Diazoxide

Abstract

Diazoxide was initially developed as a non-diuretic hypotensive agent, an action for which it is still used clinically, before it was also noted to have a significant hypoglycaemic effect. Diazoxide is primarily indicated for the treatment of severe hypertension (particularly when associated with renal disease) and chronic intractable hypoglycaemia occurring, for instance, in the context of an insulinoma. Research in the last few years has suggested other potential uses for diazoxide including hypo-glycaemia unawareness in type 1 diabetes (T1DM), hyperlipidaemia and obesity and, perhaps more surprisingly, type 2 diabetes (T2DM). See Figure 1. Diazoxide is a benzo-thiadiazine derivative (7-chloro-3-methyl-2H-1,2,4-benzothiadiazine 1,1 dioxide), that is extensively protein bound (>90%) and is excreted by the kidneys. The plasma half-life following IV administration is 28±8.3 hours. The primary mode of action of diazoxide is through ATP-sensitive potassium (KATP) channels, which are a type of potassium channel gated by ATP and hence play a critical role as sensors of the metabolic status. KATP channels are composed of Kir6.x-type subunits and sulphonylurea receptor (SUR) subunits, along with some additional components. The Kir6.x- (either Kir6.1 or Kir6.2) subunits form the inward-rectifier potassium channel, while the SUR subunits (SUR1, SUR2A or SUR2B) are transmembrane proteins that allow nucleotide modulation of the potassium channel. The mechanism of action of diazoxide Diazoxide exerts its effects through binding to the SUR subunit of the KATP channel which has the effect of ‘opening’ the channel leading to increased potassium entry into the cell and hyperpolarisation of the cell membrane (inhibiting the generation of cell membrane potential). Sulphonylureas have the opposite action and, once bound to the SUR subunit of KATP channels, have the effect of ‘closing’ the channel. KATP channels are expressed within a number of cellular compartments (nucleus, sarcolemma, plasma membrane) and different tissues types, where the conformation of the channel largely determines its function. Pancreatic beta cells, for instance, express SUR1 and ATP-binding to SUR1 closes the KATP channel, depolarising the membrane and initiating a series of intracellular mechanisms that stimulate insulin release, an effect that is antagonised by diazoxide. In contrast, cardiac, skeletal and vascular and non-vascular smooth muscle predominantly contain KATP channels of the SUR2A subtype. Diazoxide binding to this subunit leads to vasodilation, hence its use as a treatment for severe hypertension and an explanation of well-recognised adverse effects such as reactive hyperaemia. Diazoxide is a well-established treatment for congenital hyperinsulin-aemia and insulinoma and has been used in this context for over 40 years. Trials have been small, and have looked at the medical management of insulinomas as an adjunct to surgery or in those who are inoperable. To date there has not been a large randomised controlled trial looking at the efficacy of this treatment. Recent studies have suggested a number of possible novel indications for the use of diazoxide in obesity and both T1DM and T2DM. Obesity and metabolic syndrome. Studies of cell culture and animal models have demonstrated that diazoxide induces membrane hyperpolarisation in adipocytes, an action that suppresses lipogenesis and increases lipolysis through the regulation of key insulin sensitive enzymes. Diazoxide therapy in rats produces a reduced lipogenic state and results in lower levels of plasma leptin. In an open-label non-placebo controlled study of obese human subjects, oral diazoxide when combined with a reduced calorie intake and increased physical activity resulted in additional reductions in both fasting and post-meal peak insulin levels by about 65% (p<0.001), body weight by 9.4kg (p<0.001), waist circumference by -9.2cm (p<0.001), diastolic blood pressure by 10.9mmHg (p<0.001), and an increase in HDL (p<0.05).1 The results are comparable to currently available anti-obesity medications such as orlistat. Beta cell preservation in T1DM and T2DM. A more recent development has been the study of diazoxide to prevent beta cell decline in both T1DM and T2DM. Studies in animals have suggested that diazoxide might reduce beta cell apoptosis by reducing the stress within the endoplasmic reticulum as well as through their action to hyperpolarise the plasma membranes and inhibit insulin release, both actions leading to ‘beta cell rest’. Bjork et al. showed that supplementary diazoxide treatment at the onset of type 1 antibody positive adults for three months can preserve residual insulin secretion after a year. This is through initial suppression of insulin production providing a period of ‘beta cell rest’ which then preserves residual insulin secretion even after a year.2 The same group has also shown that inhibition of insulin secretion reduces autoimmune antigen expression. Based on the similar hypothesis that beta cell rest will preserve beta cell function in the long term, a proof of concept study in patients with T2DM showed that diazoxide given with night-time insulin improved beta cell function, as demonstrated by the improved C peptide glucagon tests, but there was higher postprandial blood glucose in the morning. This can be explained through a selective action, as diazoxide prevents the insulin stimulating effects of glucose, but not that of glucagon.3 Glycaemic control was not affected. Further human studies have shown that for long-term glycaemic regulation, diazoxide should be given with insulin. Hypoglycaemia unawareness in T1DM. It is now recognised that specialised glucose-sensing neurons in the brain play a key role in the detection and response to acute hypoglycaemia and that recurrent hypoglycaemia impairs the ability of these neurons to detect hypoglycaemia, contributing to the development of hypoglycaemia unawareness. As in the beta cell, SUR1 selective KATP are a key component of this sensing mechanism and this suggests a potential role for KATP channel openers in the treatment of hypoglycaemia unawareness. Rodent studies have shown that diazoxide (6mg/kg), delivered directly to the hypothalamus or systemically, amplifies the peak adrenaline response to hypoglycaemia, and therefore could potentially play a role in improving the protective counter-regulatory responses to hypoglycaemia. Studies in individuals with T1DM are currently underway that will directly test this hypothesis. The recent revelation of the mechanisms of diazoxide, i.e. KATP channel opening effects, has opened up potential therapeutic roles for diazoxide as an option in diabetes. It may prove to be beneficial in the early stages to provide beta cell rest and it may potentially be used to improve awareness in those who have recurrent hypoglycaemia. As a consequence of its non-selectivity of the SUR subunits within the KATP channel, it carries a side effect profile that could limit its use. Side effects seem to be limited to continuous use (multiple dosing daily) rather than intermittent use (once-daily dosing). Hyperglycaemia and oedema are the main dose-limiting side effects, but these are usually reversible with dose adjustment.1 There are no conflicts of interest declared. Diazoxide is an effective treatment for patients with insulinomas, and in clinical trials has shown to be a potential agent for other hyperinsulinaemic states such as obesity and the metabolic syndrome Preliminary studies have shown that through its inhibition of insulin release, it may provide a period of ‘beta cell rest’ in patients with early type 1 diabetes and type 2 diabetes Preliminary studies have shown that diazoxide could prove a potential treatment strategy in patients with impaired hypoglycaemia awareness