Clinical and genetic determinants of urinary glucose excretion in patients with diabetes mellitus

Abstract

Aims/introduction: Glucosuria is a representative symptom in diabetes patients with poor glycemic control and in those treated with sodium-glucose cotransporter 2 inhibitors. Renal threshold levels of glucose excretion are known to vary among individuals, but factors contributing to glucosuria are not well characterized. The present study aimed to clarify clinical and genetic determinants of glucosuria in individuals with diabetes mellitus.

Materials and methods: The 24-h urinary glucose excretion was measured in 135 hospitalized patients on admission, with continuous measurement for five consecutive days in 75 patients. Genetic and clinical factors contributing to glucosuria were studied. As a genetic factor, SLC5A2 polymorphism was genotyped. A total of 476 participants (266 participants with type 2 diabetes and 210 healthy controls) were additionally genotyped for the association study of SLC5A2 with type 2 diabetes. A meta-analysis was carried out with the present study and previous association studies.

Results: Multiple regression analysis showed that the independent variables of average blood glucose (β = 0.41, P = 1.4 × 10^-7 ), estimated glomerular filtration rate (β = 0.28, P = 6.0 × 10^-5 ), sex (β = 0.28, P = 5.7 × 10^-5 ) and SLC5A2 rs9934336 polymorphism (β = 0.17, P = 0.02) were significantly correlated with urinary glucose excretion. The frequency of the A allele of rs9934336 tended to be lower in participants with type 2 diabetes than in controls (odds ratio 0.78, 95% confidence interval 0.53-1.13, not significant), and meta-analysis showed a significant association between the A allele and type 2 diabetes (summary odds ratio for minor allele [A] 0.86, 95% confidence interval 0.78-0.94, P < 0.002).

Conclusions: Blood glucose, estimated glomerular filtration rate, sex and SLC5A2 polymorphism were independent determinants of glucosuria in diabetes mellitus.

Keywords: SLC5A2; Diabetes mellitus; Glucosuria.

Figure 1

Location of polymorphisms of SLC5A2. Location of tag single‐nucleotide polymorphisms (rs9934336, rs3813007, rs3813008 and rs118162329) in SLC5A2. Minor allele frequencies were 12.6% (rs9934336), 36.4% (rs3813007), 20.8% (rs3813008) and 0% (rs118162329) in 135 participants with diabetes.

Figure 2

Changes in urinary glucose excretion, average blood glucose at four points during the day and fasting blood glucose for five consecutive days after hospitalization. (a) All participants (n = 75). (b) Participants with urinary glucose excretion >0.5 g/day at day 1 (n = 48). *P < 0.05, **P < 0.005, ***P < 0.001 versus day 1. The Friedman test (multiple comparison by Scheffé) was carried out for urinary glucose excretion, and one‐way repeated measures anova (multiple comparison by Bonferroni) was carried out for average blood glucose and fasting blood glucose. Bars and numbers in each box are the median, and x represents the mean value.

Figure 3

Interindividual variation in urinary glucose excretion. (a) Changes in urinary glucose excretion of each participant for five consecutive days (n = 75). (b) Correlation between urinary glucose excretion and mean blood glucose on day 1 (n = 135).

Figure 4

SLC5A2 genotypes and urinary glucose excretion. (a) The relationship between urinary glucose excretion and average blood glucose stratified by genotypes of SLC5A2 rs9934336. Urinary glucose excretion (vertical axis) and average blood glucose (horizontal axis) were shown in men (left panel) and women (right panel). (b) The urinary glucose excretion in participants with preserved estimated glomerular filtration rate stratified by genotypes of SLC5A2 rs9934336. Bar and number in each box represent medians of urinary glucose excretion. Preserved estimated glomerular filtration rate was defined the estimated glomerular filtration rate >60 mL/min/1.73 m². NS, not significant.

Figure 5

Meta‐analysis of the association of SLC5A2 rs9934336 polymorphism with susceptibility to type 2 diabetes. P < 0.002, I ² = 0%. CI, confidence interval; OR, odds ratio.