# Targeting ADAM17 activity for correction of vascular insulin resistance in type 2 diabetes

> **NIH NIH R01** · UNIVERSITY OF MISSOURI-COLUMBIA · 2021 · $679,426

## Abstract

PROJECT SUMMARY/ABSTRACT
Vascular insulin resistance is a hallmark of type 2 diabetes (T2D) and dampening of insulin-induced
vasodilation is its primary consequence. Notably, in T2D, reduced insulin-stimulated vasodilation and blood
flow to tissues such as skeletal muscle significantly limits glucose uptake and contributes to impaired glucose
control. A detailed understanding of the precipitating factors and mechanisms underlying the defects in
vasodilator actions of insulin is critical for the development of therapeutic strategies aimed at improving
glycemic control and protecting against cardiovascular disease. Based on our prior work and most recent and
exciting preliminary data, we propose the novel hypothesis that ADAM17-mediated shedding of the insulin
receptor alpha (IRα) from endothelial cells impairs insulin-stimulated vasodilation in T2D. We further propose
that the increased activity of endothelial ADAM17 is attributed to protein kinase-C (PKC) activation and
subsequent externalization of phosphatidylserine (PS) to the outer leaflet of the cell membrane, which serves
to guide ADAM17 to its targeted substrates. As exogenous PS is a competitive inhibitor of ADAM17 sheddase
activity, we will also determine the efficacy of oral administration of PS for restoring vascular insulin sensitivity
in T2D patients. We will test our innovative hypotheses with gain- and loss-of-function genetic-manipulation
experiments in human cultured endothelial cells, in isolated resistance arteries harvested from patients
undergoing abdominal surgery, and in patients with T2D. Experimental results will determine the role of PS
externalization-ADAM17 activation-IRα shedding as a mechanism impairing the vasodilatory actions of insulin
in T2D. Specifically, in Aim 1, we will determine the mechanism by which PKC causes the externalization of
PS and whether PS externalization is needed for PKC-dependent activation of ADAM17 in endothelial cells.
Next, in Aim 2, we will determine the role of ADAM17 activity in IRα shedding and subsequent impairment of
insulin-stimulated vasodilation in T2D. Finally, in Aim 3, we will perform a randomized double-blind clinical trial
to determine the therapeutic efficacy of oral administration of the competitive inhibitor of ADAM17 sheddase
activity, PS, on insulin-stimulated leg blood flow in patients with T2D. Our team is poised to move
cardiovascular and diabetes research forward with a project that will exert a sustained, powerful impact across
a number of levels of inquiry that are novel conceptually, mechanistically, methodologically, and
therapeutically. Indeed, this proposal represents a paradigm shift from our current mechanistic understanding
of vascular insulin resistance. Targeting ADAM17 activation holds extraordinary promise for correcting
vascular insulin resistance and ultimately preventing/treating T2D-associated metabolic and cardiovascular
diseases.

## Key facts

- **NIH application ID:** 10118924
- **Project number:** 1R01HL151384-01A1
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **Principal Investigator:** Luis A Martinez-Lemus
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $679,426
- **Award type:** 1
- **Project period:** 2021-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10118924

## Citation

> US National Institutes of Health, RePORTER application 10118924, Targeting ADAM17 activity for correction of vascular insulin resistance in type 2 diabetes (1R01HL151384-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10118924. Licensed CC0.

---

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