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Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance.
Open accessAbstract
Obesity is characterized by decreased rates of skeletal muscle insulin-mediated glucose uptake (IMGU). Since IMGU equals the product of the arteriovenous glucose difference (AVGd) across muscle and blood flow into muscle, reduced blood flow and/or tissue activity (AVGd) can lead to decreased IMGU. To examine this issue, we studied six lean (weight 68 +/- 3 kg, mean +/- SEM) and six obese (94 +/- 3 kg) men. The insulin dose-response curves for whole body and leg IMGU were constructed using the euglycemic clamp and leg balance techniques over a large range of serum insulin concentrations. In lean and obese subjects, whole body IMGU, AVGd, blood flow, and leg IMGU increased in a dose dependent fashion and maximal rates of all parameters were reduced in obese subjects compared to lean subjects. The dose-response curves for whole body IMGU, leg IMGU, and AVGd were right-shifted in obese subjects with an ED50 two- to threefold higher than that of lean subjects for each parameter. Leg blood flow increased approximately twofold from basal 2.7 +/- 0.2 to 4.4 +/- 0.2 dl/min in lean, P less than 0.01, and from 2.5 +/- 0.3 to 4.4 +/- 0.4 dl/min in obese subjects, P less than 0.01. The ED50 for insulin's effect to increase leg blood flow was about fourfold higher for obese (957 pmol/liter) than lean subjects (266 pmol/liter), P less than 0.01. Therefore, decreased insulin sensitivity in human obesity is not only due to lower glucose extraction in insulin-sensitive tissues but also to lower blood flow to these tissues. Thus, in vivo insulin resistance can be due to a defect in insulin action at the tissue level and/or a defect in insulin's hemodynamic action to increase blood flow to insulin sensitive tissues.
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“First, there is increasing evidence that stimulation of blood flow to insulin-sensitive tissues during insulin/glucose and glucose infusion may be an important determinant of the rate of in vivo glucose uptake (10, 11, 38).”
From Differential effects of hyperinsulinemia and carbohydrate metabolism on sympathetic nerve activity and muscle blood flow in humans (1993) · cites this paper as [11]
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In the citing paper
“More recently, evidence has accumulated in humans, indicating that insulin's cardiovascular effects may be involved in metabolic regulation (10, 11). Insulin-induced stimulation of blood flow to skeletal muscle, a major insulin-sensitive tissue, has been found to be closely correlated with insulin-mediated muscle glucose uptake.”
From Differential effects of hyperinsulinemia and carbohydrate metabolism on sympathetic nerve activity and muscle blood flow in humans (1993) · cites this paper as [11]
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“as recent evidence indicates that insulin resistance is associated with attenuated hyperinsulinemia-induced vasodilation in skeletal muscle (10, 11).”
From Differential effects of hyperinsulinemia and carbohydrate metabolism on sympathetic nerve activity and muscle blood flow in humans (1993) · cites this paper as [11]
In the citing paper
“Laakso et al83 introduced the concept that insulin-induced increases in skeletal muscle blood flow play an important role in glucose delivery and uptake, i.e. impaired insulin-induced vasodilation in skeletal muscle contributes importantly to reduced glucose uptake in skeletal muscle and to insulin resistance.”
From The Sympathetic Nervous System Alterations in Human Hypertension (2015) · cites this paper as [83]
In the citing paper
“Laakso et al83 reported that insulin-induced vasodilation in skeletal muscle is reduced in obese, insulin resistant humans.”
From The Sympathetic Nervous System Alterations in Human Hypertension (2015) · cites this paper as [83]
In the citing paper
“Subjects who are insulin-resistant require less glucose at a fixed insulin dose than subjects with normal insulin sensitivity”
From The Vasculature in Prediabetes (2018) · cites this paper as [6]
In the citing paper
“subjects with prediabetes require more glucose than a subject with overt type 2 diabetes mellitus (T2DM).”
From The Vasculature in Prediabetes (2018) · cites this paper as [6]
In the citing paper
“Insulin vasodilates skeletal muscle6, 37 and coronary38, 39 vasculature.”
From The Vasculature in Prediabetes (2018) · cites this paper as [6]
In the citing paper
“Attenuated increases in insulin-stimulated limb blood flow result in decreased limb glucose uptake.”
From The Vasculature in Prediabetes (2018) · cites this paper as [6]
In the citing paper
“Studies with the euglycaemic clamp have yielded conflicting results in humans.A number of studies have reported an increased blood flow in skeletal muscles of the limbs [14,26,[34][35][36], whereas others have reported unchanged blood flow [37][38][39].”
From The sympathetic response to euglycaemic hyperinsulinaemia: Evidence from microelectrode nerve recordings in healthy subjects (1992) · cites this paper as [36]
In the citing paper
“Recently, a dose-response relationship between the plasma insulin concentration and enhanced leg blood flow has been established and insulin resistance was associated with a blunted vasodilatory response [36].”
From The sympathetic response to euglycaemic hyperinsulinaemia: Evidence from microelectrode nerve recordings in healthy subjects (1992) · cites this paper as [36]
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Metadata
- Authors
- Laakso, M., Edelman, S. V., Brechtel, G., & Baron, A. D.
- Affiliations
- United States Department of Veterans Affairs (US)
- Venue
- Journal of Clinical Investigation
- Published
- 1990-06-01
- Volume
- 85
- Issue
- 6
- Pages
- 1844-1852
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC296649
- OpenAlex
- W2164471793
- Cited by
- 930
- References
- 52
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 7 · 2023: 8 · 2022: 15 · 2021: 3 · 2020: 9 · 2019: 16 · 2018: 13 · 2017: 14 · 2016: 22 · 2015: 27 · 2014: 18 · 2013: 28 · 2012: 24
- FWCI
- 25.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- National Institutes of Health (1f05tw003969-01)
- Fogarty International Center (TW 03969-01)
- National Center for Research Resources (MO1 RR00827, M01RR000827)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Physiology (medical) › Cardiovascular and exercise physiology
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- insulin resistance, obesity, skeletal muscle blood flow, insulin-stimulated glucose uptake, arteriovenous glucose difference, leg blood flow, insulin dose-response, euglycemic clamp, insulin sensitivity
- MeSH terms
- Adult, Biological Transport, Fatty Acids, Nonesterified, Glucose, Humans, Insulin, Insulin Resistance, Lactates, Leg, Muscles, Obesity, Regional Blood Flow, Regression Analysis
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