# Calcium and the physiology of diabetes

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $405,000

## Abstract

Type 2 diabetes mellitus (T2DM) is a major health concern worldwide, and the prevalence is increasing.
Current therapeutics have potentially life-threatening side-effects. A better understanding of the molecular
mechanisms underlying T2DM could lead to improved therapy. Calcium (Ca2+) plays a key role in the
insulin secretion from pancreatic β cells in the islets of Langerhans. This project focuses on elucidating
novel mechanisms underlying altered Ca2+ regulation that contribute to impaired insulin secretion. We show
that in a rare genetic disorder intracellular Ca2+ leak via mutant type two ryanodine receptor/calcium
release channels (RyR2) in pancreatic β cells is associated with glucose intolerance and decreased insulin
secretion. The goal of this project is to use several murine models of T2DM to determine whether the
observation that impaired insulin secretion is linked to RyR2-mediated intracellular Ca2+ leak is a
generalized phenomenon in diverse models of T2DM. The approach will focus on examining the function of
RyR2, a Ca2+ release channel located on the endoplasmic reticulum (ER) of many cell types including
pancreatic β cells, in insulin release using biochemical, biophysical and metabolic tests. RyR2 can become
leaky either due to genetic mutations or post-translational modifications (chiefly oxidation, nitrosylation and
phosphorylation) all of which can impair stable closing of the channel resulting in pathological intracellular
Ca2+ leak. The goal is to test the hypothesis that ER Ca2+ “leak” via RyR2 contributes to impaired insulin
secretion in T2DM. The rationale is based on our recent finding that patients with leaky mutant RyR2
channels and an inherited form of exercise-induced sudden death (catecholaminergic polymorphic
ventricular tachycardia, CPVT) have abnormal glucose tolerance tests (GTT) and reduced insulin levels.
Knock-in mice developed in the applicant’s laboratory harboring these CPVT RyR2 mutations have ER
Ca2+ leak, abnormal GTT and reduced insulin levels, just like CPVT patients. The aims are: 1 Determine
how leaky RyR2 channels cause mitochondrial dysfunction, and reduced insulin release.; 2) Does
RyR2 channel dysfunction contribute to impaired insulin secretion in murine models of T2DM?
Furthermore we will assess whether pharmacologic treatment with a new class of rycal drugs that fix leaky
RyR2 channels, or genetic treatment that fixes leaky RyR2 channels, improves Ca2+ signaling, and insulin
secretion in diverse models of T2DM? The goal of the project will be to provide mechanistic links between
ER Ca2+ leak, ER stress, mitochondrial dysfunction, reduced insulin secretion and glucose intolerance, and
has significant translational implications as leaky RyR2 may represent a novel therapeutic target for the
treatment of T2DM.

## Key facts

- **NIH application ID:** 9923637
- **Project number:** 5R01DK118240-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** ANDREW Robert MARKS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $405,000
- **Award type:** 5
- **Project period:** 2019-05-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9923637

## Citation

> US National Institutes of Health, RePORTER application 9923637, Calcium and the physiology of diabetes (5R01DK118240-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9923637. Licensed CC0.

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