Abstract
Individuals with Type 1 diabetes (T1D) are often exposed to recurrent episodes of hypoglycaemia. This reduces hormonal and behavioural responses that normally counteract low glucose in order to maintain glucose homeostasis, with altered responsiveness of glucose sensing hypothalamic neurons implicated. Although the molecular mechanisms are unknown, pharmacological studies implicate hypothalamic ATP-sensitive potassium channel (KATP) activity, with KATP openers (KCOs) amplifying, through cell hyperpolarization, the response to hypoglycaemia. Although initial findings, using acute hypothalamic KCO delivery, in rats were promising, chronic exposure to the KCO NN414 worsened the responses to subsequent hypoglycaemic challenge. To investigate this further we used GT1-7 cells to explore how NN414 affected glucose-sensing behaviour, the metabolic response of cells to hypoglycaemia and KATP activity. GT1-7 cells exposed to 3 or 24 h NN414 exhibited an attenuated hyperpolarization to subsequent hypoglycaemic challenge or NN414, which correlated with diminished KATP activity. The reduced sensitivity to hypoglycaemia was apparent 24 h after NN414 removal, even though intrinsic KATP activity recovered. The NN414-modified glucose responsiveness was not associated with adaptations in glucose uptake, metabolism or oxidation. KATP inactivation by NN414 was prevented by the concurrent presence of tolbutamide, which maintains KATP closure. Single channel recordings indicate that NN414 alters KATP intrinsic gating inducing a stable closed or inactivated state. These data indicate that exposure of hypothalamic glucose sensing cells to chronic NN414 drives a sustained conformational change to KATP, probably by binding to SUR1, that results in loss of channel sensitivity to intrinsic metabolic factors such as MgADP and small molecule agonists.
Highlights
Ingestion of diazoxide by Type 1 diabetes (T1D) subjects under hyperinsulinemic hypoglycaemic clamp demonstrated an improved counterregulatory responses (CRR), which was diminished in individuals with a ATP-sensitive potassium channel (KATP) channel polymorphism that is associated with diabetes (George et al, 2015)
We have previously demonstrated that continuous central NN414 exposure, rather than defending against the development of defective CRR in response to repetitive hypoglycaemic challenge, attenuates the CRR to hypoglycaemia in vivo and reduces KATP channel conductance density in vitro (Beall et al, 2013)
We show that continuous NN414 application for 24 h blunted low-glucose sensing in the GT1-7 cell line
Summary
E. Haythorne et al / Neuropharmacology 111 (2016) 212e222 et al, 2004; Song and Routh, 2006). It is well established that the brain, in particular certain regions of the hypothalamus, regulates the physiological responses to hypoglycaemia in an effort to maintain whole body glucose homeostasis (Borg et al, 1994, 1995, 1997). There are no effective treatments for defective CRR in type 1 diabetes other than the strict avoidance of hypoglycaemia that has only been achieved in intensive clinical trials involving small numbers of participants. There is an urgent requirement to identify alternative therapies and/or adjunct molecules that act centrally to prevent, or restore, defective CRR, and to define their biological and pharmacological mechanisms
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