[F31] The Impact of Delta Cell Gap Junction Disruption on Hormone Secretion and Glucose Homeostasis
Ente: National Institute of Diabetes and Digestive and Kidney Diseases
Scadenza: 2029-06-30
Importo max: 41.618 EUR
Paese: US
Descrizione
PROJECT SUMMARY/ABSTRACT
Type 2 Diabetes (T2D) is a chronic metabolic disease characterized by dysfunction of the pancreatic islet cells
that regulate blood glucose. Insulin secretion from β-cells and glucagon secretion from α-cells work together to
maintain normoglycemia, and the dysfunction of both β- and α-cells in diabetes is well studied. However, δ-cells,
which secrete somatostatin, an intra-islet paracrine regulator of insulin and glucagon secretion, also play a critical
role in fine-tuning β- and α-cell activity to maintain glucose homeostasis. The mechanisms that regulate δ-cell
signaling and regulation in the islet are not well understood. Importantly, somatostatin secretion from δ-cells is
also disrupted in T2D, contributing to loss of islet hormone balance and impaired glucose regulation. Despite
this, the mechanisms underlying δ-cell dysfunction are largely unknown. δ-cells express Connexin-36 (Cx36)
gap junctions, which electrically couple them to neighboring β-cells. While loss of Cx36-mediated coupling in β-
cells is known to contribute to β-cell dysfunction in diabetes, the role of δ-cell Cx36 coupling in islet function and
disease has not been studied. The long-term goal of this project is to determine the physiological significance of
β-δ cell gap junctions and how their disruption affects glucose regulation and hormone secretion in the setting of
diabetes. The central hypothesis is that loss of Cx36 in δ-cells impairs somatostatin secretion under both
normo- and hyperglycemic conditions, thereby disrupting the regulation of α- and β-cell activity. To test
this, a δ-cell specific Cx36 knockout mouse model will be used to evaluate changes in δ-cell activity, hormone
secretion, and whole-animal glucose homeostasis. In Aim 1, the effects of Cx36 loss on δ-cell signaling and
somatostatin secretion will be assessed using live-cell imaging and static hormone secretion assays. In Aim 2,
the impact of δ-cell dysfunction on β-cell activity, insulin secretion, and glucose tolerance will be examined both
in vitro and in vivo. In Aim 3, the effects of diabetogenic conditions on δ-cell coupling will be evaluated, along
with the potential for dietary or pharmacologic interventions to restore gap junction connectivity and δ-cell
function. This work will provide new insight into the underexplored role of δ-cells in islet hormone coordination
and may identify δ-cell Cx36 coupling as a novel target for therapies aimed at preserving islet function and
delaying progression of T2D. The research will be conducted in a collaborative, multidisciplinary environment
and guided by a training plan that integrates advanced imaging, physiology, and translational approaches to
foster development in diabetes research.
Istituzione: UNIVERSITY OF COLORADO DENVER
PI: Carissa L Birznieks
Progetto: 1F31DK148101-01
Settori: National Institute of Diabetes and Digestive and Kidney Diseases
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