Mungkalasut Punchalee, Chanda Makamas, Jugnam-Ang Watcharapong, Cheepsunthorn Poonlarp, Ganokroj Poranee, Cheepsunthorn Chalisa L
Interdisciplinary Program of Biomedical Sciences, Graduate School, Chulalongkorn University, Bangkok, Thailand.
Medical Biochemistry Program, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
Diabetologia. 2025 Sep 1. doi: 10.1007/s00125-025-06523-2.
AIMS/HYPOTHESIS: Glucose 6-phosphate dehydrogenase (G6PD) deficiency, the most common inherited enzymopathy, can affect HbA levels and the diagnosis of type 2 diabetes. This cross-sectional study aimed to investigate the association between G6PD deficiency, its common mutations (G6PD Viangchan, G6PD Mahidol) and HbA levels in a Thai cohort.
Blood samples from 1007 healthy hospital staff were collected during annual health checkups. Individuals with diabetes, diabetes medication use and conditions affecting erythrocyte turnover were excluded. HbA levels were measured by enzymatic assay and HPLC, while fasting plasma glucose (FPG) and haematological variables were obtained from checkup records. Fructosamine levels and G6PD activity (classified as deficiency, intermediate, normal) were measured by spectrophotometric assay. Genotyping was performed using TaqMan SNP, PCR-Restriction Fragment Length Polymorphism (RFLP) and Sanger sequencing. Prediabetes and diabetes were diagnosed based on two abnormal results from FPG and HbA at the same time, following the modified ADA criteria. Optimal HbA cutoffs were determined using receiver operating characteristic curve analysis with bootstrapping in RStudio, optimising Youden's index and the harmonic mean of sensitivity and specificity.
HbA levels were significantly lower in individuals with G6PD deficiency (25.68 mmol/mol [4.50%] by enzymatic assay; 27.33 mmol/mol [4.65%] by HPLC; n=28; p<0.001) compared with those with normal G6PD levels (34.05 mmol/mol [5.27%] by enzymatic assay; 36.61 mmol/mol [5.50%] by HPLC; n=492). Similarly, individuals with G6PD Viangchan (29.46 mmol/mol [4.85%] by enzymatic assay; 31.15 mmol/mol [5.00%] by HPLC; n=52; p<0.001) and G6PD Mahidol (28.63 mmol/mol [4.77%] by enzymatic assay; 31.15 mmol/mol [5.00%] by HPLC; n=15; p<0.001) had significantly lower HbA levels. HbA levels positively correlated with G6PD activity (r=0.208, p<0.001 by enzymatic assay; r=0.211, p<0.001 by HPLC). The optimal HbA cutoffs for predicting prediabetes in participants with G6PD mutation were 33 to <42 mmol/mol (5.2% to <6.0%) by enzymatic assay (sensitivity 70%; specificity 88.64%; accuracy 86.74%) and 34 to <43 mmol/mol (5.3% to <6.1%) measured by HPLC (sensitivity 72.73%; specificity 86.21%; accuracy 84.70%). For diabetes, the optimal cutoffs were ≥42 mmol/mol (≥6.0%) by enzymatic assay (sensitivity 100%; specificity 97.92%; accuracy 97.96%) and ≥43 mmol/mol (≥6.1%) by HPLC (sensitivity 100%; specificity 96.88%; accuracy 96.94%). Using the mutation-specific HbA cutoffs resulted in the proportion of individuals being diagnosed with diabetes remaining the same but the proportion diagnosed with prediabetes rose from 8.2% (ADA criteria) to 18.4% using enzymatic assay and from 9.2% to 21.4% using HPLC.
CONCLUSIONS/INTERPRETATION: HbA levels were positively correlated with G6PD activity, with individuals carrying G6PD Viangchan and G6PD Mahidol exhibiting significantly lower HbA levels. Our findings highlight the need to consider G6PD deficiency and G6PD mutations when using HbA to diagnose type 2 diabetes in Southeast Asian populations.
目的/假设：葡萄糖-6-磷酸脱氢酶（G6PD）缺乏症是最常见的遗传性酶病，可影响糖化血红蛋白（HbA）水平及2型糖尿病的诊断。这项横断面研究旨在调查泰国队列中G6PD缺乏症及其常见突变（G6PD万象型、G6PD马希多尔型）与HbA水平之间的关联。
在年度健康检查期间收集了1007名健康医院工作人员的血样。排除患有糖尿病、正在使用糖尿病药物以及患有影响红细胞更新疾病的个体。通过酶法和高效液相色谱法（HPLC）测量HbA水平，同时从检查记录中获取空腹血糖（FPG）和血液学变量。通过分光光度法测量果糖胺水平和G6PD活性（分为缺乏、中间型、正常）。使用TaqMan单核苷酸多态性（SNP）、聚合酶链反应-限制性片段长度多态性（PCR-RFLP）和桑格测序进行基因分型。根据修改后的美国糖尿病协会（ADA）标准，同时依据FPG和HbA的两项异常结果诊断糖尿病前期和糖尿病。使用RStudio中的自抽样法通过受试者工作特征曲线分析确定最佳HbA临界值，优化约登指数以及灵敏度和特异度的调和平均数。
与G6PD水平正常的个体相比，G6PD缺乏症个体的HbA水平显著更低（酶法检测为25.68 mmol/mol [4.50%]；HPLC检测为27.33 mmol/mol [4.65%]；n = 28；p < 0.001），G6PD水平正常个体的HbA水平为（酶法检测为34.05 mmol/mol [5.27%]；HPLC检测为36.61 mmol/mol [5.50%]；n = 492）。同样，G6PD万象型个体（酶法检测为29.46 mmol/mol [4.85%]；HPLC检测为31.15 mmol/mol [5.00%]；n = 52；p < 0.001）和G6PD马希多尔型个体（酶法检测为28.63 mmol/mol [4.77%]；HPLC检测为31.15 mmol/mol [5.00%]；n = 15；p < 0.001）的HbA水平也显著更低。HbA水平与G6PD活性呈正相关（酶法检测r = 0.208，p < 0.001；HPLC检测r = 0.211，p < 0.001）。对于G6PD突变参与者，预测糖尿病前期的最佳HbA临界值，酶法检测为33至<42 mmol/mol（5.2%至<6.0%）（灵敏度70%；特异度88.64%；准确度86.74%），HPLC检测为34至<43 mmol/mol（5.3%至<6.1%）（灵敏度72.73%；特异度86.21%；准确度84.70%）。对于糖尿病，最佳临界值，酶法检测为≥42 mmol/mol（≥6.
