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Publication
Hypothalamic POMC or MC4R deficiency impairs counterregulatory responses to
hypoglycemia in mice.
Authors Tooke BP, Yu H, Adams JM, Jones GL, Sutton-Kennedy T, Mundada L, Qi NR, Low MJ,
Chhabra KH
Submitted By Submitted Externally on 4/15/2019
Status Published
Journal Molecular metabolism
Year 2019
Date Published 2/1/2019
Volume : Pages 20 : 194 - 204
PubMed Reference 30503832
Abstract Life-threatening hypoglycemia is a major limiting factor in the management of
diabetes. While it is known that counterregulatory responses to hypoglycemia are
impaired in diabetes, molecular mechanisms underlying the reduced responses
remain unclear. Given the established roles of the hypothalamic
proopiomelanocortin (POMC)/melanocortin 4 receptor (MC4R) circuit in regulating
sympathetic nervous system (SNS) activity and the SNS in stimulating
counterregulatory responses to hypoglycemia, we hypothesized that hypothalamic
POMC as well as MC4R, a receptor for POMC derived melanocyte stimulating
hormones, is required for normal hypoglycemia counterregulation., To test the
hypothesis, we induced hypoglycemia or glucopenia in separate cohorts of mice
deficient in either POMC or MC4R in the arcuate nucleus (ARC) or the
paraventricular nucleus of the hypothalamus (PVH), respectively, and measured
their circulating counterregulatory hormones. In addition, we performed a
hyperinsulinemic-hypoglycemic clamp study to further validate the function of
MC4R in hypoglycemia counterregulation. We also measured Pomc and Mc4r mRNA
levels in the ARC and PVH, respectively, in the streptozotocin-induced type 1
diabetes mouse model and non-obese diabetic (NOD) mice to delineate molecular
mechanisms by which diabetes deteriorates the defense systems against
hypoglycemia. Finally, we treated diabetic mice with the MC4R agonist MTII,
administered stereotaxically into the PVH, to determine its potential for
restoring the counterregulatory response to hypoglycemia in diabetes.,
Stimulation of epinephrine and glucagon release in response to hypoglycemia or
glucopenia was diminished in both POMC- and MC4R-deficient mice, relative to
their littermate controls. Similarly, the counterregulatory response was
impaired in association with decreased hypothalamic Pomc and Mc4r expression in
the diabetic mice, a phenotype that was not reversed by insulin treatment which
normalized glycemia. In contrast, infusion of an MC4R agonist in the PVH
restored the counterregulatory response in diabetic mice., In conclusion,
hypothalamic Pomc as well as Mc4r, both of which are reduced in type 1 diabetic
mice, are required for normal counterregulatory responses to hypoglycemia.
Therefore, enhancing MC4R function may improve hypoglycemia counterregulation in
diabetes.





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