RationaleType 2 diabetes mellitus (T2D) is an established risk factor for cerebrovascular disease but the mechanisms underlying this association remain elusive. Disentangling the causal effects of T2D, hyperglycemia, and pre-diabetic phenotypes (insulin resistance, {beta}-cell dysfunction) on major etiological stroke subtypes (ischemic stroke, intracerebral hemorrhage, ischemic stroke subtypes) could inform the development of preventive strategies. ObjectiveWe employed Mendelian randomization (MR) to explore the effects of genetic predisposition to T2D, hyperglycemia, insulin resistance, and {beta}-cell dysfunction on risk of stroke subtypes and related cerebrovascular phenotypes. Methods and ResultsWe selected instruments for genetic predisposition to T2D, HbA1c levels, fasting glucose levels, insulin resistance, and {beta}-cell dysfunction (proxied by pro-insulin levels) based on published genome-wide association studies (up to 898,130 individuals). Applying two-sample MR, we examined associations with ischemic stroke, intracerebral hemorrhage, and ischemic stroke subtypes (large artery, cardioembolic, small vessel stroke; up to 60,341 cases and 454,450 controls). We further explored associations with the related phenotypes of carotid atherosclerosis, imaging markers of cerebral white matter integrity, and brain atrophy. Genetic predisposition to T2D and elevated HbA1c levels in the pre-diabetic range were associated with higher risk of any ischemic stroke, large artery stroke, carotid plaque and small vessel stroke. Independently of HbA1c levels, we further found genetic predisposition to insulin resistance to be associated with large artery and small vessel stroke, whereas predisposition to {beta}-cell dysfunction was associated with small vessel stroke. Predisposition to {beta}-cell dysfunction was further associated with intracerebral hemorrhage, lower grey matter volume, and total brain volume. ConclusionsThis study supports causal effects of T2D and hyperglycemia on large artery and small vessel stroke. We show differential effects of genetically determined insulin resistance and {beta}-cell dysfunction on large artery and small vessel stroke that might have implications for anti-diabetic treatments targeting these mechanisms.

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