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New Uses for Old Drugs: Neonatal Diabetes & Sulphonylureas

Introduction
Rare: 1 in 200,000 live births ND = within 6 months of life. Permanent/transient >50% due to Kir6.2 and SUR1 subunit mutations in the KATP channel o Sometimes, outside neo-natal period

Symptoms
1/3 with Kir6.2 mutation also have neurological symptoms Minority have DEND Syndrome: Developmental delay, Epilepsy & Neonatal Diabetes Most have iDEND (intermediate): ND, delayed speech and walking, and muscle weakness

KATP
Links cellular metabolism and electrical excitability Low metabolism channel open membrane potential at hyperpolarised (negative) level, thus reducing electrical activity Closure (due to presence of metabolic ATP) leads to depolarisation, thus increasing electrical activity Insulin secretion = channel closure Sulphonylurea drugs bind to the KATP channel and cause it to shut o SUR1: endocrine cells, neurones o SUR2A: heart & skeletal muscles o SUR2B: smooth muscles, (neurones)

Extrapancreatic effects
Epilepsy caused by reduced activity of inhibitory interneurones Muscle weakness due to KATP channels in neurones Neurological symptoms only with high electrical activity reflect membrane potentials in different cells Cardiac cells are unaffected as there SUR2A subunits, which do not mutate, instead of SUR1, which do

Mouse models
Insulin secretion decrease reduced due to o Failure of glucose-dependent KATP channel closure o Progressive decrease in cell mass and insulin content Change in mass and content stopped by glibenclamide or insulin therapy (islet transplantation) therefore can conclude decrease is due to untreated hyperglycaemia Glibenclamide cant treat established hyperglycaemia (i.e. post Kir6.2 mutation) o So, if hyperglycaemia is prolonged, its difficult to restore cell mass Cant compare to humans, as humans will have been on insulin/sulphonylurea drugs from diagnosis.

Therapeutic implications
Originally, ND was misinterpreted as clinically early-onset type 1 diabetes Sulphonylureas reduce fluctuations in blood glucose and frequency of hypoglycaemic episodes Oral glucose is better than intravenous glucose in triggering insulin secretion in ND patients treated with sulphonylureas o Potentially due to hormones (GLP-1 and GIP in response to food in gut lumen) or neurotransmitters (acetylcholine in response to sight and smell of food) o KATP closure by sulphonylureas leads to elevation of Ca2+, so hormones and neurotransmitters are rendered operational Not all patients respond to sulphonylureas, but correlation between patient response and extent to which sulphonylurea tolbutamide blocks whole -cell current o <65% = failure o >75% = some response o Children switch more easily to sulphonylureas o Anomalies perhaps due to poor insulin therapy In type II diabetes, sulphonylureas efficacy decrease with time. Same cannot yet be said of ND, because weve only seen results for last 4 years

Sulphonylurea Therapy and Neurological Complications

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