Influence of VMH fuel sensing on hypoglycemic responses

Abstract

Hypoglycemia produces complex neural and hormonal responses that restore glucose levels to normal. Glucose, metabolic substrates and their transporters, neuropeptides and neurotransmitters alter the firing rate of glucose-sensing neurons in the ventromedial hypothalamus (VMH); these monitor energy status and regulate the release of neurotransmitters that instigate a suitable counter-regulatory response. Under normal physiological conditions, these mechanisms maintain blood glucose concentrations within narrow margins. However, antecedent hypoglycemia and diabetes can lead to adaptations within the brain that impair counter-regulatory responses. Clearly, the mechanisms employed to detect and regulate the response to hypoglycemia, and the pathophysiology of defective counter-regulation in diabetes, are complex and need to be elucidated to permit the development of therapies that prevent or reduce the risk of hypoglycemia.

Keywords: brain; diabetes; glucose sensing; hypoglycemia; recurrent hypoglycemia; ventromedial hypothalamus.

Conflict of interest statement

No potential conflicts of interest relevant to this article were reported.

Copyright © 2013 Elsevier Ltd. All rights reserved.

Figures

Figure 1. VMH glucose sensing mechanisms during acute hypoglycemia

Schematic showing pathways in the VMH involved in glucose sensing, in response to an acute bout of hypoglycemia in the non-diabetic hypoglycemia-naïve condition. In glucose excited (GE) neurons it has been postulated that a decrease in glucose entering the neuron leads to a reduction in the ATP/ADP ratio. Decreases in this ratio causes ATP-sensitive potassium channel (KATP) to open which in turn, hyperpolarizes GE neurons and prevents release of the inhibitory neurotransmitter, GABA. On the other hand, hypoglycemia, which stimulates glucose inhibited (GI) neurons, leads to activation of AMPK. AMPK then increases the production of nitric oxide (NO) which in turn, further enhances the level of AMPK activation through secondary messengers. This amplification of AMPK activity then inactivates (dotted line) the CFTR chloride channel, resulting in depolarization of glucose inhibited neurons and release of a neurotransmitter, likely glutamate. In the astrocytes/tanycytes, a reduction in glucose entry leads to the breakdown of stored glycogen and the production of lactate. Lactate is exported from the astrocyte through monocarboxylic acid transporter 1 or 4 (MCT1 or 4) and enters nearby neurons through MCT2 where it is oxidized.

Figure 2. VMH glucose sensing mechanisms during recurrent hypoglycemia

Schematic showing our current understanding of how defective fuel sensing mechanisms in the brain following recurrent exposure to hypoglycemia contribute to counterregulatory failure. The oxidation of glucose and the breakdown of stored glycogen in the astrocyte/tanycyte results in greater lactate formation. Lactate is then made available to both adjacent GE and GI neurons. The oxidation of lactate in GE neurons serves two purposes: 1) to generate ATP which leads to closure of the KATP channel and 2) to provide a substrate for the synthesis of GABA. Together, this enhances GABA release. A decrease in glucose along with increased oxidation of lactate in GI neurons, however, prevents intracellular AMP levels from rising and inhibits activation of AMPK, allowing CFTR channels to open and chloride to enter. Chloride entry then hyperpolarizes GI neurons and inhibits its firing, thereby reducing glutamate release. The resulting increase in GABAergic inhibition and reduction in glutamatergic excitation following recurrent exposure to hypoglycemia act synonymously to suppress the release of counterregulatory hormones during subsequent bouts of hypoglycemia.