CNS Impacts of Diazoxide That are Relevant to Prader-Willi Syndrome and Hypothalamic Obesity

Insulin and leptin coordinately regulate caloric intake and energy expenditure by inhibiting Neuropeptide Y/Agouti Related Protein (NPY/AGRP) neurons and stimulating proopiomelanocortin (POMC) neurons in the hypothalamus.  Deficiencies in the hypothalamus of either insulin or leptin, or resistance to either will lead to dysregulation of appetite and energy expenditure characterized by increased appetite, which may present as hyperphagia, and reduced energy expenditure.

Leptin interacting with its receptor in these neurons, or insulin interacting with its receptor triggers a cascade, one effect of which is to open the KATP channel.  Those who have studied it most closely have suggested that the KATP channel may function as the molecular end-point of the pathway following leptin activation of the leptin receptor in these hypothalamic neurons.  Treatment with DCCR can directly open the KATP channel in these neurons offering the potential to overcome hypothalamic resistance to the action of leptin and/or insulin and, thereby, re-establish control over appetite and energy expenditure.

Peripheral Effects on Lipogenesis, Lipolysis, and Resting Energy Expenditure

It is clear that the KATP channel is a central regulatory point of fatty acid biosynthesis and fat oxidation.  The channel exerts coordinate control over these processes in adipocytes, hepatocytes and other tissues that synthesize fat.  The channel appears to function as a key step in the feedback regulation of fatty acid biosynthesis by long-chain acyl CoAs, the metabolically active form of free fatty acids.  Agonizing the channel should have a very positive therapeutic impact on fat stores.

The impact of DCCR on de-novo lipogenesis and β-oxidation of fat complement the central action of DCCR on food intake and energy expenditure, resulting in highly selective loss of body fat and in improvements in circulating lipid profiles.

These central and peripheral effects are associated with an increase in basal metabolic rate (resting energy expenditure)

Effects on Insulin Sensitivity

Treatment with DCCR results in marked reductions in insulin resistance.  These improvements are achieved by increases in the expression of insulin receptors and by improved post-receptor signaling.  Improvement in insulin resistance of 40-50% have been recorded in clinical studies with DCCR and in clinical studies reported in the published literature.

Protection from Cytotoxic Stress

The KATP channel resides both in the cell membrane and in the mitochondrial inner membrane.  DCCR can agonize both channels.  Agonizing the KATP channel in the mitochondria during times of cytotoxic stress and insult preserves mitochondrial volume and function preventing cell death. There is an extensive literature on this including improving tolerance to stress from cardiac or cerebral ischemia, and many other cytotoxic insults.