Beta-klotho in type 2 diabetes mellitus: From pathophysiology to therapeutic strategies
Type 2 diabetes mellitus (T2DM) has become a global health problem with no cure. Despite lifestyle modifications and various pharmaceutical options, the achievement of stable and durable glucose control along with effective prevention of T2DM-related cardiovascular complications remains a challengin...
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| Veröffentlicht in: | Reviews in endocrine & metabolic disorders 2021-12, Vol.22 (4), p.1091-1109 |
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| creator | Hua, Shuang Liu, Qianying Li, Jufei Fan, Mengqi Yan, Kaixuan Ye, Dewei |
| description | Type 2 diabetes mellitus (T2DM) has become a global health problem with no cure. Despite lifestyle modifications and various pharmaceutical options, the achievement of stable and durable glucose control along with effective prevention of T2DM-related cardiovascular complications remains a challenging task in clinical management. With its selective high abundance in metabolic tissues (adipose tissue, liver, and pancreas), β-Klotho is the essential component of fibroblast growth factor (FGF) receptor complexes. It is essential for high-affinity binding of endocrine FGF19 and FGF21 to evoke the signaling cascade actively involved in homeostatic maintenance of glucose metabolism and energy expenditure. In this Review, we discuss the biological function of β-Klotho in the regulation of glucose metabolism and offer mechanistic insights into its involvement in the pathophysiology of T2DM. We review our current understanding of the endocrine axis comprised of β-Klotho and FGFs (FGF19 and FGF21) and its regulatory effects on glucose metabolism under physiological and T2DM conditions. We also highlight advances in the development and preclinical validation of pharmacological compounds that target β-Klotho and/or the β-Klotho-FGFRs complex for the treatment of T2DM. Given the remarkable advances in this field, we also discuss outstanding research questions and the many challenges in the clinical development of β-Klotho-based therapies. |
| doi_str_mv | 10.1007/s11154-021-09661-1 |
| format | Article |
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Despite lifestyle modifications and various pharmaceutical options, the achievement of stable and durable glucose control along with effective prevention of T2DM-related cardiovascular complications remains a challenging task in clinical management. With its selective high abundance in metabolic tissues (adipose tissue, liver, and pancreas), β-Klotho is the essential component of fibroblast growth factor (FGF) receptor complexes. It is essential for high-affinity binding of endocrine FGF19 and FGF21 to evoke the signaling cascade actively involved in homeostatic maintenance of glucose metabolism and energy expenditure. In this Review, we discuss the biological function of β-Klotho in the regulation of glucose metabolism and offer mechanistic insights into its involvement in the pathophysiology of T2DM. We review our current understanding of the endocrine axis comprised of β-Klotho and FGFs (FGF19 and FGF21) and its regulatory effects on glucose metabolism under physiological and T2DM conditions. We also highlight advances in the development and preclinical validation of pharmacological compounds that target β-Klotho and/or the β-Klotho-FGFRs complex for the treatment of T2DM. Given the remarkable advances in this field, we also discuss outstanding research questions and the many challenges in the clinical development of β-Klotho-based therapies.</description><identifier>ISSN: 1389-9155</identifier><identifier>EISSN: 1573-2606</identifier><identifier>DOI: 10.1007/s11154-021-09661-1</identifier><identifier>PMID: 34120289</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Adipose tissue ; Adipose Tissue - metabolism ; Diabetes ; Diabetes mellitus (non-insulin dependent) ; Diabetes Mellitus, Type 2 - drug therapy ; Diabetes Mellitus, Type 2 - metabolism ; Endocrinology ; Energy expenditure ; Energy metabolism ; Fibroblast growth factors ; Fibroblast Growth Factors - metabolism ; Glucose ; Glucose metabolism ; Homeostasis ; Humans ; Hyperglycemia ; Internal Medicine ; Klotho protein ; Liver - metabolism ; Medicine ; Medicine & Public Health ; Metabolism ; Pancreas ; Pathophysiology ; Public health ; Signal Transduction - physiology</subject><ispartof>Reviews in endocrine & metabolic disorders, 2021-12, Vol.22 (4), p.1091-1109</ispartof><rights>The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021</rights><rights>2021. 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Despite lifestyle modifications and various pharmaceutical options, the achievement of stable and durable glucose control along with effective prevention of T2DM-related cardiovascular complications remains a challenging task in clinical management. With its selective high abundance in metabolic tissues (adipose tissue, liver, and pancreas), β-Klotho is the essential component of fibroblast growth factor (FGF) receptor complexes. It is essential for high-affinity binding of endocrine FGF19 and FGF21 to evoke the signaling cascade actively involved in homeostatic maintenance of glucose metabolism and energy expenditure. In this Review, we discuss the biological function of β-Klotho in the regulation of glucose metabolism and offer mechanistic insights into its involvement in the pathophysiology of T2DM. We review our current understanding of the endocrine axis comprised of β-Klotho and FGFs (FGF19 and FGF21) and its regulatory effects on glucose metabolism under physiological and T2DM conditions. We also highlight advances in the development and preclinical validation of pharmacological compounds that target β-Klotho and/or the β-Klotho-FGFRs complex for the treatment of T2DM. 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Despite lifestyle modifications and various pharmaceutical options, the achievement of stable and durable glucose control along with effective prevention of T2DM-related cardiovascular complications remains a challenging task in clinical management. With its selective high abundance in metabolic tissues (adipose tissue, liver, and pancreas), β-Klotho is the essential component of fibroblast growth factor (FGF) receptor complexes. It is essential for high-affinity binding of endocrine FGF19 and FGF21 to evoke the signaling cascade actively involved in homeostatic maintenance of glucose metabolism and energy expenditure. In this Review, we discuss the biological function of β-Klotho in the regulation of glucose metabolism and offer mechanistic insights into its involvement in the pathophysiology of T2DM. We review our current understanding of the endocrine axis comprised of β-Klotho and FGFs (FGF19 and FGF21) and its regulatory effects on glucose metabolism under physiological and T2DM conditions. We also highlight advances in the development and preclinical validation of pharmacological compounds that target β-Klotho and/or the β-Klotho-FGFRs complex for the treatment of T2DM. Given the remarkable advances in this field, we also discuss outstanding research questions and the many challenges in the clinical development of β-Klotho-based therapies.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>34120289</pmid><doi>10.1007/s11154-021-09661-1</doi><tpages>19</tpages><orcidid>https://orcid.org/0000-0003-1295-3063</orcidid></addata></record> |
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| subjects | Adipose tissue Adipose Tissue - metabolism Diabetes Diabetes mellitus (non-insulin dependent) Diabetes Mellitus, Type 2 - drug therapy Diabetes Mellitus, Type 2 - metabolism Endocrinology Energy expenditure Energy metabolism Fibroblast growth factors Fibroblast Growth Factors - metabolism Glucose Glucose metabolism Homeostasis Humans Hyperglycemia Internal Medicine Klotho protein Liver - metabolism Medicine Medicine & Public Health Metabolism Pancreas Pathophysiology Public health Signal Transduction - physiology |
| title | Beta-klotho in type 2 diabetes mellitus: From pathophysiology to therapeutic strategies |
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