Neural pathways that control the glucose counterregulatory response

Abstract

Glucose is an essential metabolic substrate for all bodily tissues. The brain depends particularly on a constant supply of glucose to satisfy its energy demands. Fortunately, a complex physiological system has evolved to keep blood glucose at a constant level. The consequences of poor glucose homeostasis are well-known: hyperglycemia associated with uncontrolled diabetes can lead to cardiovascular disease, neuropathy and nephropathy, while hypoglycemia can lead to convulsions, loss of consciousness, coma, and even death. The glucose counterregulatory response involves detection of declining plasma glucose levels and secretion of several hormones including glucagon, adrenaline, cortisol, and growth hormone (GH) to orchestrate the recovery from hypoglycemia. Low blood glucose leads to a low brain glucose level that is detected by glucose-sensing neurons located in several brain regions such as the ventromedial hypothalamus, the perifornical region of the lateral hypothalamus, the arcuate nucleus (ARC), and in several hindbrain regions. This review will describe the importance of the glucose counterregulatory system and what is known of the neurocircuitry that underpins it.

Keywords: adrenaline; counterregulation; glucagon; glucose sensing; hypoglycemia; perifornical hypothalamus; rostral ventrolateral medulla; ventromedial hypothalamus.

Figure 1

Afferent inputs from the periphery to brain neurons involved in glucose homeostasis. Glucose-sensing vagal and sympathetic afferents arise from the liver and gastrointestinal tract and convey information to the nucleus of the solitary tract (NTS). Unlike their sympathetic sensory counter-parts arising near the portal vein, vagal glucose sensors probably do not contribute the counter-regulatory response. Carotid body glucose sensors may also contribute to the counter-regulatory response. Information is relayed from NTS to the dorsal motor nucleus of the vagus (DMV) which provides parasympathetic drive to the pancreatic islets and via the parabrachial nucleus (PBN) top supramedullary structures. C1 adrenergic neurons with projections ascending to hypothalamic sub-regions such as the arcuate (ARC), lateral (LH), and ventromedial hypothalamic (VMH) nuclei, are involved in the feeding response to insulin-induced hypoglycemia.

Figure 2

Descending connections and intrahypothalamic pathways involved in glucose homeostasis. Neurons in the paraventricular nucleus of the hypothalamus (PVN) and the perifornical region of the hypothalamus (PeH) have connections with important premotor sympathetic and parasympathetic neuronal groups located in the rostral ventrolateral medulla (RVLM) and the dorsal motor nucleus of the vagus (DMV) as well as to the major sensory relay structure the nucleus of the solitary tract (NTS) and sympathetic preganglionic neurons (SPNs) located in the intermediolateral cell column (IML) of the spinal cord. Glucose-sensing neurons are found in the ARC, the ventromedial hypothalamic nucleus (VMH) and the perifornical region (PeH) of the lateral hypothalamic (LH) area. Parasympathetic efferents to the pancreatic islets can activate insulin and glucagon secretion while C1 neurons in the RVLM provide drive to adrenal SPNs. Parasagittal section at the top of the figure indicates rostrocaudal locations of coronal sections (A–E).

Figure 3

Hypothalamic projections to the adenohypophysis and to parasympathetic motorneurons that innervate the pancreas (left panel) and to sympathetic premotor neurons that supply the adrenal gland (right panel). Neurons in the paraventricular nucleus of the hypothalamus (PVN) control the release of adrenocorticotropin (ACTH) into the circulation via corticotropin releasing factor (CRF) to promote secretion of cortisol from the adrenal cortex while arcuate (ARC) neurons control release of growth hormone (GH) via the release of growth hormone releasing factor (GRF). Preganglionic parasympathetic neurons of the dorsal motor nucleus of the vagus (DMV) receive inputs from neurons in the ARC and the lateral hypothalamus (LH). PVN and LH neurons send direct projections to the nucleus of the solitary tract (NTS) and to sympathetic preganglionic neurons in the intermediolateral cell column (IML). Adrenal catecholamine release is controlled by inputs from LH to C1 neurons in the rostral ventrolateral medulla (RVLM) that drive the adrenal sympathetic outflow.