Ms. Diggs-Andrews is currently a senior Ph.D. student in the Molecular Cellular Biology program in the Division of Biology and Biomedical Sciences at Washington University in St. Louis; Dr. Silverstein is currently a clinical fellow and Dr. Fisher is currently an Assistant Professor of Medicine, Cell Biology & Physiology, both in the Division of Endocrinology, Metabolism & Lipid Research, Washington University, St. Louis, MO.
Within the past 12 months, Ms. Diggs-Andrews and Dr. Silverstein report no commercial conflicts of interest; Dr. Fisher has been a member of the Speakers Bureau for Merck. This relationship will not influence his presentation.
This activity is made possible an unrestricted educational grant from 
.
Release Date: 05/12/2009
Termination Date: 05/12/2012
Estimated time to complete: 1 hour(s).
Albert Einstein College of Medicine designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.
- Identify the sites in the brain that sense and respond to changes in blood sugar
- Identify some of the key glucose sensing proteins in the brain
- Describe the hierarchy of hormones that are released in response to hypoglycemia
- Discuss the etiology of the impaired counterregulatory response and hypoglycemia unawareness that occurs in people with diabetes
- List some therapeutic interventions shown to reduce the risk of hypoglycemia.
Abbreviations: CNS, central nervous system; SNS, sympathetic nervous system; CRH, corticotrophin releasing hormone; ACTH, adrenocorticotropin hormone; HPA, hypothalamic-pituitary-adrenal; ARC, arcuate nucleus of the hypothalamus; PVN, paraventricular nucleus of the hypothalamus; VMH, ventromedial hypothalamus; ICV, intracerebroventricular; GLUT, glucose transporter; GI, glucose-inhibited neuron; GE, glucose-excited neuron; CGM, continuous glucose monitor; KATP , potassium dependent ATP channel; GK, glucokinase; AMPK, adenosine monophosphate activated protein kinase; CSII, continuous subcutaneous insulin infusion; MDI, multiple daily injections; HAAF, hypoglycemia associated autonomic failure
The brain is an obligate glucose consumer and critically dependent on glucose supply for normal function. Maintaining blood glucose levels within a tight physiological range is critical to whole-body glucose homeostasis. For patients with diabetes, many of the glucose lowering drugs used to treat hyperglycemia can reduce blood sugar below the physiological range and induce a state of hypoglycemia (low blood sugar). In response to hypoglycemia, as a means of self-preservation, the brain coordinates a stress (counterregulatory) response to rapidly restore blood sugar levels to normal. This counterregulatory response involves systemic hormone responses, including a reduction in insulin secretion from the pancreatic b-cells and an increase in glucagon secretion from the pancreatic a-cells.
The counterregulatory stress response also involves activation of critically important glucose sensing areas in the hypothalamus which respond to hypoglycemia by activating sympathetic efferent signals to the adrenal medulla to rapidly release epinephrine. The hypothalamic release of corticotrophin releasing hormone (CRH) mediates release of adrenocorticotrophin hormone (ACTH) systemically to trigger cortisol release from the adrenal cortex, which may be an important counterregulatory response to more prolonged hypoglycemia (Figure 1).
Figure 1. Glucose Sensing and the Physiological Response to Hypoglycemia.
In the normal response to hypoglycemia, the brain (especially the hypothalamus) coordinates and triggers a stress response to restore euglycemia. Key areas of the hypothalamus that sense and respond to hypoglycemia are the ventromedial hypothalamus (VMH), the arcuate nucleus (ARC) and the paraventricular nucleus (PVN). Efferent outflow from the hypothalamus results in activation of the hypothalamic-pituitary-adrenal (HPA) axis as well as the sympathetic nervous system to increase production of key counterregulatory hormones. Cortisol (via ACTH release) and epinephrine secretions arise from the adrenal cortex and medulla, respectively. Activation of the sympathetic nervous system increases both norepinephrine release (causing tremulousness, alertness and palpitations) and acetylcholine release (causing hunger and sweating). At the level of the pancreas, in response to hypoglycemia, endogenous insulin secretion from the β-cell is suppressed while glucagon release from the α-cell is elevated. By antagonizing insulin effects, these counterregulatory hormones work to increase blood glucose levels by stimulating endogenous glucose release from the liver, stimulating feeding behavior, and suppressing glucose clearance.
Hypoglycemia is an acute complication associated with the treatment of diabetes. Episodes of severe, temporarily disabling hypoglycemia, often with seizures or coma, occur yearly in 10-25% of people with Type 1 (insulin-dependent) diabetes.(1) As discussed below, there are many reasons why patients with both Type 1 and longstanding Type 2 diabetes have defective counterregulatory responses to hypoglycemia and are therefore susceptible to more frequent and more severe episodes of hypoglycemia. For these patients with diabetes, hypoglycemia becomes the rate-limiting step in the management of their blood sugar.(2) This barrier of hypoglycemia prevents people with diabetes from achieving the known microvascular benefits associated with intensive blood sugar control. This Cyberounds® will identify the key glucose sensing systems in the central nervous system and identify clinically proven therapeutic strategies to prevent hypoglycemia for patients with diabetes.
Sites of CNS Glucose Sensing
In order to detect slight fluctuations in glucose levels, the body is equipped with numerous sensors located throughout the body, including the gut, portal vein, pancreas and brain.(3)(4)(5)(6)(7) Many studies have confirmed that the brain serves as the body's primary glucose sensor and the hypothalamus functions as the hub of glucose sensing(8)(9)(10)(11). Within the hypothalamus, glucose sensing predominates in discrete regions, namely the ventromedial hypothalamus (VMH), arcuate nucleus (ARC) and paraventricular nucleus (PVN).
The VMH is the most studied region. Several studies abolishing VMH function have demonstrated its role in CNS glucose sensing. Specifically, creating lesions or chemical destruction of the VMH deregulated peripheral glucose homeostasis.(11)(12)(13) While all neurons metabolize glucose, a set of critically important neurons within the VMH and brain stem sense and respond to changes in blood sugar. By coupling their neuronal activity (i.e., firing rate) in response to their metabolism of glucose, these specialized neurons have been classified as "glucose sensing" neurons and not merely as "glucose using" neurons.
These glucose sensing neurons are categorized as glucose-excited neurons (GE), which increase their firing rate when extracellular glucose concentrations are elevated or glucose-inhibited neurons (GI), which are activated by decreases in extracellular glucose concentration or by cellular glucoprivation(14)(15)(16) (Figure 2).
Figure 2. Mechanism of Glucose Sensing in Glucose-excited (GE) Neurons.
Glucose sensing in glucose excited (GE) requires glucose uptake via glucose transporters (GLUTs), glucose phosphorylation by the rate-limiting enzyme glucokinase, and subsequent metabolism of glucose to increase the intracellular ATP-to-ADP ratio. In the setting of glucose sufficiency, ATP-sensitive K+ channels are closed, the membrane is depolarized, and neuronal firing occurs, which suppresses the counterregulatory response while glucose levels are not low. Thus a rise in plasma glucose increases neuronal activity in GE neurons. However, when glucose levels fall as would occur during hypoglycemia, the decreased metabolism of glucose leads to opening of K-ATP channels and hyperpolarization of these glucose excited neurons. Conversely, another set of less well characterized glucose sensing neurons, glucose-inhibited (GI) neurons, are activated during hypoglycemia and are quiescent during hyperglycemia. ( ΔVm: change in membrane potential, membrane depolarization).
Both neuronal populations are widely distributed throughout the brain, but display distinct enrichment in hypothalamic and hindbrain regions classically associated with neuroendocrine regulation, energy homeostasis and nutrient metabolism.