Hypoglycaemia is a common side-effect of the treatment of type 1 diabetes with insulin. The Diabetes Control and Complications Trial indicated that, while intensive insulin therapy reduced the incidence and severity of diabetic complications such as retinopathy, neuropathy and nephropathy, the incidence of severe hypoglycaemia was increased 2-3 fold. In non-diabetic individuals, hypoglycaemia triggers the glucose counter-regulatory response. This response consists of inhibition of insulin secretion and activation of glucagon secretion. Prolonged hypoglycaemia also evokes adrenaline secretion and less importantly, growth hormone and cortisol secretion. However, in individuals that have type 1 diabetes, the glucagon response to hypoglycaemia is lost. In these patients, the pancreatic α-cells continue to synthesise glucagon since glucagon secretagogues such as arginine produce a robust glucagon secretory response. Our research has examined the hypothalamic and medullary neurocircuits that mediate adrenaline and glucagon secretion under conditions of neuroglucoprivation or hypoglycaemia. These studies have shown that the response to neuroglucoprivation involves specialised sympathetic premotor neurons in the rostral ventrolateral medulla (RVLM) that mediate adrenaline secretion. These neurons are readily distinguishable from sympathetic vasomotor neurons also located in the RVLM. In addition, we have described the properties of perifornical hypothalamic (PeH) orexinergic (Ox) neurons that are activated by insulin-induced hypoglycaemia (IHH) or neuroglucoprivation. PeH neurons project to many different targets including the RVLM and the dorsal motor nucleus of the vagus (DMV). Ox2-R in the RVLM mediate the adrenaline secretory response. PeH neurons also mediate the glucagon response to IHH since the release of glucagon in response to IHH is diminished in Ataxin3 rats which have an age-related loss of PeH orexin neurons.
