# The Role of Intestinal Hypoxia Signaling in Glucose Homeostasis

> **NIH NIH R00** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $235,578

## Abstract

Project Description
Obesity and type 2 diabetes are increasing at an alarming rate in the United States and warrants novel drug
targets to culminate these diseases. Gut derived hormone glucagon like peptide-1 (GLP-1) improves glucose
homeostasis and offers great promises as therapeutic target for obesity and type 2 diabetes. The
mechanisms that regulate intestinal GLP-1 secretion are not clear. The function of intestine is dynamically
regulated by intestinal oxygenation. Low oxygen induces a hypoxic response mediated by the transcription
factors namely hypoxia inducible factor (HIF). The critical role of HIF signaling in inflammation, iron
homeostasis, and cancers has been well documented; however, its metabolic role is not well understood.
Using genetic model, we reveal that constitutive activation of intestinal hypoxia signaling improves glucose
tolerance due to augmented GLP-1 levels. The research focus of this application lies at the intersection
between intestinal hypoxia signaling and GLP-1 in the regulation of glucose homeostasis. Our central
hypothesis states that intestinal hypoxia signaling plays a key role in systemic glucose homeostasis by
regulating GLP-1 secretion. We propose a combination of complimentary in vitro and in vivo mouse studies
designed to test the following hypothesis: 1) intact intestinal hypoxia signaling is essential for systemic
glucose homeostasis; 2) intestinal hypoxia signaling regulates glucose metabolism through GLP-1 dependent
mechanism; and 3) targeting HIF signaling ameliorates glucose intolerance.
During the K99 phase of this program, Drs. Shah and Seeley in the Department of Molecular and Integrative
Physiology and Department of Surgery, respectively, will provide mentorship to the applicant. The career
development activities will take advantage of the exceptional research environment and resources at the
University of Michigan, and will be facilitated by the guidance of the highly motivated Advisory Committee of
the applicant that includes Drs. Omary, Rui and Lee, in addition to the co-mentors. The applicants experience
in several areas such as conceptual knowledge, research skills, leadership and lab management, effective
communication, and mentoring young scientists will be strengthened through various training activities as
detailed in applicants Career development activity.

## Key facts

- **NIH application ID:** 9991831
- **Project number:** 5R00DK110537-05
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Sadeesh Kumar Ramakrishnan
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $235,578
- **Award type:** 5
- **Project period:** 2018-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991831

## Citation

> US National Institutes of Health, RePORTER application 9991831, The Role of Intestinal Hypoxia Signaling in Glucose Homeostasis (5R00DK110537-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9991831. Licensed CC0.

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