# Mechanisms of Beta Cell Coordination

> **NIH NIH F30** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $29,520

## Abstract

Project Summary
Type II diabetes affects over thirty million Americans, and its yearly economic cost is estimated to be over 300
billion dollars, ten times the annual NIH budget. Peripheral insulin resistance leads to progressive dysfunction
of the insulin-secreting pancreatic islet. Since inadequate compensation for insulin resistance is a prime
contributor to diabetes progression, there is an urgent need to understand how insulin secretory failure occurs.
The prototypical pathway for insulin secretion within individual cells is well defined. Glucose metabolism leads
to ATP generation, closure of ATP-sensitive K+ channels, membrane depolarization, calcium influx, and insulin
secretion. Glucokinase, the glucose-sensing enzyme in pancreatic beta cells, is the rate-limiting enzyme in this
pathway allowing changes in enzyme activity to control insulin secretion. Even so, the organization of beta-cell
secretory responses across cells within an islet is poorly understood. Gap junctions facilitate intra-islet beta
cells communication by coupling electrical and metabolic signals between cells. Recent studies have provided
evidence that ‘hub’ beta cells within an islet disproportionately affect and even control islet electrical and
calcium activity. These cells have elevated glucokinase levels, suggesting that cells with increased metabolic
activity control islet activity. We wish to understand how glucokinase activity and expression affect the
coordination of metabolic, electrical, and calcium dynamics. We hypothesize that cells with enhanced
glucokinase activity and expression guide islet activity and that coordination is dependent on metabolite
diffusion across gap junctions. To test our hypothesis, we will first determine whether increased glucokinase
activity in single cells enhances their influence over islet glucose metabolism (Specific Aim 1). Next, we will test
how metabolite diffusion across gap junctions affects islet activity (Specific Aim 2). To investigate these
questions, our lab has generated two novel transgenic mouse models that express genetically-encoded tools
specifically in pancreatic beta cells. We will use a glucokinase biosensor to quantify its activity in living cells,
and an endoplasmic reticulum-localized channelrhodopsin2 (ER-ChR) to manipulate calcium levels in single
cells. Optogenetic ER-ChR allows for precise activation of glucokinase via changes in intracellular calcium.
Further, we will use a microfluidic pipette to influence glucokinase activity in small areas of the islet selectively,
and mathematical modeling to probe islet coordination. Findings from this study will provide insight into how
secretory failure may arise in type II diabetes and identify potential avenues for treatment.

## Key facts

- **NIH application ID:** 10140986
- **Project number:** 1F30DK124986-01A1
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Vishnu Rao
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $29,520
- **Award type:** 1
- **Project period:** 2020-09-18 → 2022-09-17

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10140986

## Citation

> US National Institutes of Health, RePORTER application 10140986, Mechanisms of Beta Cell Coordination (1F30DK124986-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10140986. Licensed CC0.

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