Other
18 Authors
- Pydi SP,
- McMillin SM,
- Wang L,
- Rotman Y,
- Cui Y,
- Liu J,
- Birnbaum MJ,
- Cyphert TJ,
- McGuinness OP,
- Zhu L,
- Finkel T,
- Lee RJ,
- Jain S,
- Rossi M,
- Ma Y,
- Wess J,
- Kaneto H,
- Cohen AH
| First Author | Rossi M | Year | 2018 |
| Journal | J Clin Invest | Volume | 128 |
| Issue | 2 | Pages | 746-759 |
| PubMed ID | 29337301 | Mgi Jnum | J:258399 |
| Mgi Id | MGI:6117900 | Doi | 10.1172/JCI94505 |
| Citation | Rossi M, et al. (2018) Hepatic Gi signaling regulates whole-body glucose homeostasis. J Clin Invest 128(2):746-759 |
| abstractText | An increase in hepatic glucose production (HGP) is a key feature of type 2 diabetes. Excessive signaling through hepatic Gs-linked glucagon receptors critically contributes to pathologically elevated HGP. Here, we tested the hypothesis that this metabolic impairment can be counteracted by enhancing hepatic Gi signaling. Specifically, we used a chemogenetic approach to selectively activate Gi-type G proteins in mouse hepatocytes in vivo. Unexpectedly, activation of hepatic Gi signaling triggered a pronounced increase in HGP and severely impaired glucose homeostasis. Moreover, increased Gi signaling stimulated glucose release in human hepatocytes. A lack of functional Gi-type G proteins in hepatocytes reduced blood glucose levels and protected mice against the metabolic deficits caused by the consumption of a high-fat diet. Additionally, we delineated a signaling cascade that links hepatic Gi signaling to ROS production, JNK activation, and a subsequent increase in HGP. Taken together, our data support the concept that drugs able to block hepatic Gi-coupled GPCRs may prove beneficial as antidiabetic drugs. |
