Exploration of individual beta cell function over time in vivo: effects of hyperglycemia and glucagon-like peptide-1 receptor (GLP1R) agonism DOI Creative Commons
Luis Fernando Delgadillo-Silva, Sergio Miguel Salazar, Livia López‐Noriega

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 5, 2025

The coordinated function of beta cells within the pancreatic islet is required for normal regulation insulin secretion and partly controlled by specialized "leader" highly connected "hub" beta-cell subpopulations. Whether these subpopulations are functionally stable in vivo remains unclear. Here, we establish an approach to monitor Ca 2+ dynamics individual over time, after engraftment into anterior eye chamber, where continuous blood perfusion near innervation pertain. Under normoglycemic conditions, network dynamics, behavior leaders hubs, remain at least seven days. Hyperglycemia, resulting from high-fat diet feeding or loss a host Gck allele, caused engrafted islets display incomplete abortive waves overall connectivity was diminished. Whereas hub cell numbers were lowered profoundly both disease models, largely persisted. Treatment with GLP1R agonist Exendin-4 led recovery islet-wide re-emergence minutes, effects incretin mimetic being more marked than those observed analogous treatments vitro . Similar observations made using 3-dimensional imaging across whole islet. Our findings thus suggest that incretins may act directly indirectly on vivo. described provide broad applicability exploration time living animal.

Language: Английский

ER calcium stores contribute to glucose-induced Ca2+ waves and intercellular connectivity in mouse pancreatic islets DOI Creative Commons
Luis Fernando Delgadillo-Silva,

Karen Dakessian,

Guy A. Rutter

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 14, 2025

Abstract Defective insulin secretion is a hallmark of diabetes mellitus. Glucose-induced Ca 2+ oscillations are critical for the stimulation secretion, though mechanisms through which these propagate across islet poorly understood. Here, we use beta cell-targeted GCaMP6f to explore role endoplasmic reticulum (ER) mobilization in response submaximal (11mM) and hyperglycemic (25mM) glucose concentrations. Inhibition inositol 1,4,5 trisphosphate (IP 3 ) receptors, other ion channels, with 2-aminoethoxydiphenyl borate (2-APB) had minimal effects on initial peak or intercellular connectivity provoked by 11mM glucose. However, 2-APB lowered subsequent glucose-induced cytosolic increases at both 11 25mM Unexpectedly, activation IP receptors muscarinic acetylcholine receptor agonist carbachol impact elicited mM glucose, but waves 25 were more coordinated. To determine whether ER calcium was sufficient initiate next blocked sarco(endo)plasmic ATPase (SERCA) pumps thapsigargin, whilst preventing plasma membrane depolarization K ATP -channel opener, diazoxide. Under conditions, an increase followed secondary that slowly subsided. The application alongside diazoxide still enhanced dynamics, this activity uncoordinated cells connected. Our results show plays relatively minor initiation propagation On hand, stores required transition sustained waves. Highlights IP3R inhibition perturbs islets store insufficient generate cell GRAPHICAL ABSTRACT

Language: Английский

Citations

0
Exploration of individual beta cell function over time in vivo: effects of hyperglycemia and glucagon-like peptide-1 receptor (GLP1R) agonism DOI Creative Commons
Luis Fernando Delgadillo-Silva, Sergio Miguel Salazar, Livia López‐Noriega

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 5, 2025

The coordinated function of beta cells within the pancreatic islet is required for normal regulation insulin secretion and partly controlled by specialized "leader" highly connected "hub" beta-cell subpopulations. Whether these subpopulations are functionally stable in vivo remains unclear. Here, we establish an approach to monitor Ca 2+ dynamics individual over time, after engraftment into anterior eye chamber, where continuous blood perfusion near innervation pertain. Under normoglycemic conditions, network dynamics, behavior leaders hubs, remain at least seven days. Hyperglycemia, resulting from high-fat diet feeding or loss a host Gck allele, caused engrafted islets display incomplete abortive waves overall connectivity was diminished. Whereas hub cell numbers were lowered profoundly both disease models, largely persisted. Treatment with GLP1R agonist Exendin-4 led recovery islet-wide re-emergence minutes, effects incretin mimetic being more marked than those observed analogous treatments vitro . Similar observations made using 3-dimensional imaging across whole islet. Our findings thus suggest that incretins may act directly indirectly on vivo. described provide broad applicability exploration time living animal.

Language: Английский

Citations

0