This page contains a Flash digital edition of a book.
Dabelea_edit_Cardiology_book_temp 22/12/2009 10:52 Page 87
Inflammation in Pediatric Patients with Type 1 Diabetes—An Early Predictor of Complications?
changes and cardiometabolic abnormalities have been detected in Based on the evidence of associations between chronic inflammation
childhood. A German study of over 27,000 children and young adults and cardiovascular disease in adults as well as vascular abnormalities in
with type 1 diabetes found high rates of cardiovascular risk factors, and youths with type 1 diabetes, it is possible that elevated inflammatory
inadequate treatment.
45
Endothelial function, a marker for vascular markers in childhood could predict the development of cardiovascular
changes associated with atherosclerosis, is impaired in children with disease later in life.
type 1 diabetes.
46
Carotid intima-media thickness (CIMT), a marker for
the development of plaque and atherosclerosis, is also increased Renal Function and Diabetic Nephropathy
among children and youths with type 1 diabetes.
47
Nearly 25% of type 1 diabetes patients develop end-stage renal disease
(ESRD),
51
and renal disease increases the risk of cardiovascular disease
Chronic low-grade inflammation has been shown to precede the and premature mortality.
52,53
The conventional theory is that the
development of atherosclerosis, and is a likely initiator of atherosclerotic sequence of events leading to diabetic nephropathy (DN) begins from
plaque development. In a study examining CIMT in 148 youths and young microalbuminuria, progressing to overt proteinuria and eventual
adults with type 1 diabetes compared with obese (n=86) and normal- reduction of glomerular filtration rate (GFR) and ESRD. Primary
weight (n=142) controls, both CRP and CIMT were increased in patients prevention of renal disease with angiotensin-converting enzyme (ACE)
with type 1 diabetes, and there was a significant association between inhibitor/angiotensin receptor blocker (ARB) treatment usually begins
higher levels of CRP and increased CIMT, indicating that systemic when persistent microalbuminuria is found. However, recent
inflammation may be responsible for the increased macrovascular prospective studies using serial measurements of GFR estimated from
disease in young patients with type 1 diabetes.
24
serum cystatin C (cysGFR) have changed this paradigm by
demonstrating that the decline in GFR may begin in the absence of
A cross-sectional report from the European Diabetes (EURODIAB) microalbuminuria or continue despite remission of microalbuminuria.
54,55
Prospective Complications Study Group examined whether inflammatory Furthermore, by the time patients with type 1 diabetes have developed
markers were associated with cardiovascular disease, defined as a microalbuminuria, there are already structural changes in the kidney,
56
cardiovascular event (myocardial infarction, coronary artery bypass graft, suggesting that subclinical renal damage occurs for a period of time
stroke), angina, or ischemic changes on electrocardiogram (ECG). A prior to the development of microalbuminuria, and could potentially be
combined risk score using CRP, IL-6, and TNF-α was associated with detected using novel biomarkers, leading to earlier intervention.
cardiovascular disease even when adjusted for age, sex, glycemic
control, diabetes duration, and blood pressure.
48
In an investigation of CRP levels and microalbuminuria in the Oxford
Regional Prospective Study, 49 youths (mean age 15.3 years) with type
Similarly, among 55 young adults (mean age 22.1±3.6 years) with type 1 1 diabetes who developed microalbuminuria were compared with 49
diabetes evaluated in Osaka, Japan, elevated CRP and fibrinogen levels normoalbuminuric subjects; CRP levels increased among subjects
and greater CIMT were reported compared with 75 healthy controls.
49
CRP who developed microalbuminuria.
57
In the EURODIAB Prospective
levels were significantly correlated with both mean and maximum CIMT in Complications Study, systemic inflammation, as evidenced by a
univariate correlation analysis and multivariate regression modeling. combined risk score using CRP, IL-6, and TNF-α levels, was associated
with albuminuria, as well as other complications of type 1 diabetes
An association has been reported between higher levels of inflammation (CAD and retinopathy).
48
Inflammatory cytokines are cleared through
and higher levels of lipids, suggesting that the effect of inflammation on the kidney, so reduced glomerular filtration may lead to higher plasma
cardiovascular risk may be at least partially mediated through levels of these factors. As a result, it is unclear whether the increased
dyslipidemia. In a study of 69 children with type 1 diabetes and 74 age- inflammation observed in association with renal disease simply
matched healthy controls under 22 years of age, children with type 1 represents a marker of decreased glomerular filtration.
diabetes were reported to have higher levels of CRP, and IL-1β was higher
among newly diagnosed children with type 1 diabetes.
50
A negative Vascular endothelial growth factor (VEGF) is a cytokine that promotes
correlation was reported between IL-1β levels and lipids, including total angiogenesis and also regulates vascular permeability. Increased VEGF
and low-density lipoprotein (LDL) cholesterol and triglycerides. has been reported to predict the development of persistent
microalbuminuria.
58
Higher levels of VEGF have been reported in a group
Potential mechanisms through which increased inflammation may of 196 children with type 1 diabetes compared with 223 age- and sex-
mediate the development of atherosclerosis include the build-up of matched controls without diabetes, and VEGF concentrations were
AGEs due to chronic hyperglycemia, which may activate macrophages. correlated with HbA
1c
and severity of microvascular complications.
59
Furthermore, hyperglycemia may induce oxidative stress. Stressed
vascular endothelial cells may release chemokines, increasing factors Uric acid is increased in renal disease, but more recently variation in uric
such as intracellular adhesion molecule-1 (ICAM-1), vascular cell acid even in the normal range has been reported to be associated with
adhesion molecule-1 (VCAM-1), and E-selectin. Pro-inflammatory genes reduced glomerular filtration rate.
60
A prospective study of uric acid
may then be activated, leading to increased secretion of IL-6, TNF-α, levels found that high normal uric acid levels predict the development
IL-18, IFN-γ, and other cytokines. In addition, macrophages and of microalbuminuria in patients with type 1 diabetes.
61
Uric acid may
endothelial cells may increase plasminogen activator inhibitor-1 (PAI-1) induce endothelial dysfunction
62,63
and can be considered a pro-
and tissue plasminogen activator (t-PA) expression, leading to higher inflammatory agent, and therefore may induce renal complications
levels of fibrinogen and factor VIII and a procoagulant state. through inflammatory pathways.
US ENDOCRINOLOGY 87
Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84  |  Page 85  |  Page 86  |  Page 87  |  Page 88  |  Page 89  |  Page 90  |  Page 91  |  Page 92  |  Page 93  |  Page 94  |  Page 95  |  Page 96  |  Page 97  |  Page 98  |  Page 99  |  Page 100  |  Page 101  |  Page 102  |  Page 103  |  Page 104  |  Page 105  |  Page 106  |  Page 107  |  Page 108  |  Page 109  |  Page 110  |  Page 111  |  Page 112  |  Page 113  |  Page 114  |  Page 115  |  Page 116  |  Page 117  |  Page 118  |  Page 119  |  Page 120  |  Page 121  |  Page 122  |  Page 123  |  Page 124
Produced with Yudu - www.yudu.com