AT EASD 2016

MUNICH (FRONTLINE MEDICAL NEWS) – Brain changes suggestive of cerebral microvascular dysfunction are already apparent in patients with prediabetes.

The changes – increased white matter hyperintensities and decreased white matter volume – are even more pronounced in subjects with type 2 diabetes, Marnix van Agtmaal, MD , said at the annual meeting of the European Association for the Study of Diabetes. Patients with frank diabetes also showed an increase in intracranial cerebrospinal fluid – a correlate of the decrease in brain volume, said Dr. van Agtmaal of Maastricht (the Netherlands) University Medical Center.

The changes are probably caused by diabetes-related endothelial dysfunction, he said.

“The brain is highly dependent on properly functioning microcirculation. This is critical, since the brain has high energy demand and no energy reserve. In prediabetes and type 2 diabetes, microvascular endothelial dysfunction occurs. This leads to cerebral hypoperfusion, which in turns causes chronic ischemia. This contributes to small vessel disease leading to brain atrophy and, eventually, cognitive decline and dementia.”

The 2,251 subjects in the analysis were drawn from the Maastricht study , an ongoing observational study of people with type 2 diabetes.

Among the group, 350 had prediabetes, defined as impaired fasting glucose, impaired glucose tolerance, or a combination of the two. Type 2 diabetes was present in 528. The rest had healthy glucose metabolism.

As the cohort progressed from healthy glucose metabolism to prediabetes and then diabetes, they became older (aged 58 years in the healthy group vs. 62 years in the diabetes group), heavier, and displayed worsening cardiovascular risk factors, with increasing systolic blood pressure and progressively poorer lipid profiles. Kidney function was preserved in all patients, however.

The groups were not balanced in terms of sex: 56% of those with healthy glucose metabolism were women, compared with 47% of those with prediabetes and 31% of those with type 2 diabetes.

Dr. van Agtmaal and his colleagues examined white matter hyperintensities, white matter volume, gray matter volume, and intracranial CSF. They conducted three linear regression models: a crude unadjusted model, a partially adjusted model that controlled for age, sex, and intracranial volume; and a fully adjusted model that controlled for those factors, plus systolic blood pressure, lipids, smoking, kidney function, and education.

There was a clear linear association between white matter hyperintensity (WMH) volume and healthy glucose metabolism, prediabetes, and type 2 diabetes. In the crude analysis, the healthy subjects carried about 0.75 mL of WMH. Prediabetic subjects carried about 1.25 mL, and those with diabetes, about 2 mL.

In both the partially and fully adjusted models, this relationship was somewhat attenuated, but it remained significant for both prediabetes and diabetes.

The crude model also found that both diabetes groups had significantly lower white matter volume than did the healthy subjects. In healthy subjects, the mean volume was about 480 mL. This was about 467 mL in those with prediabetes and 466 mL in those with type 2 diabetes. Again, the partially and fully adjusted models slightly attenuated the relationship, but it remained significant in both disease states.

The crude model showed that gray matter was decreased in both prediabetes and type 2 diabetes. In healthy subjects, total gray matter was about 667 mL. In those with prediabetes, it was about 655 mL, and in those with type 2 diabetes, about 645 mL. However, the significant associations disappeared for both diabetes and prediabetes in both adjusted models.

Intracranial CSF was also different among the three groups in the crude model. In the healthy subjects, the total intracranial CSF volume was about 248 mL. In those with prediabetes, it was about 255 mL, and in those with type 2 diabetes, about 270 mL.

The association with prediabetes disappeared in the fully adjusted model – but for type 2 diabetes, it remained strongly significant.

Dr. van Agtmaal has not correlated the imaging findings with any cognitive testing on these subjects but said that study is coming.

“Further analysis will also look at cognitive decline and the development of dementia in the group,” he said. “We also intend to look at associations with other outcomes of cerebral dysfunction, including depression.”

Dr. van Agtmaal had no financial disclosures.