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Review
. 2019 Jun 1;40(3):768-788.
doi: 10.1210/er.2018-00226.

Central Mechanisms of Glucose Sensing and Counterregulation in Defense of Hypoglycemia

Sarah Stanley  1 , Amir Moheet  2 , Elizabeth R Seaquist  2
Affiliations
Review

Central Mechanisms of Glucose Sensing and Counterregulation in Defense of Hypoglycemia

Sarah Stanley et al. Endocr Rev. .

Abstract

Glucose homeostasis requires an organism to rapidly respond to changes in plasma glucose concentrations. Iatrogenic hypoglycemia as a result of treatment with insulin or sulfonylureas is the most common cause of hypoglycemia in humans and is generally only seen in patients with diabetes who take these medications. The first response to a fall in glucose is the detection of impending hypoglycemia by hypoglycemia-detecting sensors, including glucose-sensing neurons in the hypothalamus and other regions. This detection is then linked to a series of neural and hormonal responses that serve to prevent the fall in blood glucose and restore euglycemia. In this review, we discuss the current state of knowledge about central glucose sensing and how detection of a fall in glucose leads to the stimulation of counterregulatory hormone and behavior responses. We also review how diabetes and recurrent hypoglycemia impact glucose sensing and counterregulation, leading to development of impaired awareness of hypoglycemia in diabetes.

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Figures

Figure 1.
Figure 1.
Sites of glucose-sensing neurons in mouse brain. GE and GI neurons are found in many brain regions. In the hypothalamus, these include the PVH, ARC, DMH, VMH, and LH. Outside the hypothalamus, glucose-sensing neurons have been reported in the NAc, amygdala, LC, and PBN. In the brain stem, the AP, NTS, and DMV also have glucose-sensing neurons.
Figure 2.
Figure 2.
Putative glucose-sensing mechanisms in glucose-sensing neurons. In GE cells (upper panel), glucose can enter cells via GLUTs (usually GLUT2 or GLUT3) and is phosphorylated by glucokinase to glucose-6-phosphate. This, in turn, regulates cytosolic ATP production. In GE neurons, increased ATP closes KATP channels, leading to depolarization and calcium influx through voltage-activated calcium channels. Metabolism-independent pathways have also been described using sweet taste receptors and downstream signaling, sodium/glucose cotransporter, or transient receptor potential canonical type 3 (TRPC3) channels. Both sodium/glucose cotransporter and TRPC3 channels lead to influx of cations and depolarization. In GI cells (lower panel), as glucose entry decreases, intracellular ATP falls. Low ATP leads to an increase in AMPK activity. This may reduce activity of chloride channels, possibly via neuronal NO synthase, whereas low ATP decreases activity of Na/K ATPases. Both of these lead to cell depolarization with low glucose. Alternative pathways involving closure of potassium leak channels with low glucose have also been described.
Figure 3.
Figure 3.
Connections to sympathetic and parasympathetic efferent pathways in the mouse brain. The DMV is the parasympathetic efferent pathway. The DMV receives input from the NTS and the RVLM as well as from the PVH, DMH, LH, and ARC. The VMH connects indirectly via the PVH. The sympathetic efferent pathway is via the IML of the spinal cord. This receives input from the RVLM, LC, as well as the PVH and LH. Multiple hypothalamic regions, including the ARC, VMH, DMH, project to either the PVH or LH.
Figure 4.
Figure 4.
Potential mechanisms that may contribute to the development of impaired awareness of hypoglycemia after exposure to recurrent hypoglycemia.
See this image and copyright information in PMC

References

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