Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Endocrine Disorders
Published in: BMC Endocrine Disorders 1/2021

01-12-2021 | Insulins | Review

Uric acid‐induced pancreatic β-cell dysfunction

Author: Asghar Ghasemi

Published in: BMC Endocrine Disorders | Issue 1/2021

Login to get access

Abstract

Hyperuricemia is associated with insulin resistance, pancreatic β-cell dysfunction and consequently with development of type 2 diabetes. Although a direct relationship between high levels of uric acid (UA) and the development of diabetes is still a controversial issue, there is some evidence that strongly points to pancreatic β-cells damage as a result of high serum UA levels. Here, the mechanisms underlying UA-induced β-cell damage are discussed. Available literature indicates that UA can decrease glucose-stimulated insulin secretion and cause β-cell death. The mechanisms underlying these effects are UA-induced oxidative stress and inflammation within the β-cells. UA also stimulates inducible nitric oxide (NO) synthase (iNOS) gene expression leading to NO-induced β-cell dysfunction. Thus hyperuricemia may potentially cause β-cell dysfunction, leading to diabetes. It may be hypothesized that in hyperuricemic subjects, UA-lowering drugs may be beneficial in preventing diabetes.
Literature
1.
Cho NH, Shaw JE, Karuranga S, Huang Y, da Rocha Fernandes JD, Ohlrogge AW, et al. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract. 2018;138:271–81.PubMedCrossRef
2.
Rutter GA, Pullen TJ, Hodson DJ, Martinez-Sanchez A. Pancreatic beta-cell identity, glucose sensing and the control of insulin secretion. Biochem J. 2015;466(2):203–18.PubMedCrossRef
3.
Jaacks LM, Siegel KR, Gujral UP, Narayan KM. Type 2 diabetes: A 21st century epidemic. Best Pract Res Clin Endocrinol Metab. 2016;30(3):331–43.PubMedCrossRef
4.
Kuo CF, Grainge MJ, Zhang W, Doherty M. Global epidemiology of gout: prevalence, incidence and risk factors. Nat Rev Rheumatol. 2015;11(11):649–62.PubMedCrossRef
5.
Suppiah R, Dissanayake A, Dalbeth N. High prevalence of gout in patients with Type 2 diabetes: male sex, renal impairment, and diuretic use are major risk factors. N Z Med J. 2008;121(1283):43–50.PubMed
6.
Niu SW, Chang KT, Ta A, Chang YH, Kuo IC, Hung CC, et al. Decreased incidence of diabetes in patients with gout using benzbromarone. Rheumatology. 2018;57(9):1574–82.PubMedCrossRef
7.
8.
Maiuolo J, Oppedisano F, Gratteri S, Muscoli C, Mollace V. Regulation of uric acid metabolism and excretion. Int J Cardiol. 2016;213:8–14.PubMedCrossRef
9.
10.
Benn CL, Dua P, Gurrell R, Loudon P, Pike A, Storer RI, et al. Physiology of Hyperuricemia and Urate-Lowering Treatments. Front Med (Lausanne). 2018;5:160.CrossRef
11.
12.
13.
Mandal AK, Mount DB. The molecular physiology of uric acid homeostasis. Annu Rev Physiol. 2015;77:323–45.PubMedCrossRef
14.
15.
Dehghan A, van Hoek M, Sijbrands EJ, Hofman A, Witteman JC. High serum uric acid as a novel risk factor for type 2 diabetes. Diabetes Care. 2008;31(2):361–2.PubMedCrossRef
16.
Krishnan E, Pandya BJ, Chung L, Hariri A, Dabbous O. Hyperuricemia in young adults and risk of insulin resistance, prediabetes, and diabetes: a 15-year follow-up study. Am J Epidemiol. 2012;176(2):108–16.PubMedCrossRef
17.
Bhole V, Choi JW, Kim SW, de Vera M, Choi H. Serum uric acid levels and the risk of type 2 diabetes: a prospective study. Am J Med. 2010;123(10):957–61.PubMedPubMedCentralCrossRef
18.
Juraschek SP, McAdams-Demarco M, Miller ER, Gelber AC, Maynard JW, Pankow JS, et al. Temporal relationship between uric acid concentration and risk of diabetes in a community-based study population. Am J Epidemiol. 2014;179(6):684–91.PubMedPubMedCentralCrossRef
19.
Kodama S, Saito K, Yachi Y, Asumi M, Sugawara A, Totsuka K, et al. Association between serum uric acid and development of type 2 diabetes. Diabetes Care. 2009;32(9):1737–42.PubMedPubMedCentralCrossRef
20.
Lv Q, Meng XF, He FF, Chen S, Su H, Xiong J, et al. High serum uric acid and increased risk of type 2 diabetes: a systemic review and meta-analysis of prospective cohort studies. PLoS One. 2013;8(2):e56864.PubMedPubMedCentralCrossRef
21.
Xu YL, Xu KF, Bai JL, Liu Y, Yu RB, Liu CL, et al. Elevation of serum uric acid and incidence of type 2 diabetes: A systematic review and meta-analysis. Chronic Dis Transl Med. 2016;2(2):81–91.PubMedPubMedCentral
22.
Zhu Y, Hu Y, Huang T, Zhang Y, Li Z, Luo C, et al. High uric acid directly inhibits insulin signalling and induces insulin resistance. Biochem Biophys Res Commun. 2014;447(4):707–14.PubMedCrossRef
23.
Lu J, He Y, Cui L, Xing X, Liu Z, Li X, et al. Hyperuricemia Predisposes to the Onset of Diabetes via Promoting Pancreatic β-Cell Death in Uricase-Deficient Male Mice. 2020;69(6):1149–1163.
24.
Ghasemi A, Norouzirad R. Type 2 diabetes: An updated overview. Critical Reviews™ in Oncogenesis. 2019;24(2):1–10.
25.
Facchini F, Chen YD, Hollenbeck CB, Reaven GM. Relationship between resistance to insulin-mediated glucose uptake, urinary uric acid clearance, and plasma uric acid concentration. Jama. 1991;266(21):3008–11.PubMedCrossRef
26.
27.
Volpe A, Ye C, Hanley AJ, Connelly PW, Zinman B, Retnakaran R. Changes Over Time in Uric Acid in Relation to Changes in Insulin Sensitivity, Beta-Cell Function, and Glycemia. J Clin Endocrinol Metab. 2020;105(3):e651–9.CrossRef
28.
Sluijs I, Holmes MV, van der Schouw YT, Beulens JW, Asselbergs FW, Huerta JM, et al. A Mendelian Randomization Study of Circulating Uric Acid and Type 2 Diabetes. Diabetes. 2015;64(8):3028–36.PubMedCrossRef
29.
Quiñones Galvan A, Natali A, Baldi S, Frascerra S, Sanna G, Ciociaro D, et al. Effect of insulin on uric acid excretion in humans. Am J Physiol. 1995;268(1 Pt 1):E1–5.PubMed
30.
Roncal-Jimenez CA, Lanaspa MA, Rivard CJ, Nakagawa T, Sanchez-Lozada LG, Jalal D, et al. Sucrose induces fatty liver and pancreatic inflammation in male breeder rats independent of excess energy intake. Metabolism. 2011;60(9):1259–70.PubMedPubMedCentralCrossRef
31.
Zhang Y, Yamamoto T, Hisatome I, Li Y, Cheng W, Sun N, et al. Uric acid induces oxidative stress and growth inhibition by activating adenosine monophosphate-activated protein kinase and extracellular signal-regulated kinase signal pathways in pancreatic β cells. Mol Cell Endocrinol. 2013;375(1–2):89–96.PubMedCrossRef
32.
Evans SA, Doblado M, Chi MM, Corbett JA, Moley KH. Facilitative glucose transporter 9 expression affects glucose sensing in pancreatic beta-cells. Endocrinology. 2009;150(12):5302–10.PubMedPubMedCentralCrossRef
33.
34.
Scott FW, Trick KD, Stavric B, Braaten JT, Siddiqui Y. Uric acid-induced decrease in rat insulin secretion. Proc Soc Exp Biol Med. 1981;166(1):123–8.PubMedCrossRef
35.
Lu J, Hou X, Yuan X, Cui L, Liu Z, Li X, et al. Knockout of the urate oxidase gene provides a stable mouse model of hyperuricemia associated with metabolic disorders. Kidney Int. 2018;93(1):69–80.PubMedCrossRef
36.
Simental-Mendía LE, Rodríguez-Morán M, Guerrero-Romero F. Failure of beta-cell function to compensate lack of insulin action in hyperuricemic subjects. Diabetes Metab Res Rev. 2009;25(6):535–41.PubMedCrossRef
37.
Rocić B, Vucić-Lovrencić M, Poje N, Poje M, Bertuzzi F. Uric acid may inhibit glucose-induced insulin secretion via binding to an essential arginine residue in rat pancreatic beta-cells. Bioorg Med Chem Lett. 2005;15(4):1181–4.PubMedCrossRef
38.
Xin Y, Wang K, Jia Z, Xu T, Xu Q, Zhang C, et al. Zurampic Protects Pancreatic β-Cells from High Uric Acid Induced-Damage by Inhibiting URAT1 and Inactivating the ROS/AMPK/ERK Pathways. Cell Physiol Biochem. 2018;47(3):1074–83.PubMedCrossRef
39.
Jia L, Xing J, Ding Y, Shen Y, Shi X, Ren W, et al. Hyperuricemia causes pancreatic β-cell death and dysfunction through NF-κB signaling pathway. PLoS One. 2013;8(10):e78284.PubMedPubMedCentralCrossRef
40.
Xin Y, Zhang H, Jia Z, Ding X, Sun Y, Wang Q, et al. Resveratrol improves uric acid-induced pancreatic β-cells injury and dysfunction through regulation of miR-126. Biomed Pharmacother. 2018;102:1120–6.PubMedCrossRef
41.
Zhang C, Moriguchi T, Kajihara M, Esaki R, Harada A, Shimohata H, et al. MafA is a key regulator of glucose-stimulated insulin secretion. Mol Cell Biol. 2005;25(12):4969–76.PubMedPubMedCentralCrossRef
42.
Worlicek H, Grabner W, Riemann JF. Effects of uric acid on the B cell in the isolated perfused rat pancreas [Abstract]. Res Exp Med (Berl). 1981;178(2):165–75.CrossRef
43.
Robles-Cervantes JA, Ramos-Zavala MG, González-Ortiz M, Martínez-Abundis E, Valencia-Sandoval C, Torres-Chávez A, et al. Relationship between Serum Concentration of Uric Acid and Insulin Secretion among Adults with Type 2 Diabetes Mellitus. Int J Endocrinol. 2011;2011:107904.PubMedPubMedCentralCrossRef
44.
Ding Y, Shi X, Shuai X, Xu Y, Liu Y, Liang X, et al. Luteolin prevents uric acid-induced pancreatic β-cell dysfunction. J Biomed Res. 2014;28(4):292–8.PubMedPubMedCentral
45.
Kanabrocki EL, Third JL, Ryan MD, Nemchausky BA, Shirazi P, Scheving LE, et al. Circadian relationship of serum uric acid and nitric oxide. Jama. 2000;283(17):2240–1.PubMedCrossRef
46.
Khosla UM, Zharikov S, Finch JL, Nakagawa T, Roncal C, Mu W, et al. Hyperuricemia induces endothelial dysfunction. Kidney Int. 2005;67(5):1739–42.PubMedCrossRef
47.
Bahadoran Z, Carlström M, Mirmiran P, Ghasemi A. Nitric oxide: To be or not to be an endocrine hormone? Acta Physiol. 2020;229(1):e13443.CrossRef
48.
Bahadoran Z, Mirmiran P, Ghasemi A. Role of Nitric Oxide in Insulin Secretion and Glucose Metabolism. Trends Endocrinol Metab. 2020;31(2):118–30.PubMedCrossRef
49.
Zharikov S, Krotova K, Hu H, Baylis C, Johnson RJ, Block ER, et al. Uric acid decreases NO production and increases arginase activity in cultured pulmonary artery endothelial cells. Am J Physiol Cell Physiol. 2008;295(5):C1183–90.PubMedPubMedCentralCrossRef
50.
Kang DH, Park SK, Lee IK, Johnson RJ. Uric acid-induced C-reactive protein expression: implication on cell proliferation and nitric oxide production of human vascular cells. J Am Soc Nephrol. 2005;16(12):3553–62.PubMedCrossRef
51.
Choi YJ, Yoon Y, Lee KY, Hien TT, Kang KW, Kim KC, et al. Uric acid induces endothelial dysfunction by vascular insulin resistance associated with the impairment of nitric oxide synthesis. Faseb j. 2014;28(7):3197–204.PubMedCrossRef
52.
Hong Q, Qi K, Feng Z, Huang Z, Cui S, Wang L, et al. Hyperuricemia induces endothelial dysfunction via mitochondrial Na+/Ca2 + exchanger-mediated mitochondrial calcium overload. Cell Calcium. 2012;51(5):402–10.PubMedCrossRef
53.
Nita II, Hershfinkel M, Fishman D, Ozeri E, Rutter GA, Sensi SL, et al. The mitochondrial Na+/Ca2 + exchanger upregulates glucose dependent Ca2 + signalling linked to insulin secretion. PLoS One. 2012;7(10):e46649.PubMedPubMedCentralCrossRef
54.
Nukatsuka M, Yoshimura Y, Nishida M, Kawada J. Allopurinol protects pancreatic beta cells from the cytotoxic effect of streptozotocin: in vitro study. J Pharmacobiodyn. 1990;13(4):259–62.PubMedCrossRef
55.
Cai HY, Wang T, Zhao JC, Sun P, Yan GR, Ding HP, et al. Benzbromarone, an old uricosuric drug, inhibits human fatty acid binding protein 4 in vitro and lowers the blood glucose level in db/db mice. Acta Pharmacol Sin. 2013;34(11):1397–402.PubMedPubMedCentralCrossRef
56.
Butler R, Morris AD, Belch JJ, Hill A, Struthers AD. Allopurinol normalizes endothelial dysfunction in type 2 diabetics with mild hypertension. Hypertension. 2000;35(3):746–51.PubMedCrossRef
57.
Cook DG, Shaper AG, Thelle DS, Whitehead TP. Serum uric acid, serum glucose and diabetes: relationships in a population study. Postgrad Med J. 1986;62(733):1001–6.PubMedPubMedCentralCrossRef
58.
Mazidi M, Katsiki N, Mikhailidis DP, Banach M. The link between insulin resistance parameters and serum uric acid is mediated by adiposity. Atherosclerosis. 2018;270:180–6.PubMedCrossRef
59.
Johnson RJ, Nakagawa T, Sanchez-Lozada LG, Shafiu M, Sundaram S, Le M, et al. Sugar, uric acid, and the etiology of diabetes and obesity. Diabetes. 2013;62(10):3307–15.PubMedPubMedCentralCrossRef
Metadata
Title
Uric acid‐induced pancreatic β-cell dysfunction
Author
Asghar Ghasemi
Publication date
01-12-2021
Publisher
BioMed Central
Published in
BMC Endocrine Disorders / Issue 1/2021
Electronic ISSN: 1472-6823
DOI
https://doi.org/10.1186/s12902-021-00698-6

Other articles of this Issue 1/2021

BMC Endocrine Disorders 1/2021 Go to the issue

Research article

Dynamic behavior of metabolic syndrome progression: a comprehensive systematic review on recent discoveries

Research article

Determination of adrenal hypersecretion in primary Aldosteronism without aldosterone-production adenomas

Case report

Solitary vaginal paraganglioma with mature sacrococcygeal teratoma: a rare case report

Research

Association between vitamin D deficiency and hypothyroidism: results from the National Health and Nutrition Examination Survey (NHANES) 2007–2012

Review

Skin AGEs and diabetic neuropathy

Technical advance

Measurement of salivary testosterone in adolescents and young men with Duchenne muscular dystrophy
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Image Credits