From oversight to insight: the curious case of the endothelial insulin receptor - Review

Sep 30, 2026

Review explores how endothelial insulin receptors (IR) influence insulin trafficking across vascular endothelium and thereby shape insulin sensitivity and glucose disposal. It contrasts earlier findings suggesting endothelial IR is dispensable—supported by endothelial-IR knockout mouse models—with more recent genetic evidence showing that enhancing endothelial IR activity improves insulin sensitivity. The article summarizes the insulin lifecycle, the physiology of endothelial signaling, and the emerging need to resolve why this receptor remains controversial while outlining future research directions for vascular biology.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages12

Reading Time30 min

AccessFree to download

Introduction

Diabetes, insulin signaling, and insulin resistance

Insulin lifecycle and rate-limiting trafficking

A brief history of endothelial IR and its controversy

Early detection and trafficking in endothelial cells

Animal evidence and emerging debate

REVIEW ARTICLE VTH vessels, thrombosis & hemostasis From oversight to insight: the curious case of the endothelial insulin receptor Rahul Rajala University of Oklahoma College of Medicine, University of Oklahoma Health Campus, Oklahoma City, OK; Harold Hamm Diabetes Center, University of Oklahoma Health Campus, Oklahoma City, OK; Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK; and Department of Cell Biology, University of Oklahoma Health Campus, Oklahoma City, OK Insulin is produced in the pancreas and regulates blood glucose levels by binding to the insulin receptor (IR) thereby stimulating glucose uptake into cells. Inadequate insulin production or dysregulated IR signaling leads to diabetes. Most research, to date, has focused on enhancing insulin production or correcting impaired IR signaling in tissues of nutrient exchange, for example, muscle or fat. However, the transendothelial trafficking of insulin to target tissues is also crucial in regulating organismal responses to insulin. In fact, this process has been established as the rate-limiting step for glucose disposal. Initially, it was believed that the transendothelial trafficking of insulin was dependent on endothelial IR. Unfortunately, subsequent studies have demonstrated that mice lacking endothelial IR possess minimal changes in insulin sensitivity. These studies have contributed to the widespread belief that endothelial IR does not regulate insulin trafficking and insulin sensitivity. However, recent genetic studies from our laboratory, and others, have shown that enhancing endothelial IR activity improves insulin sensitivity. These studies underscore the crucial role of endothelial IR in regulating insulin trafficking and metabolism. Now that researchers have conclusively demonstrated the presence and function of IR on endothelial cells (ECs) in vivo, it is essential to clarify why this receptor has been so controversial. Additionally, this timely review aims to encourage vascular biology researchers to explore how endothelial IR is regulated and identify new roles for this receptor on ECs. Introduction Diabetes affects >537 million adults worldwide and is projected to reach 783 million by 2045.1 The disease is driven by a failure of the hormone insulin’s ability to signal.2 In type 1 diabetes (T1D), the disease is driven by an autoimmune loss of insulin production2 whereas type 2 diabetes (T2D), is driven by metabolic inflammation-mediated insulin resistance.1 Insulin resistance refers to the loss of insulin’s action on the insulin receptor (IR), resulting in elevated blood glucose levels. Approximately 40% of adults in the United States are currently affected by insulin resistance. Both T1D and T2D lead to a decreased ability for glucose uptake in muscle and adipose tissues. Understanding the insulin lifecycle is key to designing therapeutics against diabetes. Insulin is secreted by β cells in the pancreas and released into the portal vein, allowing it to circulate in the bloodstream and reach its target tissues. Insulin then exits the vasculature and binds to Submitted 1 August 2025; accepted 10 October 2025; prepublished online 28 October 2025. [https://doi.org/10.1016/j.bvth.2025.100123](https://doi.org/10.1016/j.bvth.2025.100123) . Data are available from the corresponding author, Rahul Rajala ([rahul-rajala@ou.edu](rahul-rajala@ou.edu)), on reasonable request. © 2025 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. FEBRUARY 2026 • VOLUME 3, NUMBER 1 1 parenchymal IRs to signal various physiological actions, notably glucose uptake.3 The primary site of action for insulin is in skeletal muscle, which accounts for up to 85% of glucose uptake.4 Previous studies have dem

FAQs

Why is endothelial insulin trafficking considered rate-limiting for glucose disposal?

The review explains that insulin must traffic across the vascular endothelium to reach target tissues and that this transendothelial trafficking has been established as the rate-limiting step for glucose disposal.

What did earlier studies conclude about endothelial IR and insulin sensitivity?

Earlier reports found minimal changes in insulin sensitivity in mice lacking endothelial IR, which supported a widely held belief that endothelial IR does not regulate insulin trafficking and insulin sensitivity.

What new evidence supports a functional role for endothelial IR?

Recent genetic studies, including work from the authors’ laboratory and others, show that enhancing endothelial IR activity improves insulin sensitivity, reinforcing endothelial IR’s crucial role in regulating insulin trafficking and metabolism.

Sep 30, 2026

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