Pioglitazone Group Research Articles

Evaluation of nano-curcumin against inhaled paraquat-induced lung injury in rats.

Acute lung injury (ALI) remains a significant source of morbidity and mortality in critically ill patients and currently there is no efficient therapy for this condition. The aim of this research was to evaluate the protective activity of nano-curcumin (nano-CU) as a natural anti-inflammatory and antioxidant agent, against inhaled paraquat (PQ)-induced lung injury. One group of rats was exposed to saline (control group, Ctrl) and six groups to PQ aerosol (54mg/m3 on alternate days 8 times, each time for 30min) treated with drinking water alone (group PQ), 2 and 8mg/kg nano-CU (nano + CU(L) and nano + CU(H)), 5mg/kg pioglitazone (PIO), nano-CU(L) + PIO or 0.03mg/kg dexamethasone (Dexa) for 16days after PQ exposure period. PIO and Dexa were intraperitoneal (ip) injected and nano-CU was administered orally (po), (6 rats in each group). In the PQ group, total and differential WBC counts, malondialdehyde (MDA) in the bronchoalveolar lavage fluid (BALF), interferon gamma (INF-γ) and interleukin 10 (IL-10) levels in the lung tissues, lung pathological changes, and tracheal responsiveness were increased but the BALF thiol, catalase (CAT) and superoxide dismutase (SOD) levels were reduced. In treated groups with nano-CU(H) and PIO + nano-CU(L), all measured variables, in Dexa and nano-CU(L) treated groups, most variables and in the PIO group only a few variables were improved. The improvement of most variables in the PIO + nano-CU(L) group was significantly higher than in the PIO and nano-CU(L) groups alone. Nano-CU ameliorated lung damage induced by inhaled PQ similar to dexa and a synergic effect between nano-CU and PIO was observed, suggesting, a possible PPAR-γ receptor-mediated effect of curcumin.

Pioglitazone reduces cardiovascular events and dementia but increases bone fracture in elderly patients with type 2 diabetes mellitus: a national cohort study.

The prevalence of type 2 diabetes (T2DM) in elderly people has expanded rapidly. Considering cognitive impairment and being prone to hypoglycemia of the elder, the pros and cons of oral hypoglycemic agents (OHA) should be reassessed in this population. Pioglitazone might be appropriate for elderly DM patients because of its insulin-sensitizing effect and low risk of hypoglycemia. By using Taiwan's National Health Insurance Research Database, 191,937 types 2 diabetes patients aged ≥65 years under treatment between 2005 and 2013 were identified and further divided into two groups according to whether they received pioglitazone (pioglitazone group) or other OHAs (non-pioglitazone group) in the 3 months preceding their first outpatient visit date after 65 years of age, with a diagnosis of T2DM. Propensity score stabilization weight (PSSW) was used to balance the baseline characteristics. In results, the pioglitazone group (n = 17,388) exhibited a lower rate (per person-years) of major advanced cardiovascular events MACCE (2.76% vs. 3.03%, hazard ratio [HR]: 0.91, 95% confidence interval [CI]: 0.87-0.95), new- diagnosis dementia (1.32% vs. 1.46%, HR: 0.91, 95% CI: 0.84-0.98) but a higher rate of new-diagnosis bone fractures (5.37% vs. 4.47%, HR: 1.24, 95% CI: 1.19-1.28) than the non-pioglitazone group (n = 174,549). In conclusion, using pioglitazone may reduce the risks of MACCE and dementia but increases the probability of bone fractures in the elderly DM population.

Response to pioglitazone in non-alcoholic fatty liver disease patients with vs. without type 2 diabetes: A meta-analysis of randomized controlled trials.

Pioglitazone is considered a potential therapy for non-alcoholic fatty liver disease (NAFLD). However, different effects of pioglitazone on NAFLD have been demonstrated in diabetic and non-diabetic patients. Herein, a meta-analysis of randomized, placebo-controlled trials was carried out to indirectly compare pioglitazone in NAFLD patients with vs. without type 2 diabetes. Randomized controlled trials (RCTs) of pioglitazone vs. placebo involving NAFLD patients with or without type 2 diabetes/prediabetes collected from databases were enrolled into this analysis. Methodological quality was employed to evaluate the domains recommended by the Cochrane Collaboration. The analysis covered the changes in histology (fibrosis, hepatocellular ballooning, inflammation, steatosis), liver enzymes, blood lipids, fasting blood glucose (FBS), homeostasis model assessment-IR (HOMA-IR), weight and body mass index (BMI) before and after treatment, and adverse events. The review covered seven articles, with 614 patients in total, of which three were non-diabetic RCTs. No difference was found in patients with vs. without type 2 diabetes in histology, liver enzymes, blood lipids, HOMA-IR, weight, BMI, and FBS. Moreover, no significant difference was revealed in adverse effects between NAFLD patients with diabetes and without DM, except the incidence of edema that was found to be higher in the pioglitazone group than in the placebo group in NAFLD patients with diabetes. Pioglitazone could exert a certain effect on alleviating NAFLD, which was consistent between non-diabetic NAFLD patients and diabetic NAFLD patients in improving histopathology, liver enzymes, and HOMA-IR and reducing blood lipids. Furthermore, there were no adverse effects, except the incidence of edema which is higher in the pioglitazone group in NAFLD patients with diabetes. However, large sample sizes and well-designed RCTs are required to further confirm these conclusions.

Effects of sodium glucose cotransporter 2 inhibitors and pioglitazone on FIB-4 index in metabolic-associated fatty liver disease.

The antidiabetic drugs sodium glucose cotransporter 2 inhibitors (SGLT2is) and thiazolidinediones have beneficial effects on the liver dysfunction of patients with nonalcoholic fatty liver disease and type 2 diabetes mellitus (T2DM). We aimed to determine the efficacy of these drugs for the treatment of liver disease in patients with metabolic dysfunction-associated fatty liver disease (MAFLD) and T2DM. We undertook a retrospective study of 568 patients with MAFLD and T2DM. Of these, 210 were treating their T2DM with SGLT2is (n=95), 86 with pioglitazone (PIO), and 29 with both. The primary outcome was the change in Fibrosis-4 (FIB-4) index between baseline and 96weeks. At 96weeks, the mean FIB-4 index had significantly decreased (from 1.79±1.10-1.56±0.75) in the SGLT2i group, but not in the PIO group. The aspartate aminotransferase to platelet ratio index, serum aspartate and alanine aminotransferase (ALT), hemoglobin A1c, and fasting blood sugar significantly decreased in both groups (ALT: SGLT2i group, -17±3IU/L; PIO group, -14±3IU/L). The bodyweight of the SGLT2i group decreased, but that of the PIO group increased (-3.2kg and +1.7kg, respectively). When the participants were allocated to two groups according to their baseline ALT (>30IU/L), FIB-4 index significantly decreased in both groups. In patients taking pioglitazone, the addition of SGLT2i improved liver enzymes but not FIB-4 index for 96weeks. Treatment with SGLT2i causes a larger improvement in FIB-4 index than PIO in patients with MAFLD over 96weeks.

Outcomes of Pioglitazone and Metformin on Anthropometric, Metabolic and Endocrine variables in POS

Aim: To evaluate the outcomes of Pioglita zone and Metformin on anthropometric, metabolic and endocrine variables in PCOS. Methods: This randomized controlled trial was executed at Pharmacology Department of Bahria University Medical and Dental College in collaboration with Mamji Hospital Karachi from September 2018 to March 2019. Eighty PCOS infertile patients as per Rotterdam 2003 criteria,aged 20-40 years were enrolled. They were divided into two groups of 40 patients each by using computer generated numbers. All patients had fasting insulin levels of >9 μU/mL, serum glucose levels ≥126 mg/dl and suffering from oligomenorrhoea or amenorrhoea. Group A received Tablet Pioglitazone 30 mg once daily and group B was given tablet Metformin 500 mg for three months along with lifestyle changes. Results: Sixty-one participants completed the study. Anthropometric variables included weight, BMI and W/H ratio. Metformin treated group reduced more weight and BMI as compared to Pioglitazone. Metabolic variables included glycaemic indices, lipid profile and hs-CRP estimation. Pioglitazone group improved glycaemic indices more compared to Metformin. Serum progesterone level was significantly increased in Pioglitazone group (5.20±1.18) than Metformin group. Pioglitazone produced more ovulation in comparison to Metformin. Hence it is proved that it is better option in those patients who are unable to tolerate Metformin and cannot continue treatment for infertility. Conclusion: Pioglitazone group produced highly significant increase in serum progesterone level indicating ovulation and improved insulin resistance than the metformin group. Keywords: Female infertility, ovulation induction, Metformin, Pioglitazone, polycystic ovarian syndrome

Validation of a diet-induced Macaca fascicularis model of non-alcoholic steatohepatitis with dietary and pioglitazone interventions.

To develop an obese, insulin-resistant cynomolgus monkey model of non-alcoholic steatohepatitis (NASH) with fibrosis with a high fat/high cholesterol (HFHC) diet (with or without high fructose) and test its responsiveness to caloric restriction or pioglitazone. First, two groups of monkeys (n=24/group) with histologically proven NASH and fibrosis were fed the HFHC diet for 17 weeks. The treatment group was subjected to a 40% caloric restriction (CR) and had their diet switched from the HFHC diet to a chow diet (DSCR). Paired liver biopsies were taken before and 17 weeks after DSCR. Subsets of monkeys (nine/group) had whole liver fat content assessed by MRI. Next, two groups of monkeys with histologically proven NASH and fibrosis were treated with vehicle (n=9) or pioglitazone (n=20) over 24 weeks. The HFHC and DSCR groups lost 0.9% and 11.4% of body weight, respectively. After 17 weeks, non-alcoholic fatty liver disease activity score (NAS) improvement was observed in 66.7% of the DSCR group versus 12.5% of the HFHC group (P< .001). Hepatic fat was reduced to 5.2% in the DSCR group versus 23.0% in the HFHC group (P= .0001). After 24 weeks, NAS improvement was seen in 30% of the pioglitazone group versus 0% of the vehicle group (P= .08). Both weight loss induced by DSCR and treatment with pioglitazone improve the histological features of NASH in a diet-induced cynomolgus monkey model. This model provides a translational preclinical model for testing novel NASH therapies.

Octanoic Acid-rich Enteral Nutrition Alleviated Acute Liver Injury Through PPARγ/STAT-1/MyD88 Pathway in Endotoxemic Rats.

Acute liver injury is the hallmark of organ failure in sepsis. Enteral nutrition (EN) is an important clinical therapeutic measure in septic patients. However, the therapeutic effect of EN alone is not obvious. Here, we investigated whether octanoic acid (OA)-rich EN alleviated acute liver injury through PPARγ/STAT-1/MyD88 pathway in endotoxemic rats. First, rats were randomly divided into four groups: Sham, Lipopolysaccharide (LPS), LPS+EN and LPS+EN+OA groups to investigate the effect of OA-rich EN on LPS-induced acute liver injury in endotoxemic rats. Then rats were randomly divided into five groups: Sham, LPS, LPS+EN+OA, LPS+EN+OA+SR202 (SR) and LPS+ pioglitazone (PI) groups to examine whether OA-rich EN alleviated acute liver injury through the PPARγ/STAT-1/MyD88 pathway. Rats received nutrition support via a gastric tube for 3 days. We evaluated the liver histology, apoptosis, liver enzymes and inflammatory cytokine levels in the liver and serum. PPARγ/STAT-1/MyD88 pathway was also measured. OA-rich EN inhibited the phosphorylation of STAT-1 and the activity of MyD88 by activating PPARγ and alleviating LPS-induced acute liver injury more effectively than EN alone in endotoxemic rats. The use of SR counteracted the effect of OA-rich EN on acute liver injury. Meanwhile, PI showed effects similar to OA-rich EN in endotoxemic rats. OA-rich EN alleviated acute liver injury through PPARγ/STAT-1/MyD88 pathway in endotoxemic rats.

Effect of Pioglitazone on Nonalcoholic Fatty Liver Disease in Morbid Obese Patients; a Randomized Controlled Trial.

Nonalcoholic fatty liver disease (NAFLD) is a common obesity-related disease. In this study, we aimed to investigate the effects of pioglitazone on NAFLD in morbid obese patients. This is a randomized controlled trial study that was performed in 2020-2021 on 44 patients who had grade 3 NAFLD. At the beginning of the study, we collected the following data: age, gender, body mass index (BMI), fasting blood glucose (FBS), lipid profile, aspartate aminotransferase, alanine aminotransferase (ALT), and the total size and volume of the liver and the left lobe of the liver. Patients in the control group were given a special diet. For patients in the treatment group, pioglitazone 15 mg tablets were administered twice daily for 4 months. At the beginning of the study, all patients in both groups had grade 3 of NAFLD. After the treatments, 50% of the pioglitazone group had grade 1 NAFLD, and 50% of other patients had grade 2 that showed significant improvements in patients (P < 0.001). We also found significant improvements in the following items in the intervention group: liver size (P < 0.001), size of the left liver lobe (P < 0.001), FBS (P = 0.036), ALT (P = 0.011), and BMI (P < 0.001). No significant improvements were found in the control group (P > 0.05). The use of pioglitazone for 4 months resulted in improvements in fatty liver stage, liver size, BMI, FBS, and lipid profile. These data show the effectiveness of pioglitazone in NAFLD.

The effect of dietary pioglitazone supplementation on milk yield, insulin sensitivity and GH-IGF-I axis in Holstein dairy cows during the transition period.

High-yielding dairy cows develop insulin resistance during late gestation associated with disruption of the growth hormone (GH)-insulin-like growth factor (IGF)-I axis and cause metabolic and reproductive disorders. This study aimed to determine the effects of dietary pioglitazone (PIO) supplementation as an insulin sensitizer agent on milk yield, plasma metabolite status and GH-IGF-I axis in transition Holstein dairy cows. Twenty multiparous cows were randomly assigned into two experimental groups (n = 10 animals per group) and either fed with a basal diet (control) or the basal diet supplemented with 6mg PIO/kg body weight (BW) from day 14 before parturition to day 21 postpartum. The BW and body condition score (BCS), non-esterified fatty acids, beta-hydroxybutyrate (BHBA), insulin, glucose, GH and IGF-I concentrations, milk production and composition were measured weekly. BW and BCS losses were lower in PIO than in control cows (p<0.05). The percentage and amount of milk fat were decreased, and the amount of protein increased only in the first post-calving week in the PIO-treated cows compared to the control (p<0.05). Dietary PIO supplementation increased glucose concentration at calving, but insulin concentration was increased at calving and in the first post-calving week (p<0.05). Plasma concentrations of IGF-I and the ratio of IGF to GH were increased in the PIO group (p<0.05). The mean revised quantitative insulin sensitivity check index with BHBA, as an insulin sensitivity index, was greater in PIO-supplemented cows (p < 0.05). Our results showed beneficial effects of PIO supplementation on improving insulin sensitivity and the GH-IGF-I axis that may cause lower negative energy balance and better metabolic and health status in transition dairy cows.

Effects of Linagliptin and Pioglitazone on Fracture Healing in an Experimental Type 2 Diabetes Rat Model.

Our study aimed to examine the effects of Linagliptin, Pioglitazone, and their combination on fracture healing in a diabetes rat femur fracture model. Type 2 diabetes mellitus (T2DM) induced rats were randomly divided into four groups: non-treated diabetes group (TD), Pioglitazone group (P), Linagliptin group (L), and Pioglitazone and Linagliptin group (PL). Daily oral dosage of pioglitazone (10 mg/kg/day), linagliptin (10 mg/kg/day), and their combination were administered. Femur fractures were stabilized intramedullary. At weeks 2 and 6, rats were sacrificed for evaluation radiologically, biomechanically, histopathologically, histomorphometrically, and immunohistochemically. Flexural strength of the L and PL groups were significantly higher compared to the P group. The highest healing score was in the L group and lowest in the P group, while the highest inflammation score was in the P group and lowest in the L group. A cluster of differentiation (CD) CD 34 reactivity was highest in the L group and lowest in the PL group. Linagliptin treatment significantly increased histological healing scores, callus volume, biomechanical strength, and vascularity, however, minimized the inflammatory process, which was increased by pioglitazone. The combination of linagliptin and pioglitazone restored BMD and increased biomechanical strength. Linagliptin monotherapy is rarely indicated; hence, T2DM patients with a high risk of bone fractures can be considered for combined therapy of pioglitazone and linagliptin.

Effects of Hydroxychloroquine on Progression of Diabetic Retinopathy in Subjects with Rheumatoid Arthritis and Type 2 Diabetes Mellitus.

The study was conducted to investigate the effects of hydroxychloroquine, an anti-inflammatory drug, which was recently approved and used as an add on oral antidiabetic drug for uncontrolled Type 2 Diabetes Mellitus (DM) on an adequate dose of sulfonylurea and metformin on the progression of diabetic retinopathy (DR) in subjects with Rheumatoid Arthritis and Type 2 Diabetes Mellitus. The primary objective was to evaluate the effect of hydroxychloroquine on the onset of Diabetic Retinopathy (DR) and progression of the disease. Best-corrected visual acuity (BCVA) charts with 3 or more lines worsening of visual acuity and the development of clinically significant macular edema (CSME) were added as secondary objectives as described in the Early Treatment Diabetic Retinopathy Study (ETDRS). This retrospective analysis was done from medical records of all Rheumatoid Arthritis (RA) patients who also had T2DM and were treated with hydroxychloroquine (HCQ) 400 mg OD or 200 mg BID (N=65) and received ophthalmologic care at an endocrinology clinic in India up to a mean follow-up of 3.5±0.5 years and matched subjects taking any other disease-modifying antirheumatic drugs (DMARD) and pioglitazone (N=34). Baseline characteristics were similar in both the groups, with matched glycated haemoglobin (9.1 % and 9.2 % respectively, p=0.127). In both groups, over 3.5 years, HbA1c was reduced significantly. No new cases of DR were detected in the HCQ group, whereas 2 patients had developed DR in the pioglitazone group. At the base line visit, mild non-proliferative Diabetic Retinopathy (NPDR) was present in 18 eyes and 14 eyes in the HCQ and pioglitazone groups, respectively. Progression to moderate NPDR over 3.5 years occurred in 2 out of 18 (11 %) eyes in the HCQ group and 8 out of 14 (57 %) eyes in the pioglitazone group, respectively, representing a significant relative risk reduction (p=.001). No patients had progressed from mild NPDR to severe NPDR in the HCQ group, whereas 2 eyes had progressed from mild NPDR to severe NPDR in the pioglitazone group. None of the patients in either arm developed diabetic macular oedema. Progression of DR from mild to moderate NPDR or severe NPDR may be delayed by HCQ. Large scale randomised prospective clinical trial is required to establish the risk-benefit profiles of HCQ in T2DM.ct.

DLBS3233 reduces inflammatory marker on kidney by increasing expression GLUT1 and GLUT2 in diabetic rats

Introduction: Diabetic kidney disease (DKD), as a diabetes mellitus type 2 (DMT2) complications, is getting more prevalent nowadays. Inflammation is one of the renal injury mechanisms evaluated through the surge in in TNF-α and NF-κβ expression. Impaired expression of gluten transporter 1 (GLUT1) and GLUT2 reduces glucose uptake. DBLS3233 is a novel anti-diabetes agent and Indonesian herbal product responsible for glucose control and upregulation of insulin signal transduction. We performed an experiment on DLBS3233 to examine the response of TNF-α and NF-κβ and the expression of GLUT 1 and GLUT2. Methods: A total of 30 adult male Wistar rats were randomly divided into six groups (n=5 per group): nondiabetic rats in the control group (group 1); untreated diabetic rats (group 2); diabetic rats treated with DLBS3233 4,5mg/kgBW (group 3); 9mg/kgBW (group 4); 18mg/kgBW (group 5), and diabetic rats treated with pioglitazone (group 6). Immunohistochemistry was performed to examine the expression of GLUT1 and GLUT2 in the pancreas and expression of TNF-α and NF-κβ in the kidney. The data was then analyzed by ANOVA. Results: In the DBLS3233 group, reduced expression of both TNF-α and NF-κβ was seen through immunohistochemistry, whereas GLUT1 and GLUT2 were intensified compared to untreated groups. From statistical analysis, we obtained significantly lower expression of TNF-α and NF-κβ, as well as enhanced GLUT1 and GLUT2 expression compared to untreated groups (p&lt;0.05). Conclusions: DBLS3233 significantly reduces the inflammatory process and enhances the expression of GLUT1 and GLUT2 diabetic rats.

Comparative study to evaluate the efficacy and safety of Pioglitazone and Metformin on HOMA IR and HbA1c in patient of prediabetes

In India, the number of people with diabetes is increasing day-by-day. Due to a sole “Asian Indian Phenotype,” Indians develop diabetes an era earlier and have an earlier onset of complications. Hence, it is essential to evaluate earlier stage of disease progression. Prediabetes, typically defined as blood glucose levels above normal but below the thresholds of diagnosis of diabetes, is a risk state that defines a high chance of developing diabetes. The present study was Prospective, open label, comparative, randomized, parallel group, single center study. Comparison of two active treatment groups over a period of six months. Sixty patients of either sex in the age of more than 40 years with prediabetes, with HbAlc in the range of 5.7 to 6.4 % at screening as per ADA. The effect of metformin and pioglitazone were observed on various parameters i.e. Serum Insulin, FBG, HbA1c, HOMA-IR. In metformin group the mean change in HOMA-IR from baseline to 6 months was 3.44 to 2.21 (-1.23); on the other hand, in Pioglitazone group from baseline to 6 months was 3.30 to 1.91 (-1.39). Whereas, serum insulin from 35.58 to 26.73 (-8.85) in metformin group; in Pioglitazone group from 35.13 to 21.77 (-13.36).

Knowledge-Based Discovery of the Role and Mechanism of Resveratrol in Improving Glomerular Tether Cell Proliferation and Apoptosis in Diabetic Nephropathy.

To investigate the effects and mechanisms of resveratrol on glucolipid metabolism in diabetic humans. In this paper, we introduced the knowledge discovery theory into the data processing of the factors related to the pathogenesis of type 2 diabetes for the first time, and identified valid, potentially useful, and understandable pathogenesis patterns from a large amount of measured data. A data mining C4.5 algorithm was used to classify 17072 validated cross-sectional health survey data from the whole population according to the characteristics of type ρ diabetes data. A human model of diabetes mellitus was prepared by high sugar and high fat diet plus low dose streptozotocin (STZ, 35 mg/kg) and randomly grouped into four groups: the normal control group, the model group, the resveratrol group, and the pioglitazone group. 8 animals in each group were treated with the corresponding drugs for 8 weeks. Hepatic steatosis and damage were significantly reduced compared with the model group as observed by HE staining. Resveratrol has obvious effects on regulating glucolipid metabolism, and its mechanism of action is associated with its ability to increase the antioxidant activity of the body, activate the Akt signaling pathway, and improve liver pathological damage.

Comparison of Three Different Glucose-lowering Drugs on Serum Levels of Glucose and Pancreas Histopathology in Streptozotocin-Induced Diabetic Rats

Introduction: Diabetes mellitus is a metabolic disorder resulting from a defect in insulin secretion, insulin action, or both. The aim of the present study was to compare the effect of three different blood glucose-lowering drugs in streptozotocin-induced diabetic rats. &#x0D; Materials and methods: A total of 60 male Wistar rats (220–250 g and 2-3 months of age) were selected for the current study, and they then were divided into five equal groups. Group 1 included healthy control rats receiving standard diet, group 2 involved diabetic rats receiving standard diet plus acarbose (25mg/kg/day) via gastric feeding tube daily for 8 weeks, group 3 embraced diabetic rats receiving standard diet plus pioglitazone (1 mg/kg/day) via gastric feeding tube daily for 4 weeks, and group 4 received of diabetic rats receiving standard diet plus repaglinide (10 mg/kg/day) via gastric feeding tube daily for 4 weeks. Diabetes was induced by intraperitoneal injection of streptozotocin at a dosage of 65 mg/kg body weight. At the end of the study, the samples were taken for histopathological investigation of pancreas and serum glucose levels. The mean diameter of pancreatic islets and the percentage of beta and alpha cells were calculated in all groups.&#x0D; Results: The fasting blood glucose in three treated and normal control rats was significantly less than the diabetic control group. One hour after treatment the blood glucose level reduced significantly in three treated and normal control rats compared to the diabetic control group. On day 7, the percentage of alpha cells in the pioglitazone and acarbose groups increased significantly, compared to the diabetic control group. On day 28, the percentage of beta cells in the treated groups increased significantly, compared to normal and diabetic control groups. Moreover, the mean of islet diameter in the treated groups increased significantly, compared to the normal and diabetic control groups. The percentage of alpha cells in the repaglinide group significantly reduced on day 28, compared to the diabetic control group.&#x0D; Conclusion: Among the administrated drugs, pioglitazone had the most positive effects on controlling blood glucose, increasing beta cells as well as improving the diameter of pancreatic islets.

Pioglitazone Synthetic Analogue Ameliorates Streptozotocin-Induced Diabetes Mellitus through Modulation of ACE 2/Angiotensin 1-7 via PI3K/AKT/mTOR Signaling Pathway.

The renin angiotensin aldosterone system has a localized key regulatory action, especially in liver and body circulation. Furthermore, it accomplishes a significant role in the downregulation of the PI3K/AKT/mTOR signaling pathway that is involved in type II diabetes mellitus pathogenesis. The current study aimed to evaluate the effect of a synthetic pioglitazone analogue (benzenesulfonamide derivative) compared to the standard pioglitazone hypoglycemic drug on enhancing liver insulin sensitivity via ACE 2/Ang (1–7)/PI3K/AKT/mTOR in experimental STZ-induced diabetes. After the model was established, rats were distributed into the normal control group, diabetic group, pioglitazone group (20 mg/kg), and a benzenesulfonamide derivative group (20 mg/kg), with the last 2 groups receiving oral treatment for 14 consecutive days. Our results suggested enhancing liver insulin sensitivity against the ACE2/Ang (1–7)/PI3K/AKT/mTOR pathway. Moreover, the synthetic compound produced a reduction in blood glucose levels, restored hyperinsulinemia back to normal, and enhanced liver glycogen deposition. In addition, it up regulated the ACE2/Ang (1–7)/PI3K/AKT/mTOR signaling pathway via increasing insulin receptor substrate 1 and 2 sensitivity to insulin, while it increased glucose transporter 2 expression in the rat pancreas. The study findings imply that the hypoglycemic effect of the benzenesulfonamide derivative is due to enhancing liver sensitivity to regulate blood glucose level via the ACE2/Ang (1–7)/PI3K/AKT/mTOR pathway.

Modulatory effects of pioglitazone as a ligand for the peroxisome proliferator-activated receptor on semen quality and fertility potential of broiler breeder roosters

Fertility potential in roosters is a crucial topic in broiler breeder reproduction which is thought to be associated with age. This study aims to investigate effects of 2 levels of pioglitazone (PIO) supplementation on peroxisome proliferator-activated receptor gamma (PPAR-γ) expression, semen quality, and fertility parameters of aged broiler breeder roosters. The efficacy of PIO was divided into 2 sections: receptor-dependent and receptor-independent. Expression of PPAR-γ mRNA and protein was assessed in sperm to monitor receptor-dependent actions. Sperm motility, velocity parameters, viability, mitochondrial activity, and apoptosis were assessed for the receptor-independent actions. Broiler breeder roosters were randomly assigned to 3 groups: 1) control received a basal diet (CTRL); 2) PIO-5 received a basal diet supplemented with 5 mg PIO/bird/day, and 3) PIO-10 received a basal diet supplemented with 10 mg PIO/bird/day. In addition, semen samples were collected from 24 Ross broiler breeder roosters at 30, 43, and 53 wk of age. Effects of PIO were significant in terms of total motility, straight-line velocity, mitochondrial activity, and apoptosis (P ≤ 0.05). Total motility, straight-line velocity and mitochondrial activity improved in both PIO groups (P ≤ 0.05) along with a significant reduction in early and late apoptosis in the PIO groups (P ≤ 0.05). Pioglitazone addition affected total motility, mitochondrial activity, early apoptosis and late apoptosis in a linearly and quadratically manner (P < 0.05). PPAR-γ mRNA and protein expression were not significantly upregulated by the different doses of PIO (P > 0.05). Similarly, fertility performance was not significantly changed in the PIO groups (P > 0.05). Moreover, PIO improved mitochondrial activity and decreased the apoptosis rate in the sperm of aged broiler breeder roosters. These improvements were associated with the receptor-independent actions of PIO and the mechanism of action of PIO did not appear to be affected by the PPAR-γ receptor in broiler breeder roosters.

The efficacy of pioglitazone for renal protection in diabetic kidney disease.

There is limited information on the efficacy of pioglitazone in diabetic kidney diseases (DKD). We evaluated whether pioglitazone exerts renal-protective effects in DKD patients. We designed a retrospective cohort study, which included 742 type 2 diabetes mellitus (T2DM) patients with DKD in Taiwan, with eGFR between 30 and 90 ml/min/1.73 m2 and UACR level 300–5000 mg/g. Patients not meeting the target range for HbA1c (above 7%) were given additional medication with pioglitazone (n = 111) or received standard care (non-pioglitazone group, n = 631). The primary endpoint was the occurrence of composite renal endpoints, which was defined as sustained eGFR<15 ml/min/1.73 m2 (confirmed by two measurements within 90 days); doubling of serum creatinine (compared to baseline); and the presence of hemodialysis or renal transplantation. The median follow-up duration was two years. At baseline, the mean HbA1C levels in the pioglitazone and non-pioglitazone groups were 8.8% and 8.1%, respectively; mean ages were 64.4 and 66.2 years old, respectively; diabetes durations were 14.3 and 12.3 years, respectively. Baseline eGFR showed no significant difference between the pioglitazone and non-pioglitazone groups (55.8 and 58.8 mL/min/1.73 m2, respectively). In terms of gender, 63% of patients were male in the pioglitazone group compared with 57% in the non-pioglitazone group. Pioglitazone use did not reduce the risk of composite renal endpoints in DKD patients (HR: 0.97, 95% CI = 0.53–1.77), including persistent eGFR<15 ml/min/1.73 m2 (HR = 1.07, 95% CI = 0.46–2.52), doubling of serum creatinine (HR = 0.97, 95% CI = 0.53–1.77), or ESRD (HR = 2.58, 95% CI = 0.29–23.04). The results were not changed after various adjustments. A non-significant albuminuria reduction was also noted after pioglitazone prescription in DKD patients. Further randomized controlled studies are needed to establish the effects of pioglitazone definitively.

A Randomized Controlled Clinical Trial of Lifestyle Intervention and Pioglitazone for Normalization of Glucose Status in Chinese with Prediabetes.

Aims Prediabetes has been proved as an important risk factor of both diabetes and cardiovascular disease (CVD). Previous studies have shown that both lifestyle intervention and pioglitazone may delay the development of diabetes in patients with prediabetes. However, no study has ever explored whether these interventions could revert prediabetes to normal glycemic status as the primary outcome. Interventions that may revert prediabetes back to normal glucose status would be of great clinical importance. Materials and Methods We conducted a randomized, multicenter, 2 × 2 factorial designed study to examine whether intensive lifestyle intervention and/or pioglitazone could revert prediabetes to normal glucose tolerance. The participants were followed up for three years unless they reverted to normal glucose state or developed diabetes at the annual oral glucose tolerance test (OGTT). Reversion to normal glucose tolerance was confirmed on the basis of the results of OGTT. Results In our study, 1945 eligible patients were ultimately randomized into four groups. In this three-year follow-up study, overall, 60.0%, 50.3%, 56.6% and 65.1% reverted back to normoglycemic state over 3 years of follow-up in the conventional lifestyle intervention plus placebo, intensive lifestyle intervention plus placebo, conventional lifestyle intervention plus pioglitazone, and intensive lifestyle intervention plus pioglitazone groups, respectively. Compared to the conventional lifestyle intervention plus placebo group, all the other three groups did not show any significant benefit in terms of reverting back to normoglycemic state. Conclusion In our study, for patients with prediabetes, neither intensive lifestyle intervention nor pioglitazone had led to a higher reversion rate to normal glucose state. Trail registration.http://www.chictr.org.cn: ChiCTR-PRC-06000005.

Effects of pioglitazone on cardiovascular events and all-cause mortality in patients with type 2 diabetes: A meta-analysis of randomized controlled trials

AimIn 2019, the Italian Society of Diabetology and the Italian Association of Clinical Diabetologists nominated an expert panel to develop guidelines for drug treatment of type 2 diabetes. After identifying the effects of glucose-lowering agents on major adverse cardiovascular events (MACEs), all-cause mortality, and hospitalization for heart failure (HHF) as critical outcomes, the experts decided to perform a systematic review and meta-analysis on the effect of pioglitazone with this respect. Data synthesisA MEDLINE database search was performed to identify RCTs, up to June 1st, 2021, with duration≥52 weeks, in which pioglitazone was compared with either placebo or active comparators. The principal endpoints were MACE and HHF (restricted for RCT reporting MACEs within their outcomes), all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified outcomes). Mantel-Haenszel odds ratio (MH–OR) with 95% Confidence Interval (95% CI) was calculated for all the endpoints considered.Eight RCTs were included in the analysis for MACEs and HF (5048 and 5117 patients in the pioglitazone and control group, respectively), and 24 in that for all-cause mortality (10,682 and 9674 patients). Pioglitazone neither significantly increased nor reduced the risk of MACE, all-cause mortality, and HHF in comparison with placebo/active comparators (MH–OR: 0.90, 95% CI 0.78–1.03, 0.91, 95% CI 0.77, 1.09, and 1.16, 95% CI 0.73, 1.83, respectively). Pioglitazone was associated with a significant reduction of MACE in patients with prior cardiovascular events (MH–OR 0.84, 95% CI 0.72–0.99). ConclusionsThis meta-analysis showed no significant effects of pioglitazone on incident MACE, all-cause mortality, and HHF.