Neural and Cardiac Responses to Hypoglycemia

In the setting of insulin therapy, patients with Type 1 diabetes (T1D) are at particularly high risk for hypoglycemia (low blood sugar) because of an impaired ability of the brain to sense and respond appropriately to hypoglycemia. The physiologic basis of this impairment is, however, unclear. The laboratories of Simon Fisher, MD, Owen Chan, PhD, and Candace Reno, PhD, demonstrated that brain glucose sensing was impaired in rats with recurrent hypoglycemia as a result of defective glucose and lactate metabolism within the neurons and astrocytes in the hypothalamus. The resultant abnormal release of neurotransmitters-such as GABA, glutamate and dopamine-led to inadequate activation of hormonal responses to hypoglycemia. This detrimental effect, however, could be prevented by treatment with the beta-blocker carvedilol in rats. They further demonstrated that severe hypoglycemia led to coma, brain damage and fatal cardiac arrhythmias, and these effects were mediated by excessive activation of the autonomic nervous system. Based on these results, the investigators have launched a clinical trial to examine the efficacy of the drug metoclopramide to restore the neurotransmitter and hormonal responses and awareness to hypoglycemia in people with T1D.