Defective counterregulation and hypoglycemia unawareness in diabetes: mechanisms and emerging treatments

Abstract

For people with diabetes, hypoglycemia remains the limiting factor in achieving glycemic control. This article reviews recent advances in how the brain senses and responds to hypoglycemia. Novel mechanisms by which individuals with insulin-treated diabetes develop hypoglycemia unawareness and impaired counterregulatory responses are outlined. Prevention strategies for reducing the incidence of hypoglycemia are discussed.

Figure 1. The counterregulatory response to hypoglycemia

Hypoglycemia is first sensed in various brain regions including the hypothalamus and brain stem. Low glucose in these brain regions stimulates the autonomic nervous system to release norepinephrine and acetylcholine at postganglionic nerve terminals and induce symptoms of hypoglycemia (hypoglycemia awareness). A principal counterregulatory response is the secretion of glucagon which may be stimulated by various mechanisms including independent α-cell glucose sensing, autonomic innervation, epinephrine stimulation, and a reduction of intra-islet insulin secretion. Via autonomic stimulation, epinephrine is released from the adrenal medulla. Not shown is the hypothalamic-pituitary-adrenal axis by which the release of ACTH from the pituitary stimulates cortisol release from the adrenal cortex. The cumulative effect of the sympathetic nervous system and counterregulatory hormones at the level of the liver is to increase hepatic gluconeogeneis and glycogenolysis while the effect at muscle and adipose tissue is to decrease peripheral glucose utilization.

Figure 2. Afferent glucose sensing pathways, neural integration, and efferent autonomic pathways that mediate the counterregulatory response to hypoglycemia

During hypoglycemia, the initiation and coordinatation of the counterregulatory response is mediated by a network of glucose sensing neurons in the hypothalamus, including the ventromedial nucleus (VMN), arcuate nucleus (ARC) and lateral hypothalamus (LH). Glucose sensing also occurs in the nucleus tractus solitarius (NTS) and dorsal motor nucleus of the vagus (DVN) in the hindbrain. The NTS also receives afferent information from peripheral glucose sensors, including the portal vein. Hypothalamic and hindbrain neural networks project to the paraventricular nucleus of the hypothalamus (PVN) in order to elicit autonomic and neuroendocrine counterregulatory responses. Although not directly glucose sensing, parvicellular neurons in the PVN initiate sympathetic autonomic responses via pre-ganglionic spinal efferents. Parasympathetic (vagal) innervation is relayed from the PVN to the dorsal vagal nucleus (DVN) which then relays to peripheral organs. In addition, the hypothalamic-pituitary-adrenal axis is also initiated from a distinct set of medial parvicellar neurons within the PVN that secretes corticotropin releasing hormone (CRH). CRH acts on the anterior pituitary (Pit) to stimulate the secretion of adrenocorticotropic hormone (ACTH) which circulates to the adrenal cortex to increase cortisol secretion. Interneurons involved in the neural glucose sensing and autonomic response network shown in black. Afferent glucose sensing pathways are shown in green. Efferent autonomic responses to hypoglycemia shown in brown. Post-ganglionic vagal parasympathetic efferent pathway shown in red. Hypothalamic-Pituitary-Adrenal axis shown in blue.

Figure 3. Glucose sensing neurons of the ventromedial hypothalamus (VMH)

A) VMH glucose excited (GE) neurons are activated in response to increasing glucose. In a setting of low glucose, decreased glucose entry into the GE neuron through glucose transporters (GLUT) leads to decreased phosphorylation by glucokinase (GK) leading to an increase in the AMP/ATP ratio, thus increasing the activity of AMPK and stimulating KATP channel activation. Activation of KATP channels leads to decreased membrane depolarization and decreased action potential frequency and neurotransmitter release, in particular GABA, thus leading to activation of the hypoglycemic counterregulatory response (CRR). B) VMH glucose inhibited (GI) neurons are activated in response to decreasing glucose. Decreased glucose entry into neurons leads to an increase in the AMP/ATP ratio, activation of AMPK which activates formation of nitric oxide (NO) which can act as a neurotransmitter. Increased AMP/ATP also inhibits a chloride channel, thought to be the cystic fibrosis transmembrane conductance regulator, (CFTR), leading to membrane depolarization, increased action potential frequency, and neurotransmitter release, including glutamate, which leads to activation of the counterregulatory response. GABA and glutamate can potentially be secreted from both GE and GI neurons upon their activation but a decrease in GABA levels is required for full activation of the counterregulatory response.

Figure 4. Preconditioning through recurrent hypoglycemia leads to cellular adaptation and HAAF

Hypoglycemia is a state of energy depletion that leads to metabolic stress. Sympathetic activation leads to symptoms of hypoglycemia awareness and the adrenomedullary response. The normal response to hypoglycemia is a cellular adaptation, assuming the energy depletion and metabolic stress was not enough to induce cell death. The mechanism by which cellular adaptation occurs is unclear but may include the use of alternate fuels (such as lactate) and/or an enhanced glucose transport/phosphorylation/metabolism. During a subsequent hypoglycemic episode, the adapted cell experiences less marked energy depletion and less metabolic stress thus making the cells less susceptible to death. Less intracellular energy depletion leads to impaired sympathetic activation resulting in hypoglycemia unawareness and a reduced adrenomedullary response to subsequent hypoglycemia, collectively known as hypoglycemia associated autonomic failure (HAAF). Preconditioning through recurrent hypoglycemia, paradoxically, acts to render an individual more prone to, but less vulnerable to, an episode of severe hypoglycemia.