AVE8134, a novel potent PPARα agonist, improves lipid profile and glucose metabolism in dyslipidemic mice and type 2 diabetic rats.
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ABSTRACT:
SUBMITTER: Schafer HL
PROVIDER: S-EPMC4010268 | biostudies-other | 2012 Jan
REPOSITORIES: biostudies-other
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Project description:Diabetic retinopathy (DR) is an eye condition that develops after chronically poorly-managed diabetes, and is presently the main cause for blindness on a global scale. Current treatments for DR such as laser photocoagulation, topical injection of corticosteroids, intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents and vitreoretinal surgery are only applicable at the late stages of DR and there are possibilities of significant adverse effects. Moreover, the forms of treatment available for DR are highly invasive to the eyes. Safer and more effective pharmacological treatments are required for DR treatment, in particular at an early stage. In this review, we cover recently investigated promising oral pharmacotherapies, the methods of which are safer, easier to use, patient-friendly and pain-free, in clinical studies. We especially focus on peroxisome proliferator-activator receptor alpha (PPARα) agonists in which experimental evidence suggests PPARα activation may be closely related to the attenuation of vascular damages, including lipid-induced toxicity, inflammation, an excess of free radical generation, endothelial dysfunction and angiogenesis. Furthermore, oral administration of selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) agonists may induce hepatic fibroblast growth factor 21 expression, indirectly resulting in retinal protection in animal studies. Our review will enable more comprehensive approaches for understanding protective roles of PPARα for the prevention of DR development.
| S-EPMC7589723 | biostudies-literature
Project description:BackgroundIn previous study, we found that coenzyme Q10 (CoQ10) improved glucolipid profile in dyslipidemic individuals, but the mechanism is not yet clear. Adipokines have been demonstrated to be vital targets of metabolic diseases. The hypothesis that adipokines mediate the association of CoQ10 on glucolipid metabolism needs to be further studied in human.MethodsIn this randomized, double-blinded, placebo-controlled trial, 101 dyslipidemic individuals were administrated to 120 mg CoQ10 or placebo for 24 weeks. Anthropometric parameters, glucolipid profile, serum total adiponectin, leptin, and resistin were evaluated at baseline, week 12 and week 24.ResultsCoQ10 treatment significantly increased serum adiponectin levels at week 12 (165 [0, 362] ng/mL, p < 0.001) and at week 24 (523 [0, 1056] ng/mL, p < 0.001]), which was significant different compared with placebo (p < 0.001). The increase of adiponectin was negative associated with decrease in index of homeostasis model assessment of insulin resistance (HOMA-IR, r = - 0.465, p = 0.001), triglyceride (TG, r = - 0.297, p = 0.047), and low-density lipoprotein cholesterol (LDL-c, r = - 0.440, p = 0.002) at week 24 only in CoQ10-treated group. Resistin was reduced by CoQ10 only at week 24 (- 1.19 [- 4.35, 0.00] ng/mL, p < 0.001), which was significant different compared with placebo (p < 0.001). Reduction of resistin was positively correlated with the change in HOMA-IR (r = 0.343, p = 0.021) and TG (r = 0.323, p = 0.030) at week 24 in CoQ10-treated group but not placebo group. Leptin was not influenced by CoQ10 treatment. Mediation analysis indicated that the improvement of HOMA-IR, TG and LDL-c by CoQ10 was mediated by adiponectin but not resistin.ConclusionsOur study shows that CoQ10 ameliorates glucolipid profile and adipokines dysfunction in dyslipidemic patients in 24 weeks' intervention. The beneficial effect of CoQ10 on glucolipid profile was mediated by adiponectin.Trial registrationClinicalTrials.gov, NCT02407548. Registered on April 3, 2015, https://clinicaltrials.gov/ct2/show/NCT02407548 .
| S-EPMC8896379 | biostudies-literature
Project description:Peroxisome proliferator-activated receptor (PPAR)-α/γ dual agonists have been developed to treat metabolic diseases; however, most of them exhibit side effects such as body weight gain and oedema. Therefore, we developed a novel PPARα/γ dual agonist that modulates glucose and lipid metabolism without adverse effects. We synthesised novel compounds composed of coumarine and chalcone, determined their crystal structures, and then examined their binding affinity toward PPARα/γ. We investigated the expression of PPARα and PPARγ target genes by chemicals in HepG2, differentiated 3T3-L1, and C2C12 cells. We examined the effect of chemicals on glucose and lipid metabolism in db/db mice. Only MD001 functions as a PPARα/γ dual agonist in vitro. MD001 increased the transcriptional activity of PPARα and PPARγ, resulting in enhanced expression of genes related to β-oxidation and fatty acid and glucose uptake. MD001 significantly improved blood metabolic parameters, including triglycerides, free fatty acids, and glucose, in db/db mice. In addition, MD001 ameliorated hepatic steatosis by stimulating β-oxidation in vitro and in vivo. Our results demonstrated the beneficial effects of the novel compound MD001 on glucose and lipid metabolism as a PPARα/γ dual agonist. Consequently, MD001 may show potential as a novel drug candidate for the treatment of metabolic disorders.
| S-EPMC6367362 | biostudies-literature
Project description:Effects of ARA290 on glucose homeostasis were studied in type 2 diabetic Goto-Kakizaki (GK) rats. In GK rats receiving ARA290 daily for up to 4 wks, plasma glucose concentrations were lower after 3 and 4 wks, and hemoglobin A1c (Hb A1c) was reduced by ~20% without changes in whole body and hepatic insulin sensitivity. Glucose-stimulated insulin secretion was increased in islets from ARA290-treated rats. Additionally, in response to glucose, carbachol and KCl, islet cytoplasmic free Ca2+ concentrations, [Ca2+]i, were higher and the frequency of [Ca2+]i oscillations enhanced compared with placebo. ARA290 also improved stimulus-secretion coupling for glucose in GK rat islets, as shown by an improved glucose oxidation rate, ATP production and acutely enhanced glucose-stimulated insulin secretion. ARA290 also exerted an effect distal to the ATP-sensitive potassium (KATP) channel on the insulin exocytotic pathway, since the insulin response was improved following islet depolarization by KCl when KATP channels were kept open by diazoxide. Finally, inhibition of protein kinase A completely abolished effects of ARA290 on insulin secretion. In conclusion, ARA290 improved glucose tolerance without affecting hematocrit in diabetic GK rats. This effect appears to be due to improved γ-cell glucose metabolism and [Ca2+]i handling, and thereby enhanced glucose-induced insulin release.
| S-EPMC4818260 | biostudies-literature
Project description:BackgroundDiet acts on the human body through digestion in the stomach and absorption in the intestines. Thus, the emptying of the stomach should be the focus of the research mechanism of the combined medicine and food treatment of diabetes. The emptying function of the stomach and the secretion of related hormones may be the key points of traditional Chinese medicine. In the clinic, Yunvjian is a famous traditional Chinese formula for preventing and curing diabetes. However, the pharmacological action and mechanism of Yunvjian are also need to be probe.ObjectiveTo assess the effect of Yunvjian on glucose, insulin level and gastric emptying function and related hormones on high-fat diet combined with STZ-induced diabetic rats.MethodsHigh-fat diet combined with STZ was used to construct type 2 diabetes mellitus (T2DM) rats model and received a 4-week Yunvjian administration. The animals were divided into 6 groups, respectively, as the Control group, the DM group, the DM + Acarbose group, the DM + YNH group, and the DM + YNL group. Radionuclide single-photon emission computed tomography (SPECT) technology was used to observe the gastric emptying rate and half-empty time; blood was took to test fasting insulin, and then the insulin resistance index (HOMA-IR) was calculated; HE staining was performed to detect islets and gastric antrum, immunohistochemical staining was performed to detect the number and morphology of pancreatic β cells and gastric antrum Cajal cells, and the average optical density was calculated; the expression of ghrelin hormone in gastric antrum and serum was detected by ELISA and immunofluorescence; the expression of GHRS mRNA in gastric antrum was detected by RT-PCR method.ResultsYunvjian could significantly improve the glucose level and insulin function of rats. Compared with the DM group, Yunvjian was beneficial to low fasting blood glucose (FBG) (P < 0.01), increased glucose tolerance, and improved islet function at the same time (P < 0.05). At the same time, compared with the DM group (25.02 ± 0.05, 44 ± 12.33), the emptying rate of the DM + YNH group was significantly faster (64.98 ± 0.12), and the half row time was shortened (26 ± 8.29, P < 0.05). The gastric ghrelin levels in each group of Yunvjian increased with different degrees compared with the DM group (616.2 ± 26.23), especially in the DM + YNH group (863.51 ± 23.76, P < 0.01). Correspondingly, the expression of gastric GHSR mRNA in the DM + YNH and DM + YNL groups increased significantly compared with the DM group (P < 0.01).ConclusionsYunvjian can effectively control glucose and improve islet function, which may be closely related to its influence on gastric emptying function and related hormone secretion regulation.
| S-EPMC9867596 | biostudies-literature
Project description:Gestational diabetes mellitus (GDM) reduces maternal adiponectin and docosahexaenoic acid (DHA) materno-fetal transfer, which may have negative consequences for the offspring. Our aim was to evaluate the effects of the administration of a novel adiponectin agonist (AdipoRon) to GDM rats on the long-term consequences in glycaemia and fatty acids (FA) profile in the offspring. Pregnant rats were randomized to three groups: GDM rats (GDM, n = 8), GDM rats treated with AdipoRon (GDM + ADI, n = 9), and control rats (n = 10). Diabetes was induced with streptozotocin (50 mg/kg) on day 12 of gestation. GDM+ADI received 50 mg/kg/day AdipoRon from day 14 until delivery. Glycaemia and FA profile were determined in mothers and adult offspring (12 weeks old). AdipoRon tended to reduce fasting glucose in diabetic mothers. Diabetic rats presented the foetus with intrauterine growth restriction and higher adiposity, which tried to be counteracted by AdipoRon. In the adult offspring, both GDM + ADI and control animals showed better glucose recovery after oral glucose overload with respect to GDM. DHA in offspring plasma was significantly reduced in both GDM and GDM + ADI compared to controls (P = 0.043). Nevertheless, n-6/n-3 polyunsaturated FA (PUFA) ratio improved in plasma of GDM + ADI adult offspring (GDM: 14.83 ± 0.85a%; GDM + ADI: 11.49 ± 0.58b%; control: 10.03 ± 1.22b%, P = 0.034). Inflammatory markers and oxidative stress were reduced in the adult offspring of AdipoRon-treated mothers. In conclusion, AdipoRon administration to pregnant diabetic rats improved glycaemia in the mothers and long-term glucose tolerance in the offspring. In addition, it tended to reduce excessive foetal fat accumulation and improved n-6/n-3 PUFA ratio significantly in offspring at the adult state.
| S-EPMC8345900 | biostudies-literature
Project description:PurposeThe effects of the tail suspension and reloading on the protein and lipid metabolism in muscle and blood in type 2 diabetes mellitus (T2DM) are unclear. This study evaluated the hypothesis that skeletal muscle catabolism is greater in T2DM than in non-diabetes mellitus (non-DM) rats and that the activity-dependent changes in the intramuscular lipid accumulation and blood lipid profile are poorer in T2DM than in non-DM rats.MethodsT2DM and non-DM rats were suspended for two weeks followed by reloading for two weeks. The muscle and blood were then examined.ResultsIn contrast to our hypothesis, there was no marked difference between the T2DM and non-DM groups in terms of the skeletal muscle catabolism and activity-dependent changes in intramuscular lipid accumulation. However, the blood lipid profile increased in the T2DM group compared to the non-DM group. One interesting finding in this study was the decrease in non-high-density lipoprotein (non-HDL) cholesterol levels after one week of reloading followed by a significant increase in the non-HDL cholesterol levels after two weeks of reloading in the T2DM group.ConclusionThese results suggest that a dramatic increase in activity after a period of inactivity may rapidly improve the blood lipid profile in T2DM rats.
| S-EPMC8327430 | biostudies-literature
Project description:The objective of this study was to evaluate the biological effects of roasted Cashew nuts consumption on biochemical and murinometric parameters in dyslipidemic rats receiving lipid supplementation. Young male rats were randomly assigned to three experimental groups (n = 10). The Control group (CONT) was treated with water, the Dyslipidemic group (DL) received a high fat content emulsion throughout the experiment, and the Dyslipidemic Cashew Nuts group (DLCN) received the same high fat content emulsion throughout the experiment, yet was treated with Cashew nuts. Body parameters, biochemical, hepatic and fecal fatty acid profiles were all evaluated. The levels of total cholesterol and triglycerides were higher in the DL and DLCN groups as compared to the control group. DLCN and CONT presented no difference in HDL levels. DLCN presented higher glycemia levels than the other groups. There was reduction of body fat in DLCN as compared to other groups, but with higher accumulations of liver fat. DLCN presented a reduction in saturated hepatic fatty acids of 20.8%, and an increase of 177% in relation to CONT; there was also a 21% in increase DL for ?9 fatty acids in comparison to CONT. As for fecal fatty acids, there was a lower concentration of polysaturates in DLCN as compared to the other groups. The data showed that the consumption of Cashew nuts by the dyslipidemic animals treated with a hyperlipidic diet induced greater accumulations of liver fat and worsened glycemic levels, despite having reduced visceral fats and increased fecal fat excretion.
| S-EPMC6907795 | biostudies-literature
Project description:Background & aimsNon-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are common clinico-pathological conditions that affect millions of patients worldwide. In this study, the efficacy of saroglitazar, a novel PPARα/γ agonist, was assessed in models of NAFLD/NASH.Methods & resultsHepG2 cells treated with palmitic acid (PA;0.75 mM) showed decreased expression of various antioxidant biomarkers (SOD1, SOD2, glutathione peroxidase and catalase) and increased expression of inflammatory markers (TNFα, IL1β and IL6). These effects were blocked by saroglitazar, pioglitazone and fenofibrate (all tested at 10μM concentration). Furthermore, these agents reversed PA-mediated changes in mitochondrial dysfunction, ATP production, NFkB phosphorylation and stellate cell activation in HepG2 and HepG2-LX2 Coculture studies. In mice with choline-deficient high-fat diet-induced NASH, saroglitazar reduced hepatic steatosis, inflammation, ballooning and prevented development of fibrosis. It also reduced serum alanine aminotransferase, aspartate aminotransferase and expression of inflammatory and fibrosis biomarkers. In this model, the reduction in the overall NAFLD activity score by saroglitazar (3 mg/kg) was significantly more prominent than pioglitazone (25 mg/kg) and fenofibrate (100 mg/kg). Pioglitazone and fenofibrate did not show any improvement in steatosis, but partially improved inflammation and liver function. Antifibrotic effect of saroglitazar (4 mg/kg) was also observed in carbon tetrachloride-induced fibrosis model.ConclusionsSaroglitazar, a dual PPARα/γ agonist with predominant PPARα activity, shows an overall improvement in NASH. The effects of saroglitazar appear better than pure PPARα agonist, fenofibrate and PPARγ agonist pioglitazone.
| S-EPMC6001453 | biostudies-literature
Project description:Slow oxidative muscle, most notably the soleus, is inherently well equipped with the molecular machinery for regulating blood-borne substrates. However, the entire human musculature accounts for only ∼15% of the body's oxidative metabolism of glucose at the resting energy expenditure, despite being the body's largest lean tissue mass. We found the human soleus muscle could raise local oxidative metabolism to high levels for hours without fatigue, during a type of soleus-dominant activity while sitting, even in unfit volunteers. Muscle biopsies revealed there was minimal glycogen use. Magnifying the otherwise negligible local energy expenditure with isolated contractions improved systemic VLDL-triglyceride and glucose homeostasis by a large magnitude, e.g., 52% less postprandial glucose excursion (∼50 mg/dL less between ∼1 and 2 h) with 60% less hyperinsulinemia. Targeting a small oxidative muscle mass (∼1% body mass) with local contractile activity is a potent method for improving systemic metabolic regulation while prolonging the benefits of oxidative metabolism.
| S-EPMC9404652 | biostudies-literature