Hypoglycemia: Role of Hypothalamic Glucose-Inhibited (GI) Neurons in Detection and Correction

Abstract

Hypoglycemia is a profound threat to the brain since glucose is its primary fuel. As a result, glucose sensors are widely located in the central nervous system and periphery. In this perspective we will focus on the role of hypothalamic glucose-inhibited (GI) neurons in sensing and correcting hypoglycemia. In particular, we will discuss GI neurons in the ventromedial hypothalamus (VMH) which express neuronal nitric oxide synthase (nNOS) and in the perifornical hypothalamus (PFH) which express orexin. The ability of VMH nNOS-GI neurons to depolarize in low glucose closely parallels the hormonal response to hypoglycemia which stimulates gluconeogenesis. We have found that nitric oxide (NO) production in low glucose is dependent on oxidative status. In this perspective we will discuss the potential relevance of our work showing that enhancing the glutathione antioxidant system prevents hypoglycemia associated autonomic failure (HAAF) in non-diabetic rats whereas VMH overexpression of the thioredoxin antioxidant system restores hypoglycemia counterregulation in rats with type 1 diabetes.We will also address the potential role of the orexin-GI neurons in the arousal response needed for hypoglycemia awareness which leads to behavioral correction (e.g., food intake, glucose administration). The potential relationship between the hypothalamic sensors and the neurocircuitry in the hindbrain and portal mesenteric vein which is critical for hypoglycemia correction will then be discussed.

Identification of hypoglycemia-specific neural signals by decoding murine vagus nerve activity

“…In this study, we have found that signals from the surface of the cervical vagus nerve change with acute hypoglycemia, and that some of the signals are correlated with blood glucose levels. Prior studies have reported elevated brain activity in the hypothalamic, as well as other regions, in response to acute hypoglycemia (McCrimmon 2008;Routh 2002;Zhou et al 2018). The means of 20 s, non-overlapping sliding windows over the event rates for the previous 4 min were used as features to the lasso regression model with a regularization factor of 1.…”

Revisiting How the Brain Senses Glucose—And Why

“…While acknowledging the need for additional data on this topic, available evidence strongly suggests that glucose levels in brain ISF do not faithfully reflect the temporal dynamics of changes in the circulating level. Yet the vast majority of glucose-sensitive neurons in the brain, including those in both the hindbrain and in hypothalamic areas such as the ventromedial nucleus (VMN) that are implicated in glucose homeostasis (Kang et al, 2006; Zhou et al, 2018), are exposed only to brain ISF and not to plasma.…”

“…After all, changes in the activity of glucose-sensitive neurons in the VMN and elsewhere can potently influence both the plasma glucose level and the secretion of insulin and glucagon (via changes in autonomic output to liver and pancreas) (Fioramonti et al, 2017; Kang et al, 2006; Meek et al, 2016; Pozo and Claret, 2018; Zhou et al, 2018). Moreover, the activity of glucoregulatory neurons in the VMN comprising the efferent limb of the system is known to be influenced by ascending input from projections from the parabrachial nucleus (Flak et al, 2014; Garfield et al, 2014) (a brain area richly supplied with projections from the NTS).…”

“…Accordingly, the afferent and efferent limbs of the brain’s glucoregulatory system should be distinguishable from one another, with the afferent limb being comprised of neurons situated outside of, or with access across, the BBB and the efferent limb situated in areas behind the BBB, such as the VMN (by analogy to the organization of neurocircuits involved in thermoregulation). After all, changes in the activity of glucose-sensitive neurons in the VMN and elsewhere can potently influence both the plasma glucose level and the secretion of insulin and glucagon (via changes in autonomic output to liver and pancreas) (Fioramonti et al, 2017; Kang et al, 2006; Meek et al, 2016; Pozo and Claret, 2018; Zhou et al, 2018). Moreover, the activity of glucoregulatory neurons in the VMN comprising the efferent limb of the system is known to be influenced by ascending input from projections from the parabrachial nucleus (Flak et al, 2014; Garfield et al, 2014) (a brain area richly supplied with projections from the NTS).…”

“…Glucose-sensitive neurons can be subdivided into “glucose-excited” and “glucose-inhibited” neuronal subsets, and they are concentrated in hypothalamic areas implicated in whole-body glucose homeostasis (for reviews, see (Fioramonti et al, 2017; Pozo and Claret, 2018; Zhou et al, 2018)). Moreover, many of these neurons use the same glucose-sensing molecular machinery found in pancreatic beta cells.…”