ArticleDiabetologia2023
Upregulated TGF-β1 contributes to hyperglycaemia in type 2 diabetes by potentiating glucagon signalling.
Article in Diabetologia, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 21 citations in OpenAlex.
- Serum Advanced Glycation End Products as Drivers of Poor Tendon Outcomes in Diabetes? An Emerging Hypothesis and Narrative Review.Endocrinology, diabetes & metabolism · 2026Review
- Morphological and structural alterations in skeletal muscle of STZ-induced diabetic rats revealed by light and electron microscopy.Journal of advanced veterinary and animal research · 2026Article
- Association Between Redox and Inflammatory Biomarkers with the Presence and Severity of Obstructive Sleep Apnea.Medicina (Kaunas, Lithuania) · 2025Article
- Association between lncRNA H19 and osteoporosis in postmenopausal patients with type 2 diabetes mellitus.Journal of orthopaedic surgery and research · 2025Article
- CHIP mediates glucagon action on hepatic glucose production via regulating Smad3 ubiquitination.Diabetes, obesity & metabolism · 2025Article
- Comparative Study: Biguanide-, Sulfonamide-, and Natural Agent-Based Interventions in an In Vivo Experimental Diabetes Model.Medicina (Kaunas, Lithuania) · 2025Article
- Decreased expression of insulin-degrading enzyme increases gluconeogenesis and glucose production in cultured hepatocytes administered with glucagon.Scientific reports · 2025Article
- Multilevel Assessment of Glycemic, Hormonal, and Oxidative Parameters in an Experimental Diabetic Female Rat Model.Biomedicines · 2025Article
- Apple Polyphenol Mitigates Diabetic Nephropathy via Attenuating Renal Dysfunction with Antioxidation in Streptozotocin-Induced Diabetic Rats.Antioxidants (Basel, Switzerland) · 2025Article
- The dichotomic role of cytokines in aging.Biogerontology · 2024Review
- 1-L Transcription of SARS-CoV-2 Spike Protein S1 Subunit.International journal of molecular sciences · 2024Article
- TGF-β1 Signaling Impairs Metformin Action on Glycemic Control.International journal of molecular sciences · 2024Article
- Transcription Factor Forkhead Box O1 Mediates Transforming Growth Factor-β1-Induced Apoptosis in Hepatocytes.The American journal of pathology · 2023Article
- Reciprocal Regulation of Hepatic TGF-β1 and Foxo1 Controls Gluconeogenesis and Energy Expenditure.Diabetes · 2023Article
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Authors and funding
13 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aims/hypothesisGlucagon-stimulated hepatic gluconeogenesis contributes to endogenous glucose production during fasting. Recent studies suggest that TGF-β is able to promote hepatic gluconeogenesis in mice. However, the physiological relevance of serum TGF-β levels to human glucose metabolism and the mechanism by which TGF-β enhances gluconeogenesis remain largely unknown. As enhanced gluconeogenesis is a signature feature of type 2 diabetes, elucidating the molecular mechanisms underlying TGF-β-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-β1 in human type 2 diabetes and the molecular mechanism underlying the action of TGF-β1 in glucose metabolism.
methodsSerum levels of TGF-β1 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-β1 and glucagon signalling. To investigate the role of Smad3, a key signalling molecule downstream of the TGF-β1 receptor, in mediating the effect of TGF-β1 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.
resultsWe observed higher levels of serum TGF-β1 in participants without obesity and with type 2 diabetes than in healthy control participants, which was positively correlated with HbA CONCLUSIONS/
interpretationThe 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.
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