# Metabolic regulation of islet hormone secretion in diabetes

> **NIH VA I01** · WM S. MIDDLETON MEMORIAL VETERANS HOSP · 2022 · —

## Abstract

Over 29 million Americans suffer from diabetes, including 25% of Veterans seeking VA healthcare. A strong
contributor to type 2 diabetes (T2D) is that obesity rates have increased dramatically in the last 3 decades, now
reaching over 30% in many parts of the country with rates over 40% in Veterans, who are disproportionally
affected by diabetes. In the United States, nearly 1 in 4 Veterans receiving care from the VA, and 20% of
Veterans overall have diabetes (compared to 9% in the general population). The prevalence of diabetes is even
higher in Veterans over the age of 65, and across all ages the prevalence of diabetes in Veterans is climbing by
2% every year. Developing new methods for properly treating the failure of insulin secretion in T2D patients is
therefore a high priority for the Veteran population. One molecule that is at the cornerstone of our research
program, the glycolytic enzyme pyruvate kinase (PK), has strong potential to be of protective and therapeutic
value. We have discovered that small-molecule PK activators control multiple cell types in the pancreatic islet
and enhance insulin secretion, including in human islets from obese and T2D donors. The objective of this
proposal is to identify the mechanisms by which PK activation is able to enhance insulin secretion at the cellular
and molecular level. Based on our preliminary studies, our central hypothesis is that PK controls both α- and β-
cell hormone secretion by closing ATP-sensitive K+ channels (KATP). The physiological model being tested is that
islet α-cells, which are activated by amino acids, supercharge β-cell secretion to lower postprandial blood
glucose. We will test our central hypothesis in multiple pre-clinical models of diabetes, and accomplish the
objective of this proposal by completing the following specific aims: 1) Determine the effect of PK activation on
α-cell metabolism and hormone secretion, 2) Determine how α-cell hormones enhance the β-cell response to
PK activators, and 3) Assess the therapeutic potential of combining PK activators with Glp1 receptor agonists to
prevent and rescue obesity/T2D. With the completion of these aims, we will gain a significantly more
comprehensive understanding of PK function in the pancreatic islet, and take the critical next steps in evaluating
PK as a new target for the prevention and treatment of type 2 diabetes.

## Key facts

- **NIH application ID:** 10257534
- **Project number:** 1I01BX005113-01A2
- **Recipient organization:** WM S. MIDDLETON MEMORIAL VETERANS HOSP
- **Principal Investigator:** Matthew J. Merrins
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2021-10-01 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10257534

## Citation

> US National Institutes of Health, RePORTER application 10257534, Metabolic regulation of islet hormone secretion in diabetes (1I01BX005113-01A2). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10257534. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*