The physiology and pathophysiology of the neural control of the counterregulatory response

Abstract

Despite significant technological and pharmacological advancements, insulin replacement therapy fails to adequately replicate β-cell function, and so glucose control in type 1 diabetes mellitus (T1D) is frequently erratic, leading to periods of hypoglycemia. Moreover, the counterregulatory response (CRR) to falling blood glucose is impaired in diabetes, leading to an increased risk of severe hypoglycemia. It is now clear that the brain plays a significant role in the development of defective glucose counterregulation and impaired hypoglycemia awareness in diabetes. In this review, the basic intracellular glucose-sensing mechanisms are discussed, as well as the neural networks that respond to and coordinate the body's response to a hypoglycemic challenge. Subsequently, we discuss how the body responds to repeated hypoglycemia and how these adaptations may explain, at least in part, the development of impaired glucose counterregulation in diabetes.

Mechanisms of Hypoglycemia-Associated Autonomic Failure in Diabetes

“…1 Hypotheses regarding CNS-mediated mechanisms of the attenuated sympathoadrenal responses to hypoglycemia that cause HAAF include the systemic-mediator hypothesis, the brain fuel-transport hypothesis, the brain-metabolism hypothesis, and the cerebral-network hypothesis. 1,32,33 …”

“…Studies of the cellular and molecular biology and pathophysiology of CNS control of glucose counterregulation in rodent models have focused largely, but not exclusively, on the ventromedial hypothalamus. Potential mechanisms 32,33,[63][64][65] include decreased glucose sensing by glucose-excited or glucose-inhibited neurons in the hypothalamus, elsewhere in the brain, and in the periphery; decreased activation of AMP kinase; increased glucokinase activity; loss of a decrease in the counterregulatory inhibitor γ-aminobutyric acid; loss of an increase in the counterregulatory stimulator glutamine; increased urocortin release; and reduced actions of insulin on the brain.…”

Impaired hypoglycaemia awareness in type 1 diabetes: lessons from the lab

“…Certainly, recurrent hypoglycaemia increases the activity of neuronal glucokinase [33], the key first committed step in glucose metabolism in the cell, while pharmacological or genetic manipulation of neuronal glucokinase directly modulates the CRR [22]. Similarly, genetic manipulation of hypothalamic AMP-activated protein kinase (AMPK), an intracellular fuel gauge, also directly modulates CRRs [34].…”

Functional identification of a neurocircuit regulating blood glucose

“…Consequently, hypoglycemia elicits a robust, integrated, and redundant set of counterregulatory responses (CRRs) that ensure the rapid and efficient recovery of plasma glucose concentrations into the normal range (1). Components of the CRR include increased secretion of the hormones glucagon, epinephrine, and glucocorticoids, inhibition of glucoseinduced insulin secretion, increased sympathetic nervous system (SNS) outflow to the liver, and increased food intake (1)(2)(3). Owing to this redundancy, recovery from hypoglycemia is difficult to block in normal humans and animal models, even when adrenal or glucagon responses are prevented.…”