# Restoring vasodilator actions of insulin in patients with type 2 diabetes

> **NIH NIH R01** · UNIVERSITY OF MISSOURI-COLUMBIA · 2021 · $491,427

## Abstract

PROJECT SUMMARY/ABSTRACT
In type 2 diabetes (T2D), insulin-stimulated blood flow to skeletal muscle is markedly blunted which
significantly limits glucose uptake, thus contributing to impaired glucose homeostasis. 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 preliminary data, we
propose that in hyperglycemic T2D patients, protein kinase C (PKC) activation drives the upregulation of
endothelin-1 (ET-1) and consequent impairment in insulin-induced dilation. Furthermore, we hypothesize that
increased vascular exposure to shear stress, associated with physical activity, mitigates these toxic molecular
effects of hyperglycemia on endothelial cells and lead to substantial improvements in insulin-induced dilation in
T2D. Specifically, we will test the overarching hypothesis that endothelial PKC activation mediates the
upregulation of ET-1 and impairment in insulin-induced dilation in patients with T2D, a defect that can be
corrected with increased physical activity and shear stress. In Aims 1 and 2, ex vivo functional studies will be
performed in isolated visceral resistance arteries from obese T2D and obese non-T2D patients undergoing
Roux-en-Y gastric bypass surgery. Through gain- and loss-of-function experiments, we will examine the role
of PKC activation in mediating impaired insulin-induced dilation in arteries from T2D patients as well as the role
of hyperglycemia and shear stress in modulating insulin-induced dilation. In Aim 3, we will perform a clinical
study in patients with T2D to determine the effects of increased walking and shear stress on insulin-stimulated
leg blood flow. In particular, we will test the hypothesis that increased walking for 8 weeks decreases vascular
PKC activation and ET-1 production, thus leading to an improvement in insulin-stimulated leg blood flow. Leg
blood flow via Doppler ultrasound will be assessed during a hyperinsulinemic-euglycemic clamp. Skeletal
muscle biopsies will be performed for vascular phenotypic characterization. Furthermore, we will determine if
increased leg vascular shear stress using a non-exercise stimulus (i.e., leg heating intervention for 8 weeks)
recapitulates the beneficial vascular effects of increased walking. Targeting PKC activation and ET-1,
pharmacologically or through an increase in shear stress, may be key for correction of vascular insulin
resistance and ultimately improvement of metabolic and cardiovascular outcomes in patients with T2D.
Indeed, our research team is poised to move cardiovascular and diabetes research forward in an area
currently receiving little attention, despite its importance and clear need for investigation.

## Key facts

- **NIH application ID:** 10210288
- **Project number:** 5R01HL137769-05
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **Principal Investigator:** Jaume Padilla
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $491,427
- **Award type:** 5
- **Project period:** 2017-07-20 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10210288

## Citation

> US National Institutes of Health, RePORTER application 10210288, Restoring vasodilator actions of insulin in patients with type 2 diabetes (5R01HL137769-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10210288. Licensed CC0.

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