Evidence against hypothalamic-pituitary-adrenal axis suppression in the antidiabetic action of leptin

Leptin administration restores euglycemia in rodents with severe insulin-deficient diabetes, and recent studies to explain this phenomenon have focused on the ability of leptin to normalize excessive hypothalamic-pituitary-adrenal (HPA) axis activity. Here, we employed a streptozotocin-induced rat model (STZ-DM) of uncontrolled insulin-deficient diabetes mellitus (uDM) to investigate the contribution of HPA axis suppression to leptin-mediated glucose lowering. Specifically, we asked if HPA axis activation is required for diabetic hyperglycemia, whether HPA axis normalization can be achieved using a dose of leptin below that needed to normalize glycemia, and if the ability of leptin to lower plasma glucocorticoid levels is required for its antidiabetic action. In STZ-DM rats, neither adrenalectomy-induced (ADX-induced) glucocorticoid deficiency nor pharmacological glucocorticoid receptor blockade lowered elevated blood glucose levels. Although elevated plasma levels of corticosterone were normalized by i.v. leptin infusion at a dose that raises low plasma levels into the physiological range, diabetic hyperglycemia was not altered. Lastly, the potent glucose-lowering effect of continuous intracerebroventricular leptin infusion was not impacted by systemic administration of corticosterone at a dose that maintained elevated plasma levels characteristic of STZ-DM. We conclude that, although restoring low plasma leptin levels into the physiological range effectively normalizes increased HPA axis activity in rats with uDM, this effect is neither necessary nor sufficient to explain leptin's antidiabetic action.