nn-414 and Hypoglycemia

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 (K

Topics: Action Potentials; Animals; Bridged Bicyclo Compounds, Heterocyclic; Cell Line; Cyclic S-Oxides; Glucose; Hypoglycemia; Hypothalamus; KATP Channels; Mice; Neurons

In glucose-sensing neurons, ATP-sensitive K(+) channels (K(ATP) channels) are thought to translate metabolic signals into an alteration in neuronal firing rates. Because these neurons express the Kir6.2/SUR-1 isoform of the K(ATP) channel, we sought to examine the therapeutic potential of the SUR-1-selective potassium channel opener (KCO), NN414, to amplify counterregulatory response to hypoglycemia.. In vivo dose-response studies with NN414 delivered intravenously to normal Sprague-Dawley rats before the induction of controlled hypoglycemia were performed. Based on these studies, the potential for NN414 to restore counterregulatory responses in chronically cannulated nondiabetic and diabetic BB rats was explored using the in vivo hyperinsulinemic-hypoglycemic clamp technique.. NN414 delivered systemically amplified epinephrine responses during acute hypoglycemia and showed a persisting effect to amplify the epinephrine response when given 24 h before the hypoglycemic study. Local delivery of a potassium-channel blocker to the ventromedial hypothalamus reversed the effects of systemic NN414. In addition, NN414 amplified the epinephrine response to hypoglycemia in both nondiabetic and diabetic BB rats with defective hormonal counterregulation.. These studies demonstrate in a variety of rodent models that systemic delivery of Kir6.2/SUR-1-selective KCOs enhance the glucose counterregulatory response to insulin-induced hypoglycemia. Future studies in human subjects are now required to determine their potential as a therapy for hypoglycemia-associated autonomic failure in type 1 diabetes.

Topics: Animals; ATP-Binding Cassette Transporters; Blood Glucose; Bridged Bicyclo Compounds, Heterocyclic; Cyclic S-Oxides; Diabetes Mellitus, Type 1; Epinephrine; Homeostasis; Hypoglycemia; Potassium Channels, Inwardly Rectifying; Rats; Rats, Sprague-Dawley; Receptors, Drug; Sulfonylurea Receptors

The mechanism(s) by which glucosensing neurons detect fluctuations in glucose remains largely unknown. In the pancreatic beta-cell, ATP-sensitive K+ channels (K ATP channels) play a key role in glucosensing by providing a link between neuronal metabolism and membrane potential. The present study was designed to determine in vivo whether the pharmacological opening of ventromedial hypothalamic K ATP channels during systemic hypoglycemia would amplify hormonal counterregulatory responses in normal rats and those with defective counterregulation arising from prior recurrent hypoglycemia. Controlled hypoglycemia (approximately 2.8 mmol/l) was induced in vivo using a hyperinsulinemic (20 mU x kg(-1) x min(-1)) glucose clamp technique in unrestrained, overnight-fasted, chronically catheterized Sprague-Dawley rats. Immediately before the induction of hypoglycemia, the rats received bilateral ventromedial hypothalamic microinjections of either the potassium channel openers (KCOs) diazoxide and NN414 or their respective controls. In normal rats, both KCOs amplified epinephrine and glucagon counterregulatory responses to hypoglycemia. Moreover, diazoxide also amplified the counterregulatory responses in a rat model of defective hormonal counterregulation. Taken together, our data suggest that the K ATP channel plays a key role in vivo within glucosensing neurons in the ventromedial hypothalamus in the detection of incipient hypoglycemia and the initiation of protective counterregulatory responses. We also conclude that KCOs may offer a future potential therapeutic option for individuals with insulin-treated diabetes who develop defective counterregulation.

Topics: Animals; Blood Glucose; Bridged Bicyclo Compounds, Heterocyclic; Carbonates; Cyclic S-Oxides; Diazoxide; Epinephrine; Glucagon; Glucose; Hypoglycemia; Male; Potassium; Potassium Channels, Inwardly Rectifying; Rats; Rats, Sprague-Dawley; Ventromedial Hypothalamic Nucleus