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

Abstract

Obesity is associated with microvascular insulin resistance, which is characterized by impaired insulin-mediated microvascular recruitment. Glucagon-like peptide 1 (GLP-1) recruits skeletal and cardiac muscle microvasculature, and this action is preserved in insulin-resistant rodents. We aimed to examine whether GLP-1 recruits microvasculature and improves the action of insulin in obese humans. RESEARCH DESIGN AND METHODSFifteen obese adults received intravenous infusion of either saline or GLP-1 (1.2 pmol/kg/min) for 150 min with or without a euglycemic insulin clamp (1 mU/kg/min) superimposed over the last 120 min. Skeletal and cardiac muscle microvascular blood volume (MBV), flow velocity and blood flow, brachial artery diameter and blood flow, and pulse wave velocity (PWV) were determined. RESULTSInsulin failed to change MBV or flow in either skeletal or cardiac muscle, confirming the presence of microvascular insulin resistance. GLP-1 infusion alone increased MBV by ∼30% and ∼40% in skeletal and cardiac muscle, respectively, with no change in flow velocity, leading to a significant increase in microvascular blood flow in both skeletal and cardiac muscle. Superimposition of insulin to GLP-1 infusion did not further increase MBV or flow in either skeletal or cardiac muscle but raised the steady-state glucose infusion rate by ∼20%. Insulin, GLP-1, and GLP-1 1 insulin infusion did not alter brachial artery diameter and blood flow or PWV. The vasodilatory actions of GLP-1 are preserved in both skeletal and cardiac muscle microvasculature, which may contribute to improving metabolic insulin responses and cardiovascular outcomes. CONCLUSIONSIn obese humans with microvascular insulin resistance, GLP-1's vasodilatory actions are preserved in both skeletal and cardiac muscle microvasculature, which may contribute to improving metabolic insulin responses and cardiovascular outcomes.

Diastolic Cardiac Function Improvement by Liraglutide Is Mainly Body Weight Reduction Dependent but Independently Contributes to B-Type Natriuretic Peptide Reduction in Patients with Type 2 Diabetes with Preserved Ejection Fraction

“…The vascular and myocardial relaxation would reduce end-diastolic filling pressure, thereby improving diastolic cardiac function. A recent report has shown that the vasodilatory actions of GLP-1 analogs are preserved in the myocardial microvasculature but not in obese subjects with vascular insulin resistance [ 44 ]. Body weight reduction might therefore also have improved the sensitivity of the vascular cells to liraglutide.…”

Insulin-mediated muscle microvascular perfusion and its phenotypic predictors in humans

“…insulin deficient but receiving appropriate replacement). Portions of this data set were previously reported 20 – 22 . The studies were performed at the University of Virginia (UVA) Clinical Research Unit (CRU) under study protocols approved by the UVA Institutional Review Board (IRB) and in accordance with the World Medical Association’s 2013 Declaration of Helsinki.…”

“…It begins with a primed (2 mU/kg/min × 10 min), continuous (1 mU/kg/min × 110 min) regular insulin intravenous (IV) infusion, and plasma glucose is measured every 5 min with 20% dextrose infused at a variable rate to maintain euglycemia. This insulin infusion regimen elevates plasma insulin concentrations to high physiologic levels (200–600 pM) 22 , 26 , comparable to post-prandial levels 27 , 28 . During the clamp, plasma glucose is maintained within ~ 0.5 mmol/L (10 mg/dL) of basal levels.…”

Mechanistic Causes of Reduced Cardiorespiratory Fitness in Type 2 Diabetes

“…Glucose and oxygen are both perfusion limited in their delivery to muscle, suggesting that any underlying microvascular defects are likely to have similar effects on both oxygen and glucose [ 34 ]. Even in people with obesity and no family history of DM, insulin-mediated microvascular perfusion in heart and skeletal muscle is decreased [ 35 ]. This is important as the microvasculature provides endothelial surface area needed for tissue uptake of oxygen and substrates that are vital to tissue health and function [ 36 ].…”