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Study · Animal study (in vivo) · mouse · 2019

1 result

Hypothalamic POMC or MC4R deficiency impairs counterregulatory responses to hypoglycemia in mice.

Tooke BP, Yu H, Adams JM, Jones GL, Sutton-Kennedy T, Mundada L, Qi NR, Low MJ, Chhabra KH

Molecular metabolism20 Nov 2018Cited by 20 (Europe PMC)

PMID30503832 (opens in a new tab)PMCIDPMC6358536 (opens in a new tab)DOI10.1016/j.molmet.2018.11.004 (opens in a new tab)PepBankPUB-30503832
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Summary

ObjectiveLife-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.MethodsTo 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.ResultsStimulation 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.ConclusionIn 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.
CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study1

1 result from studies that gave the peptide. No result from this study comes from people.

  1. 01AnimalAnimal study (in vivo)Efficacy outcome

    In diabetic mice, infusion of the MC4R agonist MTII into the paraventricular hypothalamus restored the counterregulatory response to hypoglycemia.

    In plain wordsIn diabetic mice, MTII infused into a brain region restored the body's response to low blood sugar.

    Peptide
    Melanotan II
    Outcome
    IncreaseCounterregulatory response to hypoglycemia after PVH MC4R agonist infusion
    Study

    mousen: not reported in source

    Diabetic mice
    Outcome group
    Glycemic control · Endocrine and hormones
    Studied dose
    Dose not stated · stereotaxic infusion into the paraventricular hypothalamusAs given in this study (mouse).

    Source sentences

    Summary
    In contrast, infusion of an MC4R agonist in the PVH restored the counterregulatory response in diabetic mice.
    1 context sentence
    Summary · context
    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.

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Version history

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  1. Version 2Current

    10 Oct 2026, 09:43 UTC

    Study results updated

  2. Version 1

    9 Oct 2026, 03:04 UTC

    First added · source update from Europe PMC

Subjects

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