Roles of β-Cell Hypoxia in the Progression of Type 2 Diabetes

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2024 Apr 27

PMID 38673770

Authors

Kazuya Yamagata

Tomonori Tsuyama

Yoshifumi Sato

Affiliations

Soon will be listed here.

Abstract

Type 2 diabetes is a chronic disease marked by hyperglycemia; impaired insulin secretion by pancreatic β-cells is a hallmark of this disease. Recent studies have shown that hypoxia occurs in the β-cells of patients with type 2 diabetes and hypoxia, in turn, contributes to the insulin secretion defect and β-cell loss through various mechanisms, including the activation of hypoxia-inducible factors, induction of transcriptional repressors, and activation of AMP-activated protein kinase. This review focuses on advances in our understanding of the contribution of β-cell hypoxia to the development of β-cell dysfunction in type 2 diabetes. A better understanding of β-cell hypoxia might be useful in the development of new strategies for treating type 2 diabetes.

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References

Zheng X, Wang X, Ma Z, Gupta Sunkari V, Botusan I, Takeda T . Acute hypoxia induces apoptosis of pancreatic β-cell by activation of the unfolded protein response and upregulation of CHOP. Cell Death Dis. 2012; 3:e322. PMC: 3388238. DOI: 10.1038/cddis.2012.66. View

. Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the Global Burden of Disease Study 2021. Lancet. 2023; 402(10397):203-234. PMC: 10364581. DOI: 10.1016/S0140-6736(23)01301-6. View

Hu Y, Lu H, Li H, Ge J . Molecular basis and clinical implications of HIFs in cardiovascular diseases. Trends Mol Med. 2022; 28(11):916-938. DOI: 10.1016/j.molmed.2022.09.004. View

Cheng K, Ho K, Stokes R, Scott C, Lau S, Hawthorne W . Hypoxia-inducible factor-1alpha regulates beta cell function in mouse and human islets. J Clin Invest. 2010; 120(6):2171-83. PMC: 2877560. DOI: 10.1172/JCI35846. View

Bensellam M, Duvillie B, Rybachuk G, Laybutt D, Magnan C, Guiot Y . Glucose-induced O₂ consumption activates hypoxia inducible factors 1 and 2 in rat insulin-secreting pancreatic beta-cells. PLoS One. 2012; 7(1):e29807. PMC: 3250482. DOI: 10.1371/journal.pone.0029807. View

Puigserver P, Spiegelman B . Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocr Rev. 2003; 24(1):78-90. DOI: 10.1210/er.2002-0012. View

Podkalicka P, Stepniewski J, Mucha O, Kachamakova-Trojanowska N, Dulak J, Loboda A . Hypoxia as a Driving Force of Pluripotent Stem Cell Reprogramming and Differentiation to Endothelial Cells. Biomolecules. 2020; 10(12). PMC: 7759989. DOI: 10.3390/biom10121614. View

Sato Y, Endo H, Okuyama H, Takeda T, Iwahashi H, Imagawa A . Cellular hypoxia of pancreatic beta-cells due to high levels of oxygen consumption for insulin secretion in vitro. J Biol Chem. 2011; 286(14):12524-32. PMC: 3069454. DOI: 10.1074/jbc.M110.194738. View

Semenza G . Hypoxia-inducible factors: coupling glucose metabolism and redox regulation with induction of the breast cancer stem cell phenotype. EMBO J. 2016; 36(3):252-259. PMC: 5286373. DOI: 10.15252/embj.201695204. View

10.

Kahn S, Cooper M, Del Prato S . Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet. 2013; 383(9922):1068-83. PMC: 4226760. DOI: 10.1016/S0140-6736(13)62154-6. View

11.

Weir G, Marselli L, Marchetti P, Katsuta H, Jung M, Bonner-Weir S . Towards better understanding of the contributions of overwork and glucotoxicity to the beta-cell inadequacy of type 2 diabetes. Diabetes Obes Metab. 2009; 11 Suppl 4:82-90. DOI: 10.1111/j.1463-1326.2009.01113.x. View

12.

Carlsson P, Liss P, Andersson A, Jansson L . Measurements of oxygen tension in native and transplanted rat pancreatic islets. Diabetes. 1998; 47(7):1027-32. DOI: 10.2337/diabetes.47.7.1027. View

13.

Nomoto H, Pei L, Montemurro C, Rosenberger M, Furterer A, Coppola G . Activation of the HIF1α/PFKFB3 stress response pathway in beta cells in type 1 diabetes. Diabetologia. 2019; 63(1):149-161. PMC: 6945783. DOI: 10.1007/s00125-019-05030-5. View

14.

Pillai R, Paglialunga S, Hoang M, Cousteils K, Prentice K, Bombardier E . Deletion of ARNT/HIF1β in pancreatic beta cells does not impair glucose homeostasis in mice, but is associated with defective glucose sensing ex vivo. Diabetologia. 2015; 58(12):2832-42. PMC: 6338330. DOI: 10.1007/s00125-015-3768-4. View

15.

Bensellam M, Maxwell E, Chan J, Luzuriaga J, West P, Jonas J . Hypoxia reduces ER-to-Golgi protein trafficking and increases cell death by inhibiting the adaptive unfolded protein response in mouse beta cells. Diabetologia. 2016; 59(7):1492-1502. DOI: 10.1007/s00125-016-3947-y. View

16.

Sato Y, Inoue M, Yoshizawa T, Yamagata K . Moderate hypoxia induces β-cell dysfunction with HIF-1-independent gene expression changes. PLoS One. 2014; 9(12):e114868. PMC: 4264765. DOI: 10.1371/journal.pone.0114868. View

17.

Hudish L, Reusch J, Sussel L . β Cell dysfunction during progression of metabolic syndrome to type 2 diabetes. J Clin Invest. 2019; 129(10):4001-4008. PMC: 6763241. DOI: 10.1172/JCI129188. View

18.

Fex M, Nicholas L, Vishnu N, Medina A, Sharoyko V, Nicholls D . The pathogenetic role of β-cell mitochondria in type 2 diabetes. J Endocrinol. 2018; 236(3):R145-R159. DOI: 10.1530/JOE-17-0367. View

19.

Jonas J, Bensellam M, Duprez J, Elouil H, Guiot Y, Pascal S . Glucose regulation of islet stress responses and beta-cell failure in type 2 diabetes. Diabetes Obes Metab. 2009; 11 Suppl 4:65-81. DOI: 10.1111/j.1463-1326.2009.01112.x. View

20.

Cataldo L, Singh T, Achanta K, Bsharat S, Prasad R, Luan C . MAFA and MAFB regulate exocytosis-related genes in human β-cells. Acta Physiol (Oxf). 2022; 234(2):e13761. DOI: 10.1111/apha.13761. View