Brain Defense of Glycemia in Health and Diabetes

Abstract

The brain coordinates the homeostatic defense of multiple metabolic variables, including blood glucose levels, in the context of ever-changing external and internal environments. The biologically defended level of glycemia (BDLG) is the net result of brain modulation of insulin-dependent mechanisms in cooperation with the islet, and insulin-independent mechanisms through direct innervation and neuroendocrine control of glucose effector tissues. In this article, we highlight evidence from animal and human studies to develop a framework for the brain's core homeostatic functions-sensory/afferent, integration/processing, and motor/efferent-that contribute to the normal BDLG in health and its elevation in diabetes.

Figure 1

Model for CNS regulation of the BDL_G. Circulating glucose levels are detected by the CNS via multiple ascending pathways. Interoceptive pathways convey indirect measures of glucose and other fuel availability such as adipose levels via the circulating hormone leptin. Central and peripheral glucose sensors, such as sensory nerves innervating the hepatic portal vein, directly detect ambient glucose levels and relay this information via alterations in sensory neuron firing rate. Exteroceptive sensory organs, including the skin, nose, eyes, and tongue, convey information about expected challenges to glucose homeostasis, such as cold temperatures. Together, afferent glucosensory, interoceptive, and exteroceptive systems communicate current and anticipated energy demands to the CNS, which coordinates the activities of effector systems to maintain the BDL_G. Created with BioRender (biorender.com).

Figure 2

Overview of strategies for CNS regulation of the BDL_G. The CNS senses and directs glucose management throughout the body by multiple mechanisms: 1) Circulating levels of blood glucose are sensed both centrally and peripherally. In the periphery, glucose sensors have been identified in the carotid body and in the liver. In the liver, spinal and vagal sensory neurons innervate the hepatic portal vein, a conduit delivering blood and ingested nutrients directly from capillary beds in the gastrointestinal system to those in the liver, prior to entry into the systemic circulation. Rapid detection of meal-associated changes in fuel availability are conveyed to the CNS via both vagal and spinal afferents, which demonstrate specialized responses to changes in portal glycemia. Centrally, glucose sensors with the highest capacity for access to circulating glucose levels are located near circumventricular organs that lack the protection of the blood-brain barrier. Of these, the ARC-median eminence within the ventral hypothalamus is home to both glucose-excited and glucose-inhibited neurons that increase their firing rates in response to a rise or fall in ambient glucose levels, respectively. During a rapid fall in blood glucose, glucose-inhibited neurons activate downstream preautonomic and neuroendocrine systems that engage counterregulatory mechanisms that restore blood glucose levels to the normal range. 2) Indirect measures of blood glucose are conveyed by interoceptive systems, including information about how fuel is used, how much fuel is stored in adipose tissue, and how much and what types of fuel are ingested. 3) Exteroceptive systems convey to the CNS ways in which glucose levels may be challenged by environmental conditions, including the availability of food, the presence of a physical threat, and the ambient temperature. Together, these cues are integrated by the CNS to compute the anticipated glycemic effect of possible behaviors. 4) The CNS integrates myriad afferent glucosensory, interoceptive, and exteroceptive cues of current and anticipated glucose levels to coordinate the activities of peripheral glucose effector organs. Created with BioRender (biorender.com). AP, area postrema; ME, median eminence; OVLT, organum vasculosum of the lamina terminalis; SFO, subfornical organ.