Hyperglycaemia and Infarct Size in Animal Models of Middle Cerebral Artery Occlusion: Systematic Review and Meta-Analysis

Abstract

Poststroke hyperglycaemia (PSH) is common, has an unclear pathophysiology, and is associated with poor outcomes. Animal studies report conflicting findings. We systematically reviewed the effects of hyperglycaemia on infarct volume in middle cerebral artery occlusion (MCAO) models, generating weighted mean differences between groups using random effects models summarised as effect size (normalised to control group infarct volume as 100%) and 95% confidence interval. Of 72 relevant papers, 23 reported infarct volume. Studies involved 664 animals and 35 distinct comparisons. Hyperglycaemia was induced by either streptozotocin (STZ, 17 comparisons, n=303) or dextrose (18 comparisons, n=356). Hyperglycaemic animals had infarcts that were 94% larger, but STZ was associated with significantly greater increase in infarct volumes than dextrose infusion (140% larger versus 48% larger). In seven studies, insulin did not significantly reduce infarct size and results were heterogeneous. Although hyperglycaemia exacerbates infarct volume in MCAO models, studies are heterogeneous, and do not address the common clinical problem of PSH because they have used either the STZ model of type I diabetes or extremely high glucose loads. Insulin had a nonsignificant and significantly heterogeneous effect. Further studies with relevant models may inform clinical trial design.

PKC-βExacerbatesin vitroBrain Barrier Damage in Hyperglycemic Settings via Regulation of RhoA/Rho-kinase/MLC2 Pathway

“…This is particularly important given the fact that much of the existing animal data with hyperglycemic focal ischemia, although invaluable, are somewhat irrelevant to clinical scenario because of the choice of wrong animal models, excessive blood glucose levels, and inconsistent findings with insulin. 35 For instance, although the majority of stroke patients have unrecognized insulin resistance coupled with type-2 diabetes, in most of the experimental studies a streptozotocin-induced model of type-1 diabetes is used. 35 Other than being unrepresentative of 490% of clinical cases, streptozotocin has been shown to impair brain microvasculature and increase apoptosis in middle cerebral artery occlusion-induced models of focal cerebral ischemia.…”

“…35 For instance, although the majority of stroke patients have unrecognized insulin resistance coupled with type-2 diabetes, in most of the experimental studies a streptozotocin-induced model of type-1 diabetes is used. 35 Other than being unrepresentative of 490% of clinical cases, streptozotocin has been shown to impair brain microvasculature and increase apoptosis in middle cerebral artery occlusion-induced models of focal cerebral ischemia. 36 There are some limitations to the current study.…”

Role of Soluble Epoxide Hydrolase in Exacerbation of Stroke by Streptozotocin-Induced Type 1 Diabetes Mellitus

“…7,8 Preexisting hyperglycemia also increases the ischemic brain infarct in numerous animal models, as recently reviewed. 9 Etiology of hyperglycemia, whether by insulin resistance, impaired insulin secretion, or exogenous glucose challenge, does not seem to be a deciding factor. The molecular mechanism by which hyperglycemia exacerbates ischemic injury to brain remains to be elucidated.…”

Illuminating the Effects of Stroke on the Diabetic Brain: Insights From Imaging Neural and Vascular Networks in Experimental Animal Models

“…One explanation for why diabetic animals may have a reduced rate of neurological recovery is that they simply have a larger cerebral infarction, as indicated in a metaanalysis by MacDougall and Muir (12). However, most studies induced stroke shortly (a few hours to days) after the induction of hyperglycemia (12,13).…”