ArticleNature metabolism2022
β-Klotho promotes glycolysis and glucose-stimulated insulin secretion via GP130.
Article in Nature metabolism, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 37 citations in OpenAlex.
- Quantitative LFQ-DIA proteomics reveals FTH1-MCM5/WNT axis mediated osteoblastic dysfunction via ferroptosis drives diabetic osteoporosis.Scientific reports · 2025Article
- Branched-chain amino acids in muscle growth: mechanisms, physiological functions, and applications.Journal of animal science and biotechnology · 2025Review
- Article
- Klotho in diabetes mellitus: research progress and clinical implications.Frontiers in endocrinology · 2025Review
- Beta-Klotho Protein Expression in Healthy Human Tissues and Liver Biopsies From Patients With MASLD or MASH.Gastro hep advances · 2025Article
- GLP-1 Receptor Agonists Alleviate Diabetic Kidney Injury via β-Klotho-Mediated Ferroptosis Inhibition.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Cell Therapies and Gene Therapy for Diabetes: Current Progress.Current diabetes reviews · 2025Review
- Identification of Novel Proteins Mediating Causal Association Between Smoking and Essential Hypertension: A Mendelian Randomization Study.Journal of the American Heart Association · 2024Article
- Inverse association between serum klotho levels and C-reactive protein levels in the US population: a cross-sectional study.BMC cardiovascular disorders · 2024Article
- The association between circulating phenylalanine and the temporal risk of impaired insulin markers in gestational diabetes mellitus.Molecular genetics and metabolism reports · 2024Article
- Human Menstrual Blood-Derived Stem Cells Protect against Tacrolimus-Induced Islet Dysfunction via Cystathionine β-Synthase Mediated IL-6/STAT3 Inactivation.Biomolecules · 2024Article
- Noninvasive assessment of organ-specific and shared pathways in multi-organ fibrosis using T1 mapping.Nature medicine · 2024Article
- Fibroblast growth factor 21: An emerging pleiotropic regulator of lipid metabolism and the metabolic network.Genes & diseases · 2024Review
- Revisiting the mechanisms linking blood glucose to cognitive impairment: new evidence for the potential important role of klotho.Frontiers in endocrinology · 2024Article
- FGF21-dependent alleviation of cholestasis-induced liver fibrosis by sodium butyrate.Frontiers in pharmacology · 2024Article
- Klotho: A new therapeutic target in diabetic retinopathy?World journal of diabetes · 2023Review
- Periodontitis as a promoting factor of T2D: current evidence and mechanisms.International journal of oral science · 2023Review
- Fibroblast growth factor 21 in metabolic syndrome.Frontiers in endocrinology · 2023Review
- Biological and pharmacological functions of the FGF19- and FGF21-coreceptor beta klotho.Frontiers in endocrinology · 2023Review
Corrections and comments
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Authors and funding
14 authors at 6 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Impaired glucose-stimulated insulin secretion (GSIS) is a hallmark of type-2 diabetes. However, cellular signaling machineries that control GSIS remain incompletely understood. Here, we report that β-klotho (KLB), a single-pass transmembrane protein known as a co-receptor for fibroblast growth factor 21 (FGF21), fine tunes GSIS via modulation of glycolysis in pancreatic β-cells independent of the actions of FGF21. β-cell-specific deletion of Klb but not Fgf21 deletion causes defective GSIS and glucose intolerance in mice and defective GSIS in islets of type-2 diabetic mice is mitigated by adenovirus-mediated restoration of KLB. Mechanistically, KLB interacts with and stabilizes the cytokine receptor subunit GP130 by blockage of ubiquitin-dependent lysosomal degradation, thereby facilitating interleukin-6-evoked STAT3-HIF1α signaling, which in turn transactivates a cluster of glycolytic genes for adenosine triphosphate production and GSIS. The defective glycolysis and GSIS in Klb-deficient islets are rescued by adenovirus-mediated replenishment of STAT3 or HIF1α. Thus, KLB functions as a key cell-surface regulator of GSIS by coupling the GP130 receptor signaling to glucose catabolism in β-cells and represents a promising therapeutic target for diabetes.
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