# Insulin Secretion in Hyperinsulinism Human Islets

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2022 · $632,476

## Abstract

PROJECT SUMMARY
The study of human islets isolated from the pancreas of infants with congenital hyperinsulinism (HI) during the
previous funding cycle has afforded us the unique opportunity to examine the islet phenotype in KATPHI
integrating function, metabolomics, and genomics. Our findings revealed a complex pathophysiology in which
the primary KATP channel defect leads to secondary consequences affecting gene expression, fuel metabolism,
and both the triggering and amplifying pathways of insulin secretion. However, many critical questions for
addressing unmet needs for the treatment of HI and for the understanding of normal physiological mechanisms
of insulin secretion remain unanswered. We are particularly interested in examining the role of two ion
channels that are differentially expressed in HI islets in the normal regulation of insulin secretion and their
potential role in the pathophysiology of HI: TMEM16A, a Ca2+-activated Cl– channel encoded by ANO1 which is
markedly upregulated in KATPHI islets, and Kv7.1, encoded by KCNQ1, whose expression is markedly
decreased in islets isolated from the pancreases of children with Beckwith Wiedemann syndrome and HI. In
preliminary studies we found that pharmacological modulation of these channels alters insulin secretion. Our
overall hypothesis is that both Kv7.1 and TMEM16A play critical roles in the termination of insulin
secretion by keeping β-cell Vm hyperpolarized at rest and facilitating β-cell Vm repolarization after
stimulation. To test this hypothesis, we propose two aims to examine the role of Kv7.1 and TMEM16A in the
regulation of insulin secretion in normal and HI islets. To accomplish these aims we will use genetic and
pharmacological approaches to modulate the activity of these channels in normal and HI human and mouse
islets. We will examine: 1) the contribution of TMEM16A and Kv7.1 to β-cell Vm at resting and stimulated
states; 2) the effect of TMEM16A and Kv7.1 activation and inhibition on cytosolic calcium and insulin secretion
in normal human and mouse islets; 3) the effect of genetic inactivation of TMEM16A and Kv7.1 on glucose
homeostasis in vivo and fuel-stimulated insulin secretion in vivo and in isolated islets using genetically modified
mouse models. This study will expand our understanding of the pathophysiology of HI and will facilitate the
identification of new genetic causes and potential new therapeutic targets for this devastating disease. The
study may also have implications for the understanding of the mechanisms implicated in the progressive β-cell
failure that leads to type 2 diabetes.

## Key facts

- **NIH application ID:** 10348708
- **Project number:** 5R01DK098517-08
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Diva D. De Leon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $632,476
- **Award type:** 5
- **Project period:** 2013-09-15 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10348708

## Citation

> US National Institutes of Health, RePORTER application 10348708, Insulin Secretion in Hyperinsulinism Human Islets (5R01DK098517-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10348708. Licensed CC0.

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