Endocrine Abstracts

Background: Therapeutic peptides are medicines with high potency, low toxicity, and, broad disease targets. However, the widespread use of peptides is limited by their easy degradation in human body. The intestinal organoid technology can be utilized to design a novel cell-based peptide delivery system. Intestinal organoids feature intestinal epithelial tissue-like structure, harboring all the expected in vivo epithelial cell types, including enteroendocrine cells (EE...

Enteroendocrine cells (EECs) are a hormone-/neurotransmitter-producing population with well-defined physiological roles. Knowledge regarding their differentiation program in the human gut, however, is scarce. Deciphering endocrine specification could identify targets which allow the manipulation of specific EEC populations and form the basis for new treatments for metabolic, inflammatory and cognitive disorders. Isoxazole-9 (ISX-9) is a small molecule, previously used in proto...

The intestinal epithelium (IE) is populated by different cell types each with a unique set of functions. Each cell type is derived from a common progenitor, the stem cell. The hierarchy of epithelial cell fate is transcriptionally regulated for example, Notch signalling defines secretory versus absorptive destiny. Peptide hormone producing enteroendocrine (EE) cells are scattered throughout the epithelium where they integrate complex nutrient signals and respond by promoting m...

Background: Obesity is a complex metabolic disease characterised by excess adipose tissue, that increases the risk of comorbidities such as type II diabetes. Interventions that rearrange the gut architecture or exclude nutrients from the duodenum promote immediate and long-term anti-diabetic effects, placing the gut front and centre in obesity and diabetes pathology and treatment. Currently, little is known about the pathological changes which occur in the small intestine (SI)...

Type 1 diabetes (T1D) is an autoimmune, heterogenous disease caused by immune-mediated destruction of insulin-producing β-cells in the pancreas. The only approved treatment strategies are exogenous insulin replacement therapy and islet transplantation. Leading experimental approaches have focussed on suppression and/or modulation of the immune system. However, efforts to increase β-cell survival are also of great interest. Recent studies in our lab have identified ne...

Background: Inflammatory skin diseases such as psoriasis induce changes in the skin-secretome, which potentially lead to dysfunction of key metabolic tissues and increased risk of psoriasis co-morbidities, such as type 2 diabetes (T2D). However, the proteins and peptides that make up the skin-secretome remain poorly characterised. Proteomic analysis has identified vimentin, parathymosin, prothymosin-alpha, dermcidin, and desmin as potential skin-secretome factors, which may in...

In the pancreas, PYY is expressed in a subpopulation of non-beta cells in the islets of Langerhans. The role of PYY-expressing cells in the adult pancreas is unknown. We generated a mouse model in which administration of diphtheria toxin (DT) produced specific ablation of PYY-expressing cells in the colon, pancreas and brainstem. Interestingly, DT administration to adult mice resulted in severe hyperglycaemia associated with significant loss of pancreatic insulin and disrupted...

Attenuated glucoprivic feeding responses are a feature of hypoglycaemic unawareness in insulin-treated diabetes. Glucose alters the activity of hypothalamic neurones involved in regulating appetite. Arcuate nucleus (ARC) Neuropeptide Y (NPY) releasing neurones stimulate feeding. The identification of glucose-sensitive NPY releasing hypothalamic neurones suggests a strong role for these neurones in mediating changes in appetite induced by alterations of glucose. To gain a bette...

Background and aims: Ghrelin is the only known peripheral hormone, which increases food intake. It is released from the stomach and is thought to function as a meal initiator and signal of energy deficit. We used bacterial artificial chromosome transgenesis to generate a mouse model with increased ghrelin expression and production in stomach and brain. These mice exhibited increased circulating bioactive ghrelin and as expected were hyperphagic and glucose intolerant. We hypot...

Hypoglycaemia and hypoglycaemia unawareness severely limit the optimal management of diabetes mellitus and cause recurrent morbidity and even mortality in intensively controlled patients. Altered hypothalamic glucose sensing has been implicated in the development of defective counter regulatory responses to insulin induced hypoglycaemia and hypoglycaemic unawareness. This change in hypothalamic glucose sensing has been attributed, at least in part, to an increase in glucokinas...