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Volume 4, Number 2, June 2007EDITORIALEndothelial dysfunction and cardiovascular disease – the lull before the storm Diabetes Vasc Dis Res 2007;4:82-83. POPULAR The endothelium releases multiple mediators, not
only regulators of vasomotor function but also
important physiological and pathophysiological
inflammatory mediators. Endothelial dysfunction is
caused by chronic exposure to various stressors such as
oxidative stress and modified low-density lipoprotein
(LDL) cholesterol, resulting in impaired nitric oxide (NO)
production and chronic inflammation. Biomechanical
forces on the endothelium, including low shear stress
from disturbed blood flow and hypertension, are also
important causes of endothelial dysfunction. These
processes seem to be augmented in patients with diabetes.
In states of insulin resistance and in type 2 diabetes
insulin signalling is impaired. Increased vascular
inflammation, including enhanced expression of interleukin-
6 (IL-6), vascular cellular adhesion molecule-1
(VCAM-1) and monocyte chemoattractant protein (MCP-
1) are observed, as is a marked decrease in NO bioavailability.
Furthermore, hyperglycaemia leads to increased
formation of advanced glycation end products (AGE),
which quench NO and impair endothelial function. Diabetes Vasc Dis Res 2007;4:84-88. POPULAR Endothelial dysfunction is universal in diabetes, being
intimately involved with the development of cardiovascular
disease. The pathogenesis of endothelial dysfunction
in diabetes is complex. It is initially related to the
effects of fatty acids and insulin resistance on ‘uncoupling’
of both endothelial nitric oxide synthase activity and mitochondrial
function. Oxidative stress activates protein kinase
C (PKC), polyol, hexosamine and nuclear factor kappa B
pathways, thereby aggravating endothelial dysfunction.
Improvements in endothelial function in the peripheral
circulation in diabetes have been demonstrated with
monotherapies, including statins, fibrates, angiotensinconverting
enzyme (ACE) inhibitors, metformin and fish
oils. These observations are supported by large clinical
end point trials. Other studies show benefits with certain
antioxidants, L-arginine, folate, PKC-inhibitors, peroxisome
proliferator activated receptor (PPAR)-α and -γ agonists
and phosphodiesterase (PDE-5) inhibitors.
However, the benefits of these agents remain to be shown
in clinical end point trials. Combination treatments, for
example, statins plus ACE inhibitors and statins plus
fibrates, have also been demonstrated to have additive
benefits on endothelial function in diabetes, but there are
no clinical outcome data to date. Diabetes Vasc Dis Res 2007;4:89-102. POPULAR The structural and functional integrity of the vascular endothelium plays a critical role in vascular homeostasis. Insulin resistance, an important risk factor for cardiovascular disease, is thought to promote atherosclerosis through a reciprocal relationship with endothelial dysfunction. In health, cumulative damage to endothelial cells incurred by exposure to risk factors is mitigated by endogenous reparative processes. Disruption of the balance between endothelial damage and repair may mediate atherosclerotic progression. Bone marrow-derived ‘endothelial progenitor cells’ (EPC) have been identified as significant contributors to endogenous vascular repair. Insulin resistance is associated with a spectrum of biochemical abnormalities which have the potential to reduce the availability of EPCs and diminish their capacity for vascular repair. Many lifestyle and pharmacological interventions which improve insulin resistance also increase the numbers and functionality of EPCs. Cell-based therapies may also hold promise for the prevention and treatment of cardiovascular disease. Diabetes Vasc Dis Res 2007;4:103-111. POPULAR In most developed and developing countries, the proportion
of the population aged 60 years or more is growing
faster than any other age group. Given that the vast majority
of cardiovascular events occur in older individuals,
new thinking is needed to reduce their risk. Epidemiological
studies have shown an increasing prevalence of the metabolic
syndrome with age, driven by nutrition inappropriate
for a modern sedentary lifestyle. A low level of high-density
lipoprotein (HDL)-cholesterol, a component of the atherogenic
dyslipidaemia of the metabolic syndrome, has been
shown to be an important determinant of coronary risk, which
rises in prevalence with increasing age. Thus, raising HDLcholesterol,
in addition to lowering the level of low-density
lipoprotein (LDL)-cholesterol, seems a plausible approach to
reduce cardiovascular risk in an ageing population. Diabetes Vasc Dis Res 2007;4:136-142. POPULAR Elevated homocysteine (HCY) levels can be caused by
a number of factors, including folate and B-vitamin
deficiency, pre-existing atherosclerotic disease, diabetes
and various drugs. Epidemiological evidence, as
well as data from retrospective and prospective studies,
supports an association between elevated HCY levels and
increased risk of cardiovascular disease (CVD). However,
whether lowering HCY levels by administration of folate
and vitamins B6 and B12 is associated with any significant
decrease in vascular risk remains the subject of ongoing
debate. Although the major studies that have reported to
date show that vitamin supplementation was associated
with a decrease in HCY levels, this failed to have any significant
effect on cardiovascular risk. Furthermore,
although some lipid-modifying treatments have been
shown to increase HCY levels, there is no evidence that
this attenuates or compromises the beneficial effects of
such treatments on cardiovascular risk. Diabetes Vasc Dis Res 2007;4:143-150. POPULAR Roux-en-Y bypass surgery is increasingly used for treatment of gross obesity due to the general inability of lifestyle change and existing drug treatments to counter the obesity epidemic. This common form of bariatric surgery involves bypass of the small intestine with significant reduction of body of weight that is independent of malabsorption. Strikingly, obesity-related diabetes is also cured by the procedure but prior to body weight loss. This is due to rapid improvement of insulin resistance and associated pancreatic beta-cell function. Several hypotheses have been proposed to account for this phenomenon, but the most attractive concerns surgical ablation of gastric inhibitory polypetide (GIP)-secreting intestinal K-cells. Thus, circulating GIP levels are decreased after Roux-en-Y bypass surgery and GIP is known to play a key role in lipid metabolism and fat deposition. Further, both genetic and chemical ablation of GIP in animal models has been shown to protect against obesity and associated metabolic disturbances. These observations in animals and man suggest that GIP receptor antagonism may afford an alternative therapeutic option for treatment of obesity-diabetes. Diabetes Vasc Dis Res 2007;4:151-153. ORIGINAL PAPEROnly a minority of patients referred for elective coronary artery bypass surgery
have risk factors diagnosed and treated according to established guidelines Patients deserve to be medically optimised for treatment
of metabolic risk factors and hypertension
before referral for elective coronary artery bypass
grafting (CABG). We describe here a prospective study of
347 consecutive patients referred for elective CABG. An
oral glucose tolerance test (OGTT) was performed and
metabolic risk factors and hypertension were determined
pre-operatively. Compliance to treatment guidelines was
calculated. Diabetes Vasc Dis Res 2007;4:112-116. ORIGINAL PAPERThiazolidinediones inhibit the progression of established hypertension in the Dahl
salt-sensitive rat We evaluated the effects of two thiazolidinediones
(TZDs), the potent PPARγ agonist rosiglitazone
currently being used to treat diabetes, and a
structurally similar experimental compound that is a poor
PPARγ agonist, in a non-diabetic, established hypertension
model with continuous measurement of blood pressure by
telemetry. Hypertension was induced in male Dahl saltsensitive
rats by a three-week pre-treatment with 4% salt
before initiation of treatment. Fasting blood samples were
taken for analysis of a biomarker panel to assess metabolic,
anti-inflammatory and antioxidant activity of the treatments.
Both TZDs significantly reduced both systolic and
diastolic blood pressure. When used at the maximally
effective doses established for metabolic improvement,
both compounds produced equivalent reduction in lipids
and elevation of adiponectin, yet the poorer PPARγ agonist
produced significantly greater reductions in blood pressure.
Neither compound had a significant effect on circulating
glucose or insulin in this animal model. Diabetes Vasc Dis Res 2007;4:117-123. ORIGINAL PAPERThe ApoAI-CIII-AIV gene cluster and its relation to lipid levels in type 2 diabetes
mellitus and coronary heart disease: determination of a novel susceptible haplotype The present study investigated genetic variation in the
3’ flanking region of ApoA-I (PstI), the 3’ untranslated
region of ApoC-III (SstI) and intron 2 of ApoA-IV (XbaI)
in 435 type 2 diabetes mellitus patients, divided according
to the presence or absence of coronary heart disease
(CHD). Uncommon allele frequencies (P2, S2, X2) were
17.5%, 32.5%, 16.2% and 29.5%, 17.9%, 13.8% in patients
with and without CHD, respectively. Linkage disequilibrium
(D’ = 0.31–0.73, p<0.01) was observed in all diallelic pairs
except XbaI/PstI and XbaI/SstI in patients having CHD.
Haplotype analysis revealed that P1-S2-X1 is a susceptibility
haplotype that increases the risk of CHD in diabetes (OR
2.85, CI 1.51–5.61), exacerbating risk (OR 3.57, CI
1.81–7.45) even after adjustment for confounders. Diabetes Vasc Dis Res 2007;4:124-129. ORIGINAL PAPERInsulin resistance is an independent risk factor for atherosclerosis in rheumatoid
arthritis The objective of this study was to investigate the relationship
between insulin resistance (IR) and subclinical
atherosclerosis in patients with rheumatoid
arthritis (RA).
Carotid artery intima media thickness (IMT), using
ultrasound evaluation, and other clinical and laboratory
variables were investigated in 45 RA outpatients and in
48 controls with soft tissue disorders. IR was assayed by
homeostasis model assessment (HOMA2) and metabolic
syndrome by National Cholesterol Education Program
Adult Treatment Panel (NCEP ATP III) criteria. Diabetes Vasc Dis Res 2007;4:130-135. LETTERThe streptozotocin-treated Sprague-Dawley
rat: a useful model for the assessment of
acute and chronic effects of myocardial
ischaemia reperfusion injury in experimental
diabetes Diabetes Vasc Dis Res 2007;4:153-155. MEDICINE & MEDIARosiglitazone and cardiovascular disease: a diabetologist’s perspective Diabetes Vasc Dis Res 2007;4:75-76. MEDICINE & MEDIARosiglitazone and cardiovascular disease: an epidemiologist’s perspective Diabetes Vasc Dis Res 2007;4:77-79. MEDICINE & MEDIARosiglitazone and cardiovascular disease: a cardiologist’s perspective Diabetes Vasc Dis Res 2007;4:80-81. |
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