Endocrine Abstracts

Aim: One of the hallmarks of type 2 diabetes (T2D) is impaired beta cell function, which develops in part as a result of widespread cellular de-differentiation. The current state-of-the-art defines beta cells as a heterogeneous islet population, with the existence of individual subpopulations including specialised ‘pacemakers’. We sought here to understand how overexpression-induced beta cell maturity affects such heterogeneity, befo...

Aim: One of the hallmarks of type 2 diabetes (T2D) is impaired beta cell function, which develops in part as a result of widespread cellular de-differentiation. The current state-of-the-art defines beta cells as a heterogeneous islet population, with the existence of individual subpopulations including specialised ‘pacemakers’. We sought here to understand how overexpression-induced beta cell maturity affects such heterogeneity, befo...

Background: Both metabolic surgery and sodium glucose co-transporter (SGLT2) inhibitors have been demonstrated to improve insulin sensitivity and glucose clearance, but also increase glucagon secretion and cardiovascular health.Aim: To examine the effect of metabolic surgery (Vertical Sleeve Gastrectomy; VSG) on SGLT2 expression in kidney cortex of lean mice.Methods: In order to assess whether exogenous SGLT2 inhibition has the sam...

Background: A normal islet includes both mature and immature β-cells, with the former possessing higher insulin content and the latter displaying better proliferative capacity. However, it remains unknown whether immature β-cells also contribute to the regulation of insulin release, especially by commanding the activity of their mature counterparts.Materials and methods: Pdx1, Mafa, and Ngn3 were overexpressed in &#94...

Background: Islet transplantation is an established treatment for type 1 diabetes mellitus. However, many recipients do not achieve independence from exogenous insulin since up to 50–70% of islets are lost post-transplant. An important factor determining transplant success is graft vascularisation. The epidermal growth factor receptor (EGFR) is a key pro-survival and proliferation factor. Here, we investigate for the first time if EGFR overexpression in pancreatic islets ...

MicroRNAs (miRNAs) are small non-coding RNAs that repress protein production post-transcriptionally. MiRNAs play crucial roles in metabolism, endocrine cells development and in processes altered in T2D, such as insulin secretion. MiR-125b controls proliferation, apoptosis and differentiation of various cell types, although its role in β-cells remains unclear. Recent studies show an association between high levels of circulating miR-125b and hyperglycaemia (HbA1c) in predi...

Glucagon-like peptide-1 receptor (GLP-1R) agonists are effective treatments for type 2 diabetes and obesity. We recently described ‘biased’ peptide GLP-1R agonists modelled on exendin-4 which uncouple the pronounced endocytosis that usually accompanies GLP-1R activation, leading to prolongation of intracellular signalling responses. Here, we show that the metabolic consequences of biased GLP-1R activation in vivo are dominated by improvements in blood glucos...

Background and Aims: β cell connectivity is a feature of pancreatic islets in vitro but its existence in vivo, when innervated and continuously perfused with blood, has not yet been demonstrated. We imaged islets engrafted in the anterior chamber of the mouse eye (ACE) to explore this question.Methods: Mouse (C57BL6, Ins1Cre::GCaM6mf/f) or human islets infected with adenovirus to express GCaMP6m, were engrafted and Ca<su...

As the nation gets fatter, the incidence of diabetes is also rising. The brain is now emerging as a critical mediator of blood sugar control, re-directing focus away from the traditional pancreas-centred model. The enzyme glucokinase (GK) acts as a glucose sensor in many tissues including glucose-sensitive neurones within the hypothalamic arcuate nucleus. However, the role of GK here is unclear. We investigated the role of arcuate GK in glucose homeostasis in both healthy and ...

Subpopulations of beta cells dictate overall ‘pacing’ of insulin secretion across the islet and therefore the control of glycaemia. Functional beta cell subpopulations also exist in human islets and have an altered subtype distribution in type 2 diabetes. However, the molecular control of the establishment and maintenance of beta cell hierarchy is poorly understood. We hypothesised that the epigenome would govern this heterogeneity. We have identified a novel subpopu...