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

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-κB 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.

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The dipeptidyl peptidase-4 inhibitor teneligliptin improved endothelial dysfunction and insulin resistance in the SHR/NDmcr-cp rat model of metabolic syndrome

Hypertension Research ◽

10.1038/hr.2014.53 ◽

2014 ◽

Vol 37 (7) ◽

pp. 629-635 ◽

Cited By ~ 20

Author(s):

Hironori Nakagami ◽

Zhengda Pang ◽

Takashi Shimosato ◽

Toshinori Moritani ◽

Hitomi Kurinami ◽

...

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Endothelial Dysfunction ◽

Rat Model ◽

Dipeptidyl Peptidase ◽

Dipeptidyl Peptidase 4 ◽

Dipeptidyl Peptidase 4 Inhibitor

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Role of Cannabinoid Receptor Type 1 in Insulin Resistance and Its Biological Implications

International Journal of Molecular Sciences ◽

10.3390/ijms20092109 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2109 ◽

Cited By ~ 6

Author(s):

Arulkumar Nagappan ◽

Jooyeon Shin ◽

Myeong Ho Jung

Keyword(s):

Insulin Resistance ◽

Body Weight ◽

Insulin Sensitivity ◽

Hepatic Steatosis ◽

Cannabinoid Receptor ◽

Inflammatory Responses ◽

Hepatic Insulin Resistance ◽

Leptin Resistance ◽

Peripheral Tissues

Endogenous cannabinoids (ECs) are lipid-signaling molecules that specifically bind to cannabinoid receptor types 1 and 2 (CB1R and CB2R) and are highly expressed in central and many peripheral tissues under pathological conditions. Activation of hepatic CB1R is associated with obesity, insulin resistance, and impaired metabolic function, owing to increased energy intake and storage, impaired glucose and lipid metabolism, and enhanced oxidative stress and inflammatory responses. Additionally, blocking peripheral CB1R improves insulin sensitivity and glucose metabolism and also reduces hepatic steatosis and body weight in obese mice. Thus, targeting EC receptors, especially CB1R, may provide a potential therapeutic strategy against obesity and insulin resistance. There are many CB1R antagonists, including inverse agonists and natural compounds that target CB1R and can reduce body weight, adiposity, and hepatic steatosis, and those that improve insulin sensitivity and reverse leptin resistance. Recently, the use of CB1R antagonists was suspended due to adverse central effects, and this caused a major setback in the development of CB1R antagonists. Recent studies, however, have focused on development of antagonists lacking adverse effects. In this review, we detail the important role of CB1R in hepatic insulin resistance and the possible underlying mechanisms, and the therapeutic potential of CB1R targeting is also discussed.

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