GIP Acutely Blunts Insulin- and GLP-1–Induced Muscle Microvascular Perfusion

Changzoon Chun; Thomas K. Sin; Kevin W. Aylor; Nusrat J. Tushi; Shengyi Sun; Zhenqi Liu

doi:10.2337/db25-1009

GIP Acutely Blunts Insulin- and GLP-1–Induced Muscle Microvascular Perfusion | ResearchHub

Glucose-dependent insulinotropic polypeptide (GIP) promotes nutrient storage, but its vascular actions in skeletal muscle remain unclear. To determine whether GIP regulates muscle microvascular perfusion, a key determinant of substrate use, we examined GIP receptor (GIPR) expression in vascular endothelium and assessed GIP effects in vivo in chow-fed and high-fat diet (HFD)–fed rats. Overnight-fasted rats received 120-min infusions of saline or GIP, with or without concurrent insulin or glucagon-like peptide 1 (GLP-1). Immunofluorescence microscopy demonstrated clear GIPR expression in conduit, resistance, and microvascular vessel endothelium. GIP alone did not alter muscle microvascular perfusion in either group but completely abolished insulin- and GLP-1–induced microvascular recruitment. In cultured endothelial cells, GIP dose-dependently increased endothelin-1 (ET-1) secretion and suppressed insulin- or GLP-1–stimulated nitric oxide production. Transcriptomic profiling implicated activation of the GIP–angiotensin II type 1 receptor–ET-1 pathway. In conclusion, GIPR is widely expressed in vascular endothelium. While GIP does not independently recruit muscle microvasculature, it antagonizes insulin- and GLP-1–mediated vasodilation, identifying GIP as a conditional regulator of skeletal muscle perfusion and nutrient delivery, consistent with its physiological effect in directing nutrients toward storage depots. Article Highlights Skeletal muscle microvasculature is essential for nutrient delivery and metabolic regulation, but the vascular actions of glucose-dependent insulinotropic polypeptide (GIP) in muscle are unknown. We investigated whether GIP regulates skeletal muscle microvascular perfusion and interacts with insulin and GLP-1 signaling. GIP receptors are expressed in vascular endothelium, yet GIP alone does not increase muscle perfusion and instead antagonizes insulin- and GLP-1–mediated microvascular recruitment via possibly angiotensin II type 1 receptor–dependent endothelin-1/nitric oxide imbalance. GIP acts as a conditional regulator of skeletal muscle microvascular perfusion, revealing a novel mechanism of tissue-specific incretin regulation of nutrient partitioning.

External reference records

The endothelial cell: an “early responder” in the development of insulin resistance

10.1007/s11154-012-9232-6 · 2013

Insulin regulates its own delivery to skeletal muscle by feed-forward actions on the vasculature

10.1152/ajpendo.00186.2011 · 2011

Blood flow and muscle metabolism: a focus on insulin action

10.1152/ajpendo.00408.2002 · 2003

Diabetic microvascular disease: an Endocrine Society scientific statement

10.1210/jc.2017-01922 · 2017

The vascular endothelium in diabetes and its potential as a therapeutic target

10.1007/s11154-013-9238-8 · 2013

Diabetes pathogenesis and management: the endothelium comes of age

10.1093/jmcb/mjab024 · 2021

Insulin-stimulated activation of eNOS is independent of Ca2+ but requires phosphorylation by Akt at Ser1179

10.1074/jbc.m103702200 · 2001

Inhibition of phosphatidylinositol 3-kinase enhances mitogenic actions of insulin in endothelial cells

10.1074/jbc.m103728200 · 2002

Microvascular recruitment is an early insulin effect that regulates skeletal muscle glucose uptake in vivo

10.2337/diabetes.53.6.1418 · 2004

Salsalate attenuates free fatty acid-induced microvascular and metabolic insulin resistance in humans

10.2337/dc10-2345 · 2011

Vasodilatory actions of glucagon-like peptide 1 are preserved in skeletal and cardiac muscle microvasculature but not in conduit artery in obese humans with vascular insulin resistance

10.2337/dc19-1465 · 2019

The potential beneficial role of glucagon-like peptide-1 in endothelial dysfunction and heart failure associated with insulin resistance

10.1055/s-0028-1082326 · 2008

GLP-1 and insulin regulation of skeletal and cardiac muscle microvascular perfusion in type 2 diabetes

10.1111/1753-0407.13045 · 2020

The cardiovascular biology of glucagon-like peptide-1

10.1016/j.cmet.2016.06.009 · 2016

Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease

10.1152/ajpendo.00237.2004 · 2004

Protein kinase A mediates glucagon-like peptide 1-induced nitric oxide production and muscle microvascular recruitment

10.1152/ajpendo.00473.2012 · 2013

Glucagon-like peptide 1 recruits microvasculature and increases glucose use in muscle via a nitric oxide-dependent mechanism

10.2337/db11-1073 · 2012

Glucagon-like peptide 1 recruits muscle microvasculature and improves insulin’s metabolic action in the presence of insulin resistance

10.2337/db13-1597 · 2014

Difference in protective effects of GIP and GLP-1 on endothelial cells according to cyclic adenosine monophosphate response

10.3892/etm.2017.4279 · 2017

Glucose-dependent insulinotropic peptide: differential effects on hepatic artery vs. portal vein endothelial cells

10.1152/ajpendo.00507.2003 · 2004

Glucose-dependent insulinotropic peptide signaling pathways in endothelial cells

10.1016/s0196-9781(00)00287-4 · 2000

Glucose-dependent insulinotropic polypeptide is involved in postprandial regulation of splanchnic blood supply

10.2337/db25-0149 · 2025

Effects of meal and incretins in the regulation of splanchnic blood flow

10.1530/ec-17-0015 · 2017

Insulin plays a permissive role for the vasoactive effect of GIP regulating adipose tissue metabolism in humans

10.1210/jc.2016-1933 · 2016

Glucose-dependent insulinotropic polypeptide in incretin physiology: role in health and disease

10.1210/endrev/bnaf006 · 2025

Angiotensin II receptors modulate muscle microvascular and metabolic responses to insulin in vivo

10.2337/db10-1691 · 2011

Angiotensin II type 1 and type 2 receptors regulate basal skeletal muscle microvascular volume and glucose use

10.1161/hypertensionaha.109.145409 · 2010

Liraglutide and exercise synergistically attenuate vascular inflammation and enhance metabolic insulin action in early diet-induced obesity

10.2337/db22-0745 · 2023

Metformin prevents endothelial oxidative stress and microvascular insulin resistance during obesity development in male rats

10.1152/ajpendo.00240.2021 · 2022

High metabolic substrate load induces mitochondrial dysfunction in rat skeletal muscle microvascular endothelial cells

10.14814/phy2.14855 · 2021

The expanding incretin universe: from basic biology to clinical translation

10.1007/s00125-023-05906-7 · 2023

Inflammation-induced microvascular insulin resistance is an early event in diet-induced obesity

10.1042/cs20150143 · 2015

Effects of GIP on regional blood flow during normoglycemia and hyperglycemia in anesthetized rats

10.14814/phy2.13685 · 2018

Defective glucose-dependent insulinotropic polypeptide receptor expression in diabetic fatty Zucker rats

10.2337/diabetes.50.5.1004 · 2001

Glucose-dependent insulinotropic polypeptide secretion after oral macronutrient ingestion: the human literature revisited and a systematic study in model experiments in mice

10.1111/jdi.13836 · 2022

The vasodilatory actions of insulin on resistance and terminal arterioles and their impact on muscle glucose uptake

10.1002/dmrr.414 · 2004

Skeletal muscle capillary responses to insulin are abnormal in late-stage diabetes and are restored by angiogensin-converting enzyme inhibition

10.1152/ajpendo.00498.2007 · 2007

Lipid infusion impairs physiologic insulin-mediated capillary recruitment and muscle glucose uptake in vivo

10.2337/diabetes.51.4.1138 · 2002

GLP-1 and insulin recruit muscle microvasculature and dilate conduit artery individually but not additively in healthy humans

10.1210/js.2017-00446 · 2018

GLP-1 at physiological concentrations recruits skeletal and cardiac muscle microvasculature in healthy humans

10.1042/cs20130708 · 2014

Additional external references

Ang II promotes ET-1 production by regulating NOX2 activity through transcription factor Oct-1

10.1161/atvbaha.122.318764 · doi-reference

Endothelin stimulated by angiotensin II augments contractility of spontaneously hypertensive rat resistance arteries

10.1161/01.hyp.19.2.131 · doi-reference

Candesartan acutely recruits skeletal and cardiac muscle microvasculature in healthy humans

10.1210/jc.2011-3455 · doi-reference

Losartan increases muscle insulin delivery and rescues insulin’s metabolic action during lipid infusion via microvascular recruitment

10.1152/ajpendo.00537.2012 · doi-reference

Cardiovascular actions of insulin

10.1210/er.2007-0006 · doi-reference

Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms

10.1161/circulationaha.105.563213 · doi-reference

Oral and intravenous glucose administration elicit opposing microvascular blood flow responses in skeletal muscle of healthy people: role of incretins

10.1113/jp282428 · doi-reference

The influence of glucose-dependent insulinotropic polypeptide (GIP) on human adipose tissue and fat metabolism: implications for obesity, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD)

10.1016/j.peptides.2019.170208 · doi-reference

GIP increases human adipocyte LPL expression through CREB and TORC2-mediated trans-activation of the LPL gene

10.1194/jlr.m006841 · doi-reference

GIP Acutely Blunts Insulin- and GLP-1–Induced Muscle Microvascular Perfusion

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