Effect of Insulin‐Induced Hypoglycaemia on theCentral Nervous System: Evidence from Experimental Studies

Abstract

Insulin-induced hypoglycaemia (IIH) is a major acute complication in type 1 as well as in type 2 diabetes, particularly during intensive insulin therapy. The brain plays a central role in the counter-regulatory response by eliciting parasympathetic and sympathetic hormone responses to restore normoglycaemia. Brain glucose concentrations, being approximately 15-20% of the blood glucose concentration in humans, are rigorously maintained during hypoglycaemia through adaptions such as increased cerebral glucose transport, decreased cerebral glucose utilisation and, possibly, by using central nervous system glycogen as a glucose reserve. However, during sustained hypoglycaemia, the brain cannot maintain a sufficient glucose influx and, as the cerebral hypoglycaemia becomes severe, electroencephalogram changes, oxidative stress and regional neuronal death ensues. With particular focus on evidence from experimental studies on nondiabetic IIH, this review outlines the central mechanisms behind the counter-regulatory response to IIH, as well as cerebral adaption to avoid sequelae of cerebral neuroglycopaenia, including seizures and coma.

Chronic Hyperinsulinaemic Hypoglycaemia in Rats Is Accompanied by Increased Body Weight, Hyperleptinaemia, and Decreased Neuronal Glucose Transporter Levels in the Brain

“…Frequent episodes are likely to weaken the normal counterregulatory responses and patient awareness of hypoglycaemia and may thus over time increase the incidence and severity of such episodes [4–6]. Due to the high metabolic activity of neurons, requiring a continuous supply of nutrients such as glucose or glucose-derived lactate, the brain is vulnerable to acute severe hypoglycaemia [7], which may lead to coma and neuronal necrosis [7–10]. …”

“…Several studies have investigated the effect of acute insulin-induced hypoglycaemia in rats with blood glucose levels of 2-3 mmol/l or even below 2 mmol/l, that is, levels that may induce isoelectric EEG and coma [7, 8, 11–14]. Acute severe insulin-induced hypoglycaemia (<2.3 mM, ≤5 days) causes an adaptive increase in mRNA and protein levels of neuronal and blood-brain barrier (BBB) glucose transporters most likely to ensure adequate glucose supply to neurons [7, 11, 12, 15].…”

“…Acute severe insulin-induced hypoglycaemia (<2.3 mM, ≤5 days) causes an adaptive increase in mRNA and protein levels of neuronal and blood-brain barrier (BBB) glucose transporters most likely to ensure adequate glucose supply to neurons [7, 11, 12, 15]. Indeed, insufficient cerebral glucose influx during hypoglycaemia has detrimental consequences leading to oxidative stress and regional neuronal death [7, 9, 16–18]. Thus, increased lipid oxidation can occur in the brain of rats and mice already after a single episode of insulin-induced hypoglycaemia if the hypoglycaemia is severe enough [17–19].…”

“…In contrast, effects of chronic (≥2 weeks) insulin-induced hypoglycaemia on cerebral glucose transporter levels or extent of oxidative damage to brain lipids have only been sparingly investigated [7]. The brain may be better equipped for prolonged but moderate lowering of blood glucose levels in contrast to acute or recurrent severe hypoglycaemia, which usually represents iatrogenic low blood glucose levels far below fasting levels, approaching a coma-inducing hypoglycaemic level.…”

Diabetic Ketoacidosis Presenting with Metabolic Alkalosis

“…Benzer şekilde ülkemizde de son yıllarda DM prevelansı ve komplikasyonları artış göstermektedir (1). Modern tedavi yöntemlerinin kullanılması ve hastalıkla ilgili eğitim düzeyinin artırımasıyla diyabetin akut komplikasyonlarında azalma sağlanabilmiştir.…”