saroglitazar and Insulin-Resistance

Diabetes mellitus and concomitant dyslipidemia, being referred to as 'diabetic dyslipidemia', are the foremost detrimental factors documented to play a pivotal role in cardiovascular illness. Diabetic dyslipidemia is associated with insulin resistance, high plasma triglyceride levels, low HDL-cholesterol concentration and elevated small dense LDL-cholesterol particles. Maintaining an optimal glucose and lipid levels in patients afflicted with diabetic dyslipidemia could be a major task that might require a well-planned diet-management system and regular physical activity, or otherwise an intake of combined antidiabetic and antihyperlipidemic medications. Synchronized treatment which efficiently controls insulin resistance-associated diabetes mellitus and co-existing dyslipidemia could indeed be a fascinating therapeutic option in the management of diabetic dyslipidemia. Peroxisome proliferator-activated receptors α/γ (PPARα/γ) dual agonists are such kind of drugs which possess therapeutic potentials to treat diabetic dyslipidemia. Nevertheless, PPARα/γ dual agonists like muraglitazar, naveglitazar, tesaglitazar, ragaglitazar and aleglitazar have been reported to have undesirable adverse effects, and their developments have been halted at various stages. On the other hand, a recently introduced PPARα/γ dual agonist, saroglitazar is an emerging therapeutic agent of glitazar class approved in India for the management of diabetic dyslipidemia, and its treatment has been reported to be generally safe and well tolerated.. Some additional and new compounds, at initial and preclinical stages, have been recently reported to possess PPARα/γ dual agonistic potentials with considerable therapeutic efficacy and reduced adverse profile. This review sheds light on the current status of various PPARα/γ dual agonists for the management of diabetic dyslipidemia.

Topics: Diabetes Mellitus, Type 2; Disease Management; Dyslipidemias; Humans; Insulin Resistance; Phenylpropionates; PPAR alpha; PPAR gamma; Pyrroles

NAFLD is characterized by insulin resistance and dysregulated lipid and glucose metabolism. Saroglitazar, a dual peroxisome proliferator activated receptor-α/γ agonist, improves insulin sensitivity, and lipid and glycemic parameters. Saroglitazar improved NASH histology in animal studies. In this randomized controlled clinical trial, we evaluated the efficacy and safety of saroglitazar in patients with NAFLD/NASH.. Saroglitazar 4 mg significantly improved ALT, LFC, insulin resistance, and atherogenic dyslipidemia in participants with NAFLD/NASH. (ClinicalTrials.gov identifier: NCT03061721.).

Topics: Adipose Tissue; Adult; Alanine Transaminase; Alkaline Phosphatase; Aspartate Aminotransferases; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cholesterol, VLDL; Double-Blind Method; Elasticity Imaging Techniques; Female; gamma-Glutamyltransferase; Humans; Insulin Resistance; Liver; Magnetic Resonance Imaging; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Phenylpropionates; PPAR alpha; PPAR gamma; Pyrroles; Triglycerides

Saroglitazar is a dual PPAR-α/γ agonist approved for the treatment of diabetic dyslipidemia. In addition to reduction in atherogenic lipids, it may also contribute to improvement in insulin sensitivity through PPAR-α/γ agonism, which remains unexplored. We conducted a randomized, double-blind, placebo-controlled trial in treatment-naive T2DM individuals with serum triglyceride >150 mg/dL. Participants were randomized to receive either saroglitazar 4 mg or placebo (1:1) daily for 4 months (n = 30). Insulin sensitivity (SI

Topics: Adult; Diabetes Mellitus, Type 2; Double-Blind Method; Endpoint Determination; Female; Glycated Hemoglobin; Humans; Hypertriglyceridemia; Insulin Resistance; Lipids; Male; Phenylpropionates; PPAR alpha; PPAR gamma; Pyrroles

Higher global prevalence of non-alcoholic fatty liver disease (NAFLD) is associated with obesity, steatosis, and insulin resistance (IR), and often progresses to steatohepatitis (NASH). Even after more than twenty years of research, there is still no FDA approved therapy for the treatment of fatty liver disease/NASH though, Saroglitazar - a dual PPAR α/γ agonist has been recently approved as a therapeutic option for the fatty liver disease in India. Hepatoprotective Ayurvedic formulations are widely used and are considered safe. In the present study, C57BL/6 male mice on HFHF diet for four weeks were treated with vehicle, Saroglitazar (3 mg/kg/po), and Hepano - a formulation of five herbs (200 mg/kg/po), at the human equivalent therapeutic doses for additional eight weeks. These animals were evaluated after 12 weeks for obesity, body mass index (BMI), systemic insulin resistance, hyperglycaemia, dyslipidaemia, and hepatic lipid accumulation. Differential liquid chromatography-mass spectrometry (LC-MS/MS) based lipidomics analysis demonstrated significant changes in the different class of lipids [phospholipids, sphingolipids, diglycerides and triglycerides (TG)] in HFHF fed group. The protective effects of both Saroglitazar and Hepano were evident against IR, obesity and in the modulation of different class of lipids in the circulation and hepatic tissue. Saroglitazar reduced TG as well as modulated phospholipids levels, while Hepano modulated only phospholipids, ceramides, oxidised lipids, and had no effect on hepatic or circulating TG levels in HFHF fed mice. In addition, in vitro studies using HepG2, THP1 and LX2 cells demonstrated safety of both the test substances where Hepano possess better anti-inflammatory as well as anti-fibrotic potential. Overall, Saroglitazar seems to be more efficacious than Hepano in the regimen used against HFHF induced IR, obesity, and dyslipidaemia.

Topics: Animals; Cell Line; Diet; Diet, High-Fat; Fatty Liver; Fructose; Humans; Hypolipidemic Agents; Insulin Resistance; Lipid Metabolism; Lipidomics; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Obesity; Phenylpropionates; Pyrroles

Insulin resistance and hepatic lipid accumulation constitute the metabolic underpinning of nonalcoholic steatohepatitis (NASH). We tested the hypothesis that saroglitazar, a PPAR α/γ agonist would improve NASH in the diet-induced animal model of NAFLD. Mice received chow diet and normal water (CDNW) or high fat western diet and ad lib sugar water (WDSW). After 12 weeks, WDSW fed mice were randomized to receive (1) WDSW alone, (2) WDSW + vehicle, (3) WDSW + pioglitazone or (4) WDSW + saroglitazar for an additional 12 weeks. Compared to mice on WDSW and vehicle controls, mice receiving WDSW + saroglitazar had lower weight, lower HOMA-IR, triglycerides, total cholesterol, and ALT. Saroglitazar improved steatosis, lobular inflammation, hepatocellular ballooning and fibrosis stage. NASH resolved in all mice receiving saroglitazar. These effects were at par with or superior to pioglitazone. Molecular analyses confirmed target engagement and reduced oxidative stress, unfolded protein response and fibrogenic signaling. Transcriptomic analysis further confirmed increased PPAR-target expression and an anti-inflammatory effect with saroglitazar. Lipidomic analyses demonstrated that saroglitazar also reduced triglycerides, diglycerides, sphingomyelins and ceramides. These preclinical data provide a strong rationale for developing saroglitazar for the treatment of NASH in humans.

Topics: Animals; Diet, High-Fat; Disease Models, Animal; Dyslipidemias; Endoplasmic Reticulum Stress; Gene Expression Profiling; Insulin Resistance; Liver; Liver Cirrhosis; Metabolomics; Non-alcoholic Fatty Liver Disease; Phenylpropionates; PPAR alpha; PPAR gamma; Pyrroles; Signal Transduction

Insulin resistance (IR) is an important determinant of type-2 diabetes mellitus (T2DM). Free fatty acids (FFAs) induce IR by various mechanisms. A surfeit of circulating FFA leads to intra-myocellular lipid accumulation that induces mitochondrial ROS generation and worsens IR. However, the molecular mechanisms behind are unclear. We identified thioredoxin interacting protein (TxNIP), which is overexpressed in T2DM, to be a promoter of ROS-induced IR. We observed upregulation of TxNIP upon palmitate treatment in skeletal muscle cells that led to ROS generation and Glut-4 downregulation resulting in impaired glucose-uptake. FFA-induced overexpression of TxNIP gene was mediated through the activation of its bona-fide trans activator, ChREBP. Further, Palmitate-induced impairment in AMPK-SIRT-1 pathway resulted in overexpression of ChREBP. While Fenofibrate, abrogated PA-induced TxNIP expression and ROS generation in skeletal muscle cells, Saroglitazar, a dual PPARα/γ-agonist, not only inhibited PA-induced TXNIP expression but also led to greater improvement in glucose uptake. Taken together, TxNIP appears to be an important factor in FFA-induced ROS generation and IR in skeletal muscle cells, which can be modulated for the management of this complex disorder.

Topics: AMP-Activated Protein Kinases; Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Biological Transport, Active; Carrier Proteins; Cell Line; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Fenofibrate; Glucose; Glucose Transporter Type 4; Insulin Resistance; Mice; Muscle Fibers, Skeletal; Nuclear Proteins; Palmitic Acid; Phenylpropionates; Pyrroles; Reactive Oxygen Species; Sirtuin 1; Thioredoxins; Transcription Factors