Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2013 Mar;42(1):15-38.
doi: 10.1016/j.ecl.2012.11.005. Epub 2012 Dec 12.

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

Candace M Reno  1 , Marina Litvin, Amy L Clark, Simon J Fisher
Affiliations
Review

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

Candace M Reno et al. Endocrinol Metab Clin North Am. 2013 Mar.

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.

PubMed Disclaimer

Figures

Figure 1
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
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
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
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.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Duckworth W, Abraira C, Moritz T, et al. Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes. New England Journal of Medicine. 2009;360:129–U162. - PubMed
    1. Terry T, Raravikar K, Chokrungvaranon N, et al. Does aggressive glycemic control benefit macrovascular and microvascular disease in type 2 diabetes? Insights from ACCORD, ADVANCE, and VADT. Curr Cardiol Rep. 2012;14:79–88. - PubMed
    1. The Diabetes Control and Complications Trial Research Group The effect of intensive treatment of diabetes on the development and progression of lon-term complications in insulin-dependent diabetes mellitus. New England Journal of Medicine. 1993;329:977–996. - PubMed
    1. Turner RC, Holman RR, Stratton IM, et al. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34) Lancet. 1998;352:854–865. - PubMed
    1. The ADVANCE collaborative group Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. New England Journal of Medicine. 2008:358. - PubMed
  NODES
Association 3
INTERN 2
Project 1
twitter 2