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Prediabetes: the latest thinking

22nd December 2021

With type 2 diabetes cases still rising, it becomes ever more important to understand the role of prediabetes. Lisa Buckingham reports.

At the latest EASD conference, Coen Stehouwer, Professor of Medicine at Maastricht University, presented ‘Prediabetes: innnocent or guilty as charged?and made a compelling case for the latter.

He began with the statement that, in terms of its consequences, prediabetes is simply early diabetes. Prevalence is extremely high and varies greatly according to age and body mass index (BMI) – for example, for the over-60s, it’s 5% if your BMI is below 25, but about 40% if BMI is 35 or higher. It’s strongly associated with cardiovascular death and the idea that hyperglycaemia may play a causal role is supported by evidence – and Professor Stehouwer detailed how this happens.

The evidence for microsvascular dysfunction is more complex, he said. In the Maastricht Study, they attempted to investigate this as extensively as possible, despite the challenges of accessibility and acceptability as some organs (heart, liver and pancreas, for example) are hard to access. However, they were able to study the retina, brain, plasma, urine, skin and sublingual tissue.

He discussed in detail what these can show – for example, vasodilation in the retina and skin is impaired in type 2 diabetes and prediabetes.

And in whatever organ that’s studied, they find a similar pattern. For instance, when they look at cerebral white matter hyperintensities and volume loss (which, collectively, are signs of small vessel disease), it’s seen in both type 2 diabetes and prediabetes. This is important, he said, because they are strongly associated with depression and cognitive impairment. A meta-analysis of the literature on cerebral small vessel disease shows that it also predisposes people to stroke. Several mechanisms are probably responsible, such as blood-brain barrier leakiness and impaired autoregulation.

When they looked at microvascular dysfunction and cognitive performance, these associations are continuous, meaning that each level of dysfunction is associated with less cognitive performance. This includes memory, processing speed and executive function.

It’s not limited to the brain – when you measure microsvascular function outside of the brain, there tends to be an association with impairment of cognitive performance. In addition, there is also an association with depressive symptoms.

Part of the problem with even mild hyperglycaemia, said Professor Stehouwer, is that the idea that endothelial cells get damaged by it is probably also true for neural cells because they also can’t regulate intercellular glucose.

In the Maastricht Study, they found that type 2 diabetes is associated with impairment of peroneal and tibial large fibre nerve conduction velocity (NCV), assessed by EMG. For prediabetes, measurements sat in the middle of people with type 2 diabetes and people without. The same was found for impairment of cardiac autonomic function.

Wherever we measure it, we find a similar pattern, he said. He highlighted two pieces of data showing that reduced corneal nerve fibre length is seen in type 2 diabetes and prediabetes, as well as thinning of the retinal nerve fibre layer.

This is important because retinal nerve neurodegeneration is associated with brain atrophy and a greater risk of dementia. The Maastricht Study found that it’s associated with seven-year incidence of depressive symptoms.

This may simply be a measure of exposure to hyperglycaemia. Professor Stehouwer showed two examples of continuous glucose monitoring (CGM) data – a well-controlled person with type 2 diabetes spent about 4.5 hours per day in hyperglycaemia and, while you would expect it to be much less in a person with prediabetes, they still spend about two hours per day in hyperglycaemia, even with an HbA1c that would not ring alarm bells. 

So hyperglycaemia, even when mild, is important, he concluded. And it’s treatable with lifestyle intervention and pharmacological means such as metformin and pioglitazone, as demonstrated in a recently published meta-analysis. The evidence that it is useful in preventing complications is less extensive, but there is some that shows benefit.

In summary, he said, diabetes is a progressive macrovascular, microvascular and neuronal disorder that affects many organs, and that all of this starts in prediabetes.

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.

Webcasts from the EASD’s 2021 virtual meeting are now available free to all on the EASD website.

To view Professor Stehouwer’s presentation, go to:!resources/b-prediabetes-and-diabetic-complications-maastricht-study-b

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