# Mechanisms underlying exacerbation of inflammatory bowel disease by diabetes

> **NIH NIH F32** · UNIVERSITY OF WASHINGTON · 2022 · $73,946

## Abstract

Project Summary
Type 2 diabetes (T2D) and inflammatory bowel disease (IBD) are among the most challenging and costly medical
disorders of modern society. Both disease processes also share a common pathophysiology characterized by a
chronic inflammatory state, altered gut microbiome, and dysfunctional intestinal barrier. Hyperglycemia is the
primary cause of the many complications of diabetes, and recent studies have shown that hyperglycemia is
capable of directly impairing intestinal barrier function independent of diet and obesity. Population-based studies
have shown that patients with IBD also have an increased risk of T2D, which has important clinical consequences
as comorbid T2D in patients with IBD is a predictor of poor disease-related outcomes, though the causative
mechanisms remain unknown. In this proposal, we will investigate the novel hypothesis that diabetic
hyperglycemia in the setting of diet-induced obesity (DIO) worsens IBD disease activity by increasing intestinal
inflammation and associated barrier dysfunction. Specifically, we propose to characterize the effect of diabetic
hyperglycemia on clinical and biochemical measures of intestinal inflammation and barrier function in murine
models of IBD, and to determine the extent to which control of glycemia decreases intestinal inflammation and
improves clinical outcomes in diabetic murine models of IBD. Diabetic-range hyperglycemia will be induced by
administration of low-dose streptozotocin (STZ) in two independent models of IBD: 1) C57BL/6J wild-type (WT)
mice treated with dextran sodium sulfate (DSS) and 2) Mdr1 knockout mice that spontaneously develop colitis,
made obese by consumption of an obesogenic high-fat diet (HFD) or fed standard chow. The impact of
hyperglycemia on intestinal barrier function and IBD pathology in the setting of DIO will be assessed using
immunohistochemical staining, dextran-FITC permeability assays, and characterization of the components of
the intestinal extracellular matrix. We will then investigate the translational potential of treating diabetic
hyperglycemia to decrease IBD progression by administering a sodium-glucose cotransportor-2 (SGLT2)
inhibitor to normalize glycemia in diabetic murine models of IBD. Lastly, SGLT2 inhibitors will be administered in
combination with topical 5-aminosalysilic acids, which are standard first line therapy for mild-to-moderate
ulcerative colitis but often fail to control more significant disease, to determine whether treating diabetic
hyperglycemia improves the efficacy of introductory IBD therapies. The proposed project unites the clinical
gastroenterology, hepatology and nutrition interests and research skills of the applicant as well as the
considerable multi-disciplinary resources of the University of Washington Diabetes Institute to advance
understanding of the mechanisms by which diabetic hyperglycemia influences intestinal inflammation, with the
ultimate goal of understanding shared pathogenic mechanisms an...

## Key facts

- **NIH application ID:** 10465801
- **Project number:** 1F32DK131695-01A1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Kendra Leigh Francis-Stream
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $73,946
- **Award type:** 1
- **Project period:** 2022-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10465801

## Citation

> US National Institutes of Health, RePORTER application 10465801, Mechanisms underlying exacerbation of inflammatory bowel disease by diabetes (1F32DK131695-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10465801. Licensed CC0.

---

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