g6pd and diabetes

G6PD Deficiency and Diabetes

by

Why People with G6PD Deficiency Should Be Cautious About Developing Diabetes

A concise, evidence-based review with clinical implications and citations

Abstract

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common X-linked enzymopathy affecting hundreds of millions worldwide. Growing evidence from observational, genetic and clinical studies indicates that G6PD deficiency is associated with a higher probability of abnormal glucose metabolism and diabetes, and—critically—can cause systematic underestimation of glycemic control when HbA1c is used alone. This combination (increased risk + diagnostic pitfalls) creates a special clinical challenge: people with G6PD deficiency may both be more likely to develop diabetes and more likely to have that diabetes missed, undertreated, or identified late. Below I summarize mechanisms, the key studies, diagnostic consequences (especially HbA1c bias), and practical clinical recommendations. (PubMed, PMC, ScienceDirect)

1. Biological plausibility: how G6PD deficiency could affect glucose metabolism

G6PD is the rate-limiting enzyme of the pentose phosphate pathway and is essential for generating NADPH — a reducing equivalent required for antioxidant defenses (glutathione recycling) and for normal cellular metabolism. Reduced G6PD activity can increase oxidative stress in tissues including pancreatic β-cells, interfere with normal lipid and cholesterol metabolism, and alter redox-sensitive signaling pathways that regulate insulin secretion and insulin action. Animal and cellular data suggest these redox changes can impair β-cell function and insulin sensitivity, providing a biologic rationale for an elevated risk of dysglycemia in G6PD-deficient individuals. (PubMed, Wiley Online Library)

2. Key human evidence linking G6PD deficiency and diabetes

2.1 Systematic review and meta-analysis

A pooled analysis of multiple studies (meta-analysis) found that G6PD deficiency was associated with higher odds of diabetes (overall OR ≈ 2.37; 95% CI 1.50–3.73) — an effect that appeared stronger in men. This meta-analytic result summarizes data from diverse populations and provides the clearest quantitative signal to date that G6PD deficiency and diabetes are linked. (PubMed)

2.2 Large cohort and registry data

A matched retrospective cohort from a large Israeli health service found higher diabetes prevalence among G6PD-deficient individuals (for example an OR ≈ 1.44 in men aged 45–64 in one analysis) and later analyses from the same healthcare dataset indicate G6PD-deficient patients with diabetes suffered higher rates of severe diabetes complications (adjusted hazard ratios: kidney insufficiency ≈1.44; myocardial infarction ≈1.75; neuropathy ≈1.27). These are clinically important differences that suggest not only higher prevalence but worse outcomes in those who develop diabetes. (PMC, Tel Aviv University)

2.3 Regional observational studies

Population studies in malaria-endemic regions (for example in the Western Brazilian Amazon) observed a higher frequency of impaired fasting glucose and diabetes among G6PD-deficient males compared with local controls. Although such studies can be influenced by local confounders, they repeatedly show higher dysglycemia prevalence in G6PD-affected populations. (PMC)

2.4 Genetic and integrative analyses

Recent work using genetic data and interaction models also points toward a potential causal relationship between G6PD variants and diabetes risk—while emphasizing that the mechanisms are complex and likely influenced by sex and other genetic/environmental modifiers. These studies add weight to the observational signals but do not yet replace prospective randomized evidence. (Nature)

3. Diagnostic problem: why HbA1c underestimates glycemia in G6PD deficiency

HbA1c assumes a typical red blood cell (RBC) lifespan so that average glucose is reflected in the percentage of glycated hemoglobin. G6PD deficiency shortens RBC lifespan (hemolysis episodes or increased RBC fragility), so there is less time for hemoglobin glycation and HbA1c values are artifactually lower than the true average glucose. Multiple studies and reviews document this effect:

  • Laboratory and clinical reports show G6PD deficiency leads to lower HbA1c for the same measured plasma glucose, and higher fasting-glucose / HbA1c ratios have been proposed as a clue. (ScienceDirect)
  • Population genetic analyses (e.g., in cohorts with African ancestry) estimate that common G6PD variants can reduce measured HbA1c by clinically meaningful amounts (one study reported reductions up to ~0.8 percentage points for a common variant), which would shift many patients from “diabetic” to “non-diabetic” HbA1c categories if HbA1c were used alone. (ResearchGate)

Clinical consequence: relying solely on HbA1c in G6PD-deficient patients risks under-diagnosis (missed cases of diabetes), undertreatment, and delays in initiating preventive therapies. This also helps explain observations that G6PD-deficient diabetic patients in some datasets receive fewer guideline therapies (e.g., GLP-1 receptor agonists, SGLT2 inhibitors), presumably because their HbA1c readings appear deceptively good. (PubMed, Tel Aviv University)

4. Clinical outcomes and disparity signals

Beyond diagnostic bias, cohort analyses show G6PD-deficient patients who do have diabetes face higher rates of severe complications (adjusted hazard ratios reported for kidney failure, myocardial infarction, neuropathy), and appear to receive fewer guideline-recommended medications. These patterns suggest a double jeopardy: higher risk and poorer recognition/management leading to worse outcomes. The Israeli health-service analyses and related cohort work highlight these concerning disparities. (Tel Aviv University, Frontiers)

5. What clinicians and patients should do — practical recommendations

  1. Screen proactively for diabetes with glucose-based tests (fasting plasma glucose and/or 2-hour oral glucose tolerance test [OGTT]) in patients known to have G6PD deficiency, especially men aged >40 or those with risk factors (obesity, family history, hypertension). Do not rely on HbA1c alone. (PMC, ScienceDirect)
  2. If HbA1c is used, interpret it cautiously. Consider that HbA1c may understate average glucose; suspect underestimation if symptoms, risk factors, or concurrent glucose measures disagree with HbA1c. Use fasting glucose and OGTT to confirm diagnosis. (ScienceDirect, ResearchGate)
  3. Use alternate glycemic markers when appropriate. Fructosamine reflects shorter-term glycemic control (≈2–3 weeks) and is not affected by RBC lifespan; it may be useful for monitoring in G6PD deficiency though it has its own limitations. Continuous glucose monitoring (CGM) or frequent self-monitoring of blood glucose are also valuable. (ScienceDirect)
  4. Monitor for complications and treat proactively. Given the higher complication rates seen in cohorts, clinicians should maintain guideline-recommended screening for microvascular and macrovascular complications, and avoid therapeutic inertia because of deceptively low HbA1c values. (Tel Aviv University)
  5. Patient education. Inform G6PD-deficient patients about the possibility that routine HbA1c could miss diabetes and advise on lifestyle measures, and on the need for glucose tests if symptoms or risk factors develop. (PMC)

6. Gaps in knowledge and research priorities

  • Causality and mechanisms. While observational and genetic data are suggestive, prospective mechanistic and interventional studies are needed to determine whether correcting redox imbalance or targeted therapies can reduce diabetes risk in G6PD-deficient people. (Nature, Wiley Online Library)
  • Population-level burden. No global estimate exists for how many of the ≈400 million people with G6PD deficiency will develop diabetes during their lifetimes; large, population-based longitudinal studies are needed. (The Lancet)
  • Diagnostic algorithms. Research to develop and validate practical diagnostic pathways (e.g., when to use OGTT, CGM, or fructosamine instead of HbA1c) specifically for G6PD-deficient populations would improve care. (ScienceDirect)

7. Conclusion

Current evidence supports three closely related points: (1) G6PD deficiency is associated with increased odds of dysglycemia and diabetes in multiple populations; (2) G6PD deficiency shortens RBC lifespan and therefore systematically underestimates HbA1c, risking under-diagnosis and undertreatment; and (3) G6PD-deficient patients with diabetes appear to have higher rates of severe complications, possibly amplified by diagnostic and treatment gaps. For these reasons, clinicians and public-health programs should treat G6PD deficiency as a meaningful context for more vigilant diabetes screening and alternative glycemic monitoring. (PubMed, PMC, ScienceDirect, Tel Aviv University)

Representative references (selected for immediate follow-up)

  1. Lai YK, et al. Glucose-6-phosphate dehydrogenase deficiency and risk of diabetes: a systematic review and meta-analysis. (2017). (PubMed)
  2. Heymann AD, et al. Glucose-6-Phosphate Dehydrogenase Deficiency and… (Large Israeli cohort; 2012). PMC article. (PMC)
  3. Santana MS, et al. High frequency of diabetes and impaired fasting glucose in patients with G6PD deficiency in the Western Brazilian Amazon. Am J Trop Med Hyg. 2014. (PMC)
  4. Chang Y-S, et al. Fasting glucose-to-HbA1c ratio is a good indicator of G6PD deficiency in diabetic patients. (2020). — on HbA1c bias and diagnostic clues. (ScienceDirect)
  5. Israel A, et al. The challenge of G6PD deficiency (2025 / retrospective analyses) — documents underestimation of HbA1c and higher complication rates. (PubMed, Tel Aviv University)