Pregnancy complications are more likely to occur in obese women because of defective decidualization. However, the specific mechanism of glycolysis in decidual modulation associated with obesity remains unknown. Therefore, we explored the role of glycolysis in the endometrium of obese pregnant mice during decidualization. C57BL/6J mice were fed a high-fat diet (HFD) to induce obesity. All obesity related parameters were significantly higher in the HFD mice than control. Furthermore, the HFD mice had fewer implantation sites, a smaller decidual area growth, and decreased decidualization marker protein expression than control. The HFD mice also had significantly decreased lactate production and glycolytic enzyme expression. To confirm the functional role of glycolysis during the decidual period in obese pregnant mice, we extracted endometrial stromal cells (ESCs) and treated them with oleic acid (OA) and palmitic acid (PA) to mimic a high-fat environment. Decidualization and glycolysis were significantly restricted in the OA-and PA-treated groups. Moreover, we administered a glycolytic inhibitor, 2-DG, and an agonist, pioglitazone. 2-DG treatment considerably decreased the cells' glycolysis and decidualization. However, pioglitazone treatment improved glycolysis and alleviated defective decidualization. In conclusion, obesity-induced endometrial glycolysis modifications and key glycolytic enzyme downregulation during early pregnancy might cause abnormal decidualization, leading to an unsustainable pregnancy.

Polycystic ovary syndrome (PCOS) is a common reproductive and metabolic disorder that is closely correlated with insulin resistance. Sex hormone-binding globulin (SHBG) is an important carrier for regulating androgen activity and is affected by insulin level, which is related to metabolic abnormalities and long-term prognosis of PCOS. Insulin sensitizer pioglitazone can improve the SHBG level and dyslipidaemia in PCOS, but the mechanism remains unclear. We investigated liver SHBG expression, liver lipid levels, and the effects and potential mechanisms of pioglitazone on reproductive and metabolic disorders in a rat model of polycystic ovary syndrome with insulin resistance (PCOS-IR). PCOS-IR was induced by letrozole and a high-fat diet. Metformin was used as a positive control. Additionally, dihydrotestosterone and oleic acid combined with palmitic acid were used to induce the HepG2 cell models with IR. The cells were exposed to pioglitazone alone or in combination with a hepatocyte nuclear factor (HNF)-4α inhibitor. Changes in biochemical characteristics were analysed using an enzyme-linked immunosorbent assay. Vaginal smears were used to analyse the oestrous cycle, and ovarian histology was used to analyse the changes in ovarian morphology. The degree of IR in vivo and in vitro was measured using the hyperinsulinaemic-euglycaemic clamp and glucose oxidase techniques. The levels of key anabolism-related proteins, including SHBG, HNF-4α, and peroxidase proliferator-activated receptor (PPAR-γ), were measured using western blots. Pioglitazone and metformin significantly increased the SHBG levels in the sera and livers. Compared to metformin, pioglitazone significantly improved the lipid droplet deposition, triglyceride (TG) and total cholesterol (TC) levels, HNF-4α protein expression, and weights of the livers in the PCOS-IR rats. After applying pioglitazone with an HNF-4α inhibitor in the PCOS-IR cell models, we found that pioglitazone may increase SHBG and improve IR, TG, and TC levels by upregulating HNF-4α. Similar to metformin, pioglitazone also restored the oestrous cycle and ovarian morphology, ameliorated IR and hyperandrogenaemia in the PCOS-IR rats. Our findings hint at the value of HNF-4α in the treatment of PCOS by PIO, which could shed light on potential targets that may be used in treatments for PCOS with metabolic disorders.

This study evaluated the effect of Pluchea indica leaf extract (PIE) on dyslipidemia and lipid accumulation in the liver, emphasizing its molecular mechanisms in regulating lipid metabolism in rats fed a high fat-high fructose diet (HFFD). Male rats were fed HFFD (40% lard and 20% fructose) for ten weeks. They were then divided into four groups receiving distilled water, PIE (100 or 300 mg/kg/d), and pioglitazone (10 mg/kg/d) for a further six weeks, during which the HFFD was continued. After the experiment, fasting blood glucose (FBG), oral glucose tolerance (OGT), serum insulin and leptin levels, lipid profiles, and hepatic triglyceride content were measured. Histological examination and expression levels of lipid metabolism-related genes in the liver were measured. HFFD-fed rats indicated a significantly increased FBG, serum leptin, and homeostasis model assessment of insulin resistance (HOMA-IR) scores with impaired OGT and dyslipidemia compared to rats fed a normal diet. PIE significantly reduced FBG, serum leptin, and HOMA-IR scores and improved OGT. Additionally, PIE significantly improved dyslipidemia and decreased serum-free fatty acids and liver triglyceride content. Hepatic histological examination showed a marked reduction lipid accumulation in relation to HFFD controls. Interestingly, PIE significantly downregulated the expression of lipid synthesis-related genes and upregulated the expression of fatty-acid oxidation-related genes. In conclusion, PIE alleviates dyslipidemia and hepatic steatosis in HFFD rats plausibly by increasing insulin resistance and modifying the gene expression associated with lipid metabolism. PIE may be used as preventive nutrition for dyslipidemia and hepatic steatosis.

The NLRP3 inflammasome plays a crucial role in innate immunity and is involved in the pathogenesis of autoinflammatory diseases. Glycolysis regulates NLRP3 inflammasome activation in macrophages. However, how lactic acid fermentation and pyruvate oxidation controlled by the mitochondrial pyruvate carrier (MPC) affect NLRP3 inflammasome activation and autoinflammatory disease remains elusive. We found that inactivation of MPC with genetic depletion or pharmacological inhibitors, MSDC-0160 or pioglitazone, increased NLRP3 inflammasome activation and IL-1β secretion in macrophages. Glycolytic reprogramming induced by MPC inhibition skewed mitochondrial ATP-associated oxygen consumption into cytosolic lactate production, which enhanced NLRP3 inflammasome activation in response to monosodium urate (MSU) crystals. As pioglitazone is an insulin sensitizer used for diabetes, its MPC inhibitory effect in diabetic individuals was investigated. The results showed that MPC inhibition exacerbated MSU-induced peritonitis in diabetic mice and increased the risk of gout in patients with diabetes. Altogether, we found that glycolysis controlled by MPC regulated NLRP3 inflammasome activation and gout development. Accordingly, prescriptions for medications targeting MPC should consider the increased risk of NLRP3-related autoinflammatory diseases. This article is protected by copyright. All rights reserved.

Tyrosine kinase inhibitors (TKIs) have improved outcomes of chronic myeloid leukemia (CML). However, 20-30% of patients require second-line TKIs following suboptimal response. The cost and adverse events limit their use in resource-constraint settings. We conducted a pilot study to ascertain the benefit of adding pioglitazone to TKIs with suboptimal response in real-world resource-constraint settings. In this pragmatic pilot study from 01 Jan 2017 to 31 July 2021, CML patients from a tertiary care center in North India with sub-optimal response to TKIs were additionally given pioglitazone after ruling out imatinib resistance mutation (n - 31). Pioglitazone was stopped if there was disease progression on follow-up, and second-line TKI was started. The data were analyzed with the intention-to-treat principle using JMP Ver.15.1.1. The median age of the study population was 54y (27-82), who were followed up for a median duration of 1023.5d (59-1117). Pioglitazone showed the benefit of one-log reduction in BCR-ABL in 89.7% of the study participants. 1y, 2y and 3y-PFS were 92.57%, 76.5%, and 68.3% respectively. During follow-up period, the disease progressed in 38.7%, of which two succumbed. No adverse events to Pioglitazone were documented. This study proved that adding Pioglitazone to the existing TKI regime in CML with sub-optimal response can benefit. The addition of Pioglitazone was well tolerated.

Introduction Polycystic ovary syndrome (PCOS) in women associates with raised levels of circulating thyroid stimulating hormone (TSH) and with high rates of gestational complications. A low range of preconception TSH is followed by low rates of gestational complications. It is unknown whether TSH levels are elevated in adolescents with PCOS and, if so, whether traditional or exploratory treatments can lower them into safe preconception range. We investigated TSH in non-obese adolescents with PCOS, including the effects of randomized interventions. Methods Morning TSH was a safety marker in randomized pilot studies comparing the effects of an oral contraceptive (OC) versus those of a low-dose combination of spironolactone-pioglitazone-metformin (SPIOMET) in non-obese adolescents with PCOS. A post-hoc analysis compared: TSH levels in PCOS (N= 62) vs controls; TSH changes on treatment (for 1 year); TSH levels post treatment (for 1 year). Results Mean TSH levels were higher in PCOS patients than in control girls (P<0.01). On-treatment TSH levels diverged (P<0.001), remaining elevated on OC, and descending swiftly on SPIOMET, well into safe preconception range. Post-treatment TSH levels were stable in both subgroups. On-treatment changes of circulating TSH associated to those of liver fat (R= 0.307, P= 0.017). Conclusion The endocrine signature of early PCOS is herewith extended to include modestly raised levels of circulating TSH; the normalizing effects of SPIOMET intervention in non-obese adolescents with PCOS are herewith extended to include on- and post-treatment TSH.

The aim was to assess the protective effect of pioglitazone (PGZ) on retinal ganglion cells (RGCs) after anterior ischemic optic neuropathy (AION) in diabetic and non-diabetic mice. Adult C57BL/6 mice with induced diabetes were divided into three groups: group 1: oral PGZ (20 mg/kg) in 0.1% dimethyl sulfoxide (DMSO) for 4 weeks; group 2: oral PGZ (10 mg/kg) in 0.1% DMSO for 4 weeks; and group 3: oral DMSO only for 4 weeks (control group). Two weeks after treatment, AION was induced through photochemical thrombosis. For non-diabetic mice, adult C57BL/6 mice were divided into four groups after AION was induced: group 1: oral DMSO for 4 weeks; group 2: oral PGZ (20 mg/kg) in 0.1% DMSO for 4 weeks; group 3: oral PGZ (20 mg/kg) in 0.1% DMSO + peritoneal injection of GW9662 (one kind of PPAR-γ inhibitor) (1 mg/kg) for 4 weeks; group 4: peritoneal injection of GW9662 (1 mg/kg) for 4 weeks; One week after the induction of AION in diabetic mice, apoptosis in RGCs was much lower in group 1 (8.0 ± 4.9 cells/field) than in group 2 (24.0 ± 11.5 cells/field) and 3 (25.0 ± 7.7 cells/field). Furthermore, microglial cell infiltration in the retina (group 1: 2.0 ± 2.6 cells/field; group 2: 15.6 ± 3.5 cells/field; and group 3: 14.8 ± 7.5 cells/field) and retinal thinning (group 1: 6.7 ± 5.7 μm; group 2: 12.8 ± 6.1 μm; and group 3: 15.8 ± 5.8 μm) were also lower in group 1 than in the other two groups. In non-diabetic mice, preserved Brn3A+ cells were significantly greater in group 2 (2382 ± 140 Brn3A+ cells/mm2, n = 7) than in group 1 (1920 ± 228 Brn3A+ cells/mm2; p = 0.03, n = 4), group 3 (1938 ± 213 Brn3A+ cells/mm2; p = 0.002, n = 4), and group 4 (2138 ± 126 Brn3A+ cells/mm2; p = 0.03, n = 4), respectively; PGZ confers protection to RGCs from damage caused by ischemic optic neuropathy in diabetic and non-diabetic mice.

The role of peroxisome proliferator activated receptor gamma (PPARγ) in the regulation of adipocyte differentiation has been well characterized. Besides adipose tissue, PPARγ is also highly expressed in the intestine. However, the functional role of PPARγ in the regulation of intestinal function still remains poorly understood. In the present study, we sought to understand the role of PPARγ activation on regulation of intestinal barrier function in intestinal porcine epithelial cells (IPEC-J2) and weaned piglets exposed to the mycotoxin, deoxynivalenol (DON). PPARγ activation by rosiglitazone and troglitazone, two pharmacological PPARγ ligands, increased the protein expression of tight junction proteins (TJP), claudin-3 and 4. PPARγ inhibition increased endocytosis of claudin-4 which was reversed by its activation with troglitazone. DON exposure decreased the protein expression of TJP, and also significantly suppressed PPARγ transcriptional activity. Interestingly, PPARγ activation reversed the reduction of claudin-3 and 4 caused by DON in vitro and in vivo. PPARγ activation also partially restored the transepithelial electrical resistance (TEER) and reduced the permeability of fluorescein isothiocyanate-dextran (FITC-dextran) that have been negatively impacted by DON. These effects were lost in the presence of a specific PPARγ antagonist or in PPARγ knockout cells, confirming the importance of PPARγ in the regulation of intestinal barrier function and integrity. Likewise, in weaned pigs exposed to DON, the PPARγ agonist pioglitazone mitigated the impaired villus-crypt morphology caused by DON. Therefore, pharmacological and natural bioactive compounds with PPARγ stimulatory activities could be effective in preventing DON-induced gut barrier dysfunction.

Stroke is a major cause of death and long-term disability worldwide. Diabetes is associated with an increased risk of cardiovascular complications, including stroke. People with diabetes have a 1.5-2 times higher risk of stroke compared with people without diabetes, with risk increasing with diabetes duration. These risks may also differ according to sex, with a greater risk observed among women versus men. Several mechanisms associated with diabetes lead to stroke, including large artery atherosclerosis, cerebral small vessel disease, and cardiac embolism. Hyperglycemia confers increased risk for worse outcomes in people presenting with acute ischemic stroke, compared with people with normal glycemia. Moreover, people with diabetes may have poorer post-stroke outcomes and higher risk of stroke recurrence than those without diabetes. Appropriate management of diabetes and other vascular risk factors may improve stroke outcomes and reduce the risk for recurrent stroke. Secondary stroke prevention guidelines recommend screening for diabetes following a stroke. The diabetes medications pioglitazone and glucagon-like peptide-1 receptor agonists have demonstrated protection against stroke in randomized controlled trials; this protective effect is believed to be independent of glycemic control. Neurologists are often involved in the management of modifiable risk factors for stroke (including hypertension, hyperlipidemia, and atrial fibrillation), but less often in the direct management of diabetes. This review provides an overview of the relationships between diabetes and stroke, including epidemiology, pathophysiology, post-stroke outcomes, and treatments for people with stroke and diabetes. This should aid neurologists in diabetes-related decision-making when treating people with acute or recurrent stroke.

Non-alcoholic fatty liver disease (NAFLD) is becoming a major cause of liver disease-related morbidity, as well as mortality. Importantly, NAFLD is considered a mediator of systemic diseases including cardiovascular disease. Its prevalence is expected to increase, mainly due to its close association with obesity and type 2 diabetes mellitus (T2D). In addition, T2D and NAFLD share common pathophysiological mechanisms, and one can lead to or worsen the other. Therefore, a close collaboration between primary care physician, endocrinologists and hepatologists is essential to optimize the management of patients with NAFLD and T2D. Here, we summarize relevant aspects about NAFLD and T2D that all clinician managing these patients should know as well as current therapeutic options for the treatment of T2D associated with NAFLD.

Anti-diabetic therapies possess many side effects; thus, searching for alternative strategies with low cost, minimal side effects, and high therapeutic value is very important. The present study aimed to explore the combined use of selenium yeast (SY) and standard anti-diabetic drug pioglitazone (PGZ) for diabetes mellitus (DM) treatment in streptozotocin (STZ)-induced DM. STZ was injected daily intraperitoneally with a low dose (40 mg/kg) into Sprague-Dawley rats to induce DM. The synergistic effect of the SY (0.2 mg/kg) and PGZ (0.65 mg/kg) on DM complications was evaluated after 88 weeks of treatment. The impact of our medication on glucose levels, insulin sensitivity, lipid abnormalities, oxidative mediators, and inflammatory markers was assessed by biochemical techniques. STZ-induced diabetes has toxic effects, including toxic hepatic tissues, lipid disturbances, massive oxidative damage, and hyperinflammation. Experimental rats either treated with monotherapy alone or combined therapy resulted in a significant anti-diabetic effect. The PGZ+ SY combination has the best effect, as illustrated by significant (P < 0.05) decreases in fasting blood glucose, (FBG) insulin, HbA1c, and HOMA-IR levels. This combination attenuated (P < 0.05) lipid disturbances and their associated elevated atherogenicity biomarkers. At the same time, treatments with PGZ+ SY exhibited an anti-inflammatory effect as they ameliorated the increase in inflammatory parameters (CRP, TNF-α, IL-6). Also, it restored the total antioxidant capacity and peroxisome proliferator-activated receptor (PPARƔ) levels that were decreased by STZ-DM induction. In conclusion, this study finds PGZ+ SY as a promising DM therapeutic alternative. This synergistic combination alleviates most DM-related complications and insulin resistance.

Pioglitazone shows potential benefits in inflammatory bowel disease (IBD) in preclinical studies, but its effect in humans has not been researched. We used a nationwide database of Taiwan's National Health Insurance to investigate whether pioglitazone might affect IBD risk. We enrolled 12,763 ever users and 12,763 never users matched on a propensity score from patients who had a new diagnosis of type 2 diabetes mellitus between 1999 and 2008. The patients were alive on 1 January 2009, and they were followed up for a new diagnosis of IBD until 31 December 2011. Propensity score-weighted hazard ratios were estimated, and the interactions between pioglitazone and major risk factors of IBD (i.e., psoriasis, arthropathies, dorsopathies, chronic obstructive pulmonary disease/tobacco abuse, and any of the above) and metformin were investigated. At the end of the follow-up, 113 ever users and 139 never users were diagnosed with IBD. When compared to never users, the hazard ratio for ever users was 0.809 (95% confidence interval: 0.631-1.037); and none of the hazard ratios for ever users categorized by tertiles of cumulative duration and cumulative dose reached statistical significance. No interactions with major risk factors or metformin were observed. Our findings suggested a null effect of pioglitazone on IBD.

Diabetes is considered a new pandemic of the modern world, and the number of sufferers is steadily increasing. Sustained hyperglycemia promotes the production of free radicals and leads to persistent, low-grade inflammation. Oxidative stress causes mitochondrial destruction, which along with activation of the hexosamine pathway, nuclear factor-κB (Nf-κb), p38 mitogen-activated protein kinase (p38 MAPK), c-jun NH2 terminal kinase/stress-activated protein kinase (JNK/SAPK) or toll-like receptors (TLRs), leads to pancreatic β-cell dysfunction. However, there is also the protective mechanism that counteracts oxidative stress and inflammation in diabetes, mitophagy, which is a mitochondrial autophagy. An important part of the strategy to control diabetes is to lead a healthy lifestyle based on, among other things, regular physical activity, giving up smoking, eating a balanced diet containing ingredients with antioxidant potential, including vegetables and fruits, and using hypoglycemic pharmacotherapy. Tobacco smoke is a recognized modifiable risk factor for many diseases including diabetes, and it has been shown that the risk of the disease increases in proportion to the intensity of smoking. Physical activity as another component of therapy can effectively reduce glucose fluctuations, and high intensity interval exercise appears to have the most beneficial effect. A proper diet not only increases cellular sensitivity to insulin, but is also able to reduce inflammation and oxidative stress. Pharmacotherapy for diabetes can also affect oxidative stress and inflammation. Some oral drugs, such as metformin, pioglitazone, vildagliptin, liraglutide, and exenatide, cause a reduction in markers of oxidative stress and/or inflammation, while the new drug Imeglimin reverses pancreatic β-cell dysfunction. In studies of sitagliptin, vildagliptin and exenatide, beneficial effects on oxidative stress and inflammation were achieved by, among other things, reducing glycemic excursions. For insulin therapy, no corresponding correlation was observed. Insulin did not reduce oxidative stress parameters. There was no correlation between glucose variability and oxidative stress in patients on insulin therapy. The data used in this study were obtained by searching PubMed online databases, taking into account recent studies.

Thiazolidinediones (TZDs) are a group of diabetes medications currently being investigated for anti-arthritis effectiveness, one of which is pioglitazone. The purpose of this scoping review is to evaluate the potential use of pioglitazone in the treatment of temporomandibular joint (TMJ) arthritis. The criteria of eligibility were studies with the diagnosis of arthritis and pioglitazone treatment with a change in any inflammation index as an outcome. Of the 1169 records initially identified following the selection process, two animal studies and four clinical studies were included in the review. Improvements from the baseline were observed in each treatment group for each inflammation indicator. The results of the animal studies on the temporomandibular joints and on patients with rheumatoid and psoriatic arthritis indicate that the drug in question may have potential to treat arthritis, including within the temporomandibular joint.

We previously showed that green tea polyphenols (GTPs) exert antiadipogenic effects on preadipocyte proliferation. Here, we investigated the regulatory effects of GTPs on osteogenesis and adipogenesis during early differentiation of human adipose tissue-derived stem cells (hADSC). Adipogenesis of hADSCs was determined by oil-red-O staining and triglycerides synthesis measurement. Osteoporosis of hADSC was measured using alkaline phosphatase assays and intracellular calcium levels. Immunofluorescence staining and qRT-PCR were used to detect PPARγ-CEBPA regulated adipogenic pathway regulated by PPAR-CEBPA and the osteogenic pathway mediated by RUNX2-BMP2. We found that GTPs treatment significantly decreased lipid accumulation and cellular triglyceride synthesis in mature adipocytes and attenuated pioglitazone-induced adipogenesis in a dose-dependent manner. GTPs downregulated protein and mRNA expression of Pparγ and attenuated pioglitazone-stimulated-Cebpa expression. GTPs treatment significantly enhanced hADSCs differentiation into osteoblasts compared to control and pioglitazone-treated cells. GTPs upregulated RunX2 and Bmp2 proteins and mRNA expression compared to control and significantly attenuated decreased RunX2 and Bmp2 mRNA expression by pioglitazone. In conclusion, our data demonstrates GTPs possesses great ability to facilitate osteogenesis and simultaneously inhibits hADSC differentiation into adipogenic lineage by upregulating the RUNX2-BMP2 mediated osteogenic pathway and suppressing PPARγ-induced signaling of adipogenesis. These findings highlight GTPs' potential to combat osteoporosis associated with obesity.