Could a common enzyme deficiency be hiding diabetes in plain sight?

A genetic condition affecting hundreds of millions worldwide may be masking diabetes risk and contributing to worse outcomes, according to new research by Martin et al. published in Diabetes Care.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, an X-linked disorder, is one of the most common enzymatic disorders globally, particularly among people of African, Asian, Middle Eastern, and Mediterranean ancestry. G6PD variants cause red blood cells to have a shorter lifespan due to the deficient enzyme, which leads to lower glycated haemoglobin (HbA1c) levels for the same blood glucose level. Because HbA1c is the standard test used worldwide to diagnose and monitor type 2 diabetes, this effect can make diabetes appear less severe than it really is, thereby delaying diagnosis and treatment.

Researchers studied genetic and health records from two large U.K. cohorts: the UK Biobank, which includes more than 467,000 participants, and the Genes & Health study, involving over 43,000 Bangladeshi and Pakistani individuals. They identified two common G6PD variants (the Asahi variant in Black populations and the Mediterranean variant in South Asians) and compared HbA1c, blood glucose, diabetes diagnoses, and complication rates between carriers and noncarriers. They also tested how G6PD deficiency affected widely used diabetes risk calculators such as the QDiabetes-2018 score.

The results showed that G6PD deficiency is widespread but under-recognised. One in seven Black men and one in sixty-three Asian men carried G6PD variants (compared to fewer than 1 in 10,000 White men), yet fewer than one in fifty with the condition had been diagnosed. Carriers had HbA1c readings almost one percentage point lower than noncarriers despite similar glucose levels. This led to type 2 diabetes being diagnosed an average of 4.1 years later, and to a 37% higher risk of microvascular complications, particularly diabetic eye disease. Risk models that included HbA1c consistently underestimated diabetes risk in carriers.

The findings suggest that undiagnosed G6PD deficiency is contributing to health inequities by delaying treatment and worsening treatment outcomes, especially for Black and Asian men. Since HbA1c testing is used in 136 countries, the researchers warn the issue has major global implications. They argue that ancestry-specific screening or alternative diagnostic strategies may be required to ensure earlier and more equitable detection of diabetes.

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Notes from a Pathologist

Assimilation is often discussed in the context of immigration - the idea that newcomers should adapt to the existing culture, language, and norms of the host country.

But as the population in countries like Australia becomes increasingly diverse, when do we ask the reverse: how far should a country whose health systems were built on European norms adapt to meet the needs of people whose ancestry and physiology are different?

It’s not an easy or comfortable question. It cuts across politics, economics, and public health. Underlying much of this is utilitarianism - the idea of the greatest good for the greatest number. But how large does the “smaller number” need to be before a society decides it’s worth adapting its systems to fit them?

What research like this reminds us is that we are, in fact, different - genetically and physiologically. These are stark biological realities.

But they matter in ways that are profoundly practical. A “normal” laboratory reference range may be accurate for one group but misleading for another. The same can be said for drug dosages, risk prediction tools, and even how skin conditions appear on different skin tones.

Our definitions of normality and abnormality in healthcare must evolve with the populations they serve. There is an irony here: in healthcare, acknowledging our differences may be the first step towards true equity.

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