Upregulated TGF-β1 contributes to hyperglycaemia in type 2 diabetes by potentiating glucagon signalling
Authors' conclusion
The hepatic TGF-β1/Smad3 pathway sensitises the effect of glucagon/PKA signalling on gluconeogenesis and synergistically promotes hepatic glucose production. Reducing serum levels of TGF-β1 and/or preventing hyperactivation of TGF-β1 signalling could be a novel approach for alleviating hyperglycaemia in type 2 diabetes.
Study context
- Population
- Humans with and without T2D (serum TGF-β1, liver tissue from participants without obesity); Smad3 knockout and wild-type (WT) mice; mouse primary hepatocytes
- Participants
- 75 vs 74
- Comparison
- T2D vs normal glucose tolerance controls; Smad3 knockout vs WT mice
- T2Dn = 75
- Controln = 74reference
Main finding
As reported in the abstract
- Higher serum TGF-β1 in participants without obesity and with T2D than in healthy controls, positively correlated with HbA1c and fasting blood glucose
- Hyperactivation of CREB and Smad3 signalling in liver of participants with T2D
- TGF-β1 greatly potentiated glucagon-stimulated protein kinase A (PKA)/CREB phosphorylation and hepatic gluconeogenesis in WT mouse primary hepatocytes
- TGF-β1 induced Smad3 binding to PKA-R, preventing PKA-R association with PKA-C and potentiating glucagon-stimulated PKA signalling and gluconeogenesis
Original publication
Upregulated TGF-β1 contributes to hyperglycaemia in type 2 diabetes by potentiating glucagon signalling. Diabetologia. Published 14 March 2023. doi:10.
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