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World Journal of
Diabetes
World J Diabetes 2019 February 15; 10(2): 63-136
ISSN 1948-9358 (online)
Published by Baishideng Publishing Group Inc
W J D World Journal of
Diabetes
Contents Monthly Volume 10 Number 2 February 15, 2019
REVIEW
63 Insulin resistance is associated with subclinical vascular disease in humans
Adeva-Andany MM, Ameneiros-Rodríguez E, Fernández-Fernández C, Domínguez-Montero A, Funcasta-Calderón R
ORIGINAL ARTICLE
Retrospective Cohort Study
78 New results on the safety of laparoscopic sleeve gastrectomy bariatric procedure for type 2 diabetes patients
Guetta O, Vakhrushev A, Dukhno O, Ovnat A, Sebbag G
Observational Study
87 Quantities of comorbidities affects physical, but not mental health related quality of life in type 1 diabetes
with confirmed polyneuropathy
Wegeberg AML, Meldgaard T, Hyldahl S, Jakobsen PE, Drewes AM, Brock B, Brock C
SYSTEMATIC REVIEWS
96 Effectiveness of royal jelly supplementation in glycemic regulation: A systematic review
Omer K, Gelkopf MJ, Newton G
114 SGLT-2 inhibitors in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus: A systematic
review
Raj H, Durgia H, Palui R, Kamalanathan S, Selvarajan S, Kar SS, Sahoo J
CASE REPORT
133 Bilateral gangrene of fingers in a patient on empagliflozin: First case report
Ramachandra Pai RP, Kangath RV
WJD https://www.wjgnet.com
February 15, 2019 Volume 10 Issue 2
I
Contents World Journal of Diabetes
Volume 10 Number 2 February 15, 2019
ABOUT COVER Editorial Board Member of World Journal of Diabetes, Boon How Chew, MD,
PhD, Associate Professor, Doctor, Department of Family Medicine, Faculty
of Medicine & Health Sciences, University Putra Malaysia, Serdang 43400,
Selangor, Malaysia
AIMS AND SCOPE World Journal of Diabetes (World J Diabetes, WJD, online ISSN 1948-9358, DOI:
10.4239) is a peer-reviewed open access academic journal that aims to guide
clinical practice and improve diagnostic and therapeutic skills of clinicians.
WJD covers topics concerning α, β, δ and PP cells of the pancreatic islet,
the effect of insulin and insulinresistance, pancreatic islet transplantation,
adipose cells and obesity.
We encourage authors to submit their manuscripts to WJD. We will give
priority to manuscripts that are supported by major national and
international foundations and those that are of great clinical significance.
INDEXING/ABSTRACTING The WJD is now abstracted and indexed in Emerging Sources Citation Index (Web of
Science), PubMed, PubMed Central, Scopus, China National Knowledge
Infrastructure (CNKI), China Science and Technology Journal Database (CSTJ), and
Superstar Journals Database.
RESPONSIBLE EDITORS
FOR THIS ISSUE Responsible Electronic Editor: Han Song Proofing Editorial Office Director: Jin-Lei Wang
NAME OF JOURNAL
World Journal of Diabetes
ISSN
ISSN 1948-9358 (online)
LAUNCH DATE
June 15, 2010
FREQUENCY
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Timothy R Koch
EDITORIAL BOARD MEMBERS
https://www.wjgnet.com/1948-9358/editorialboard.htm
EDITORIAL OFFICE
Jin-Lei Wang, Director
PUBLICATION DATE
February 15, 2019
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February 15, 2019 Volume 10 Issue 2
II
W J D World Journal of
Diabetes
Submit a Manuscript: https://www.f6publishing.com World J Diabetes 2019 February 15; 10(2): 63-77
DOI: 10.4239/wjd.v10.i2.63 ISSN 1948-9358 (online)
REVIEW
Insulin resistance is associated with subclinical vascular disease in
humans
María M Adeva-Andany, Eva Ameneiros-Rodríguez, Carlos Fernández-Fernández,
Alberto Domínguez-Montero, Raquel Funcasta-Calderón
ORCID number: María M Adeva-
Andany (0000-0002-9997-2568).
Author contributions: Each author
contributed to this manuscript;
Adeva-Andany MM designed the
study, performed the literature
search, analyzed the data and
drafted the manuscript;
Ameneiros-Rodríguez E
contributed to the literature search
and analysis of data; Fernández-
Fernández C and Domínguez-
Montero A contributed to the
analysis of data and organization
of the article; Funcasta-Calderón R
contributed to the conception and
design of the study and on-going
progress; all authors reviewed and
approved the final manuscript.
Conflict-of-interest statement: The
authors declare that they have no
conflict of interest.
Open-Access: This article is an
open-access article which was
selected by an in-house editor and
fully peer-reviewed by external
reviewers. It is distributed in
accordance with the Creative
Commons Attribution Non
Commercial (CC BY-NC 4.0)
license, which permits others to
distribute, remix, adapt, build
upon this work non-commercially,
and license their derivative works
on different terms, provided the
original work is properly cited and
the use is non-commercial. See:
http://creativecommons.org/licen
ses/by-nc/4.0/
Manuscript source: Unsolicited
manuscript
Received: January 16, 2019
María M Adeva-Andany, Eva Ameneiros-Rodríguez, Carlos Fernández-Fernández, Alberto
Domínguez-Montero, Raquel Funcasta-Calderón, Internal Medicine Department, Hospital
General Juan Cardona, Ferrol 15406, Spain
Corresponding author: María M Adeva-Andany, MD, PhD, Attending Doctor, Internal
Medicine Department, Hospital General Juan Cardona, c/Pardo Bazán s/n, Ferrol 15406,
Spain. madevaa@yahoo.com
Telephone: +34-60-4004309
Abstract
Insulin resistance is associated with subclinical vascular disease that is not
justified by conventional cardiovascular risk factors, such as smoking or
hypercholesterolemia. Vascular injury associated to insulin resistance involves
functional and structural damage to the arterial wall that includes impaired
vasodilation in response to chemical mediators, reduced distensibility of the
arterial wall (arterial stiffness), vascular calcification, and increased thickness of
the arterial wall. Vascular dysfunction associated to insulin resistance is present
in asymptomatic subjects and predisposes to cardiovascular diseases, such as
heart failure, ischemic heart disease, stroke, and peripheral vascular disease.
Structural and functional vascular disease associated to insulin resistance is
highly predictive of cardiovascular morbidity and mortality. Its pathogenic
mechanisms remain undefined. Prospective studies have demonstrated that
animal protein consumption increases the risk of developing cardiovascular
disease and predisposes to type 2 diabetes (T2D) whereas vegetable protein
intake has the opposite effect. Vascular disease linked to insulin resistance begins
to occur early in life. Children and adolescents with insulin resistance show an
injured arterial system compared with youth free of insulin resistance, suggesting
that insulin resistance plays a crucial role in the development of initial vascular
damage. Prevention of the vascular dysfunction related to insulin resistance
should begin early in life. Before the clinical onset of T2D, asymptomatic subjects
endure a long period of time characterized by insulin resistance. Latent vascular
dysfunction begins to develop during this phase, so that patients with T2D are at
increased cardiovascular risk long before the diagnosis of the disease.
Key words: Diabetes; Cardiovascular risk; Arterial stiffness; Arterial elasticity; Intima-
media thickness; Vascular calcification; Insulin resistance; Animal protein; Vegetable
protein
WJD https://www.wjgnet.com
February 15, 2019 Volume 10 Issue 2
63
Peer-review started: January 17,
2019
First decision: January 25, 2019
Revised: February 1, 2019
Accepted: February 11, 2019
Article in press: February 12, 2019
Published online: February 15,
2019
©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
Core tip: Vascular injury associated to insulin resistance includes impaired vasodilation
in response to chemical mediators, reduced distensibility of the arterial wall (arterial
stiffness), vascular calcification, and increased thickness of the arterial wall. Vascular
dysfunction associated to insulin resistance is present in asymptomatic subjects and
predisposes to cardiovascular diseases, such as heart failure, ischemic heart disease,
stroke, and peripheral vascular disease. Structural and functional vascular disease
associated to insulin resistance is highly predictive of cardiovascular morbidity and
mortality.
Citation: Adeva-Andany MM, Ameneiros-Rodríguez E, Fernández-Fernández C, Domínguez-
Montero A, Funcasta-Calderón R. Insulin resistance is associated with subclinical vascular
disease in humans. World J Diabetes 2019; 10(2): 63-77
URL: https://www.wjgnet.com/1948-9358/full/v10/i2/63.htm
DOI: https://dx.doi.org/10.4239/wjd.v10.i2.63
INTRODUCTION
Cardiovascular disease is a major cause of morbidity and mortality particularly in
patients with diabetes. Cardiovascular risk in this population group begins decades
prior the clinical diagnosis of the disease and is not fully explained by traditional risk
factors such as hypercholesterolemia and smoking. Multiple investigations provide
compelling evidence of an association between insulin resistance by itself and
cardiovascular risk in the general population and patients with diabetes. More
insulin-resistant subjects endure higher cardiovascular risk compared to those who
are more insulin-sensitive[1]. A causative link between insulin resistance by itself and
vascular disease is very likely to exist, but the pathogenic mechanisms that explain the
vascular dysfunction related to insulin resistance remain elusive. There is conclusive
evidence that dietary habits that include animal protein increase the risk of type 2
diabetes (T2D) and cardiovascular disease whereas dietary patterns with elevated
content of vegetable protein reduce the risk of both disorders[2]. Population groups
that change their dietary routine to augment animal protein intake experience a
dramatic increase in the rate of T2D and cardiovascular events[3]. Animal protein
consumption activates glucagon secretion. Glucagon is the primary hormone that
opposes insulin action. Animal protein ingestion may predispose to T2D and
cardiovascular events by intensifying insulin resistance via glucagon secretion (Figure
1)[4].
Asymptomatic individuals with insulin resistance experience striking vascular
damage that is not justified by traditional cardiovascular risk factors, such as
hypercholesterolemia or smoking. Vascular injury related to insulin resistance
develops progressively in asymptomatic subjects during a period of time that may
begin during childhood. A long phase of insulin resistance and latent vascular injury
precedes the clinical onset of T2D increasing cardiovascular risk before the diagnosis
of the disease[5-7]. Accordingly, subclinical vascular dysfunction is evident in patients
with screen-detected T2D[8]. Vascular damage associated with insulin resistance
includes functional and structural vascular injury, such as impaired vasodilation, loss
of elasticity of the arterial wall (arterial stiffness), increased intima-media thickness of
the arterial wall, and vascular calcification. (Figure 2) The presence of subclinical
vascular disease associated with insulin resistance is highly predictive of future
cardiovascular events[9-12].
INSULIN RESISTANCE IS INDEPENDENTLY ASSOCIATED
WITH SUBCLINICAL IMPAIRMENT OF VASCULAR
REACTIVITY
Vascular smooth muscle cells normally undergo contraction or relaxation to regulate
the magnitude of the blood flow according to physiological conditions. Normal
endothelial cells generate vasoactive substances that modulate the reactivity of
vascular smooth muscle cells. Among them, nitric oxide is a short-lived gas that
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Figure 1
Figure 1 A simplified proposed mechanism underlying vascular disease associated with insulin resistance.
induces vasodilation. Acetylcholine is an endogenous transmitter that activates
endothelial nitric oxide production by acting on muscarinic receptors. Acetylcholine
induces endothelium-dependent vasodilation while exogenous sources of nitric oxide
(such as nitroglycerin and sodium nitroprusside) induce endothelium-independent
vasodilation. In response to increased blood flow, vascular smooth muscle cells
normally relax to produce vasodilation and accommodate the elevated blood flow.
Flow-mediated vasodilation is attributed to nitric oxide release by endothelial cells.
The degree of flow-mediated vasodilation is considered a measure of endothelium-
dependent vasodilation and can be determined by ultrasonography performed at the
brachial artery[13-15].
A number of investigations show that insulin resistance is independently
associated with blunted flow-mediated arterial vasodilation in asymptomatic healthy
individuals compared to control subjects[5,16,17].
Similarly, insulin resistance is associated with limited vasodilation in response to
metacholine chloride, a muscarinic agent. The increment in blood flow in response to
metacholine is lower in insulin-resistant subjects compared to insulin-sensitive
controls[18].
Likewise, arterial response to exogenous sources of nitric oxide, such as
nitroglycerin, sodium nitroprusside, and nitrates is impaired in subjects with insulin
resistance compared to control subjects[10,16,18].
Similarly to healthy subjects, flow-mediated vasodilation is defective in nondiabetic
patients with coronary heart disease, compared to control subjects. On multivariate
analysis, the extent of flow-mediated vasodilation is correlated with serum high-
density lipoprotein (HDL)-c, but not with low-density lipoprotein (LDL)-c or total
cholesterol levels[10].
Impairment of flow-mediated vasodilation associated with insulin resistance is
already apparent in childhood. Obese children show impaired arterial vasodilation
compared to control children. Further, regular exercise over 6 mo restores abnormal
vascular dysfunction in obese children. The improvement in flow-mediated
vasodilation after 6-mo exercise program correlates with enhanced insulin sensitivity,
reflected by reduced body mass index (BMI), waist-to-hip ratio, systolic blood
pressure, fasting insulin, triglycerides, and LDL/HDL ratio[19].
In normal weight and overweight adolescents, there is a gradual deterioration of
flow-mediated vasodilation with worsening of insulin resistance evaluated by the
euglycemic hyperinsulinemic clamp[20].
INSULIN RESISTANCE IS INDEPENDENTLY ASSOCIATED
WITH SUBCLINICAL ARTERIAL STIFFNESS
Loss of distensibility of the arterial wall (arterial stiffness) leads to elevated systolic
blood pressure and consequently increases cardiac afterload resulting in left
ventricular hypertrophy that contributes to the development of congestive heart
failure. In addition, arterial stiffness leads to reduced diastolic blood pressure, which
may deteriorate diastolic coronary blood flow contributing to ischemic heart
disease[21,22] (Figure 3). Arterial stiffness is associated with wide pulse pressure
(systolic blood pressure minus diastolic blood pressure)[7,23].
Parameters that estimate arterial stiffness include blood pressure, pulse pressure,
pulse-wave velocity, augmentation index, coefficients of distensibility and
compliance, and the Young’s elastic modulus, which includes intima-media thickness
and estimates arterial stiffness controlling for arterial wall thickness[6]. Pulse-wave
velocity is the speed of the pressure wave generated by left ventricular contraction.
Arterial stiffness impairs the ability of the arterial wall to cushion the pressure wave
and increases pulse-wave velocity[21]. Augmentation is the pressure difference
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Figure 2
Figure 2 Pathophysiological changes associated with insulin resistance-mediated vascular disease.
between the second and first systolic peaks of the central arterial pressure waveform.
Increased augmentation reflects arterial stiffness[24,25]. The augmentation index has
been defined as augmentation divided by pulse pressure, being a measure of
peripheral wave reflection. A higher augmentation index reflects increased arterial
stiffness[26,27].
Age is consistently associated with arterial stiffness, but the loss of arterial elasticity
related with age is not justified by conventional cardiovascular risk factors. Insulin
resistance becomes deeper with age and may be a major pathophysiological
determinant of arterial stiffness in the elderly population[12,28,29].
Numerous investigations document an association between insulin resistance and
subclinical arterial stiffness in nondiabetic individuals across all ages. Arterial
stiffness related to insulin resistance begins early in life and progresses in
asymptomatic subjects during a latent period of time before the diagnosis of
cardiovascular disease. Subclinical arterial stiffness associated with insulin resistance
strongly predicts future cardiovascular events. Conventional cardiovascular risk
factors do not explain the loss of arterial elasticity related to insulin resistance[7,22].
Arterial stiffness is apparent in asymptomatic subjects with insulin resistance
ascertained either by its clinical expression, the metabolic syndrome, or by estimates
of insulin sensitivity.
Estimates of insulin resistance are associated with subclinical arterial stiffness
In a variety of population groups, insulin resistance identified by different estimates is
consistently associated with measures of arterial stiffness independently of classic
cardiovascular risk factors (Table 1).
The Atherosclerosis Risk in Communities study is a prospective population-based
trial with African American and Caucasian participants. A cross-sectional analysis
showed an independent association between insulin resistance (assessed by glucose
tolerance tests) and arterial stiffness. Subjects with insulin resistance had stiffer
arteries compared to those with normal glucose tolerance after adjustment for
confounding factors[6].
Similarly, insulin resistance (glucose tolerance tests) in individuals from the general
population was independently associated with arterial stiffness estimated by
distensibility and compliance of the carotid, femoral and brachial arteries, compared
to normal glucose tolerance. Arterial stiffness worsened with deteriorating glucose
tolerance[22].
Comparable findings were obtained in healthy Chinese subjects. Insulin resistance
(impaired glucose tolerance) was independently associated with arterial stiffness
(estimated by brachial-ankle pulse-wave velocity) compared to normal glucose
tolerance. Normoglycemic subjects with altered glucose metabolism have increased
arterial stiffness[30].
Likewise, arterial stiffness (brachial artery pulse-wave velocity) is positively
correlated with postprandial glucose and negatively correlated with plasma
adiponectin level, suggesting that arterial stiffness is greater in patients with insulin
resistance compared to those with normal glucose tolerance[17].
Assessment of insulin resistance with the euglycemic hyperinsulinemic clamp is
also independently associated with subclinical arterial stiffness of the common carotid
and femoral arteries evaluated by pulse-wave velocity in asymptomatic healthy
adults[21]. In patients with hypertension, insulin resistance (glucose tolerance tests) is
independently associated with arterial stiffness (carotid-femoral pulse-wave velocity
and pulse pressure) as well[31,32].
Several studies document an association between insulin resistance evaluated by
the homeostasis model assessment (HOMA) index and arterial stiffness in
asymptomatic individuals from different population groups. In healthy subjects and
in Korean post-menopausal women, insulin resistance is independently associated
with increased arterial stiffness (evaluated by brachial-ankle, aortic and peripheral
pulse-wave velocity). Arterial stiffness increases sequentially with the degree of
insulin resistance[33,34]. Analogous findings are observed in normotensive
normoglycemic first-degree relatives of patients with diabetes. Arterial stiffness
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Figure 3
Figure 3 Cardiovascular disease associated to arterial stiffness.
(carotid-femoral pulse-wave velocity) is increased in the relatives with insulin
resistance compared to those more insulin-sensitive[35]. Insulin resistance and arterial
stiffness (augmentation index and pulse-wave velocity) were compared in Indigenous
Australians (a population group with elevated rate of T2D) and European
Australians. The Indigenous population group had higher HOMA-IR values and
increased arterial stiffness compared to their European counterparts, suggesting that
intensified insulin resistance among Indigenous participants contributes to explain
increased arterial stiffness in this group[4].
Subclinical arterial stiffness is already present in children and adolescents with
insulin resistance, compared to insulin-sensitive control subjects. In healthy children
and adolescents from the general population of different countries, insulin resistance
(HOMA-IR values) is independently associated with increased arterial stiffness
evaluated by carotid-femoral pulse-wave velocity or brachial artery distensibility
compared to control subjects[11,36,37]. In obese children and adolescents, a profound
independent effect of insulin resistance on vascular compliance has been observed.
Insulin-resistant subjects (HOMA-IR) experience increased vascular stiffness (aortic
pulse-wave velocity) compared to control individuals[38-40]. In normal weight and
overweight adolescents, insulin resistance assessed by euglycemic hyperinsulinemic
clamp is associated with higher augmentation index, indicating that insulin resistance
in adolescents is related to increased arterial stiffness[20].
Clinical manifestations of insulin resistance are associated with subclinical arterial
stiffness
The metabolic syndrome is a cluster of clinical features that reflects insulin resistance,
including obesity, systolic hypertension, dyslipemia (hypertriglyceridemia and low
HDL-c), and hyperinsulinemia. The metabolic syndrome and its individual
components have been independently associated with arterial stiffness. Patients with
any clinical expression of insulin resistance experience subclinical arterial stiffness
that is not explained by conventional cardiovascular risk factors. Arterial stiffness has
been considered a further clinical manifestation of insulin resistance[7] (Table 2).
The metabolic syndrome is associated with arterial stiffness: The longitudinal
association between the metabolic syndrome and arterial stiffness was investigated in
the Cardiovascular Health Study. Metabolic syndrome at baseline (obesity, systolic
hypertension, hyperinsulinemia and hypertriglyceridemia) independently predicted
increased arterial stiffness (aortic pulse-wave velocity) at follow-up[28].
In the Atherosclerosis Risk in Communities study, the joint effect of elevated
glucose, hyperinsulinemia and hypertriglyceridemia (reflecting insulin resistance) is
independently associated with arterial stiffness in subjects from the general
population[6]. Similarly, the clustering of at least three components of the metabolic
syndrome is related with increased carotid artery stiffness among healthy participants
across all age groups in the Baltimore Longitudinal Study on Aging independently of
other cardiovascular risk factors[41].
Likewise, the metabolic syndrome is strongly and independently associated with
reduced distensibility of the common carotid artery in healthy women from the
general population[9]. In 12517 subjects with no history of cardiovascular disease,
systolic hypertension, obesity, hypertriglyceridemia, and hyperuricemia are
independent determinants for arterial stiffness (brachial-ankle pulse-wave velocity)
on multiple regression analysis[29]. Arterial stiffness (augmentation index and pulse-
wave velocity) was compared in Indigenous and European Australians. Factor
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Table 1 Studies that find an independent association between insulin resistance and subclinical arterial stiffness unexplained by classic
cardiovascular risk factors
Ref.Population group Insulin resistance Arterial stiffness
Salomaa et al[6]African American and Caucasian IGT Arterial compliance, Young’s elastic modulus
Henry et al[22]General population IGT Arterial compliance
Shin et al[30]Healthy Chinese subjects IGT Brachial-ankle PWV
Liye et al[17]IGT versus normal glucose tolerance IGT, serum adiponectin levels Brachial artery PWV
Giltay et al[21]Healthy subjects Hyperinsulinemic euglycemic clamp Carotid-femoral PWV
Vyssoulis et al[32]Patients with hypertension IGT Carotid-femoral PWV
Sengstock et al[31]Patients with hypertension Frequently sampled IV tolerance test Aortic PWV, pulse pressure
Kasayama et al[33]Healthy adults HOMA Brachial-ankle PWV
Park et al[34]Postmenopausal women HOMA-IR Aortic and peripheral PWV
Maple-Brown et al[4]Indigenous Australians HOMA-IR Augmentation index
Scuteri et al[35]Family history of diabetes HOMA-IR Carotid-femoral PWV
Sakuragi et al[36]Prepubescent children HOMA-IR Carotid-femoral PWV
Whincup et al[11]British children HOMA-IR Brachial artery distensibility
Gungor et al[38]Children and adolescents HOMA-IR Aortic PWV
Iannuzzi et al[39]Children and adolescents HOMA-IR Aortic PWV
Tomsa et al[20]Adolescents Hyperinsulinemic euglycemic clamp Augmentation index
IGT: Impaired glucose tolerance; PWV: Pulse-wave velocity; HOMA: Homeostasis model assessment; HOMA-IR: Homeostasis model assessment-insulin
resistance.
analysis revealed that metabolic syndrome components clustered with Indigenous
Australian participants. Arterial stiffness was more pronounced among Indigenous
compared to European Australians[4].
Subclinical arterial stiffness is already present in children and adolescents with the
metabolic syndrome, suggesting that insulin resistance plays an important role in the
early pathogenesis of vascular disease. British and Chinese children and adolescents
with the metabolic syndrome have increased arterial stiffness compared to control
children after adjustment for covariates. There is a strong graded inverse relationship
between the number of metabolic syndrome components and brachial artery
distensibility[11,37]. In obese children, common carotid artery stiffness is more
prominent in the group with the metabolic syndrome compared to the control
group[42]. Normoglycemic young adults (mean age 20 years) with a positive family
history of T2D have higher BMI and fasting insulin and increased arterial stiffness
(aortic pulse-wave velocity) than their counterparts without T2D relatives[43]. The
longitudinal relationship between the metabolic syndrome identified in childhood
and arterial elasticity assessed in adulthood was investigated in a prospective
population-based cohort study with 21 years of follow-up, the Cardiovascular Risk in
Young Finns Study. Childhood metabolic syndrome (obesity, systolic hypertension,
hypertriglyceridemia and hyperinsulinemia) predicts independently carotid artery
stiffness in adulthood[44].
Obesity is associated with arterial stiffness: Longitudinal and cross-sectional studies
consistently show that measures of adiposity (BMI, waist circumference, waist-to-hip
ratio, body fat, and abdominal fat) are independently associated with estimates of
arterial stiffness in diverse population groups. This association is already apparent
during childhood and cannot be explained by traditional cardiovascular risk factors.
In a population-based setting, adulthood obesity (BMI and waist-to-hip ratio) is
associated with increased stiffness of carotid, femoral, and brachial arteries after
adjusting for cardiovascular risk factors. Arterial distensibility consistently decreased
with higher BMI[9,45]. Similarly, obesity (BMI and waist circumference) is
independently related to increased arterial stiffness (augmentation index) in
Indigenous Australians free of T2D compared to European Australians[46]. In female
twins, abdominal adiposity is a determinant of arterial stiffness (augmentation index)
independent of genetic effects and other confounding factors[47].
The association between adiposity parameters and increased arterial stiffness
begins during childhood. In obese children, there is a marked effect of insulin
resistance associated with obesity on vascular compliance. Obese children are more
insulin-resistant and have stiffer arteries compared with lean controls[39,40]. In a
population-based setting, childhood obesity (BMI and waist circumference) is
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Table 2 Studies that find an independent association between the clinical expression of insulin resistance and subclinical arterial
stiffness unexplained by classic cardiovascular risk factors
Ref.Population group Insulin resistance Arterial stiffness
Mackey et al[28]Elderly Metabolic syndrome Aortic pulse-wave velocity
Salomaa et al[6]General population Metabolic syndrome Arterial compliance, Young’s elastic modulus
Hyperinsulinemia
Scuteri et al[41]Healthy subjects Metabolic syndrome Carotid artery stiffness
Van-Popele et al[9]Women Metabolic syndrome Carotid artery stiffness
Obesity
Dyslipemia
Tomiyama et al[29]Healthy subjects Metabolic syndrome Brachial-ankle pulse-wave velocity
Systolic hypertension
Maple-Brown et al[4]Indigenous versus European Australians Metabolic syndrome Augmentation index, pulse-wave velocity
Whincup et al[11]British children Metabolic syndrome Brachial artery distensibility
Obesity
Hyperinsulinemia
Xi et al[37]Chinese children Metabolic syndrome Brachial artery distensibility
Ianuzzi et al[42]Obese children Metabolic syndrome Carotid artery stiffness
Hopkins et al[43]Relatives of patients with type 2 diabetes Metabolic syndrome Aortic pulse-wave velocity
Juonala et al[44]Children Metabolic syndrome Carotid artery stiffness
Hyperinsulinemia
Zebekakis et al[45]General population Obesity Carotid, femoral, and brachial arteries stiffness
Maple-Brown et al[46]Indigenous versus European Australians Obesity Augmentation index
Greenfield et al[47]Female twins Abdominal obesity Augmentation index
Sakuragi et al[35]Children Obesity Brachial artery distensibility
Dyslipemia
Hyperinsulinemia
Gungor et al[38]Adolescents and young adults Obesity Aortic pulse-wave velocity
Jourdan et al[47]Dyslipemia
Urbina et al[49]
Kappus et al[50]
Wildman et al[51]Young and older adults Obesity Aortic pulse-wave velocity
Iannuzzi et al[39]Systolic hypertension Aortic pulse-wave velocity
Kasayama et al[33]Dyslipemia
Ceceija et al[12]Hyperinsulinemia
Urbina et al[52]Triglyceride/HDL-c Aortic pulse-wave velocity
associated with increased arterial stiffness after adjustment for confounding factors.
There is a strong graded inverse relationship between BMI and brachial artery
distensibility, This association is apparent even at BMI levels below those considered
to represent obesity[11,36]. Similar results are observed in adolescents and young adults.
Obesity is associated with subclinical arterial stiffness independently of
cardiovascular risk factors[38,48-50].
The association between obesity and arterial stiffness (aortic pulse-wave velocity)
was evaluated in young adults (20 to 40 years, 50% African American) and older
adults (41 to 70 years, 33% African American). Obesity parameters (BMI, waist
circumference, hip circumference, and waist-to-hip ratio) were strongly correlated
with higher aortic pulse-wave velocity, independently of risk factors. Obesity is an
independent and strong predictor of aortic stiffness for both races and age groups[51].
Systolic hypertension, dyslipemia, and hyperinsulinemia are associated with
arterial stiffness: Other clinical manifestations of insulin resistance, including systolic
hypertension[12,29,39,40], dyslipemia[9,33,36,38-40,52], and hyperinsulinemia[6,11,36,40,44] are also
consistently associated with different measures of arterial stiffness independently of
other cardiovascular risk factors, in diverse population groups, across all ages.
Longitudinal studies such as the Atherosclerosis Risk in Communities study and the
Multi-Ethnic Study of Atherosclerosis have shown that arterial stiffness predicts the
development of systolic hypertension[53,54]. In healthy subjects 10 to 26 years old,
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Adeva-Andany MM et al. Insulin resistance is associated to subclinical vascular disease
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triglyceride-to-HDL-c ratio is an independent predictor of arterial stiffness after
adjustment for cardiovascular risk factors, particularly in the obese. Arterial stiffness
rose progressively across tertiles of triglyceride-to-HDL-c ratio[52].
INSULIN RESISTANCE IS INDEPENDENTLY ASSOCIATED
WITH SUBCLINICAL STRUCTURAL CHANGES OF THE
ARTERIAL WALL
Similarly to arterial stiffness, a gradual increase in carotid intima-media thickness
occurs with age. A systematic review documents a strong association between age
and carotid intima-media thickness in healthy subjects and individuals with
cardiovascular disease. This relationship is not affected by cardiovascular risk factors.
Ageing is associated with magnification of insulin resistance that may explain the
increase in intima-media thickness[55].
Insulin resistance either ascertained by estimates or by its clinical expression is
associated with increased intima-media thickness and increased calcification of the
arterial wall in asymptomatic subjects. This association is not mediated by classic
cardiovascular risk factors, suggesting that insulin resistance plays a crucial role in the
development of initial vascular damage (Table 3).
Estimates of insulin resistance are associated with increased thickness of the
arterial wall and increased coronary calcification
Increased thickness of the arterial wall: In healthy subjects from the Kuopio Ischemic
Heart Disease Risk Factor study, insulin resistance was determined by the euglycemic
hyperinsulinemic clamp technique and the presence of subclinical vascular disease in
the femoral and carotid arteries was evaluated by ultrasonography. Subjects with
asymptomatic vascular disease were more insulin-resistant compared to control
subjects[56].
The association between insulin resistance and subclinical vascular disease was
confirmed in healthy Swedish men. Insulin resistance was determined by the
hyperinsulinemic euglycemic clamp in subjects with high cardiovascular risk
(hypercholesterolemia, smoking) and subjects with no cardiovascular risk factors.
Asymptomatic vascular disease was evaluated by B-mode ultrasound of the common
carotid artery. A negative correlation between insulin sensitivity and carotid intima-
media thickness was observed in both population groups (high and low
cardiovascular risk). Participants with insulin resistance had greater carotid wall
thickness compared to insulin-sensitive subjects[57].
A similar association between insulin resistance and subclinical vascular disease
(increased intima-media thickness of the arterial wall) was observed in healthy
Caucasian participants of the Insulin Resistance Atherosclerosis Study. Insulin
sensitivity was evaluated by the frequently sampled intravenous glucose tolerance
test with analysis by the minimal model of Bergman. Asymptomatic vascular disease
was assessed by the measurement of intima-media thickness of the carotid artery by
B-mode ultrasonography. In Caucasian men, insulin resistance is associated with a
subclinical increase in carotid intima-media thickness, after adjustment for traditional
cardiovascular risk factors[58].
The independent association between insulin resistance (HOMA-IR) and subclinical
vascular disease (increased carotid intima-media thickness) has been confirmed in
healthy subjects of four ethnic groups (non-Hispanic Whites, African-Americans,
Hispanic Americans, and Chinese Americans) from the Multi-Ethnic Study of
Atherosclerosis[59].
In asymptomatic patients with impaired glucose tolerance, insulin resistance
(calculated by the insulin sensitivity check index) is strongly associated with severe
carotid atherosclerosis (assessed by ultrasonography) on multiple regression analysis
after adjustment for confounders. Carotid intima-media thickness correlated inversely
with insulin sensitivity[60].
The association between insulin resistance and asymptomatic increased intima-
media thickness is apparent in childhood. In healthy children, insulin resistance
measured with the euglycemic hyperinsulinemic clamp is associated with higher
carotid intima-media thickness[61]. Likewise, obese children aged 6-14 years with
higher HOMA-IR had increased carotid intima-media thickness compared to control
children[39].
Increased coronary artery calcification: Insulin resistance is also associated with
subclinical coronary artery calcification. Asymptomatic subjects with insulin
resistance (HOMA-IR) have increased coronary calcification score (derived from
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Table 3 Studies that find an independent association between insulin resistance and subclinical vascular calcification or increased
intima-media thickness of the arterial wall unexplained by traditional cardiovascular risk factors
Ref.Population group Insulin resistance Vascular disease
Laakso et al[56]Healthy subjects Euglycemic hyperinsulinemic clamp Increased carotid IMT
Agewall et al[57]Healthy men Euglycemic hyperinsulinemic clamp Increased carotid wall thickness
Howard et al[58]Healthy Caucasians Frequently sampled IV glucose tolerance
test
Increased carotid IMT
Bertoni et al[59]Multiethnic healthy subjects HOMA-IR Increased carotid IMT, elevated coronary
calcium
Rajala et al[60]Healthy subjects Insulin sensitivity check index Increased carotid IMT
Iannuzzi et al[39]Obese children HOMA-IR Increased carotid IMT
Ryder et al[61]Healthy children Euglycemic hyperinsulinemic clamp Increased carotid IMT
Arad et al[62]Healthy subjects HOMA-IR Elevated coronary calcium score
Ong et al[63]Healthy subjects HOMA-IR Elevated coronary calcium score
Meigs et al[64]Healthy subjects Glucose tolerance tests Coronary artery calcification
Dabelea et al[65]Healthy and type 1 diabetes children Glucose disposal rate Coronary artery calcification
Reilly et al[66]Family history of cardiovascular
disease
HOMA-IR Coronary artery calcification
Qasim et al[67]Family history of cardiovascular
disease
HOMA-IR Coronary artery calcification
Young et al[68]Patients with coronary artery disease Glucose tolerance test Coronary artery calcification
Shinozaki et al[69]Family history of cardiovascular
disease
Glucose tolerance test Coronary artery calcification
HOMA-IR: Homeostasis model assessment-insulin resistance; IMT: Intima-media thickness.
electron-beam computed tomography) that is not explained by traditional
cardiovascular risk factors[59,62,63].
In the Framingham Offspring Study, there is a graded increase in subclinical
coronary artery calcification with worsening insulin resistance (impaired glucose
tolerance) among asymptomatic subjects[64].
The association between insulin resistance (estimated glucose disposal rate) and
coronary artery calcification was examined among patients with type 1 diabetes and
healthy subjects in the Coronary Artery Calcification in Type 1 Diabetes study. Insulin
resistance was independently associated with coronary artery calcification (electron-
beam computed tomography) in both population groups[65].
In the Study of Inherited Risk of Coronary Atherosclerosis, insulin resistance
(HOMA-IR) is associated with coronary artery calcification after adjustment for
confounding factors in asymptomatic subjects with a family history of premature
cardiovascular disease. The HOMA-IR index predicts coronary artery calcification
scores beyond other cardiovascular risk factors in this population group[66,67].
In normoglycemic patients with coronary artery disease, insulin resistance (glucose
tolerance tests) is associated with severity of the coronary disease documented by
coronary arteriography compared to control subjects. Nondiabetic patients with
coronary artery disease are insulin-resistant compared to control subjects[68,69].
Clinical manifestations of insulin resistance are associated with subclinical
structural damage to the arterial wall
The metabolic syndrome and its individual components are associated with
subclinical structural vascular disease that is not explained by conventional
cardiovascular risk factors.
The metabolic syndrome: In healthy participants of several studies, including the
Atherosclerosis Risk in Communities study, the Baltimore Longitudinal Study on
Aging study, and the Multi-Ethnic Study of Atherosclerosis, the metabolic syndrome
is independently associated with asymptomatic increased carotid intima-media
thickness across all age groups and ethnicities[6,41,59,70]. Likewise, the metabolic
syndrome is associated with coronary artery calcification independently of other
cardiovascular risk factors in asymptomatic subjects with a family history of
premature cardiovascular disease participants of the Study of Inherited Risk of
Coronary Atherosclerosis[66].
Subclinical vascular damage is detectable at young age in the presence of metabolic
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syndrome. Asymptomatic carotid intima-media thickness is increased in children
with metabolic syndrome as compared with healthy control children, after adjustment
for confounders[71]. Regular exercise over 6 mo improves the metabolic syndrome and
reduces carotid intima-media thickness in obese children compared to control
subjects[19].
In analyses from four cohort studies (Cardiovascular Risk in Young Finns study,
Bogalusa Heart study, Princeton Lipid Research study, Insulin study) with a mean
follow-up of 22.3 years, the presence of the metabolic syndrome during childhood is
associated with higher carotid intima-media thickness in adulthood[72].
In the Bogalusa Heart study, postmortem examinations performed in children and
adolescents from a biracial (African American and Caucasian) community showed
that the antemorten presence of the metabolic syndrome (obesity, dyslipemia, and
hypertension) strongly predicted the extent of vascular disease in the aorta and
coronary arteries[73].
In the Pathobiological Determinants of Atherosclerosis in Youth study, arteries
collected from autopsies aged 15-34 years whose deaths were accidental showed that
vascular disease in the aorta and right coronary artery is associated with the presence
of impaired glucose tolerance, obesity, hypertension, and low HDL-c level. This
association is not explained by hypercholesterolemia or smoking[74].
Obesity: In healthy asymptomatic adults, greater BMI and waist-to-hip ratio are
independently associated with increased carotid intima-media thickness[70,75].
Increased diameter of the arterial wall associated with obesity is present in several
areas of the arterial system, including carotid, femoral and brachial arteries. Across a
wide age range, intima-media thickness of several arteries increased with higher BMI
in a population-based sample of participants[45].
The independent relationship between obesity and subclinical increased intima-
media thickness of carotid and femoral arteries is present in children and adolescents.
Obese children have increased carotid and femoral intima-media thickness compared
to control children[39,48,50]. In a prospective cohort of children and adolescents, BMI
assessed at 11, 15, and 18 years was associated with higher carotid intima-media
thickness after controlling for confounders. Overweight/obese subjects had higher
carotid intima-media thickness compared to subjects with normal BMI[76].
In analyses from four cohort studies (Cardiovascular Risk in Young Finns study,
Bogalusa Heart study, Princeton Lipid Research study, Insulin study) with a mean
follow-up of 22.3 years, childhood BMI was associated with higher carotid intima-
media thickness in adulthood[72].
Systolic hypertension, dyslipemia, and hyperinsulinemia: Fasting hyperinsulinemia
is independently associated with greater carotid intima-media thickness and coronary
artery calcification in asymptomatic healthy subjects[6,62,64,70]. The association between
hyperinsulinemia and increased carotid intima-media thickness is similar in African
American and Caucasian subjects[6,70]. The Mexico City Diabetes study investigated the
longitudinal relationship between systolic hypertension and vascular damage in a
population-based prospective trial. In normotensive subjects who progress to
hypertension (prehypertensive subjects), baseline carotid intima-media thickness
increased in comparison with subjects who remained normotensive. After adjusting
for multiple cardiovascular risk factors, converter status was independently
associated with a higher carotid intima-media thickness[77].
Autopsy examinations from the Pathobiological Determinants of Atherosclerosis in
Youth study show that systolic hypertension is associated with greater vascular injury
in both the aorta and right coronary artery (particularly fibrous plaques) in subjects
throughout the 15-34 year age span. The association of hypertension with vascular
damage remained after adjusting for BMI and glycohemoglobin[74].
Longitudinal autopsy studies conducted in children and adults show that low
HDL-c is independently associated with vascular disease. The degree of vascular
lesions in both the aorta and right coronary artery is negatively associated with serum
HDL-c on multiple regression analysis[73,74,78,79].
SUBCLINICAL VASCULAR DISEASE ASSOCIATED WITH
INSULIN RESISTANCE PREDICTS CARDIOVASCULAR
DISEASE
Subclinical structural and functional vascular dysfunction associated with insulin
resistance in otherwise healthy subjects is highly predictive of future cardiovascular
events. Reduced vasodilation, loss of arterial distensibility, and increased arterial
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intima-media thickness in asymptomatic subjects are all associated with future
cardiovascular disease.
In a systematic review and meta-analysis of prospective studies, impaired brachial
flow-mediated vasodilatation was associated with future cardiovascular events both
in asymptomatic and diseased population groups[15]. Impaired nitroglycerin-mediated
vasodilatation of the brachial artery has been independently associated with coronary
artery calcification in a population-based study[80]. In a prospective study, impaired
coronary vasoreactivity was independently associated with a higher incidence of
cardiovascular events. Baseline coronary vasoreactivity in response to several stimuli
(acetylcholine, sympathetic activation, increased blood flow, and nitroglycerin)
predicted incident cardiovascular events at follow-up, after adjustment for traditional
cardiovascular risk factors[81].
The ability of arterial stiffness to predict cardiovascular events independently of
other cardiovascular risk factors has been documented in cross-sectional and
prospective studies, systemic reviews and meta-analyses.
Prospective studies show that increased arterial stiffness (estimated by wide pulse
pressure, carotid-femoral pulse-wave velocity, and common carotid distensibility) is a
powerful predictor of incident cardiovascular events in asymptomatic individuals
from the general population, patients with hypertension, subjects with impaired
glucose tolerance, and patients with T2D beyond classic cardiovascular risk
factors[82-84]. A systematic review of cross-sectional studies concludes that arterial
stiffness is highly predictive of cardiovascular events[12]. A systematic review and
meta-analysis of longitudinal studies that followed-up 15877 subjects for a mean of 7.7
years concludes that aortic stiffness (expressed as aortic pulse-wave velocity) is a
strong predictor of future cardiovascular events, cardiovascular mortality, and all-
cause mortality, independently of classic cardiovascular risk factors. The predictive
value of increased arterial stiffness is larger in patients with higher baseline
cardiovascular risk states, such as renal disease, coronary artery disease, or
hypertension compared with low-risk subjects (general population)[85].
The prospective association between arterial stiffness and postmortem vascular
damage was investigated among elderly subjects. There was a weak correlation
between baseline arterial stiffness (pulse-wave velocity) and the degree of vascular
damage observed at autopsy[86].
A large cross-sectional study with 10828 participants investigated the ability of
brachial-ankle pulse-wave velocity for screening cardiovascular risk in the general
population. On multivariate analysis, brachial-ankle pulse-wave velocity was
associated with cardiovascular risk independently from conventional risk factors[87].
In a population-based cohort study in the elderly (Rotterdam study), arterial
stiffness had a strong positive association with structural vascular disease. Aortic and
carotid stiffness (assessed by carotid-femoral pulse-wave velocity and common
carotid distensibility) was associated with carotid intima-media thickness after
adjustment for cardiovascular risk factors[88].
Subclinical carotid intima-media thickness predicts cardiovascular events in
healthy subjects and patients with coronary artery disease. A systematic review and
meta-analysis concluded that carotid intima-media thickness is a strong independent
predictor of future vascular events, although data for younger individuals are
limited[89]. A prospective cohort study of women shows that increased carotid intima-
media thickness predicts cardiovascular events during 7-year follow-up regardless of
glucose tolerance and other cardiovascular risk factors[90]. In a systematic review,
population groups with cardiovascular disease had a higher carotid intima-media
thickness compared to population groups free of cardiovascular disease[55].
CONCLUSION
Numerous studies provide compelling evidence of an association between insulin
resistance and subclinical cardiovascular disease that is not explained by traditional
cardiovascular risk factors, such as hypercholesterolemia or smoking. Pathogenic
mechanisms underlying vascular damage linked to insulin resistance are undefined.
Vascular injury associated with insulin resistance begins early in life and includes
impaired vasodilation, loss of arterial distensibility, increased intima-media thickness
of the arterial wall and increased arterial calcification. Subclinical vascular
dysfunction associated with insulin resistance in otherwise healthy subjects is highly
predictive of future cardiovascular events. Reduced vasodilation, loss of arterial
distensibility, increased arterial intima-media thickness and vascular calcification in
asymptomatic subjects are associated with future cardiovascular disease.
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ACKNOWLEDGEMENTS
We wish to thank Ms. Gema Souto for her help during the writing of this manuscript.
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P- Reviewer: Koch TR
S- Editor: Ji FF L- Editor: A E- Editor: Song H
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