Abstract
Severe hypogylcemia has been found to induce cerebral damage. While a number of illnesses can lead to hypoglycemic episodes, antidiabetic medications prescribed for glycemic control are a common cause. Considering the rising prevalence of diabetes mellitus in the population, we investigated neuroprotective strategies during hypoglycemia in the form of a systematic review in adherence to the PRISMA statement. A review protocol was registered in the PROSPERO database. A systematic literature search of PubMed, Web of Science, and CENTRAL was performed in September 2018. Based on a predefined inclusion protocol, results were screened and evaluated by two researchers. Both animal experiments and human studies were included, and their risk of bias was assessed with SYRCLE’s and the Cochrane risk of bias tools, respectively. Of a total of 16,230 results, 145 were assessed in full-text form: 27 articles adhered to the inclusion criteria and were qualitatively analyzed. The retrieved neuroprotective strategies could be categorized into three subsets: (1) Energy substitution, (2) hypoglycemia unawareness, and (3) other neuroprotective strategies. While on a study level, the individual results appeared promising, more research is required to investigate not only specific neuroprotective strategies against hypoglycemic cerebral damage, but also its underlying pathophysiological mechanisms.
Highlights
Despite decades of intense research and strict treatment regimes, diabetes mellitus (DM) remains an impactful diagnosis
Chan et al investigated the effects of local lactate delivery through microdialysis to the ventromedial hypothalamus (VMH) of rats in the context of counter-regulatory suppression of gamma-aminobutyric acid (GABA) and subsequent glucagon and epinephrine release
Preceding studies by the same research group had revealed that both recurrent hypoglycemia (RH) and diabetic rats showed increased extracellular lactate levels and higher extracellular GABA concentrations in the VMH
Summary
Despite decades of intense research and strict treatment regimes, diabetes mellitus (DM) remains an impactful diagnosis. The desire to limit, and if possible avoid, the aforementioned complications of long-term DM oftentimes leads to strict glycemic control with glucose-lowering agents. This measure is accompanied by a risk of iatrogenic hypoglycemia, though, especially in intensively treated patients who receive insulin or sulfonylureas [7,8]. Because of the subsequent development of decreased sympathoadrenal activity, even moderate recurrent episodes of hypoglycemia reduce the glucose threshold at which autonomic and neuroglycopenic symptoms are experienced by the patient and at which counter-regulatory physiological responses can be measured [8]. This state of impaired awareness of hypoglycemia (IAH) can, in combination with a defective glucose counter-regulation, lead to hypoglycemia-associated autonomic failure, a vicious cycle that exposes the patient to a 25-fold higher risk of further episodes of hypoglycemia [8,9]
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