Glucocorticoid rhythm disruption drives hyperinsulinaemia in mice through beta cell glucocorticoid receptor signalling
Wilson, J.; Arzeno, A. S.; Sharma, S.; Agas, A.; Lungstrum, J.; Teruel, M. N. · physiology · 2026-09-06 · 原文
DOI：10.64898/2026.06.03.730005作者：6 位
Aims/hypothesis: Hyperinsulinaemia is typically viewed as a secondary, compensatory response to insulin resistance or elevated glycaemia. However, we previously found that disrupting the daily glucocorticoid rhythm in mice rapidly increases circulating insulin several-fold while fasting glucose remains normal. This raised the question of what generates and sustains the hyperinsulinaemia. Because glucocorticoids act directly on beta cells through the glucocorticoid receptor (GR), we tested whether beta cell GR is required for this rise in insulin and whether elevated insulin is necessary to maintain glucose homeostasis. Methods: Glucocorticoid rhythms were disrupted in male C57BL/6J mice by subcutaneously implanting corticosterone pellets that raise the trough and lower the peak while maintaining near-physiological mean glucocorticoid exposure, a manipulation we refer to as GC-flattening. Placebo-treated mice served as controls, and high-fat-diet-fed mice provided a metabolic comparison. Beta cell function was assessed by dynamic glucose stimulated insulin secretion and beta cell specific Ca2+ imaging. The requirement for beta cell GR was tested using adult-inducible beta cell speci
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1. 人话版
Aims/hypothesis: Hyperinsulinaemia is typically viewed as a secondary, compensatory response to insulin resistance or elevated glycaemia.
However, we previously found that disrupting the daily glucocorticoid rhythm in mice rapidly increases circulating insulin several-fold while fasting glucose remains normal.
2. 领域脉络
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3. 机制拆解
This raised the question of what generates and sustains the hyperinsulinaemia.
Because glucocorticoids act directly on beta cells through the glucocorticoid receptor (GR), we tested whether beta cell GR is required for this rise in insulin and whether elevated insulin is necessary to maintain glucose homeostasis.
4. 证据与数字
Methods: Glucocorticoid rhythms were disrupted in male C57BL/6J mice by subcutaneously implanting corticosterone pellets that raise the trough and lower the peak while maintaining near-physiological mean glucocorticoid exposure, a manipulation we refer to as GC-flattening.
Beta cell function was assessed by dynamic glucose stimulated insulin secretion and beta cell specific Ca2+ imaging.
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