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Journal of Diabetes Investigation May 2024We conducted a 5 year post-trial monitoring study of our previous randomized 24 week, open-label, active-controlled trial that showed beneficial effects of ipragliflozin...
Long-term effects of ipragliflozin and pioglitazone on metabolic dysfunction-associated steatotic liver disease in patients with type 2 diabetes: 5 year observational follow-up of a randomized, 24 week, active-controlled trial: Effect of ipragliflozin in MASLD.
AIMS/INTRODUCTION
We conducted a 5 year post-trial monitoring study of our previous randomized 24 week, open-label, active-controlled trial that showed beneficial effects of ipragliflozin on metabolic dysfunction-associated steatotic liver disease (MASLD), identical to those of pioglitazone.
MATERIALS AND METHODS
In our previous trial, 66 patients with MASLD and type 2 diabetes were randomly assigned to receive either ipragliflozin (n = 32) or pioglitazone (n = 34). Upon its conclusion, 61 patients were monitored for 5 years for outcome measures of MASLD, glycemic, and metabolic parameters. Differences between the two groups were analyzed at baseline, 24 weeks, and 5 years; changes in outcome measures from baseline were also evaluated.
RESULTS
At 5 years, the mean liver-to-spleen attenuation ratio increased by 0.20 (from 0.78 ± 0.24 to 0.98 ± 0.20) in the ipragliflozin group and by 0.26 (from 0.76 ± 0.26 to 1.02 ± 0.20) in the pioglitazone group (P = 0.363). Similarly, ipragliflozin and pioglitazone significantly improved serum aminotransferase, HbA1c, and fasting plasma glucose levels over 5 years. In the ipragliflozin group, significant reductions in body weight and visceral fat area observed at 24 weeks were sustained throughout the 5 years (-4.0%, P = 0.0075 and -7.6%, P = 0.045, respectively). Moreover, ipragliflozin significantly reduced the values of fibrosis markers (serum ferritin and FIB-4 index), was well tolerated, and had a higher continuation rate for 5 years compared with pioglitazone.
CONCLUSIONS
Ipragliflozin and pioglitazone improved MASLD and glycemic parameters over 5 years. In the ipragliflozin group, significant reductions in body weight and visceral fat mass persisted for 5 years.
PubMed: 38775319
DOI: 10.1111/jdi.14246 -
Computational Biology and Chemistry Aug 2024A new series of 2H-chromene-based sulfonamide derivatives 3-12 has been synthesized and characterized using different spectroscopic techniques. The synthesized...
Discovery of novel 6-(piperidin-1-ylsulfonyl)-2H-chromenes targeting α-glucosidase, α-amylase, and PPAR-γ: Design, synthesis, virtual screening, and anti-diabetic activity for type 2 diabetes mellitus.
A new series of 2H-chromene-based sulfonamide derivatives 3-12 has been synthesized and characterized using different spectroscopic techniques. The synthesized 2H-chromenes were synthesized by reacting activated methylene with 5-(piperidin-1-ylsulfonyl)salicylaldehyde through one-step condensation followed by intramolecular cyclization. Virtual screening of the designed molecules on α-glucosidase enzymes (PDB: 3W37 and 3A4A) exhibited good binding affinity suggesting that these derivatives may be potential α-glucosidase inhibitors. In-vitro α-glucosidase activity was conducted firstly at 100 µg/mL, and the results demonstrated good inhibitory potency with values ranging from 90.6% to 96.3% compared to IP = 95.8% for Acarbose. Furthermore, the IC values were determined, and the designed derivatives exhibited inhibitory potency less than 11 µg/mL. Surprisingly, two chromene derivatives 6 and 10 showed the highest potency with IC values of 0.975 ± 0.04 and 0.584 ± 0.02 µg/mL, respectively, compared to Acarbose (IC = 0.805 ± 0.03 µg/mL). Moreover, our work was extended to evaluate the in-vitro α-amylase and PPAR-γ activity as additional targets for diabetic activity. The results exhibited moderate activity on α-amylase and potency as PPAR-γ agonist making it a multiplet antidiabetic target. The most active 2H-chromenes 6 and 10 exhibited significant activity to PPAR-γ with IC values of 3.453 ± 0.14 and 4.653 ± 0.04 µg/mL compared to Pioglitazone (IC = 4.884±0.29 µg/mL) indicating that these derivatives improve insulin sensitivity by stimulating the production of small insulin-sensitive adipocytes. In-silico ADME profile analysis indicated compliance with Lipinski's and Veber's rules with excellent oral bioavailability properties. Finally, the docking simulation was conducted to explain the expected binding mode and binding affinity.
Topics: PPAR gamma; Benzopyrans; Hypoglycemic Agents; alpha-Glucosidases; Diabetes Mellitus, Type 2; Glycoside Hydrolase Inhibitors; alpha-Amylases; Drug Design; Humans; Structure-Activity Relationship; Molecular Structure; Molecular Docking Simulation; Drug Evaluation, Preclinical; Drug Discovery; Dose-Response Relationship, Drug
PubMed: 38772048
DOI: 10.1016/j.compbiolchem.2024.108097 -
Clinical and Translational Science May 2024Pioglitazone is class of thiazolidinediones that activates peroxisome proliferator-activated receptors (PPARs) in adipocytes to improve glucose metabolism and insulin...
Pioglitazone is class of thiazolidinediones that activates peroxisome proliferator-activated receptors (PPARs) in adipocytes to improve glucose metabolism and insulin sensitivity and has been used as a treatment for type 2 diabetes. However, the underlying mechanisms of associated pioglitazone-induced effects remain unclear. Our study aimed to investigate endogenous metabolite alterations associated with pioglitazone administration in healthy male subjects using an untargeted metabolomics approach. All subjects received 30 mg of pioglitazone once daily in the assigned sequence and period. Urine samples were collected before pioglitazone administration and for 24 h after 7 days of administration. A total of 1465 compounds were detected and filtered using a coefficient of variance below 30% and 108 metabolites were significantly altered upon pioglitazone administration via multivariate statistical analysis. Fourteen significant metabolites were identified using authentic standards and public libraries. Additionally, pathway analysis revealed that metabolites from purine and beta-alanine metabolisms were significantly altered after pioglitazone administration. Further analysis of quantification of metabolites from purine metabolism, revealed that the xanthine/hypoxanthine and uric acid/xanthine ratios were significantly decreased at post-dose. Pioglitazone-dependent endogenous metabolites and metabolic ratio indicated the potential effect of pioglitazone on the activation of PPAR and fatty acid synthesis. Additional studies involving patients are required to validate these findings.
Topics: Humans; Male; Pioglitazone; Purines; Adult; Healthy Volunteers; Thiazolidinediones; Metabolomics; Young Adult; Hypoglycemic Agents
PubMed: 38771175
DOI: 10.1111/cts.13834 -
Journal of Molecular Medicine (Berlin,... Jul 2024The development and progression of hyperglycemia (HG) and HG-associated atherosclerosis are exacerbated by mitochondrial dysfunction due to dysregulated...
The development and progression of hyperglycemia (HG) and HG-associated atherosclerosis are exacerbated by mitochondrial dysfunction due to dysregulated mitochondria-derived ROS generation. We recently synthesized a novel mitochondria-targeted esculetin (Mito-Esc) and tested its dose-response therapeutic efficacy in mitigating HG-induced atherosclerosis in db/db mice. In comparison to simvastatin and pioglitazone, Mito-Esc administration resulted in a considerable reduction in body weights and improved glucose homeostasis, possibly by reducing hepatic gluconeogenesis, as indicated by a reduction in glycogen content, non-esterified free fatty acids (NEFA) levels, and fructose 1,6-bisphosphatase (FBPase) activity. Interestingly, Mito-Esc treatment, by regulating phospho-IRS and phospho-AKT levels, greatly improved palmitate-induced insulin resistance, resulting in enhanced glucose uptake in adipocytes and HepG2 cells. Also, and importantly, Mito-Esc administration prevented HG-induced atheromatous plaque formation and lipid accumulation in the descending aorta. In addition, Mito-Esc administration inhibited the HG-mediated increase in VACM, ICAM, and MAC3 levels in the aortic tissue, as well as reduced the serum pro-inflammatory cytokines and markers of senescence. In line with this, Mito-Esc significantly inhibited monocyte adherence to human aortic endothelial cells (HAECs) treated with high glucose and reduced high glucose-induced premature senescence in HAECs by activating the AMPK-SIRT1 pathway. In contrast, Mito-Esc failed to regulate high glucose-induced endothelial cell senescence under AMPK/SIRT1-depleted conditions. Together, the therapeutic efficacy of Mito-Esc in the mitigation of hyperglycemia-induced insulin resistance and the associated atherosclerosis is in part mediated by potentiating the AMPK-SIRT1 axis. KEY MESSAGES: Mito-Esc administration significantly mitigates diabetes-induced atherosclerosis. Mito-Esc improves hyperglycemia (HG)-associated insulin resistance. Mito-Esc inhibits HG-induced vascular senescence and inflammation in the aorta. Mito-Esc-mediated activation of the AMPK-SIRT1 axis regulates HG-induced endothelial cell senescence.
Topics: Animals; Insulin Resistance; Hyperglycemia; Atherosclerosis; Umbelliferones; Humans; Mice; Mitochondria; Male; Hep G2 Cells; Sirtuin 1; Disease Models, Animal; Mice, Inbred C57BL; Glucose
PubMed: 38758435
DOI: 10.1007/s00109-024-02449-1 -
RSC Advances May 2024A new series of 2-imino or 2-oxo-2-chromene-6-sulfonamide derivatives 2-9 with potential anti-diabetic activity were designed and synthesized. The new 6-sulfonamide...
A new series of 2-imino or 2-oxo-2-chromene-6-sulfonamide derivatives 2-9 with potential anti-diabetic activity were designed and synthesized. The new 6-sulfonamide chromenes were synthesized by reacting 3-formyl-4-hydroxybenzenesulfonyl chloride with activated methylene derivatives in the presence of ammonium acetate as a catalyst. The structure of the products was confirmed by spectroscopic analysis. All the designed derivatives 2-9 were evaluated for their activity against α-amylase and exhibited inhibitory percentage values higher than 93% at 100 μg mL. Additionally, the IC values represented a variable degree of activity with two derivatives 2 and 9 exhibiting the most promising derivative results with IC values of 1.76 ± 0.01 and 1.08 ± 0.02 μM, respectively, compared to Acarbose (IC = 0.43 ± 0.01 μM). Additionally, these derivatives showed potency against the α-glucosidase enzyme with IC values of 0.548 ± 0.02 and 2.44 ± 0.09 μg mL, compared to Acarbose (0.604 ± 0.02 μg mL). Moreover, the PPAR-γ transactivation assay revealed that chromene-6-sulfonamide derivatives 2 and 9 exhibited potential PPAR-γ activity with IC values of 3.152 ± 0.03 and 3.706 ± 0.32 μg mL, respectively, compared to Pioglitazone (4.884 ± 0.29 μg mL). This indicates that these derivatives have insulin sensitivity and glucose metabolism activity. The ADMET prediction showed that these derivatives have an acceptable range of oral bioavailability, drug-likeness, and a safe toxicity profile, including being non-cytotoxic, non-mutagenic, non-immunotoxic, and non-carcinogenic. Finally, computational docking analysis demonstrated the ability of these derivatives to interact with α-amylase, α-glucosidase, and PPAR-γ enzymes, with confirmed successful placement due to good binding energy values and various interactions within the pocket.
PubMed: 38746843
DOI: 10.1039/d4ra02143f -
The Journal of the Association of... Jan 2024The efficacy and safety of lobeglitazone sulfate has been reported only in the Korean population, and no study has been conducted in India. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The efficacy and safety of lobeglitazone sulfate has been reported only in the Korean population, and no study has been conducted in India.
MATERIALS AND METHODS
In this 16-week randomized, double-blind, and multicenter study, the efficacy and safety of lobeglitazone sulfate 0.5 mg were evaluated with pioglitazone 15 mg. Type 2 diabetes mellitus (T2DM) patients with ≥7.5% glycated hemoglobin (HbA1c) ≤10.5% and on stable metformin dose were assigned to both treatment arms. The primary outcome was a mean change in HbA1c. Safety assessments included adverse events (AE), home-based glucose monitoring, vital parameters, electrocardiogram (ECG), and laboratory assessments.
RESULTS
A total of 328 subjects were randomized equally in two groups. A statistically significant reduction in HbA1c at week 16 in the lobeglitazone group with the least square (LS) mean change: 1.01 [standard error (SE): 0.09] ( < 0.0001) was seen. The LS mean difference between the two groups was 0.05 (SE: 0.12) [95% confidence interval (CI): -0.18, 0.27], which was statistically significant ( = 0.0013). Statistically significant reductions were also observed in fasting and postprandial glucose. Treatment-emergent Aes (TEAE) were comparable between both groups.
CONCLUSION
Lobeglitazone 0.5 mg once daily was found to be efficacious and safe in the treatment of T2DM in the Indian population. Lobeglitazone significantly improved glycemic parameters and was noninferior to pioglitazone; hence, it could be a promising insulin sensitizer in T2DM management in India.
Topics: Humans; Diabetes Mellitus, Type 2; Metformin; Hypoglycemic Agents; Male; Middle Aged; Double-Blind Method; Female; Thiazolidinediones; Glycated Hemoglobin; Drug Therapy, Combination; India; Pioglitazone; Blood Glucose; Adult; Treatment Outcome; Aged; Pyrimidines
PubMed: 38736072
DOI: 10.59556/japi.71.0445 -
Molecules (Basel, Switzerland) May 2024Fluorescence lifetime imaging microscopy (FLIM) has proven to be a useful method for analyzing various aspects of material science and biology, like the supramolecular...
Fluorescence lifetime imaging microscopy (FLIM) has proven to be a useful method for analyzing various aspects of material science and biology, like the supramolecular organization of (slightly) fluorescent compounds or the metabolic activity in non-labeled cells; in particular, FLIM phasor analysis (phasor-FLIM) has the potential for an intuitive representation of complex fluorescence decays and therefore of the analyzed properties. Here we present and make available tools to fully exploit this potential, in particular by coding via hue, saturation, and intensity the phasor positions and their weights both in the phasor plot and in the microscope image. We apply these tools to analyze FLIM data acquired via two-photon microscopy to visualize: (i) different phases of the drug pioglitazone (PGZ) in solutions and/or crystals, (ii) the position in the phasor plot of non-labelled poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), and (iii) the effect of PGZ or PGZ-containing NPs on the metabolism of insulinoma (INS-1 E) model cells. PGZ is recognized for its efficacy in addressing insulin resistance and hyperglycemia in type 2 diabetes mellitus, and polymeric nanoparticles offer versatile platforms for drug delivery due to their biocompatibility and controlled release kinetics. This study lays the foundation for a better understanding via phasor-FLIM of the organization and effects of drugs, in particular, PGZ, within NPs, aiming at better control of encapsulation and pharmacokinetics, and potentially at novel anti-diabetics theragnostic nanotools.
Topics: Pioglitazone; Nanoparticles; Animals; Cell Line, Tumor; Humans; Microscopy, Fluorescence; Rats; Polylactic Acid-Polyglycolic Acid Copolymer; Hypoglycemic Agents
PubMed: 38731628
DOI: 10.3390/molecules29092137 -
Saudi Journal of Gastroenterology :... May 2024Metabolic dysfunction associated steatotic liver disease (MASLD) is the most common cause of chronic hepatitis in adult and pediatric patients. Adolescents with severe...
BACKGROUND
Metabolic dysfunction associated steatotic liver disease (MASLD) is the most common cause of chronic hepatitis in adult and pediatric patients. Adolescents with severe MASLD can demonstrate a more aggressive disease phenotype as they more commonly develop liver fibrosis than BMI matched adults. Therefore, MASLD is the fastest growing indication for liver transplants in young adults.
METHODS
Pioglitazone has been shown to improve liver histology in adult patients with MASLD, and in some studies, it attenuated liver fibrosis. Despite its perceived efficacy, pioglitazone is not widely used, likely due to its side effect profile, specifically increased weight gain. Topiramate lowers body weight in adolescents and in combination with phentermine, is one of the few FDA-approved medications for the management of obesity in children over 12 years of age. We performed a retrospective review of the outcomes in pediatric patients with severe MASLD, treated with the combined pioglitazone and topiramate therapy.
RESULTS
Here, we report a case series of seven adolescents with severe MASLD and ≥F2 liver fibrosis treated with the combined pioglitazone and topiramate therapy. The combined therapy improved mean serum ALT from 165 ± 80 U/L to 89 ± 62 U/L after 12 months mean duration of treatment. One patient who completed 24 months of the combined therapy demonstrated a decrease in liver stiffness from 8.9 kPa to 5.6 kPa, as assessed by FibroScan elastography. There was a significant increase in body weight during this time, however, body mass index as a percentage of the 95th percentile adjusted for age and gender did not increase significantly, 151 ± 29% vs. 152 ± 28%. Moreover, waist circumference, mid-upper arm circumference, percent body fat, and muscle mass were not significantly different before and after treatment. Serum lipid levels and hemoglobin A1c also did not change with the treatment.
CONCLUSION
In summary, this case series provides encouraging results about the efficacy of the combined pioglitazone and topiramate therapy for the management of adolescents with severe MASLD, which should be further explored in clinical studies.
PubMed: 38726916
DOI: 10.4103/sjg.sjg_428_23 -
Frontiers in Endocrinology 2023The most common cause of infertility and metabolic problems among women of reproductive age is polycystic ovary syndrome (PCOS), a multifaceted disorder. It is an... (Review)
Review
The most common cause of infertility and metabolic problems among women of reproductive age is polycystic ovary syndrome (PCOS), a multifaceted disorder. It is an endocrine disorder that occurs in approximately one in seven women. Among these PCOS patients, two thirds will not ovulate on a regular basis and seek treatment for ovulation induction. The symptoms vary in their severity, namely ovulation disorders, excessive androgen levels, or polycystic ovarian morphology. All these symptoms require a therapeutic approach. Many drugs are used to eradicate PCOS symptoms, like metformin, clomiphene citrate, spironolactone, and pioglitazone. Long-term treatment is required to achieve the desired outcome, which is often accompanied by significant adverse reactions. Some herbs and phytochemicals are equally effective for treating PCOS and produce minimal side effects. Recently, herbal products are gaining popularity due to their wide biological activities, safety, availability, and efficacy. The present review covers aetiology, current treatment, pathophysiology, and detailed pre-clinical and clinical studies on plants and phytochemicals that are proven to be useful for the treatment of symptoms associated with PCOS.
Topics: Polycystic Ovary Syndrome; Humans; Female; Phytotherapy; Phytochemicals; Animals; Plant Extracts
PubMed: 38725974
DOI: 10.3389/fendo.2023.1294406 -
Journal of Pharmacy Practice May 2024Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) help manage type 2 diabetes (T2DM) and may have efficacy in steatotic liver disease. To determine the prevalence...
Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) help manage type 2 diabetes (T2DM) and may have efficacy in steatotic liver disease. To determine the prevalence and clinical impact of GLP-1 RA use in patients with T2DM and liver disease. This was a retrospective study of adult patients with T2DM and nonalcoholic fatty liver disease (NAFLD), nonalcoholic fatty liver (NAFL), or nonalcoholic steatohepatitis (NASH) between 1/1/21-12/31/21. Patients with hepatitis B or C, or on pioglitazone were excluded. Eligible patients treated with a GLP-1 RA were compared to controls. The primary outcome was change in Fibrosis-4 (FIB-4) score, with NAFLD Fibrosis Score (NFS) as a secondary outcome. Follow-up scores were calculated from labs within 3 to 15 months after baseline. Of 242 eligible patients, 79 patients (32.6%) were treated with a GLP-1 RA. At baseline, FIB-4 score was lower and NFS was higher in the GLP-1 RA group vs controls (1.80 vs 2.33; P = .101, .36 vs -.47, P < .001; respectively). At follow up, FIB-4 score decreased to 1.77 in the GLP-1 RA group and increased to 2.71 in controls (P = .045). Follow up NFS was stable in the GLP-1 RA group and increased in the control group (.36 vs -.43; P = .308). Patients treated with GLP-1 RAs had less evidence of liver fibrosis progression compared to no treatment, although the differences were small. These results suggest that treatment with GLP-1 RAs may have clinical impact on slowing liver fibrosis, however results should be confirmed in a larger, more diverse sample.
PubMed: 38720191
DOI: 10.1177/08971900241253661