Decreased incidence of diabetes in patients with gout using benzbromarone

Niu, Sheng‐Wen; Chang, Kai-Ting; Ta, Albert; Chang, Yo-Chen; Kuo, I‐Ching; Hung, Chi‐Chih; Chiu, Yi‐Wen; Hwang, Shang‐Jyh; Lin, Sheng-Fung; Lin, Hugo You-Hsien

doi:10.1093/rheumatology/key138

Cited by 19 publications

(18 citation statements)

References 43 publications

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“…Randomized trials have reported that ULT by allopurinol improves insulin resistance in asymptomatic HU individuals ( 27 , 28 ), and similar improvement in insulin resistance has been observed with the use of benzbromarone ( 29 ). However, in a gout population, the incidence of diabetes was lower in urate-lowering drug (ULD) users than in nonusers ( 30 ). In vivo study showed oral administration of ULD dose-dependently reduced the blood glucose level and improved glucose tolerance and insulin resistance in db / db mice ( 31 ).…”

Section: Discussionmentioning

confidence: 99%

Hyperuricemia Predisposes to the Onset of Diabetes via Promoting Pancreatic β-Cell Death in Uricase-Deficient Male Mice

Lü¹,

He²,

Cui³

et al. 2020

Diabetes

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Clinical studies have shown a link between hyperuricemia (HU) and diabetes, while the exact effect of soluble serum urate on glucose metabolism remains elusive. This study aims to characterize the glucose metabolic phenotypes and investigate the underlying molecular mechanisms using a novel spontaneous HU mouse model in which the uricase ( Uox ) gene is absent. In an attempt to study the role of HU in glycometabolism, we implemented external stimulation on Uox knockout (KO) and wild-type (WT) males with a high-fat diet (HFD) and/or injections of multiple low-dose streptozotocin (MLD-STZ) to provoke the potential role of urate. Notably, while Uox- KO mice developed glucose intolerance in the basal condition, no mice spontaneously developed diabetes, even with aging. HFD-fed Uox- KO mice manifested similar insulin sensitivity compared with WT controls. HU augmented the existing glycometabolism abnormality induced by MLD-STZ and eventually led to diabetes, as evidenced by the increased random glucose. Reduced β-cell masses and increased terminal deoxynucleotidyl TUNEL-positive β-cells suggested that HU-mediated diabetes was cell death dependent. However, urate-lowering therapy (ULT) cannot ameliorate the diabetes incidence or reverse β-cell apoptosis with significance. ULT displayed a significant therapeutic effect of HU-crystal–associated kidney injury and tubulointerstitial damage in diabetes. Moreover, we present transcriptomic analysis of isolated islets, using Uox -KO versus WT mice and streptozotocin-induced diabetic WT (STZ-WT) versus diabetic Uox -KO (STZ-KO) mice. Shared differentially expressed genes of HU primacy revealed Stk17β is a possible target gene in HU-related β-cell death. Together, this study suggests that HU accelerates but does not cause diabetes by inhibiting islet β-cell survival.

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Section: Discussionmentioning

confidence: 99%

Hyperuricemia Predisposes to the Onset of Diabetes via Promoting Pancreatic β-Cell Death in Uricase-Deficient Male Mice

Lü¹,

He²,

Cui³

et al. 2020

Diabetes

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“…Moreover, experimental studies demonstrated that uric acid could directly impair insulin signaling by interfering with it at receptor level42 and raising uric acid with fructose could cause insulin resistance 43. In addition, evidence from human intervention studies indicated that uric acid-lowering treatment could improve insulin resistance in chronic heart failure subjects with hyperuricemia44 and decrease diabetes risk in patients with gout,45 while other intervention study showed that urate acid-lowering agent could not improve endothelial function in type 2 diabetes cases 46. Although numerous studies indicated that uric acid plays an important role in the development of diabetes,43 45 47 however, evidences also suggested that uric acid was also related to diabetes risk markers5 48 49 and uric acid might only play bystander role in diabetes risk.…”

Section: Discussionmentioning

confidence: 99%

Mendelian randomization study of serum uric acid levels and diabetes risk: evidence from the Dongfeng-Tongji cohort

Keerman

Yang

et al. 2020

BMJ Open Diab Res Care

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ObjectiveLimited Mendelian randomization (MR) studies have assessed the causal relationship between serum uric acid levels and diabetes risk. Here we investigated causality between the serum uric acid concentration and diabetes risk in Chinese population.Research design and methodsThe observational analysis, based on the Dongfeng-Tongji prospective cohort (n=15 195) we tested the association of serum uric acid levels with incident diabetes risk. In the instrumental variable analysis, we examined the association of the genetic risk score (GRS) of serum uric acid with diabetes risk in case-control design (2539 cases and 4595 controls) via MR analysis.ResultsDuring a mean (SD) follow-up of 4.5 (0.5) years, 1156 incident diabetes cases were identified. Compared with those in the lowest quintile of serum uric acid levels, the HRs of incident diabetes were 1.19 (95% CI 0.96 to 1.48), 1.12 (95% CI 0.90 to 1.40), 1.38 (95% CI 1.12 to 1.70), and 1.51 (95% CI 1.23 to 1.87) for Q2, Q3, Q4 and Q5, respectively (P-trend <0.001). The GRS was strongly associated with serum uric acid levels (β=0.17, 95% CI 0.15 to 0.19; P=2.81×10-67). However, no significant association was observed between the GRS and diabetes risk (OR=1.01, 95 CI 0.95 to 1.06; P=0.75).ConclusionsEven though serum uric acid levels were significantly associated with increased incident diabetes risk, the results did not provide evidence for a causal relationship between them.

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“…Recently, serum uric acid (SUA) has been regarded as a risk factor for T2DM (Kodama et al, 2009) since hyperuricemia stimulates insulin secretion and aggravates insulin resistance (Hu et al, 2018;Zhong et al, 2019). A clinical study from 8,678 patients with gout reports that uric acid-lowering therapy improves insulin resistance and reduces the incidence of T2DM (Niu et al, 2018). However, a meta-analysis included six trials with 455 patients suggests that uric acid-lowering therapy with allopurinol may be effective at reducing glycemia, but such an improvement does not observed in patients with diabetes (Chen et al, 2020) , suggesting that the significance of uric acid to T2DM might not be restricted to the incidence.…”

Section: Introductionmentioning

confidence: 99%

The association between serum uric acid and diabetic complications in patients with type 2 diabetes mellitus by gender: a cross-sectional study

Qing-e

Min

et al. 2021

PeerJ

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Background The relationship between serum uric acid (SUA) and several diabetic complications or co-morbidities remains a matter of debate. The study aims to explore the association between SUA levels and the prevalence of non-alcoholic fatty liver disease (NAFLD), diabetic retinopathy (DR), diabetic nephropathy (DN) and diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes mellitus (T2DM). Methods A total of 2,809 participants (1,784 males and 1,025 females) were included in this cross-sectional study. Clinical characteristics and the prevalence of each of the four diseases were analyzed based on gender-specific quartiles of SUA levels. The Pearson correlation analysis and linear-regression analysis were used to access the correlation between SUA levels and clinical characteristics. Furthermore, a binary logistic regression analysis was carried out to determine whether SUA was an independent risk factor for each of the four complications. Results SUA levels were positively correlated to BMI, BUN, Scr and TG, but negatively associated with eGFR, HDL, FBG, 2h-PG and HbA1c% for the patients with T2DM. The prevalence of NAFLD and DN, but not DR or DPN, were increased with SUA levels from the first to the fourth quartile. Binary logistic regression further disclosed that SUA was an independent risk factor for NAFLD (ORs Male = 1.002, ∗P = 0.0013; ORs Female = 1.002, ∗P = 0.015) and DN (ORs Male = 1.006, ∗P < 0.001; ORs Female = 1.005, ∗P < 0.001), but not for DR and DPN. After adjustment for the confounders, SUA levels were significantly associated with NAFLD within the 3rd (ORs = 1.829, P = 0.004) and 4th quartile (ORs = 2.064, P = 0.001) for women, but not independently associated with SUA for man. On the other hand, our results revealed increased prevalence of DN for SUA quartile 2 (ORs = 3.643, P = 0.039), quartile 3 (ORs = 3.967, P = 0.024) and quartile 4 (ORs = 9.133, P < 0.001) in men; however, SUA quartiles were significantly associated with DN only for quartile 4 (ORs = 4.083, P = 0.042) in women Conclusion For patients with T2DM, elevated SUA concentration is an independent risk factor for the prevalence of NAFLD and DN after adjustment for other indicators, but not DR or DPN.

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Decreased incidence of diabetes in patients with gout using benzbromarone

Abstract: In the gout population, the incidence of DM was lower in benzbromarone users than in benzbromarone non-users.

Cited by 19 publications

References 43 publications

Hyperuricemia Predisposes to the Onset of Diabetes via Promoting Pancreatic β-Cell Death in Uricase-Deficient Male Mice

Hyperuricemia Predisposes to the Onset of Diabetes via Promoting Pancreatic β-Cell Death in Uricase-Deficient Male Mice

Mendelian randomization study of serum uric acid levels and diabetes risk: evidence from the Dongfeng-Tongji cohort

The association between serum uric acid and diabetic complications in patients with type 2 diabetes mellitus by gender: a cross-sectional study

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