Understanding putative beta-cell subtypes

Active Project Grant Awarded Last action

Award ID
R01DK139630
Recipient
Awarding agency
Obligated
$2,725,584

Award facts

Completion date 54% complete
Place of performance
Wyoming, MI 49503, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Type 2 diabetes (T2D) is a disease that results from relative pancreatic Β-cell dysfunction, and affects >400 million people. We (RUTTER) previously identified functional Β-cell subsets based upon analysis of real-time CA2+ responses and cell-cell connectivity. A "βleader" population (~5% of Β-cells) exhibits fast and robust CA2+ influx that controls the timing of islet-wide glucose responses, and a separate population of highly interconnected βhub -cells (5-10% of Β-cells) that synchronizes glucose responses, islet-wide. More recently, we (POSPISILIK) discovered that H3K27ME3 dosage is a novel regulator of Β-cell lineage differentiation, stability, and functional specification. We identified two epigenetically distinct Β-cell populations (ΒHI and ΒLO) that are conserved across mice and humans and comprise >90% of the Β-cell compartment. They are distinguished by distinct nuclear and cell surface protein expression, by distinct epigenomes and transcriptomes, and by a series of morphological and functional differences. Importantly, ΒHI and ΒLO cells can be purified by facs, and their relative ratios are altered in mouse models and human T2D. Our preliminary data now suggest that βleader and βhub cells together comprise the epigenetically-defined ΒHI cells, and that βfollower cells are synonymous with ΒLO cells. The objective of this project is to test this hypothesis, and define the functional and disease relevance of these putative Β-cell subtypes. In aim 1, we will use novel single-cell epigenomic tools to determine the extent to which functionally- and epigenetically-defined Β-cell subsets are the same. In aim 2, we will use conditional deletion mouse models to determine when and how H3K27ME3 levels control the emergence of each Β-cell subset, and their relative ratios. In aim 3, we will use the same mouse models to determine if and how Β-cell subtype ratios relate to obesity-associated diabetes, and if subtype proportions can be reversed by diet, SGLT2I, or GLP1R agonist treatments. We will perform parallel studies in human SC-islets to determine if HNF1A mutants (a causal T2D genetic variant) alter Β-cell subtype ratio and function, and if those effects are reversible. Finally, we will screen biobanked npod and ADI pancreatic samples for the relative proportions of these functional subsets across metabolic diseases. Thus, aim 3 will establish the extent and impact of subtype-specific Β-cell dysfunction in T2D. By using this unified theoretical and experimental framework, we will establish an epigenetic basis for understanding and manipulating putative Β-cell subtype number and function in vitro and in vivo, and novel methods for generating SC-islets with preferential skews in Β-cell subtypes.

Transactions

Action Obligated Date
Amendment $1,351,292
Amendment $0
Amendment $675,646
Original award $698,646

Subawards

Subrecipient Amount Awarded
Sante Quebec Centre Hospitalier De L'universite De Montreal This subaward will encompass experiments towards understanding the regulation and role of beta cell heterogeneity, its regulation by the epigenome, and… $152,010

Quick answers

Who received award R01DK139630?

R01DK139630 was awarded to Van Andel Research Institute by National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health) on September 1, 2024.

How much is award R01DK139630 worth?

$2,725,584 has been obligated on R01DK139630.

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