Reconfiguração da Memória Metabólica em Células Delta Endócrinas Durante Hipoglicemia Grave Episódica

Diabetes affects >400 million people worldwide and >25% of the patients with diabetes suffer from debilitating recurrent hypoglycaemia – a potentially fatal condition that is caused by impaired counter-regulation. Hypoglycaemia negatively affects patients’ quality of life and is the most common endocrine emergency for hospitalisation (Cryer et al., 2009). It is associated with significant direct and indirect burden on the society. Efficient prevention measures of hypoglycaemia will greatly benefit patients with diabetes, their families, and health care systems, and will have an overall strong positive socio-economic impact. Importantly, iatrogenic hypoglycaemia remains the major limiting factor for the treatment of diabetes to date and up to 10% of insulin-treated patients eventually succumb to hypoglycaemia (Cryer, 2014; Gagnum et al., 2017; Tunbridge, 1981). How counter-regulation becomes defective in diabetes remains unknown, but it involves insufficient release of glucagon from the pancreatic alpha cells. Glucagon is a glucose-elevating hormone normally secreted in response to hypoglycaemia. Its secretion is controlled by alpha cell intrinsic glucose sensing and paracrine regulation from the neighbouring cells. Somatostatin (SST), secreted by pancreatic delta cells, is a strong inhibitory paracrine factor of glucagon secretion; and over-secretion of SST contributes to glucagon secretion failure in diabetes. However, the exact regulatory mechanisms of SST secretion remain elusive, and little is known about how it becomes dysregulated in diabetes. Our preliminary study shows that alpha and delta cells are tightly coupled in a way akin to neuronal synapses: electrical stimulation of an alpha cell activates its neighbouring delta cells, which in turn inhibit glucagon secretion. Importantly, this paracrine interaction can be strengthened by pre-exposure to hypoglycaemia, which leads to over-secretion of SST and inadequate glucagon secretion, reminiscent of recurrent hypoglycaemia in patients with diabetes. These observations suggest a novel mechanism of SST secretion regulation – delta cells can detect neighbouring alpha cell activity, and execute spatiotemporally precise negative feedback to prevent overshooting of glucagon. The plasticity of this interaction (‘metabolic memory’) may contribute to recurrent hypoglycaemia. In the proposed project, by integrating electrophysiology, optical imaging, biochemical assays and animal models of diabetes, we aim to dissect the molecular mechanisms underlying this feedback loop and design novel therapeutic approaches that will effectively prevent/reverse hypoglycaemia-induced islet hormone defects. Specifically, we aim to address the following questions: 1. What are the factors involved in the alpha-delta cell coupling? 2. What are the downstream signalling pathways involved in this interaction? 3. How does antecedent hypoglycaemia sensitise the cellular communication between alpha and delta cells? 4. What is the impact of diabetes on alpha-delta cell coupling and how can we correct defective islet cell responses in hypoglycaemia? These studies will add exciting new knowledge of islet physiology and provide novel solutions for resolving hypoglycaemia as a clinical barrier to the treatment of diabetes.