Antidiabetic thiazolidinediones induce ductal differentiation but not apoptosis in pancreatic cancer cells

AIM: Thiazolidinediones (TZD) are a new class of oral antidiabetic drugs that have been shown to inhibit growth of same epithelial cancer cells. Although TZD were found to be ligands for peroxisome proliferator-activated receptor γ (PPARγ), the mechanism by which TZD exert their anticancer effect is presently unclear. In this study, we analyzed the mechanism by which TZD inhibit growth of human pancreatic carcinoma cell lines in order to evaluate the potential therapeutic use of these drugs in pancreatic adenocarcinoma. METHODS: The effects of TZD in pancreatic cancer cells were assessed in anchorage-independent growth assay. Expression of PPARy was measured by reverse-transcription polymerase chain reaction and confirmed by Western blot analysis. PPARy activity was evaluated by transient reporter gene assay. Flow cytometry and DMA fragmentation,assay were used to determine the effect of TZD on cell cycle progression and apoptosis respectively. The effect of TZD on ductal differentiation markers was performed by Western blot. RESULTS: Exposure to TZD inhibited colony formation in a PPARγ-dependent manner. Growth inhibition was linked to G1 phase cell cycle arrest through induction of the ductal differentiation program without any increase of the apoptotic rate. CONCLUSION: TZD treatment in pancreatic cancer cells has potent inhibitory effects on growth by a PPAR-dependent induction of pacreatic ductal differentiation.

Design,synthesis and in vitro evaluation of a series thiazolidinediones analogs as PPAR modulators

A series of thiazolidinediones analogs, as PPAR modulators, were designed, synthesized and evaluated in vitro.

Oral bisphosphonates improve the bone mineral density in men with diabetes with or without thiazolidinediones

Objective: Osteoporosis and type 2 diabetes mellitus (DM) two of the most common chronic conditions and represent major public health burdens. Epidemiological and observational studies indicate that thiazolidinedione (TZD) therapy with rosiglitazone and pioglitazone is associated with an increased risk of fractures and decreased bone mineral density (BMD). To our knowledge, no data are available to evaluate bisphosphonate therapy in thiazolidinedione-treated patients. The aim of this study was to investigate the benefit of bisphosphonates to improve changes in BMD in subjects with DM associated with TZDs. Methods: In a cross-sectional observational study using a retrospective review of electronic medical records, the changes in BMD in subjects with type 2 DM. The study subjects were divided into four groups. First group with DM receiving both TZDs and BPs;second group neither;third group receiving only TZDs and the fourth only BPs. The comparison of annual percent changes in BMD between the groups were carried out. Results: Decreased BMD noted in subjects with DM on TZDs. Bisphosphonates improved BMD in subjects with DM on TZDs. BMD improved in subjects with DM in those not receiving TZDs also. Conclusion: We conclude that concomitant treatment with bisphosphonates improves BMD in subjects with diabetes and on TZDs.

Synthesis of Chiral Hydantoins and Thiazolidinediones via Iridium-Catalyzed Asymmetric Hydrogenation

Herein,we report an iridium-catalyzed asymmetric hydrogenation of hydantoin and thiazolidinedione derived exocyclic alkenes using our developed BiphPHOX as a ligand.The transformation shows good functional group tolerance,and gives the hydrogenated prod-ucts with excellent yields(up to 99%)and enantioselectivities(up to 98%ee).A gram-scale reaction was also carried out,and pro-vided the hydrogenated product in excellent yield with no erosion in enantioselectivity.Finally,the transformation of the hydrogen-ated product provided an efficient approach for the synthesis of the intermediate of a HIV protease inhibitor.

Indirect comparison of efficacy and safety of chiglitazar and thiazolidinedione in patients with type 2 diabetes:A meta-analysis

BACKGROUND Chiglitazar is an emerging pan-agonist of all peroxisome proliferator activated receptors(PPAR)-α,δandγ,and has therapeutic potential for type 2 diabetes(T2D).However,to date,no clinical studies or meta-analyses have compared the efficacy and safety of chiglitazar and traditional PPAR-γagonist thiazolidinediones(TZDs).A meta-analysis concerning this topic is therefore required.AIM To compare the efficacy and safety of chiglitazar and TZD in patients with T2D.METHODS PubMed,Medline,Embase,the Cochrane Central Register of Controlled Trials,Reference Citation Analysis and Clinicaltrial.gov websites were searched from August 1994 to March 2022.Randomized controlled trials(RCTs)of chiglitazar or TZD vs placebo in patients with T2D were included.Indirect comparisons and sensitivity analyses were implemented to evaluate multiple efficacy and safety endpoints of interest.RESULTS We included 93 RCTs that compared TZD with placebo and one that compared chiglitazar with placebo.For efficacy endpoints,the augmented dose of chiglitazar resulted in greater reductions in hemoglobin(Hb)A1c[weighted mean difference(WMD)=-0.15%,95%confidence interval(CI):-0.27 to-0.04%],triglycerides(WMD=-0.17 mmol/L,95%CI:-0.24 to-0.11 mmol/L)and alanine aminotransferase(WMD=-5.25 U/L,95%CI:-8.50 to-1.99 U/L),and a greater increase in homeostasis model assessment-β(HOMA-β)(WMD=17.75,95%CI:10.73-24.77)when compared with TZD treatment.For safety endpoints,the risks of hypoglycemia,edema,bone fractures,upper respiratory tract infection,urinary tract infection,and weight gain were all comparable between the augmented dose of chiglitazar and TZD.In patients with baseline HbA1c≥8.5%,body mass index≥30 kg/m^(2)or diabetes duration<10 years,the HbA1c reduction and HOMA-βincrease were more conspicuous for the augmented dose of chiglitazar compared with TZD.CONCLUSION Augmented dose of chiglitazar,a pan-activator of PPARs,may serve as an antidiabetic agent with preferable glycemic and lipid control,betterβ-cell function preserving capacity,and does not increase the risk of safety concerns when compared with TZD.

Peroxisome proliferator activated receptors at the crossroad of obesity, diabetes, and pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is the fourth cause of cancer death with an overall survival of 5% at five years. The development of PDAC is characteristically associated to the accumulation of distinctive genetic mutations and is preceded by the exposure to several risk factors. Epidemiology has demonstrated that PDAC risk factors may be non-modifiable risks (sex, age, presence of genetic mutations, ethnicity) and modifiable and co-morbidity factors related to the specific habits and lifestyle. Recently it has become evident that obesity and diabetes are two important modifiable risk factors for PDAC. Obesity and diabetes are complex systemic and intertwined diseases and, over the years, experimental evidence indicate that insulin-resistance, alteration of adipokines, especially leptin and adiponectin, oxidative stress and inflammation may play a role in PDAC. Peroxisome proliferator activated receptor-&#x003b3; (PPAR&#x003b3;) is a nuclear receptor transcription factor that is implicated in the regulation of metabolism, differentiation and inflammation. PPAR&#x003b3; is a key regulator of adipocytes differentiation, regulates insulin and adipokines production and secretion, may modulate inflammation, and it is implicated in PDAC. PPAR&#x003b3; agonists are used in the treatment of diabetes and oxidative stress-associated diseases and have been evaluated for the treatment of PDAC. PPAR&#x003b3; is at the cross-road of diabetes, obesity, and PDAC and it is an interesting target to pharmacologically prevent PDAC in obese and diabetic patients.

Insulin sensitizers for the treatment of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD) is the leading cause of liver disease in the Western world and is closely associated with metabolic syndrome,which includes hypertension,central obesity,dyslipidemia and insulin resistance.NAFLD includes a wide spectrum of liver alterations,ranging from simple hepatic steatosis to variable degrees of fibrosis,cirrhosis and even hepatocellular carcinoma.Although the etiology and progression of the disorder remain poorly understood,insulin resistance is considered to play a pivotal role in the pathogenesis.Insulin sensitizers such as biguanides,thiazolidinediones(TZDs),glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase 4 inhibitors have been studied as therapeutic approaches for NAFLD in recent years.Metformin improves insulin sensitivity and serum alanine transaminase and aspartate transaminase(ALT/AST) levels in the majority of subjects; however,it has no significant effect on liver histology.TZDs improve insulin sensitivity,serum ALT/ AST levels and histology in some cases,but there are some concerns about the safety of long-term therapy.Selection of appropriate patients for avoiding side effects and the treatment of underlying disease are themain points.These drugs are the best choice for the treatment of NAFLD in patients with type 2 DM who are also candidates for treatment with an insulin sensitizer.The present review provides an overview of insulin sensitizers in the treatment of NAFLD.

PPARγ activator,rosiglitazone:Is it beneficial or harmful to the cardiovascular system?

Rosiglitazone is a synthetic agonist of peroxisome proliferator-activated receptor γ which is used to improve insulin resistance in patients with type II diabetes. Rosiglitazone exerts its glucose-lowering effects by improving insulin sensitivity. Data from various studies in the past decade suggest that the therapeutic effects of rosiglitazone reach far beyond its use as an insulin sensitizer since it also has other benefits on the cardiovascular system such as improvement of contractile dysfunction, inhibition of the inflammatory response by reducing neutrophil and macrophage accumulation, and the protection of myocardial injury during ischemic/reperfusion in different animal models. Previous clinical studies in type II diabetes patients demonstrated that rosiglitazone played an important role in protecting against arteriosclerosis by normalizing the metabolic disorders and reducing chronic inflammation of the vascular system. Despite these benefits, inconsistent findings have been reported, and growing evidence has demonstrated adverse effects of rosiglitazone on the cardiovascular system, including increased risk of acute myocardial infarction, heart failure and chronic heart failure. As a result, rosiglitazone has been recently withdrawn from EU countries. Nevertheless, the effect of rosiglitazone on ischemic heart disease has not yet been firmly established. Future prospective clinical trials designed for the specific purpose of establishing the cardiovascular benefit or risk of rosiglitazone would be the best way to resolve the uncertainties regarding the safety of rosiglitazone in patients with heart disease.

Peroxisome proliferator-activated receptor gamma as a therapeutic target for hepatocellular carcinoma:Experimental and clinical scenarios

Hepatocellular carcinoma(HCC)is the most common type of liver cancer worldwide.Viral hepatitis is a significant risk factor for HCC,although metabolic syndrome and diabetes are more frequently associated with the HCC.With increasing prevalence,there is expected to be>1 million cases annually by 2025.Therefore,there is an urgent need to establish potential therapeutic targets to cure this disease.Peroxisome-proliferator-activated receptor gamma(PPARγ)is a ligand-activated transcription factor that plays a crucial role in the pathophysiology of HCC.Many synthetic agonists of PPARγsuppress HCC in experimental studies and clinical trials.These synthetic agonists have shown promising results by inducing cell cycle arrest and apoptosis in HCC cells and preventing the invasion and metastasis of HCC.However,some synthetic agonists also pose severe side effects in addition to their therapeutic efficacy.Thus natural PPARγagonists can be an alternative to exploit this potential target for HCC treatment.In this review,the regulatory role of PPARγin the pathogenesis of HCC is elucidated.Furthermore,the experimental and clinical scenario of both synthetic and natural PPARγagonists against HCC is discussed.Most of the available literature advocates PPARγas a potential therapeutic target for the treatment of HCC.

Effectiveness of drug interventions in nonalcoholic fatty liver disease:A network meta-analysis

BACKGROUND Nonalcoholic fatty liver disease(NAFLD)is a major chronic liver disorder worldwide,and there is no established treatment for this disease.We conducted a network meta-analysis(NMA)to compare existing treatments,which include four classes of antidiabetic drugs,and examined the optimum treatments for NAFLD.AIM To compare the effectiveness of different treatments for NAFLD.METHODS An NMA was conducted using Stata 14.0(Corporation LLC,College Station,United States)and R(X643.6.3 version)in this study.Eligible randomized controlled trials(RCTs)were searched in the PubMed,Cochrane Library,Embase,Medline and Web of Science databases from database inception to April 2021.Two researchers independently screened the available studies in strict accordance with inclusion and exclusion criteria.The Cochrane Risk of Bias tool was used to evaluate the risk of bias of the included studies.The variables with and without dimensional differences were calculated as the standardized mean difference and weighted mean difference,respectively.An inconsistency model and“nodesplitting”technique were used to test for inconsistency.Funnel plots were used to evaluate publication bias.RESULTS Twenty-two eligible RCTs involving 1377 participants were eventually included in our analysis.Data were pooled using a random-effects model.Our NMA results revealed that glucagon-like peptide-1 receptor agonists(GLP-1RAs)were the most effective treatment,yielding improvements in hepatic fat content(HFC),alanine aminotransferase(ALT),aspartate aminotransferase(AST),serumγ-glutamyl transferase(GGT)and body weight[surface under the cumulative ranking curve(SUCRA)=99.6%,92.6%,82.8%,92.3%and 99.6%,respectively],while thiazolidinediones(TZDs)were the best intervention for reducing the NAFLD activity score(NAS;SUCRA=98.9%).In addition,moderate performance was observed for the sodium glucose cotransporter-2 inhibitors groups(SUCRA=25.1%,66.2%,63.5%,58.2%and 71.9%for HFC,ALT,AST,GGT and body weight,respectively).However,metformin performed poorly according to most indicators(SUCRA=54.5%,0.3%,19.5%,33.7%,57.7%and 44.3%for HFC,NAS,ALT,AST,GGT and body weight,respectively).CONCLUSION GLP-1RAs may be the optimum choice for most patients with NAFLD.However,TZDs are considered the most effective therapies in NAFLD patients with histological disease activity.

Activation of peroxisome proliferator activated receptor-gamma results in an atheroprotective apolipoprotein profile in HepG2 cells

Background: Insulin resistance is linked to dyslipidemia, characterized by a decrease in high density lipo-proteins and an increase in low density lipoproteins. Thiazolidinediones (TZDs) are insulin-sensitizing agents used to improve glycemic control in patients with type 2 diabetes. Recently, the safety of certain TZD regimens has been questioned because of associated adverse effects on the plasma lipid profile. We examined the effect of a TZD, Ciglitazone, on apolipoprotein synthesis and secretion in human liver HepG2 cells. Methods and Results: The effect of Ciglitazone treatment on apolipoprotein synthesis was addressed at the level of transcription, translation and secretion. RT-PCR showed that Ciglitazone increased the transcription of apoE and apoAI but reduced the levels of apoCI and apoB mRNA. Western blot analysis showed an increase in apoAI and apoE secreted in the cell culture media, whereas the amounts of apoB100 and apoCI were reduced. To confirm that Ciglitazone regulates apolipoprotein translation, its effect on de novo protein synthesis was evaluated by metabolic labeling with [35S]-methionine/cysteine, and a similar pattern of regulation was observed. The change in apolipoprotein levels was not secondary to cholesterol biosynthesis or clearance, since Ciglita-zone did not regulate the transcription of HMGCoA reductase, or the LDL receptor. However, mRNA levels for both PPAR-γ and LXRα were induced, suggesting a role for either or both receptors in modulating the hepatic apolipoprotein profile. The involvement of these nuclear receptor transcription factors was confirmed since direct activation of these receptors by endogenous PPAR-γ ligand, 15d-prostaglandin J2, or LXRα ligand, 22(R)hydroxycholesterol, similarly upregulated apoAI and apoE, but down-regulated apoB100 protein synthesis. Conclusion: Our results suggest that Ciglita-zone treatment results in an atheroprotective lipoprotein profile in liver cells. Thus, while the adipose and muscle tissues may be primary targets in TZD-mediated glucose homeostasis, liver PPAR-γ contributes significantly to the regulation of plasma lipoprotein profile.

Therapeutic strategies for pediatric non-alcoholic fatty liver disease: A challenge for health care providers

Non-alcoholic steato-hepatitis (NASH) is related to insulin resistance and, thus, frequently occurs as part of the metabolic changes that accompany obesity, diabetes and hyperlipidemia. In childhood, the overwhelming boost of obesity and its co-morbidities have lead to the extraordinarily increased prevalence of NASH. Establishing effective therapeutic strategies to treat the disease represents the challenge for hepatologists and gastroenterologists in the next decade. Therapeutic approaches have aimed at treating associated conditions (obesity, insulin resistance, hyperlipemia, etc ) or reducing liver oxidative damage (vitamin E).

Clinical effects of antidiabetic drugs on psoriasis:The perspective of evidence-based medicine

Psoriasis and diabetes shared common underlying pathophysiological mechanisms.Emerging data suggested that antidiabetic medications may improve the psoriasis severity in patients with diabetes mellitus.Several hypoglycemic agents including thiazolidinediones,glucagon-like peptide-1 receptor agonists,dipeptidyl peptidase-4 inhibitors,and biguanides have been reported to make a remarkable reduction in the Psoriasis Area and Severity Index score from baseline.This antipsoriatic effect could be mediated not only by the glucoselowering action of these agents but also via inhibition of keratinocyte over proliferation,increase expression of differentiation markers,suppression the immune inflammatory pathway,and blocking the calcium channels and mitogen-activated protein kinase signaling pathways.On the other hand,there was no significant increase in adverse reactions associated with the treatment of pioglitazone or metformin.However,previous studies often had the relatively short duration of the trials,and did not have enough power to assess recurrence of psoriasis.Potential bias in the study and missing data could undermine the reliability of the results.Therefore,the appropriately randomized controlled studies with large sample sizes and long-term durations in various psoriasis patients are warranted for further support.

The Effects of Insulin Resistance and Inflammation on Renal Proximal Tubule Sodium Transport and Hypertension

Insulin resistance, closely linked to inflammation, is recognized as a key factor in the onset and aggravation of diabetes, cardio-renal syndrome, hypertension, and obesity. In the renal proximal tubule, insulin resistance may increase renal sodium reabsorption, leading to hypertension, edema and sometimes heart failure. Recently some anti-diabetic agents have been shown to have effects on the transporters in renal proximal tubule. Because renal proximal tubule mediates about 70% of sodium reabsorption, it is quite important to clarify the function of renal proximal tubule under insulin resistance and inflammation.

Role of renal proximal tubule transport in thiazolidinedioneinduced volume expansion

Thiazolidinediones （TZDs）, pharmacological activa-tors of peroxisome-proliferator-activated receptors γ （PPARγ）, significantly improve insulin resistance and lower plasma glucose concentrations. However, the use of TZDs is associated with plasma volume expansion, the mechanism of which has been a matter of contro-versy. Originally, PPARγ-mediated enhanced transcrip-tion of the epithelial Na channel （ENaC） γ subunit was thought to play a central role in TZD-induced volume expansion. However, later studies suggested that the activation of ENaC alone could not explain TZD-induced volume expansion. We have recently shown that TZDs rapidly stimulate sodium-coupled bicarbonate absorp-tion from renal proximal tubule （PT） in vitro and in vivo. TZD-induced transport stimulation was dependent on PPARγ/Src/EGFR/ERK, and observed in rat, rabbit and human. However, this stimulation was not observed in mouse PTs where Src/EGFR is constitutively activated. Analysis in mouse embryonic fbroblast cells confrmed the existence of PPARγ/Src-dependent non-genomic signaling, which requires the ligand binding ability but not the transcriptional activity of PPARγ. The TZD-in-duced enhancement of association between PPARγ and Src supports an obligatory role for Src in this signal-ing. These results support the view that TZD-induced volume expansion is multifactorial. In addition to the PPARγ-dependent enhanced expression of the sodium transport system（s） in distal nephrons, the PPARγ-dependent non-genomic stimulation of renal proximal transport may be also involved in TZD-induced volume expansion.

Species differences in regulation of renal proximal tubule transport by certain molecules

Renal proximal tubules （PTs） play important roles in the regulation of acid/base, plasma volume and blood pressure. Recent studies suggest that there are substantial species differences in the regulation of PT transport. For example, thiazolidinediones （TZDs） are widely used for the treatment of type 2 diabetes mellitus, but the use of TZDs is associated with fluid overload. In addition to the transcriptional enhancement of sodium transport in distal nephrons, TZDs rapidly stimulate PT sodium transport via a non-genomic mechanism depending onperoxisome proliferator activated receptor g/Src/epidermal growth factor receptor （EGFR）/MEK/ERK. In mouse PTs, however, TZDs fail to stimulate PT transport probably due to constitutive activation of Src/EGFR/ERK pathway. This unique activation of Src/ERK may also affect the effect of high concentrations of insulin on mouse PT transport. On the other hand, the effect of angiotensin Ⅱ （Ang Ⅱ） on PT transport is known to be biphasic in rabbits, rats, and mice. However, Ang Ⅱ induces a concentration-dependent, monophasic transport stimulation in human PTs. The contrasting responses to nitric oxide/guanosine 3’,5’-cyclic monophosphate pathway may largely explain these different effects of Ang Ⅱ on PT transport. In this review, we focus on the recent fndings on the species differences in the regulation of PT transport, which may help understand the species-specific mechanisms underlying edema formation and/or hypertension occurrence.

Nonalcoholic fatty liver disease:A comprehensive review of a growing epidemic

Nonalcoholic fatty liver disease(NAFLD)is quickly becoming one of the most prominent causes of liver disease worldwide.The increasing incidence of NAFLD is tied to the obesity epidemic and the subsequent metabolic derangements brought along with it.Current efforts to elucidate the mechanism and causes of the disease have answered some questions,but much remains unknown about NAFLD.The aim of this article is to discuss the current knowledge regarding the pathogenesis of the disease,as well as the current and future diagnostic,preventative,and therapeutic options available to clinicians for the management of NAFLD.

Effects of glucose-lowering agents on cardiorespiratory fitness

Exercise therapy is essential for the management of type 2 diabetes(T2 D). However, patients with T2 D show lower physical activity and reduced cardiorespiratory fitness than healthy individuals. It would be ideal for clinicians to co-prescribe glucose-lowering agents that improve cardiorespiratory fitness or exercise capacity in conjunction with exercise therapy. Metformin does not improve cardiorespiratory fitness and may attenuate any beneficial effect of exercise in patients with T2 D. In contrast, thiazolidinediones appear to improve cardiorespiratory fitness in patients with T2 D. Although evidence is limited, sodium–glucose cotransporter 2(SGLT2) inhibitors may improve cardiorespiratory fitness in patients with heart failure, and the effect of glucagon-like peptide-1(GLP-1) receptor agonists on cardiorespiratory fitness is controversial. Recent clinical trials have shown that both SGLT2 inhibitors and GLP-1 receptor agonists exert a favorable effect on cardiovascular disease. It becomes more important to choose drugs that have beneficial effects on the cardiovascular system beyond glucose-lowering effects. Further studies are warranted to determine an ideal glucose-lowering agent combined with exercise therapy for the treatment of T2 D.

Rosiglitazone could improve clinical outcomes after coronary stent implantation in nondiabetic patients with metabolic syndrome

Background Recent studies have shown that thiazolidinediones （TZDs） could reduce in-stent restenosis and improve clinical outcomes in patients with type 2 diabetes after coronary stent implantation. It remains unclear whether nondiabetic patients with metabolic syndrome after stenting could also benefit from the treatment with TZDs. Methods Three hundred and sixty patients with metabolic syndrome who underwent coronary stent implantation were randomly assigned to a rosiglitazone group （n= 180） or a control group （n= 180）. Patients in the rosiglitazone treatment group were treated with rosiglitazone 1 day before coronary stenting （4 mg once daily） and treatment was continued until the 9 months follow-up; while in the control group, patients were treated with placebo 1 day before the procedure and until the 9 months follow-up. Adverse events were death, myocardial infarction and urgent target vessel revascularization within 9 months after coronary stenting. Results One hundred and fifty two patients in the rosiglitazone group and 145 patients in the control group survived during the follow-up. Baseline characteristics among patients in the two groups were well balanced. There was no significant difference in target vessels or the procedure of stent implantation. Compared with the control group, treatment with rosiglitazone was associated with a lower rate of death, myocardial infarction and urgent target vessel revascularization （7.2% vs 14.5%, P=0.044）. Conclusion Rosiglitazone could reduce the risk of the adverse cardiovascular event and improve clinical outcomes in nondiabetic patients with metabolic syndrome after coronary stent implantation.

CMHX008,a PPAR γ partial agonist,enhances insulin sensitivity with minor influences on bone loss

Traditional thiazolidinediones(TZDs),such as rosiglitazone,are peroxisome proliferator-activated receptor g(PPARg)potent agonists that can be used to treat type 2 diabetes but carry unwanted effects,including increased risk for fracture.The present work aimed to compare the insulin-sensitizing efficacies and bone-loss side effects of CMHX008,a novel TZDs-like PPARg partial agonist,with those of rosiglitazone.A TR-FRET PPARg competitive binding assay was used to compare the binding affinity between CMHX008 and rosiglitazone.Mice were administered vehicle,CMHX008 or rosiglitazone for 16 weeks.Mesenchymal stem cells(MSCs)were used to examine differences in differentiation into osteoblasts after compounds treatment.TR-FRET showed lower affinity to PPARg by CMHX008 compared with rosiglitazone.Mice treated with CMHX008 showed insulin sensitization similar to that of mice treated with rosiglitazone,which was related to the significant inhibition of PPARg Ser273 phosphorylation and improved insulin sensitivity by facilitating the phosphorylation of insulin receptor and Akt in adipose tissues.Micro-CT and histomorphometric analyses demonstrated that the degree of trabecular bone loss after treatment with CMHX008 was weaker than that observed with rosiglitazone,as evidenced by consistent changes in BV/TV,Tb.N,Tb.Th,Tb.Sp,and the mineral apposition rate.MSCs treated with CMHX008 showed higher ALP activity and mRNA levels of bone formation markers than did cells treated with rosiglitazone in the osteoblast differentiation test.Thus,CMHX008 showed insulin-sensitizing effects similar to those of rosiglitazone with a lower risk of bone loss,suggesting that PPARg sparing eliminates the skeletal side effects of TZDs while maintaining their insulin-sensitizing properties.