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Dipeptidyl-Peptidase 4 Inhibitor Sitagliptin Ameliorates Hepatic Insulin Resistance by Modulating Inflammation and Autophagy in ob/ob Mice.

ABSTRACT: Obesity and type 2 diabetes are the most common metabolic diseases globally. They are associated with inflammation, oxidative stress, autophagy, and insulin resistance. Sitagliptin, a dipeptidyl-peptidase 4 inhibitor, has been reported to show multiple biological activities beyond the antidiabetic property. This study was aimed at investigating the effect of sitagliptin on hepatic steatosis, insulin resistance, inflammation, and autophagy and exploring the underlying molecular mechanism. In the current study, ob/ob mice, a mouse model of genetic obesity and diabetes, were administered via gavage with sitagliptin 50?mg/kg daily for 4 weeks. Changes in glycolipid metabolism, inflammatory responses, and autophagy in the liver were evaluated. Body weight gain, lipid metabolic disorder, and hepatic steatosis as well as systemic and hepatic insulin sensitivity in ob/ob mice were significantly attenuated after sitagliptin treatment. Furthermore, sitagliptin decreased inflammatory responses by regulating macrophage M1/M2 polarization and inhibiting the activities of NF-?B and JNK. Moreover, sitagliptin increased the levels of phosphorylation of AMPK and decreased those of mTOR. This study indicates that sitagliptin significantly ameliorates the development of hepatic steatosis and insulin resistance in ob/ob mice by inhibiting inflammatory responses and activating autophagy via AMPK/mTOR signaling pathway.

SUBMITTER: Zheng W

PROVIDER: S-EPMC6079465 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Dipeptidyl-Peptidase 4 Inhibitor Sitagliptin Ameliorates Hepatic Insulin Resistance by Modulating Inflammation and Autophagy in ob/ob Mice.

Zheng Wenbin W Zhou Jing J Song Shasha S Kong Wen W Xia Wenfang W Chen Lulu L Zeng Tianshu T Zeng Tianshu T

International journal of endocrinology 20180719

Obesity and type 2 diabetes are the most common metabolic diseases globally. They are associated with inflammation, oxidative stress, autophagy, and insulin resistance. Sitagliptin, a dipeptidyl-peptidase 4 inhibitor, has been reported to show multiple biological activities beyond the antidiabetic property. This study was aimed at investigating the effect of sitagliptin on hepatic steatosis, insulin resistance, inflammation, and autophagy and exploring the underlying molecular mechanism. In the ...[more]

PMID: 30123267

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Project description:IntroductionSaxagliptin, sitagliptin, and vildagliptin are dipeptidyl peptidase-4 (DPP-4) inhibitors widely approved for use in patients with type 2 diabetes. Using a crossover design, the present study compared trough levels of DPP-4 inhibition provided by these agents in a single cohort of patients with type 2 diabetes.MethodsThis was a randomized, placebo-controlled, open-label, five-period crossover study. Eligible patients were 18-65 years of age, either treatment-naïve or off prior antihyperglycemic agent therapy for at least 6 or 12 weeks (depending on the prior therapy), and had glycated hemoglobin (HbA1C) ≥6.5% and ≤10.0%. In separate study periods, patients received 5 mg saxagliptin q.d. (saxa-5), 100 mg sitagliptin q.d. (sita-100), 50 mg vildagliptin q.d. (vilda-50-q.d.), 50 mg vildagliptin b.i.d. (vilda-50-b.i.d.), or placebo for 5 days. The primary endpoint was trough %DPP-4 inhibition, derived by comparing DPP-4 activity 24 h after the Day-5 morning dose with predose activity in the same period and analyzed using a linear mixed-effects model with fixed-effects terms for treatment and period.ResultsMean (range) baseline HbA1C was 7.4% (6.4-9.0%; N = 22). Least-squares (LS) mean trough %DPP-4 inhibition was 73.5%, 91.7%, 28.9%, 90.6%, and 3.5% after saxa-5, sita-100, vilda-50-q.d., vilda-50-b.i.d., and placebo, respectively. In patients treated with sita-100, the LS-mean difference in trough %DPP-4 inhibition was 18.2% greater than with saxa-5 (p < 0.001), 62.9% greater than with vilda-50-q.d. (p < 0.001), 1.1% greater than with vilda-50-b.i.d. (p = 0.128), and 87.8% greater than with placebo (p < 0.001). Mean %DPP-4 inhibition was nearly maximal at 12 h postdose regardless of active treatment. Thus, these between-group comparisons at trough primarily reflected differences in duration of action. Adverse events reported during the study were transient and mild or moderate in intensity.ConclusionOnce daily treatment with sitagliptin provided trough DPP-4 inhibition significantly greater than saxagliptin or vildagliptin administered once daily, and similar to that provided by vildagliptin administered twice daily.

Project description:BackgroundEquine metabolic syndrome (EMS) is a multifactorial pathology gathering insulin resistance, low-grade inflammation and past or chronic laminitis. Among the several molecular mechanisms underlying EMS pathogenesis, increased negative insulin signalling regulation mediated by protein tyrosine phosphatase 1 B (PTP1B) has emerged as a critical axis in the development of liver insulin resistance and general metabolic distress associated to increased ER stress, inflammation and disrupted autophagy. Thus, the use of PTP1B selective inhibitors such as MSI-1436 might be considered as a golden therapeutic tool for the proper management of EMS and associated conditions. Therefore, the present investigation aimed at verifying the clinical efficacy of MSI-1436 systemic administration on liver metabolic balance, insulin sensitivity and inflammatory status in EMS affected horses. Moreover, the impact of MSI-1436 treatment on liver autophagy machinery and associated ER stress in liver tissue has been analysed.MethodsLiver explants isolated from healthy and EMS horses have been treated with MSI-1436 prior to gene and protein expression analysis of main markers mediating ER stress, mitophagy and autophagy. Furthermore, EMS horses have been intravenously treated with a single dose of MSI-1436, and evaluated for their metabolic and inflammatory status.ResultsClinical application of MSI-1436 to EMS horses restored proper adiponectin levels and attenuated the typical hyperinsulinemia and hyperglycemia. Moreover, administration of MSI-1436 further reduced the circulating levels of key pro-inflammatory mediators including IL-1β, TNF-α and TGF-β and triggered the Tregs cells activation. At the molecular level, PTP1B inhibition resulted in a noticeable mitigation of liver ER stress, improvement of mitochondrial dynamics and consequently, a regulation of autophagic response. Similarly, short-term ex vivo treatment of EMS liver explants with trodusquemine (MSI-1436) substantially enhanced autophagy by upregulating the levels of HSC70 and Beclin-1 at both mRNA and protein level. Moreover, the PTP1B inhibitor potentiated mitophagy and associated expression of MFN2 and PINK1. Interestingly, inhibition of PTP1B resulted in potent attenuation of ER stress key mediators' expression namely, CHOP, ATF6, HSPA5 and XBP1.ConclusionPresented findings shed for the first time promising new insights in the development of an MSI-1436-based therapy for proper equine metabolic syndrome intervention and may additionally find potential translational application to human metabolic syndrome treatment.

Dataset Information

Dipeptidyl-Peptidase 4 Inhibitor Sitagliptin Ameliorates Hepatic Insulin Resistance by Modulating Inflammation and Autophagy in ob/ob Mice.

Publications

Dipeptidyl-Peptidase 4 Inhibitor Sitagliptin Ameliorates Hepatic Insulin Resistance by Modulating Inflammation and Autophagy in ob/ob Mice.

Similar Datasets

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