# Platelet Metabolism in Diabetes Mellitus

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2024 · $520,852

## Abstract

Project Summary/Abstract
 Heart disease and stroke are the No. 1 and 5 causes of deaths in the US. Type 1 diabetes mellitus (T1DM)
significantly increases the risk for heart attacks and strokes. Intense glycemic control has been reported to
reduce major cardiovascular events by >30%, suggesting that hyperglycemia is one of the major contributors to
T1DM-associated heart attack and stroke risk escalation. However, how T1DM and hyperglycemia exacerbate
such risk is unclear. Platelets are vascular first-responders that activate for hemostasis upon blood vessel
damage; whereas pathogenic platelet activation leads to spurious thrombosis and acute vascular obstruction.
T1DM and hyperglycemia lead to platelet hyperactivity and increased propensity to form thrombi. This proposals
aims to understand how hyperglycemia causes platelet hyperactivity and thrombosis in T1DM, and to develop
new therapeutic strategies to mitigate T1DM-associated heart attacks and strokes. Utilizing an integrated
metabolism toolkit including state-of-the-art Stable Isotope Resolved Metabolomics (SIRM), we demonstrated
critical role of altered platelet metabolism in thrombin-induced platelet activation. Specifically, thrombin
stimulation alters platelet metabolism that is centered on glycogen metabolism, pentose phosphate pathway
(PPP), and fructose 1,6-bisphosphate (F1,6BP), namely, “the glycogen-PPP-F1,6BP axis”, modulating energy,
redox and calcium homeostasis in platelets and leading to their activation. Literature and our compelling
preliminary data further reveal that hyperglycemia increases glycogen storage and its mobilization that generates
ATP, PPP inhibition, reactive oxygen species, and intracellular calcium, all of which are in line with increased
propensity for platelets to activate. Therefore, our overarching hypothesis is that hyperglycemia changes the
glycogen-PPP-F1,6BP axis in platelets to drive platelet hyperactivity and thus thrombotic risk in T1DM. In Aim 1,
we will delineate these hyperglycemia-induced changes in the glycogen-PPP-F1,6BP axis in platelets isolated
from T1DM patients and normal healthy platelets subject to acute hyperglycemia in vitro. In Aim 2, we will
determine how modulation of the glycogen-PPP-F1,6BP axis by pharmacological and genetic means suppresses
hyperglycemia-induced platelet hyperactivity in vitro. In Aim 3, we will determine how modulation of the glycogen-
PPP-F1,6BP axis by pharmacological and genetic means reduces hyperglycemia-exacerbated thrombosis and
stroke in animal models. Our team is in a unique position to address our hypothesis, as we possess recognized
expertise in metabolism and metabolomics (Qingjun Wang PhD and Matthew Gentry PhD), platelet biology
(Sidney Whiteheart PhD), T1DM (Lisa Tannock MD), and stroke (Justin Fraser MD and Jill Roberts PhD), and
we have strong partnership with the University of Kentucky Metabolomics, Redox Metabolism, and Rodent
Surgery Cores. Upon completion of the proposed project, we will h...

## Key facts

- **NIH application ID:** 10884522
- **Project number:** 5R01HL160910-03
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Qingjun Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $520,852
- **Award type:** 5
- **Project period:** 2022-09-20 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10884522

## Citation

> US National Institutes of Health, RePORTER application 10884522, Platelet Metabolism in Diabetes Mellitus (5R01HL160910-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10884522. Licensed CC0.

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