# Glut1 and the microvascular complications of diabetes

> **NIH VA I01** · LOUIS STOKES CLEVELAND VA MEDICAL CENTER · 2022 · —

## Abstract

The goal of this proposal is to determine whether systemic reduction of the facilitative glucose transporter,
Glut1 (Slc2a1), prevents the major microvascular complications of diabetes: diabetic retinopathy (DR), diabetic
kidney disease (DKD) and diabetic peripheral neuropathy (DPN) and/or augments the current standard of care
for Type 2 diabetes. Each microvascular complication is mitigated by tight glycemic control, but efforts to maintain
euglycemia in diabetic patients has been elusive. Here, we will investigate whether the systemic reduction of
Glut1 using a genetic approach prevents DR, DKD and DPN phenotypes in mouse models of both Type 1 and
Type 2 diabetes for the following reasons: (1) Glut1 is highly expressed in the retina and the cells that comprise
the inner and outer blood retinal barriers, throughout the nephron and tubules of the kidney and in the paranodal
region of the peripheral nerves as well as the Schwann cells that surround the nerves. (2) Reduction of Glut1 in
the eye via pharmacology, siRNA or genetic approaches reduces hallmarks of DR and reduction of Glut1 in
mesangial cells of the nephron prevents DKD phenotypes in mouse models of Type 1 diabetes. (3) Inhibition of
the sodium-glucose cotransporter-2 (Sglt2) is insufficient to fully prevent DR, DKD and DPN phenotypes. (4)
Small nucleotide polymorphisms in Glut1 are associated with increased risk of both DR and DKD. (5) Intensive
insulin therapy, which lowers prevalence of DR, DKD and DPN can regulate Glut1 at both transcription and post-
translational levels. Because Glut1 is elevated in the diabetic retina and kidney, reduced Slc2a1/Glut1 expression
and increased Glut1 turnover may contribute to the mechanism by which intensive insulin therapy reduces DR,
DKD and DPN.
 These observations form the premise for our hypothesis that reduction of Glut1 will prevent the
microvascular complications of diabetes, augment the current standard of care for Type 2 diabetes, and
contributes to the mechanism by which intensive insulin therapy confers protection against DR, DKD
and DPN. We will test this hypothesis with the following specific aims. In Aim 1 we will utilize the Glut1+/- mouse
which harbors a hemizygous Glut1 deletion to determine if systemic reduction of Glut1 prevents DR, DKD and
DPN in a STZ-induced mouse model of Type 1 diabetes or in the Leprdb/dbeNOS-/- mouse model of progressive
Type 2 diabetes. We will further determine if the addition of systemic Glut1 reduction to the current standard of
care for Type 2 diabetes, treatment of hyperglycemia (metformin), hypertension (ramipril) and inhibition of Sglt2
(empaglifozin), augments protection from diabetic phenotypes. In Aim 2 we will test the hypothesis that intensive
insulin therapy regulates Glut1 by utilizing the STZ-induced mouse model of Type 1 diabetes. Activation of the
Forkhead Box O transcription factor, FOXO1, downstream signal transduction molecules, and Slc2a1 mRNA
levels will be measured in each microvas...

## Key facts

- **NIH application ID:** 10368340
- **Project number:** 1I01BX005844-01
- **Recipient organization:** LOUIS STOKES CLEVELAND VA MEDICAL CENTER
- **Principal Investigator:** Ivy S Samuels
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2022-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10368340

## Citation

> US National Institutes of Health, RePORTER application 10368340, Glut1 and the microvascular complications of diabetes (1I01BX005844-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10368340. Licensed CC0.

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