulin resistance, a proposed risk factor for certain cancers. Based on this prior knowledge, we tested pioglitazone and metformin individually and in combination for preventive efficacy in both rat (ER-positive) and mouse (ER-negative) mammary cancer models, using high-fat and high-fructose diets. Pioglitazone in both rats and mice at doses as high as 20 mg/kg BW/day, 7X/week was not toxic, although the high-fat diets resulted in weight gain. Rats: Pioglitazone alone in rats receiving a high-fat diet led to a 2% increase in mammary cancer multiplicity at a high dose (20 mg/kg BW/day) and a 21% decrease in multiplicity at a low dose (10 mg/kg BW/day). In rats fed a high-fructose diet, the combination of pioglitazone and metformin caused a 20% decrease in multiplicity, in contrast to pioglitazone alone which led to a 10% decrease in mammary cancer number. In rats fed a high-fat diet, the combination caused a 24% increase versus a 1.0% decrease in cancer multiplicity with pioglitazone alone. Mice: Pioglitazone alone at a high or low dose (20 or 10 mg/kg BW/day) in mice fed a high-fat diet resulted in a 28% and 47% reduction in mammary cancer multiplicity, respectively. In mice fed a high-fructose diet in a combination study, pioglitazone alone caused a 7% decrease in mammary cancer whereas the combination of pioglitazone with metformin showed no effect on mammary cancer reduction. Metformin alone in rats on a high-fat diet caused a 35% decrease in mammary cancer multiplicity at 150 mg/kg BW/day but a 9% decrease at 300 mg/kg BW/day. Metformin alone in rats on a high-fructose diet caused an 11% increase but the combination with pioglitazone caused a 20% decrease in cancer multiplicity. When rats were given a high-fat diet, metformin alone caused a 14% decrease and in combination with pioglitazone caused a 24% decrease in ER-positive mammary cancers. The conclusions are: (1) Pioglitazone is not active as a chemopreventive agent when given alone or in combination with metformin in rats treated with MNU on a high-fat or a high-fructose diet. (2) Pioglitazone is not active as a chemopreventive agent when given alone or in combination with metformin in MMTV/Neu mice treated with DMBA on a high-fat or a high-fructose diet. (3) Metformin is not active as a chemopreventive agent when given alone or in combination with pioglitazone in rats treated with MNU on a high-fat or a high-fructose diet. (4) Metformin showed some chemopreventive efficacy when given alone to MMTV/Neu mice receiving DMBA and on a high-fat diet. Efficacy was also observed with metformin alone and in combination with pioglitazone in mice receiving a high-fructose diet. Citation Format: Barbara K. Dunn, Chen Suen, Clinton Grubbs. Evaluation of the prevention by pioglitazone/metformin of ER-positive and ER-negative mammary cancers occurring in rodents on a high-fat diet [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1250.

Abstract 1835: PPARγ agonist in combination with bcr/abl tyrosine kinase inhibitors in patients of chronic myeloid leukemia in chronic phase with suboptimal molecular response

Abstract Introduction &amp; background: Ten to 20 % of patients of Chronic Myeloid Leukemia in chronic phase (CML CP) have suboptimal molecular response (MR) to first line Imatinib maleate (IM). Treatment options include IM dose increase or switch to a 2nd generation tyrosine kinase inhibitor (TKI), Nilotinib or Dasatinib. Recently, synergy has been demonstrated when PPAR γ agonists are added to TKIs. We describe our initial results on 15 patients of CML CP treated with the combination of IM and pioglitazone, a PPAR γ agonist. Patients and methods: Fifteen patients of CML CP with suboptimal MR (bcr/abl:abl RQ-PCR between 1 to 10) after more than two years of IM were recruited in this pilot study. Because of economic considerations, these patients were not candidates for 2nd gen. TKIs. Patients given IM 600 mg/day and pioglitazone 30 mg/day. Blood counts and biochemistry monitored monthly, bcr/abl tested every 3 months using a cartridge based IS assay using the Cepheid GenXpert. Results &amp; conclusions: Twelve of the 15 patients achieved significant MR, with 6/16 achieving a major MR at 9 months. Only 3/15 did not show a response (Table). Treatment with pioglitazone was well tolerated. One patient was not analysed due to intolerance to pioglitazone are first dose. Two patients had grade 1 elevation of hepatic enzymes which returned to normal after one week treatment cessation. We conclude that the combination of imatinib with pioglitazone is effective and well tolerated in patients with a sub-optimal MR to TKI in patients with CML-CP. The combination could be a cost-effective strategy in treating imatinib non/sub-optimal responders in the developing world. The combination needs further and larger studies for confirmation and evaluation of the mechanisms of the synergy. S. No.Patient ID/SexDiagnosis dateBCR-ABL (Before Pio)BCR-ABL (After Pio)At 3 monthAt 6 monthAt 9 month1SCM/MOct 20125.352.741.830.0052MD/FAug 20061.130.880.480.13GPJ/MJan 20142.860.43ND0.54RRC/MOct 20082.861.070.25ND5RK/MMar20081.390.770.350.416RDS/FOct 200010.15.994.870.677RDR/FApril 20039.045.780.360.058MM/MMay 20114.48NDND0.149RD/FJuly 20108.331.290.440.7310RB/FJuly 20153.253.022.891.3911BRR/MJan 20107.135.613.821.7712BK/FNov 20042.060.040.030.0713DPS/MJan 20116.155.471.020.8414JKM/MApril 20074.2215.49.117.6215CS/MOct 20121.721.170.840.08 Citation Format: Hemant Malhotra, Ajay Yadav, Ashwin Mathur, Debashish Biswas, Bharti Malhotra. PPARγ agonist in combination with bcr/abl tyrosine kinase inhibitors in patients of chronic myeloid leukemia in chronic phase with suboptimal molecular response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1835.

SAFETY AND EFFICACY OF PIOGLITAZONE AMONG TYPE 2 DIABETES MELLITUS PATIENTS RECEIVING LONG TERM HEMODIALYSIS

Background: Type 2 diabetes mellitus (T2DM) frequently causes end stage renal disease (ESRD). Glucose-lowering treatment options for patients with T2DM with ESRD are limited. Thiazolidinedione is an oral glucose lowering agent used to treat patients with ESRD. We evaluated the potential for pioglitazone in combination with other hypoglycemic medications among patients with T2DM receiving long term hemodialysis Objectives: To evaluate the safety and efficiency of pioglitazone among patients with ESRD receiving hemodialysis. Methods: The retrospective study was conducted in the outpatient clinic of Phramongkutklao Hospital during 2006 and 2015. HemoglobinA1C (HbA1c), fasting plasma glucose (FPG), body weight, hematocrit and history of diagnosed chronic heart failure were evaluated after starting medication and 1 year of follow-up Results: Data for hemodialysis patients on pioglitazone were analyzed (n=50). Mean FPG changes from baseline were -28.8+-80.0 mg/dL after 12 weeks (p=0.018) and -59.2+-80.0 mg/dL after 12 months of treatment (p &lt; 0.001). Mean HbA1c changes from baseline were also-0.25+-1.62% after 12 weeks (p=0.318) and -1.52+-1.77% after 12 months of treatment (p &lt; 0.001). The differences in mean body weight (63.2+-13.0 kg; p= 0.139) and hematocrit (33.4+-5.5 vs. 33.6+-5.3; p= 0.929) at baseline and 12 months were not significant, while episodes of congestive heart failure were low (4%). No serious adverse effects such as hypoglycemia with hospitalization or liver failure were observed in any of the patients Conclusion: These data suggest that adding pioglitazone to standard hypoglycemic agents patients with T2DM undergoing hemodialysis glucose control and was well tolerated

Small Proliferative Adipocytes, Newly Identified Adipose Progenitor, as the Precursors of Beige Cells

We previously identified proliferative cells in adipose tissue expressing adipocyte specific genes and preadipocyte specific genes, which were named small proliferative adipocytes (SPA). Furthermore, we found that SPA specifically express proliferin (PLF) and have superior potential for adipogenic differentiation as compared to stromal vascular cells (SVC). In this study, we investigated the role of SPA. A comparison between differentiated SPA (D-SPA) and differentiated SVC (D-SVC) revealed that UCP1 and PLF were strongly expressed in D-SPA. Therefore, we speculated that SPA might be progenitor of beige cells. The real time PCR analyses and the immunohistochemical studies revealed that beige cells associated genes, including UCP1, PPARα and PGC1α were significantly increased in D-SPA. Treatment with pioglitazone and CL316234, a specific β3-adrenergic receptor agonist, converted cultured SPA into cell clusters like beige cells which expressed UCP1 and activation of mitochondrial function confirmed by MitoRed stain. Furthermore, PLF was expressed in beige cells induced by continuous injection of CL316243. In conclusion, since D-SPA were found to express UCP1 and PLF, which were detected in beige cells, but not WAT, SPA were considered to be a progenitor of beige cells. There might be two lineages of cells in adipose tissue; adipose progenitor cells in SVC and WAT (PLF-), and SPA and beige cells (PLF+). The combination of pioglitazone and CL316423 produced an additive effect of inducing browning in SPA. Disclosure K. Taguchi: None. K. Kajita: None. M. Fuwa: None. M. Asano: None. Y. Kitada: None. T. Ikeda: None. T. Ishizuka: None. H. Morita: None.

Role of Vitamin E for the Treatment of Nonalcoholic Steatohepatitis (NASH) in Patients with T2DM—A Randomized, Controlled Trial

While the use of vitamin E (Vit E) in nondiabetic patients with NASH has proven to be effective in the PIVENS study (NEJM 2010), there is no information about its effect in patients with NASH and T2DM. To examine this, we performed a randomized, double blind, controlled trial assessing the efficacy of Vit E, alone or combined with pioglitazone (PIO) in this population. Patients (n=105) were randomized 1:1:1 to Vit E 400 U BID, Vit E 400 U BID + PIO 45mg QD, or placebo for 18 months. The primary endpoint was histological improvement, defined as a 2-point reduction in the NAFLD activity score from 2 different parameters, without worsening of fibrosis. Secondary outcomes: resolution of NASH, individual histological scores, and metabolic parameters. Based on 2 planned primary comparisons, a p&amp;lt;0.025 was considered to indicate statistical significance. Groups were well matched at baseline. A total of 87 patients completed 18 months of follow-up. More patients on Vit E and PIO combination achieved the primary outcome compared to placebo (65% vs. 22%, p&amp;lt;0.001), but not in the Vit E alone group (36% vs. 22%, p=0.18). The same trend was observed for resolution of NASH, with a significant improvement only in the combination group (57% vs. 18%, p&amp;lt;0.001), but not with Vit E alone (42% vs. 18%, p=0.036). While steatosis grade improved with either combination (p&amp;lt;0.001) or Vit E alone (p=0.018), inflammation (p=0.018) and ballooning (p=0.022) grades only improved with Vit E + PIO. No improvement in fibrosis was observed in any group. Four patients died of cardiovascular causes during the study (2 on Vit E alone and 2 on combination). Weight gain, peripheral edema and hypoglycemia were more frequent in the combination group. Conclusion: Vit E alone was ineffective to treat NASH in patients with T2DM. While the combination of Vit E and PIO was significantly better than placebo, response rate was similar to that reported for PIO alone in patients with T2DM, suggesting no role of Vit E in this population. Disclosure F. Bril: None. D.M. Biernacki: None. R. Lomonaco: None. S. Kalavalapalli: None. S.K. Subbarayan: None. J. Lai: None. F.O. Tio: None. A. Suman: None. B.K. Orsak: None. J. Hecht: None. K. Cusi: Consultant; Self; Janssen Global Services, LLC., Eli Lilly and Company. Research Support; Self; Cirius Therapeutics. Other Relationship; Self; Nordic Bioscience. Research Support; Self; Novartis Pharmaceuticals Corporation, Novo Nordisk Inc.. Other Relationship; Self; Quest Diagnostics. Research Support; Self; Zydus Pharmaceuticals (USA) Inc.. Other Relationship; Self; OWL metabolomics, Echosens. Research Support; Self; Janssen Global Services, LLC.. Consultant; Self; Tobira Therapeutics, Pfizer Inc..

Additive effects of evogliptin in combination with pioglitazone on fasting glucose control through direct and indirect hepatic effects in diabetic mice

Due to very limited preclinical reports, pharmacodynamic interactions between dipeptidyl peptidase 4 (DPP4) inhibitors and peroxisome proliferator-activated receptor γ (PPARγ) agonists are not conclusive yet. This study aimed to evaluate the pharmacological responses from adding evogliptin, a DPP4 inhibitor, to pioglitazone, a PPARγ agonist, in diabetic db/db mice after a 2-week treatment. This combination led to further decrease in both fasting and fed blood glucose levels compared to evogliptin alone (P < 0.05), but combination effects were more dramatic in fasting glucose levels (P < 0.05 vs. each treatment alone). Of note, plasma glucagon and high-molecular-weight (HMW) form of adiponectin were also further altered by the combination (P < 0.05 vs. each treatment alone). In line with these results, hepatic gluconeogenic gene expression was normalized by this combination. However, although evogliptin or pioglitazone directly suppressed glucose output in HepG2 hepatocytes, their combination did not further reduce hepatic glucose output. By contrast, glucose utilization of HepG2 cells was synergistically enhanced by this combination regardless of insulin presence (P < 0.05 vs. each treatment alone). These results suggest that the combination of evogliptin and pioglitazone is more efficacious in fasting glucose control through systemic alterations such as decreasing glucagon and increasing adiponectin, and through enhancing glucose utilization. To our knowledge, this is the first report regarding the significant combination effects of DPP4 inhibitors plus PPARγ agonists on plasma HMW adiponectin and hepatic glucose utilization. Our findings provide insight that the evogliptin and pioglitazone combination therapy may be more beneficial in type 2 diabetic patients characterized by exaggerated glucagon dysregulation.

Glucose lowering strategies and cardiovascular disease in type 2 diabetes – teachings from the TOSCA.IT study

TOSCA.IT is an institutional, non-industry-supported, head-to-head study comparing long term cardiovascular effects, efficacy and safety of two antidiabetes drugs (pioglitazone vs sulphonylureas) used in combination with metformin in patients with type 2 diabetes mellitus. The study results show that in the absence of clinically evident cardiovascular disease both treatment strategies represent suitable alternatives; however, in consideration of the greater durability of the metabolic effects, the lower risk of hypoglycemia and the potential benefit on atherosclerotic cardiovascular disease, the combination of metformin and pioglitazone may be considered as the preferential therapeutic option. In this review the study is critically evaluated against the background of the evidence accumulated over the last decade on the impact of different glucose lowering drugs on cardiovascular events in people with type 2 diabetes.

Insulin Monotherapy Versus Insulin Combined with Other Glucose-Lowering Agents in Type 2 Diabetes: A Narrative Review.

ContextInsulin can be prescribed as a monotherapy or a combined therapy with other anti-diabetic medications. In this narrative review, the authors aimed to gather data related to comparison of insulin monotherapy versus combination of insulin and other anti-diabetic treatments with regards to different outcome measures in type 2 diabetes.Evidence AcquisitionThis study searched and focused on the most recently published systematic reviews and their references investigating issues related to the primary aim.ResultsThe current data available on this topic is heterogeneous and suffers from low quality with respect to most combination treatments. Considering the efficacy and safety of combination therapy of insulin with older hypoglycemic agents, in general metformin and pioglitazone have the best and worst profiles, respectively. Compared to insulin monotherapy, combination of insulin and metformin is associated with better glycemic control, reduced daily insulin dose, less hypoglycemia, and weight gain; combination of insulin and pioglitazone results in greater hypoglycemia and weight gain and is associated with increased risk of edema and heart failure. Regarding sulphonylurea, there is some concern regarding hypoglycemia and weight gain. Addition of dipeptidyl peptidase-4 inhibitors to insulin seems to be beneficial with respect to glycemic control without any significant adverse effects. New drugs, including glucagon-like peptide-1 agonists and sodium glucose co-transporter 2 inhibitors, have acceptable profiles with significant benefits regarding weight reduction when added on insulin therapy.ConclusionsConsidering the quality and longevity of evidence, compared to insulin monotherapy, insulin combined with metformin and pioglitazone has the best and worst profiles, respectively. New anti-diabetic medications have acceptable profiles yet are expensive. It is important for clinicians to meticulously weigh the advantages of combination therapy against the possible adverse effects with each drug class in every patient, individually.

Assessment of the Ameliorative Effect of Ruzu Herbal Bitters on the Biochemical and Antioxidant Abnormalities Induced by High Fat Diet in Wistar Rats

Background and Objective: Ruzu herbal bitters (RHB) is a poly-herbal preparation that is widely taken in Nigeria and it is used as an anti-obesity medicinal concoction. The concoction is an aqueous composition of different plant parts of Curculigo pilosa , Uvaria chamae and Citrullus colocynthis and so far, there has been no published scientific verification on the health enhancing claims of RHB’s intake. This study is aimed at evaluating the anti-obesity and the biochemical and antioxidant effects of RHB’s consumption, using an albino Wistar high-fat dietary model rats. Materials and Methods: A total of thirty-six (n = 36) rats were divided into six groups of six animals each. Group 1: The negative control animals (NEC), received the high-fat diet, group 2: The normal control animals (NC), was fed on standard rat chow and distilled water, groups 3-6 were placed on the high-fat diet and then dosed orally with the following: Pioglitazone (PIO) (30 mg kgG1 b.wt.,), RHB (0.3 mL kgG1), vitamin E (Vit. E) (10 IU kgG1) and a combination of PIO and Vit. E, respectively for 8 weeks. The animals were then sacrificed and antioxidant and biochemical tests on blood and other tissue samples were carried out by standard methods. Statistical analysis of the results was carried out by one-way analysis of variance with the SPSS. Results: The group 4 RHB administered animals had a significant reduction (p<0.05) in total body weight, in comparison with group 1 animals. As well as a significant (p<0.05) reduction the plasma activities of alanine aminotransaminase (ALT) and aspartate aminotransaminase (AST) and concentrations of LDL-cholesterol, triglyceride, fasting blood glucose, total and indirect bilirubin when compared with group 1. A significant (p<0.05) increase in the concentrations of plasma HDL-cholesterol and reduced glutathione in the brain, spleen and liver of rats were also observed in group 4 while a significant (p<0.05) increase was observed in the activity of peroxidase in the liver and brain of rats in the RHB group in comparison with group 1. Conclusion: These findings validate the anti-obesity and antioxidant claims of RHB and these activities were attributed to its plant’s constituents.

Resveratrol Combined with Pioglitazone Ameliorates Cardiovascular Complications in db/db Diabetic Mice

Type 2 Diabetes Mellitus patients are predisposed to serious cardiovascular morbidity and mortality. Diabetes causes different structural and functional alterations in the myocardial tissue, which are induced by hyperglycemia, insulin resistance, and hyperlipidemia. The resulting cardiomyopathy is characterized by myocardial fibrosis, dysfunctional remodeling and eventually, clinical heart failure. This study addressed the effects of resveratrol and pioglitazone to ameliorate diabetic cardiovascular complications using a db/db diabetic mice model. Male db/db diabetic mice were randomly assigned to orally receive resveratrol (50 mg/kg, n=5), resveratrol/pioglitazone (50 mg/kg and 20 mg/day, respectively, n=5) for the space of 6 weeks. Non-diabetic lean mice (n=5) were included as a control group. Histopathological analyses were performed in heart and aortic vessel tissue samples using hematoxylin and eosin, as well as Masson Trichromic staining. VCAM-1 immunohistochemistry was also assessed. Blood glucose, hemoglobin A1c, insulin, glycosuria, triglycerides, cholesterol, and LDL cholesterol were all examined. Present data suggest that the combination of pioglitazone plus resveratrol significantly lower circulating levels of insulin, hemoglobin A1c, glucose, triglycerides, cholesterol, and LDL levels. Our results also show that tissue damage to the heart and aortic vessels caused by diabetes can also be improved by the administration of said combination. The present study demonstrates that resveratrol/pioglitazone combination therapy improves carbohydrate and lipid metabolism, as well as improving diabetic cardiomyopathy in diabetic mice by producing a synergistic pharmacological effect. The combination of resveratrol plus pioglitazone has therapeutic potential against diabetic cardiomyopathy.