# Metabolic crosstalk through vascular endothelium-secreted factors

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $400,000

## Abstract

Abstract
The metabolic disorders of obesity and type 2 diabetes mellitus (T2DM) impact one in three adults. The
inability of insulin to suppress hepatic glucose production and promote glucose uptake into peripheral tissues is
a hallmark of T2DM. However, the underlying mechanism of liver insulin resistance remains incompletely
understood. This gap in knowledge is an important problem because it hinders the development of targeted
metabolic therapies to manage the growing clinical burden of T2DM.
The vascular endothelium coordinates the delivery of endocrine hormones and small molecules to target
tissues. Yet, how specific endothelial factors exert impacts in metabolic tissues remains undefined. Bone
morphogenetic protein (BMP)-binding endothelial regulator (BMPER), highly secreted from vascular
endothelium, adapts endothelial cells (ECs) to inflammatory and nutrient stress in diverse organ
microenvironments. In new studies, we observed inducible knockout of BMPER (iKO) globally or specifically in
endothelium caused hyperinsulinemia, glucose intolerance and insulin resistance independently from obesity
and inflammation. These results suggest the vascular endothelium secretes BMPER to maintain glucose
homeostasis. Subsequent experiments demonstrated adeno-associated viral BMPER delivery dramatically
alleviated diabetes in mice. In humans, BMPER plasma levels are reduced in insulin resistant subjects
compared to normoglycemic subjects, supporting an important role for BMPER in defending insulin sensitivity.
Mechanistically, we observed BMPER transactivated the insulin signaling pathway in metabolic tissues.
Therefore, we hypothesize that BMPER endocytosis promotes insulin sensitivity. To test this hypothesis, we
propose the following aims: 1) determine the metabolic consequences of BMPER depletion; 2) establish the
anti-diabetic potential of recombinant BMPER; and 3) define the mechanisms that govern BMPER regulation of
insulin action. Collectively, these studies suggest an uncharacterized pathway that may define new therapies
to minimize the long-term clinical burden of T2DM.

## Key facts

- **NIH application ID:** 10120347
- **Project number:** 1R01DK123186-01A1
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Xinchun Pi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $400,000
- **Award type:** 1
- **Project period:** 2020-09-15 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10120347

## Citation

> US National Institutes of Health, RePORTER application 10120347, Metabolic crosstalk through vascular endothelium-secreted factors (1R01DK123186-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10120347. Licensed CC0.

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