Huntington’s disease (HD) is a progressive and fatal neurodegenerative disease caused by CAG repeat expansion in the coding region of huntingtin (HTT) protein. The accumulation of mutant HTT (mHTT) contributes to neurotoxicity by causing autophagy defects and oxidative stress that ultimately lead to neuronal death. Interestingly, epidemiologic studies have demonstrated that the prevalence of type-2 diabetes, a metabolic disease mainly caused by defective insulin signaling, is higher in patients with HD than in healthy controls. Although the precise mechanisms of mHTT-mediated toxicity remain unclear, the blockade of brain insulin signaling may initiate or exacerbate mHTT-induced neurodegeneration. In this study, we used an in vitro HD model to investigate whether neuronal insulin signaling is involved in mHTT-mediated neurotoxicity. Our results demonstrated that mHTT overexpression significantly impairs insulin signaling and causes apoptosis in neuronal cells. However, treatment with liraglutide, a GLP-1 analogue, markedly restores insulin sensitivity and enhances cell viability. This neuroprotective effect may be attributed to the contribution of the upregulated expression of genes associated with endogenous antioxidant pathways to oxidative stress reduction. In addition, liraglutide stimulates autophagy through AMPK activation, which attenuates the accumulation of HTT aggregates within neuronal cells. Our findings collectively suggest that liraglutide can rescue impaired insulin signaling caused by mHTT and that GLP-1 may potentially reduce mHTT-induced neurotoxicity in the pathogenesis of HD.

Huntington's disease (HD) is a progressive and fatal neurodegenerative disease caused by CAG repeat expansion in the coding region of huntingtin (HTT) protein. The accumulation of mutant HTT (mHTT) contributes to neurotoxicity by causing autophagy defects and oxidative stress that ultimately lead to neuronal death. Interestingly, epidemiologic studies have demonstrated that the prevalence of type-2 diabetes, a metabolic disease mainly caused by defective insulin signaling, is higher in patients with HD than in healthy controls. Although the precise mechanisms of mHTT-mediated toxicity remain unclear, the blockade of brain insulin signaling may initiate or exacerbate mHTT-induced neurodegeneration. In this study, we used an in vitro HD model to investigate whether neuronal insulin signaling is involved in mHTT-mediated neurotoxicity. Our results demonstrated that mHTT overexpression significantly impairs insulin signaling and causes apoptosis in neuronal cells. However, treatment with liraglutide, a GLP-1 analogue, markedly restores insulin sensitivity and enhances cell viability. This neuroprotective effect may be attributed to the contribution of the upregulated expression of genes associated with endogenous antioxidant pathways to oxidative stress reduction. In addition, liraglutide stimulates autophagy through AMPK activation, which attenuates the accumulation of HTT aggregates within neuronal cells. Our findings collectively suggest that liraglutide can rescue impaired insulin signaling caused by mHTT and that GLP-1 may potentially reduce mHTT-induced neurotoxicity in the pathogenesis of HD.

Evidence is now revealed that the cytotoxic effect caused by elevated levels of plasma glucose and free fatty acids, also called as glucolipotoxicity, is particularly harmful for pancreatic β-cell. In fact, the mammalian Ste20-like kinase 1 (MST1) can mediate glucolipotoxicity-induced β-cell damages by degradation of pancreatic and duodenal homeobox 1 (PDX-1), which is known to play an essential role in maintaining β-cell function and survival. Interestingly, the activation of the pluripotency-related microRNA cluster miR-302 can protect β-cells from glucolipotoxicity-induced apoptosis. However, few studies have examined the related mechanism in detail. In the present study, we investigated the protective roles of miR-302 on rat pancreatic RINm5F β-cells, and demonstrated that MST1 was confirmed as a target of miR-302. As a result, the activation of miR-302restored the expression of PDX1 by inactivating MST1 thus ameliorating glucolipotoxicity-induced β-cell impairments. In addition, miR-302 also upregulated endogenous antioxidant signaling and autophagic activities during glucolipotoxicity, suggesting the anti-aging process may be also involved in miR-302-mediated protection. In conclusion, our study suggests that miR-302 may serve as a potential target for developing new diagnoses and therapies to reduce glucolipotoxicity in β-cells. Disclosure C. Huang: None. H. Li: None. E. Kornelius: None. Y. Yang: None. H. Ho: None. Y. Bai: None. C. Kuo: None. C. Peng: None. C. Lin: None. Funding Ministry of Science and Technology of Taiwan (105-2314-B-040-013-MY3)