| First Author | Xiao Y | Year | 2023 |
| Journal | Diabetologia | Volume | 66 |
| Issue | 6 | Pages | 1142-1155 |
| PubMed ID | 36917279 | Mgi Jnum | J:337741 |
| Mgi Id | MGI:7496150 | Doi | 10.1007/s00125-023-05889-5 |
| Citation | Xiao Y, et al. (2023) Upregulated TGF-beta1 contributes to hyperglycaemia in type 2 diabetes by potentiating glucagon signalling. Diabetologia 66(6):1142-1155 |
| abstractText | AIMS/HYPOTHESIS: Glucagon-stimulated hepatic gluconeogenesis contributes to endogenous glucose production during fasting. Recent studies suggest that TGF-beta is able to promote hepatic gluconeogenesis in mice. However, the physiological relevance of serum TGF-beta levels to human glucose metabolism and the mechanism by which TGF-beta enhances gluconeogenesis remain largely unknown. As enhanced gluconeogenesis is a signature feature of type 2 diabetes, elucidating the molecular mechanisms underlying TGF-beta-promoted hepatic gluconeogenesis would allow us to better understand the process of normal glucose production and the pathophysiology of this process in type 2 diabetes. This study aimed to investigate the contribution of upregulated TGF-beta1 in human type 2 diabetes and the molecular mechanism underlying the action of TGF-beta1 in glucose metabolism. METHODS: Serum levels of TGF-beta1 were measured by ELISA in 74 control participants with normal glucose tolerance and 75 participants with type 2 diabetes. Human liver tissue was collected from participants without obesity and with or without type 2 diabetes for the measurement of TGF-beta1 and glucagon signalling. To investigate the role of Smad3, a key signalling molecule downstream of the TGF-beta1 receptor, in mediating the effect of TGF-beta1 on glucagon signalling, we generated Smad3 knockout mice. Glucose levels in Smad3 knockout mice were measured during prolonged fasting and a glucagon tolerance test. Mouse primary hepatocytes were isolated from Smad3 knockout and wild-type (WT) mice to investigate the underlying molecular mechanisms. Smad3 phosphorylation was detected by western blotting, levels of cAMP were detected by ELISA and levels of protein kinase A (PKA)/cAMP response element-binding protein (CREB) phosphorylation were detected by western blotting. The dissociation of PKA subunits was measured by immunoprecipitation. RESULTS: We observed higher levels of serum TGF-beta1 in participants without obesity and with type 2 diabetes than in healthy control participants, which was positively correlated with HbA(1c) and fasting blood glucose levels. In addition, hyperactivation of the CREB and Smad3 signalling pathways was observed in the liver of participants with type 2 diabetes. Treating WT mouse primary hepatocytes with TGF-beta1 greatly potentiated glucagon-stimulated PKA/CREB phosphorylation and hepatic gluconeogenesis. Mechanistically, TGF-beta1 treatment induced the binding of Smad3 to the regulatory subunit of PKA (PKA-R), which prevented the association of PKA-R with the catalytic subunit of PKA (PKA-C) and led to the potentiation of glucagon-stimulated PKA signalling and gluconeogenesis. CONCLUSIONS/INTERPRETATION: The hepatic TGF-beta1/Smad3 pathway sensitises the effect of glucagon/PKA signalling on gluconeogenesis and synergistically promotes hepatic glucose production. Reducing serum levels of TGF-beta1 and/or preventing hyperactivation of TGF-beta1 signalling could be a novel approach for alleviating hyperglycaemia in type 2 diabetes. |
