This document discusses the relationship between insulin resistance, endothelial dysfunction, and inflammation. Some key points: 1) Insulin resistance is associated with increased cardiovascular risk factors like hypertension and dyslipidemia. The author proposes that endothelial dysfunction and chronic inflammation may underlie this relationship. 2) Markers of endothelial dysfunction and the acute phase response (inflammation) were correlated with measures of insulin resistance. Chronic inflammation, indicated by cytokines like TNF-α and IL-6, was also related to obesity and insulin resistance variables. 3) Abdominal fat tissue may contribute to chronic inflammation through local production and release of cytokines like IL-6, though no significant differences were found for TNF-α between abdominal vein

1. Diabetologia (1997) 40: S 145–S 146
© Springer-Verlag 1997
Is insulin vasculotoxic?
J.S. Yudkin
Centre for Diabetes and Cardiovascular Risk, Department of Medicine, University College London Medical School, London, UK
Insulin resistance is generally taken to imply insensi- tissues. It has been suggested that the haemodynamic
tivity of insulin sensitive tissues to the glucose effects action of insulin underlies as much as 40 % of its ef-
of insulin. These actions include stimulation of glu- fect on peripheral glucose uptake. The endothelium
cose uptake, mainly by skeletal muscle, and suppres- also acts as a barrier to insulin transport from the lu-
sion of hepatic glucose output. Normal glucose toler- minal to the interstitial compartment, where it can
ance can be maintained in such subjects by increased bind to insulin receptors, and this may offer a second
beta-cell output of insulin, but these people show sev- mechanism of association of endothelial dysfunction
eral other phenotypic characteristics which are asso- with impaired insulin action. Our own experimental
ciated with increased cardiovascular risk. Thus, insu- data have shown relationships between levels of von
lin resistance and hyperinsulinaemia cluster with ele- Willebrand factor, a marker of endothelial dysfunc-
vated blood pressure, hypertriglyceridaemia and low tion, and impaired insulin mediated glucose uptake.
concentrations of high density lipoprotein choles- Endothelial dysfunction is not a disease entity in its
terol, and elevated levels of plasminogen activator in- own right, and may be the consequence of other
hibitor-1, an inhibitor of fibrinolysis. These risk fac- pathological processes. Although the proposed mech-
tors are individually associated with cardiovascular anisms could underlie the association of insulin resis-
disease, but prospective epidemiological studies sug- tance with microalbuminuria or cigarette smoking,
gest an additional, independent, role for hyperinsu- no experimental data exist which show impaired
linaemia in predicting coronary heart disease. It has transport in subjects with endothelial dysfunction.
been proposed that insulin may exert pro-athero- We have previously reported associations between
genic effects, but it is also possible that hyperinsulin- concentrations of fibrinogen, an acute phase marker,
aemia represents a surrogate marker for insulin resis- and hyperinsulinaemia in population studies, which
tance, which has been put forward as the true culprit. are difficult to explain through the known actions of
As an alternative explanation, insulin resistance insulin. For this reason, we have explored the links
and cardiovascular disease may both represent conse- between features of the insulin resistance cluster,
quences of a common antecedent. Endothelial dys- markers of endothelial dysfunction, and acute phase
function plays an important role in both atherogene- markers and their determinants. We studied 107
sis and coagulation, and the endothelium has recently Europid non-diabetic subjects (59 male, 48 female;
also been shown to play an important role in insulin age 59.0 ± 10.9 years). Standard cardiovascular risk
action. During a hyperinsulinaemic clamp, limb factors were measured, together with albumin excre-
blood flow increases, and this enhances the delivery tion rate, three serum markers of endothelial dys-
of both insulin and substrate to insulin sensitive function, C-reactive protein, and circulating levels of
tumour necrosis factor- (TNF- ) and interleukin-6
a a
(IL-6). We created sum scores for insulin resistance,
Corresponding author: Professor J. S. Yudkin, Centre for Dia- endothelial dysfunction and acute phase response by
betes and Cardiovascular Risk, Department of Medicine, Uni- calculating the mean value of each of the variables
versity College London Medical School, G Block, Archway
Wing, Whittington Hospital, Archway Road, London N19
as Z-scores, so providing a unit-free score for the
3UA, UK three clusters. The insulin resistance and endothelial
Abbreviations: TNF , Tumour necrosis factor-alpha; IL-6, in-
a scores correlated with a coefficient of 0.32
terleukin-6. (p = 0.0008), but there was a strong relationship

2. S 146 J.S. Yudkin: Is insulin vasculotoxic?
between the insulin resistance and acute phase scores calculated that adipose tissue produced 15–25 % of
(r = 0.59, p < 0.00 005). The third of these correla- the systemic IL-6 in the fasting state and 30–45 %
tions, between endothelial and acute phase scores, is post-prandially.
also significant (r = 0.43, p < 0.00 005). If the acute Among the known metabolic effects of TNF- are a
phase and endothelial scores were included in the inhibition of the action of lipoprotein lipase and stim-
same model, the former remained significantly asso- ulation of lipolysis, these actions being shared with
ciated with insulin resistance score (partial r = 0.61, IL-6, perhaps affecting insulin action through Randle
p < 0.00 005) but not the latter (partial r = –0.02, cycle mechanisms. TNF- impairs the function of the
a
p = 0.82). Circulating concentrations of TNF- were
a insulin signalling pathway by effects on phosphoryla-
related to all insulin resistance variables. Concentra- tion of both the insulin receptor and its substrate,
tions of IL-6 were also related to several of the insulin IRS-1. In addition, cytokines have significant damag-
resistance cluster and endothelial markers, including ing effects on the endothelial cell. We postulate that
albumin excretion rate, while the relationships for the cluster of variables that have been attributed to
C-reactive protein were generally stronger. Both the insulin resistance (dyslipidaemia, hypertension and
acute phase score and concentrations of C-reactive impaired fibrinolysis), as well as insulin resistance it-
protein correlated weakly with titres of helicobacter, self, might all result as consequences of a common
chlamydia and cytomegalovirus antibodies but the antecedent. We found close relationships with each
acute phase score as a whole, and the concentrations of the anthropometric measures of obesity, but no in
of IL-6, TNF- and C-reactive protein, were strongly
a vivo release of TNF- by adipose tissue, suggesting
a
related to measures of total, and particularly central, that influences of adipocyte-generated TNF- on in- a
obesity. sulin action occur in the interstitial compartment in
In 24 healthy Caucasian subjects subcutaneous ab- adipose tissue, and perhaps within muscle, as auto-
dominal vein cannulation was used to study adipose crine or paracrine effects.
tissue production of cytokines. Venous concentra- We conclude that circulating concentrations of the
tions of IL-6 were consistently greater than arterial proinflammatory cytokines TNF- and IL-6 are re-
a
levels both fasting and at 1, 3 and 5 h following a lated to elevated levels of both insulin resistance vari-
high carbohydrate meal but there were no significant ables and endothelial markers and may underlie the
differences in the concentration of TNF- between
a relationship between obesity and cardiovascular risk.
the abdominal venous and arterial samples. We