Neuronal regulation of glucagon secretion and gluconeogenesis

Abstract

Hypoglycemia almost never develops in healthy individuals, because multiple hypoglycemia sensing systems, located in the periphery and in the central nervous system, trigger a coordinated counterregulatory hormonal response to restore normoglycemia. This involves not only the secretion of glucagon, but also of epinephrine, norepinephrine, cortisol and growth hormone. Increased hepatic glucose production is also stimulated by direct autonomous nervous connections to the liver that stimulate glycogenolysis and gluconeogenesis. This counterregulatory response, however, becomes deregulated in a significant fraction of diabetes patients that receive insulin therapy. This leads to the risk of developing hypoglycemic episodes, of increasing severity, which negatively impact the quality of life of the patients. How hypoglycemia is detected by the central nervous system is being actively investigated. Recent studies using novel molecular biological, optogenetic and chemogenetic techniques allow the characterization of glucose-sensing neurons, the mechanisms of hypoglycemia detection, the neuronal circuits in which they are integrated and the physiological responses they control. This review discusses recent studies aimed at identifying central hypoglycemia sensing neuronal circuits, how neurons are activated by hypoglycemia and how they restore normoglycemia.

Keywords: Glucagon; Hypoglycemia; Hypothalamus.

Figure 1

Pathways for hypoglycemia activation of the vagal nerve. Glucose‐sensing neurons that transmit a hypoglycemia signal are located in the portal vein area, the brainstem and the hypothalamus. In the portal vein area, hypoglycemia‐sensitive nerve terminals send projections to the DVC and this signal is further conveyed to the hypothalamus. At the level of the brainstem, hypoglycemia activates neurons in all three nuclei of the dorsal vagal complex (DVC), and these can directly or indirectly through hypothalamic nuclei control the activity of the dorsal motor nucleus of the vagus (DMNX) and, thus, the vagal nerve. Hypoglycemia can also activate neurons in the indicated nuclei of the hypothalamus, which send direct or indirect projections to the DVC for the control of vagal activity and glucagon secretion. AP, area postrema; ARH, arcuate nucleus; DMH, dorsomedial nucleus; LH, lateral nucleus; NTS, nucleus of the tractus solitarius; PVN, paraventricular nucleus; VMN, ventromedial nucleus.

Figure 2

Pathways for hypoglycemia activation of the sympathetic nerve. Glucose‐sensing neurons that transmit hypoglycemia signals to the sympathetic nerve are located in the brainstem and the hypothalamus. In the brainstem, epinephrine and norepinephrine neurons of the ventrolateral medulla (VLM) can be activated by hypoglycemia or neuroglucopenia. They activate the sympathetic glucagon response indirectly through projections to the hypothalamus or directly through connections to the intermediolateral cell column (IML). Cholecystokinin neurons of the parabrachial nucleus (PBN) send projections to the ventromedial nucleus (VMN) to control glucagon secretion, as discussed in the text. The indicated hypothalamic nuclei also contain neurons that can detect hypoglycemia and activate the sympathetic nerve either through intrahypothalamic connections to the paraventricular nucleus (PVN), which send direct projections to the IML or indirect projections through the VLM. The lateral nucleus (LH) also sends projection to the VLM and IML to control sympathetic activity. The activated sympathetic nerve stimulates epinephrine secretion from the adrenals, which increases glucagon secretion and hepatic glucose production; it activates lipolysis in adipose tissue to provide free fatty acids required to fuel hepatic neoglucogenesis; it inhibits insulin secretion and directly stimulates glucagon secretion; it also directly stimulates hepatic glucose production.

Figure 3

Identification of Fgf15 neurons that control glucagon secretion and hepatic glucose production. Recombinant inbred BXD mouse lines derived from the initial cross of C57Bl/6 and DBA/2J mice have been used to search for genomic intervals (QTL) that control neuroglucopenia‐induced glucagon secretion (top left). This led to the identification of Fgf15 on the distal part of chromosome 7 (top right). Fgf15 was found to be expressed in a subpopulation of dorsomedial (DMH) neurons (lower part). Expression of the hM3Dq receptor (blue) specifically in these neurons allowed their specific activation by i.p. injection of clozapine‐N‐oxide. This suppressed hypoglycemia‐induced glucagon secretion by blocking the activation of dorsal vagal complex (DVC) neurons. In contrast, activation of the Fgf15 neurons led to increased sympathetic nerve firing, leading to the induction of neoglucogenic genes in the liver and increased hepatic glucose production.