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Diabetes Spectrum : a Publication of... 2024Nonalcoholic fatty liver disease (NAFLD) and its more severe form, nonalcoholic steatohepatitis (NASH), can promote the development of cirrhosis, hepatocellular...
Nonalcoholic fatty liver disease (NAFLD) and its more severe form, nonalcoholic steatohepatitis (NASH), can promote the development of cirrhosis, hepatocellular carcinoma, cardiovascular disease, and type 2 diabetes. Similarly, type 2 diabetes confers the greatest risk for the development of NASH, especially when associated with obesity. Although lifestyle changes are critical to success, early implementation of pharmacological treatments for obesity and type 2 diabetes are essential to treat NASH and avoid disease progression. This article reviews current guidance regarding the use of pharmacological agents such as pioglitazone, glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors in the setting of NAFLD and NASH. It also reviews the latest information on new drugs currently being investigated for the treatment of NASH.
PubMed: 38385098
DOI: 10.2337/dsi23-0012 -
BMC Cancer Feb 2024Peroxisome proliferator-activated receptor gamma (PPARG) is a member of the nuclear receptor family. It is involved in the regulation of adipogenesis, lipid metabolism,...
BACKGROUND
Peroxisome proliferator-activated receptor gamma (PPARG) is a member of the nuclear receptor family. It is involved in the regulation of adipogenesis, lipid metabolism, insulin sensitivity, vascular homeostasis and inflammation. In addition, PPARG agonists, known as thiazolidinediones, are well established in the treatment of type 2 diabetes mellitus. PPARGs role in cancer is a matter of debate, as pro- and anti-tumour properties have been described in various tumour entities. Currently, the specific role of PPARG in patients with colorectal cancer (CRC) is not fully understood.
MATERIAL AND METHODS
The prognostic impact of PPARG expression was investigated by immunohistochemistry in a case-control study using a matched pair selection of CRC tumours (n = 246) with either distant metastases to the liver (n = 82), lung (n = 82) or without distant metastases (n = 82). Its effect on proliferation as well as the sensitivity to the chemotherapeutic drug 5-fluorouracil (5-FU) was examined after activation, inhibition, and transient gene knockdown of PPARG in the CRC cell lines SW403 and HT29.
RESULTS
High PPARG expression was significantly associated with pulmonary metastasis (p = 0.019). Patients without distant metastases had a significantly longer overall survival with low PPARG expression in their tumours compared to patients with high PPARG expression (p = 0.045). In the pulmonary metastasis cohort instead, a trend towards longer survival was observed for patients with high PPARG expression in their tumour (p = 0.059). Activation of PPARG by pioglitazone and rosiglitazone resulted in a significant dose-dependent increase in proliferation of CRC cell lines. Inhibition of PPARG by its specific inhibitor GW9662 and siRNA-mediated knockdown of PPARG significantly decreased proliferation. Activating PPARG significantly increased the CRC cell lines sensitivity to 5-FU while its inhibition decreased it.
CONCLUSION
The prognostic effect of PPARG expression depends on the metastasis localization in advanced CRC patients. Activation of PPARG increased malignancy associated traits such as proliferation in CRC cell lines but also increases sensitivity towards the chemotherapeutic agent 5-FU. Based on this finding, a combination therapy of PPARG agonists and 5-FU-based chemotherapy constitutes a promising strategy which should be further investigated.
Topics: Humans; Fluorouracil; PPAR gamma; Diabetes Mellitus, Type 2; Case-Control Studies; Cell Line, Tumor; Colorectal Neoplasms; Cell Proliferation; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic
PubMed: 38378472
DOI: 10.1186/s12885-024-11985-5 -
Journal of Cancer Research and... Oct 2023Oral administration (2 mg mL-1) of aqueous extract of betel nut (AEBN) for 24 weeks induced oncogenic alterations in the liver of female Swiss Albino mice concomitant...
The antidiabetic drug pioglitazone ameliorates betel-nut-induced carcinogenesis in mice by restoring normal lipid metabolism, reducing oxidative stress, and inducing apoptosis.
CONTEXT
Oral administration (2 mg mL-1) of aqueous extract of betel nut (AEBN) for 24 weeks induced oncogenic alterations in the liver of female Swiss Albino mice concomitant with aberrant lipid metabolism, overactivation of Akt/mTOR signaling, and loss of apoptosis.
AIM
This study was designed to investigate the potential of repurposing the antidiabetic drug pioglitazone for alleviating AEBN-induced carcinogenesis.
METHODS
Sera of animals were evaluated for lipid profile and free fatty acid levels. Liver tissues were investigated for oxidative stress, histopathology, and expression of proteins involved in lipid metabolism and oncogenesis by western blotting. Apoptosis was determined using TUNEL assay.
RESULTS
Coadministration of pioglitazone (10 mg kg-1 b.w) with AEBN for 8 weeks restored normal lipid profile and AMPK/ACC signaling, reduced FASN and HMGCR expressions and oxidative stress, and actively induced Akt/mTOR-mediated apoptosis in the liver.
CONCLUSIONS
Pioglitazone can effectively alleviate AEBN-induced carcinogenesis in mice.
Topics: Female; Animals; Mice; Lipid Metabolism; Pioglitazone; Hypoglycemic Agents; Areca; Nuts; Proto-Oncogene Proteins c-akt; Oxidative Stress; Carcinogenesis; Apoptosis; TOR Serine-Threonine Kinases; Lipids
PubMed: 38376305
DOI: 10.4103/jcrt.jcrt_844_22 -
Journal of Ovarian Research Feb 2024To investigate the effects of metformin (MET) monotherapy and pioglitazone plus MET (PIOMET) therapy on gonadal and metabolic profiles in normal-weight women with... (Randomized Controlled Trial)
Randomized Controlled Trial
Metformin versus metformin plus pioglitazone on gonadal and metabolic profiles in normal-weight women with polycystic ovary syndrome: a single-center, open-labeled prospective randomized controlled trial.
OBJECTIVE
To investigate the effects of metformin (MET) monotherapy and pioglitazone plus MET (PIOMET) therapy on gonadal and metabolic profiles in normal-weight women with polycystic ovary syndrome (PCOS).
METHODS
Sixty normal-weight women with PCOS were recruited between January and September 2022 at the Shengjing Hospital of China Medical University. They were randomly assigned to the MET or PIOMET groups for 12 weeks of MET monotherapy or PIOMET therapy. Anthropometric measurements, menstrual cycle changes, gonadal profiles, and the oral glucose insulin-releasing test (OGIRT) were performed at baseline and after the 12-week treatment.
RESULTS
Thirty-six participants completed the trial. MET and PIOMET therapies improved menstrual cycles after the 4- and 12-week treatments; however, there was no statistical difference between the two groups. PIOMET therapy improved luteinizing hormone (LH), luteinizing hormone/follicle stimulating hormone (LH/FSH) ratio, and free androgen index (FAI) levels after the 4-week treatment, whereas MET monotherapy only improved total testosterone (TT) levels compared to baseline (P < 0.05). Both MET and PIOMET therapies improved TT and anti-Mullerian hormone (AMH) levels after the 12-week treatment (P < 0.05). In addition, only PIOMET therapy significantly improved sex hormone-binding globulin (SHBG), FAI, and androstenedione (AND) levels than the baseline (P < 0.05). PIOMET therapy improved SHBG and AMH levels more effectively than MET monotherapy (P < 0.05). Furthermore, PIOMET treatment was more effective in improving blood glucose levels at 120 and 180 min of OGIRT compared to MET monotherapy (P < 0.05).
CONCLUSIONS
In normal-weight women with PCOS, PIOMET treatment may have more benefits in improving SHBG, AMH, and postprandial glucose levels than MET monotherapy, and did not affect weight. However, the study findings need to be confirmed in PCOS study populations with larger sample sizes.
Topics: Female; Humans; Metformin; Polycystic Ovary Syndrome; Pioglitazone; Prospective Studies; Testosterone; Luteinizing Hormone; Follicle Stimulating Hormone; Anti-Mullerian Hormone; Metabolome; Glucose
PubMed: 38374053
DOI: 10.1186/s13048-024-01367-7 -
International Immunopharmacology Mar 2024The immune escape stage in cancer immunoediting is a pivotal feature, transitioning immune-controlled tumor dormancy to progression, and augmenting invasion and...
The immune escape stage in cancer immunoediting is a pivotal feature, transitioning immune-controlled tumor dormancy to progression, and augmenting invasion and metastasis. Tumors employ diverse mechanisms for immune escape, with generating immunosuppressive cells from skewed hematopoiesis being a crucial mechanism. This led us to suggest that tumor cells with immune escape properties produce factors that induce dysregulations in hematopoiesis. In support of this suggestion, this study found that mice bearing advanced-stage tumors exhibited dysregulated hematopoiesis characterized by the development of splenomegaly, anemia, extramedullary hematopoiesis, production of immunosuppressive mediators, and expanded medullary myelopoiesis. Further ex vivo studies exhibited that conditioned medium derived from EL4lu2 cells could mediate the expansion of myeloid derived suppressor cells (MDSCs) in bone marrow cell cultures. The protein array profiling results revealed the presence of elevated levels of osteopontin (OPN), prostaglandin E2 (PGE2) and interleukin 17 (IL-17) in the culture medium derived from EL4luc2 cells. Accordingly, substantial levels of these factors were also detected in the sera of mice bearing EL4luc2 tumors. Among these factors, only PGE2 alone could increase the number of MDSCs in the BM cell cultures. This effect of PGE2 was significantly potentiated by the presence of OPN but not IL-17. Finally, in vitro treatment of EL4luc2 cells with pioglitazone, a modulator of OPN and cyclooxygenase 2 (COX-2) resulted in a significant reduction in cell proliferation in EL4luc2 cells. Our findings highlight the significant role played by tumor cell-derived OPN and PGE2 in fostering the expansion of medullary MDSCs and in promoting tumor cell proliferation. Furthermore, these intertwined cancer processes could be key targets for pioglitazone intervention.
Topics: Animals; Mice; Dinoprostone; Myeloid-Derived Suppressor Cells; Osteopontin; Pioglitazone; Tumor Escape
PubMed: 38364741
DOI: 10.1016/j.intimp.2024.111584 -
Journal of Tissue Engineering 2024Osteogenesis is caused by multiple factors, and the inflammatory response, osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), regeneration of...
Osteogenesis is caused by multiple factors, and the inflammatory response, osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), regeneration of blood vessels, and other factors must be considered in bone tissue engineering. To effectively repair bone defect, it is important to decrease excessive inflammation, enhance the differentiation of mesenchymal stem cells into osteoblasts, and stimulate angiogenesis. Herein, nano-attapulgite (ATP), polyvinyl alcohol (PVA), and gelatin (GEL) scaffolds were produced using 3D printing technology and pioglitazone (PIO)-containing polylactic acid-glycolic acid (PLGA) nanospheres were added. In both in vitro and in vivo studies, material scaffolds with PIO-loaded polylactic acid-glycolic acid nanospheres could reduce the inflammatory response by encouraging macrophage polarization from M1 to M2 and promoting the osteogenic differentiation of BMSCs by activating the BMP2/Smad/RUNX2 signal pathway to repair bone defects. The vascularization of human umbilical vein endothelial cells (HUVECs) through the PI3K/AKT/HIF1-/VEGF pathway was also encouraged. In vivo research using PIO-containing PLGA nanospheres revealed massive collagen deposition in skin models. These findings indicate a potentially effective scaffold for bone healing, when PLGA nanospheres-which contain the drug PIO-are combined with ATP/PVA/GEL scaffolds.
PubMed: 38361536
DOI: 10.1177/20417314241231452 -
Medicine and Pharmacy Reports Jan 2024Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, with an increasing prevalence in all regions of the world. Its spectrum includes... (Review)
Review
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, with an increasing prevalence in all regions of the world. Its spectrum includes hepatic steatosis (HS) and non-alcoholic steatohepatitis (NASH) with progression to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). NAFLD may represent the hepatic manifestation of the metabolic syndrome (MS), with a prevalence directly proportional to the prevalence of obesity and MS. The standard treatment for patients with NAFLD is lifestyle modification, which in medical practice has many limitations. To overcome them, numerous drugs with benefits in the prevention and treatment of the disease have been studied. Currently, the most used substances are vitamin E and Pioglitazone, with numerous benefits. Furthermore, new strategies and beneficial treatments are needed for the prevention of the disease, which is currently a priority in both the health and research fields. One of the most studied agents in the last decades has been ursodeoxycholic acid (UDCA), which is of great interest in the treatment of NAFLD due to its hepatoprotective effects.
PubMed: 38344336
DOI: 10.15386/mpr-2629 -
ACS Omega Feb 2024Sixteen novel thiazolidinedione (TZD) and rhodanine (RD) derivatives were designed and synthesized by introducing a pyrimidine moiety at different sites of...
Novel Thiazolidinedione and Rhodanine Derivatives Regulate Glucose Metabolism, Improve Insulin Sensitivity, and Activate the Peroxisome Proliferator-Activated γ Receptor.
Sixteen novel thiazolidinedione (TZD) and rhodanine (RD) derivatives were designed and synthesized by introducing a pyrimidine moiety at different sites of pioglitazone's structure. The effects of synthesized compounds on regulating glucose metabolism, improving insulin sensitivity, and activating the peroxisome proliferator-activated γ receptor (PPAR-γ) were evaluated in βTC6 cells. Compounds TZDs # , , , and reduced the basal insulin secretion by ∼20.0-67.0% and increased insulin secretion stimulated by glucose by ∼25.0-50.0% compared to control. Compounds TZDs # and RDs # and - increased basal insulin secretion by ∼20.0-100.0%, while its glucose-stimulated secretion remained unchanged. These findings suggested that the former compounds can act as antihypoglycemic during fasting and antihyperglycemic during postprandial conditions. The latter compounds should be administered before meals to avoid their hypoglycemic effect. Additionally, both TZDs and RDs improved insulin sensitivity by increasing glucose uptake by 17.0-155.0% relative to control. In silico molecular docking of synthesized drugs onto the PPAR-γ structure revealed exothermic binding modes through hydrogen bonding, van der Waals forces, and π-π stacking with binding affinities of -6.02 to -9.70 kcal/mol. Insights into the structure-activity relationship revealed that the introduction of pyrimidine linked to sulfonyl or peptide groups accounted for increased antidiabetic activity. These results demonstrated novel TZDs and RDs with high potency in stimulating insulin secretion, enhancing insulin sensitivity, and activating PPAR-γ relative to pioglitazone. They are recommended for further development as potential antidiabetic agents.
PubMed: 38343951
DOI: 10.1021/acsomega.3c07149 -
Clinical Diabetes and Endocrinology Feb 2024Due to the progressive decline in β-cell function, it is often necessary to utilize multiple agents with complementary mechanisms of action to address various facets...
BACKGROUND
Due to the progressive decline in β-cell function, it is often necessary to utilize multiple agents with complementary mechanisms of action to address various facets and achieve glycemic control. Thus, this study aimed to evaluate the efficacy and safety of a fixed-dose combination (FDC) of metformin/sitagliptin/pioglitazone (MSP) therapy vs. metformin/sitagliptin (MS) in type 2 diabetes mellitus (T2DM).
METHODS
In this phase 3, multicenter, double-blind study, patients with T2DM who exhibited inadequate glycemic control with HbA1c of 8.0-11.0% while taking ≥1500 mg/day metformin for at least 6 weeks were randomized to receive either FDC of MSP (1000/100/15 mg) or MS (1000/100 mg) per day for 24 weeks. The primary outcome measure was the change in HbA1c, and secondary outcomes included changes in fasting plasma glucose (FPG), postprandial plasma glucose (PPG), and body weight from baseline to 24 weeks along with safety and tolerability.
RESULTS
Among the 236 patients randomized, 207 (87.71%) successfully completed the study. All baseline characteristics were comparable between the FDC of MSP and MS groups. There was a subsequent significant reduction of HbA1c in FDC of MSP (- 1.64) vs. MS (- 1.32); between groups was [- 0.32% (95% CI, - 0.59, - 0.05)], P = 0.0208. Similar reductions were found in FPG [- 13.2 mg/dL (95% CI, - 22.86, - 3.71)], P = 0.0068, and PPG [- 20.83 mg/dL (95% CI, - 34.11, - 7.55)], P = 0.0023. There were no significant changes in body weight. A total of 27 adverse effects (AEs) and one severe AE were reported, none of which were related to the study drug.
CONCLUSION
The FDC of MSP demonstrated significant efficacy in managing glycemic indices and could serve as a valuable tool for physicians in the management of Indian patients with T2DM.
TRIAL REGISTRATION
Clinical Trials Registry of India, CTRI/2021/10/037461.
PubMed: 38336931
DOI: 10.1186/s40842-023-00161-6 -
The Lancet Regional Health. Europe Mar 2024Despite the overall improvement in care, people with type 2 diabetes (T2D) experience an excess risk of end-stage kidney disease. We evaluated the long-term...
Long-term benefits of dapagliflozin on renal outcomes of type 2 diabetes under routine care: a comparative effectiveness study on propensity score matched cohorts at low renal risk.
BACKGROUND
Despite the overall improvement in care, people with type 2 diabetes (T2D) experience an excess risk of end-stage kidney disease. We evaluated the long-term effectiveness of dapagliflozin on kidney function and albuminuria in patients with T2D.
METHODS
We included patients with T2D who initiated dapagliflozin or comparators from 2015 to 2020. Propensity score matching (PSM) was performed to balance the two groups. The primary endpoint was the change in estimated glomerular filtration rate (eGFR) from baseline to the end of observation. Secondary endpoints included changes in albuminuria and loss of kidney function.
FINDINGS
We analysed two matched groups of 6197 patients each. The comparator group included DPP-4 inhibitors (40%), GLP-1RA (22.3%), sulphonylureas (16.1%), pioglitazone (8%), metformin (5.8%), or acarbose (4%). Only 6.4% had baseline eGFR <60 ml/min/1.73 m and 15% had UACR >30 mg/g. During a mean follow-up of 2.5 year, eGFR declined significantly less in the dapagliflozin vs comparator group by 1.81 ml/min/1.73 m (95% C.I. from 1.13 to 2.48; p < 0.0001). The mean eGFR slope was significantly less negative in the dapagliflozin group by 0.67 ml/min/1.73 m/year (95% C.I. from 0.47 to 0.88; p < 0.0001). Albuminuria declined significantly in new-users of dapagliflozin within 6 months and remained on average 44.3 mg/g lower (95% C.I. from -66.9 to -21.7; p < 0.0001) than in new-users of comparators. New-users of dapagliflozin had significantly lower rates of new-onset CKD, loss of kidney function, and a composite renal outcome. Results were confirmed for all SGLT2 inhibitors, in patients without baseline CKD, and when GLP-1RA were excluded from comparators.
INTERPRETATION
Initiating dapagliflozin improved kidney function outcomes and albuminuria in patients with T2D and a low renal risk.
FUNDING
Funded by the Italian Diabetes Society and partly supported by a grant from AstraZeneca.
PubMed: 38328413
DOI: 10.1016/j.lanepe.2024.100847