# Glucagon suppression and diabetes-associated variation in TCF7L2

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2021 · $538,797

## Abstract

The overall aim of this application is to better understand the role of impaired glucagon suppression in the
mechanisms that lead to diabetes. Of the various common genetic variants associated with type 2 diabetes
that in TCF7L2, has the strongest effect on disease predisposition and might provide insight into various
diverse mechanisms that drive the progression of prediabetes to diabetes. We have discovered an effect of
diabetes-associated variation in TCF7L2 on glucagon suppression. The product of this locus is an important
constituent of the wnt-signaling cascade that was originally shown to regulate proglucagon gene expression. In
addition, β-cell function as quantified by the Disposition Index (DI) is also impaired. We propose to examine the
temporal relationship of the effects of this locus on α-cell and on β-cell function in people with normal glucose
tolerance or prediabetes to help examine if impaired glucagon suppression contributes to an increased rate of
β-cell dysfunction or if the two processes develop independently. Since α-cell dysfunction has previously been
overlooked in the pathogenesis of prediabetes, we will harness the Mayo Autopsy resource to examine islet
morphology in humans with and without diabetes-associated variation at this locus. Our preliminary data
suggests that α-cell size and glucagon expression is increased in subjects with the T-allele at rs7903146 in the
TCF7L2 locus. Finally we hope to improve the ability of the oral minimal model – the gold standard used to
measure β-cell function in vivo – to measure glucose homeostasis by incorporating a component that
describes glucagon secretion and action. This will help elucidate the mechanism by which TCF7L2 leads to
type 2 diabetes in humans but will also provide insights into the role of glucagon in the pathogenesis of
prediabetes and progression to diabetes.

## Key facts

- **NIH application ID:** 10215489
- **Project number:** 5R01DK116231-05
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Adrian Vella
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $538,797
- **Award type:** 5
- **Project period:** 2017-09-25 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10215489

## Citation

> US National Institutes of Health, RePORTER application 10215489, Glucagon suppression and diabetes-associated variation in TCF7L2 (5R01DK116231-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10215489. Licensed CC0.

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