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Type 1 Diabetes
Table 1: Association Between Inflammatory Markers and
(interleukin-2 [IL-2], interferon-γ [INF-γ], and tumor necrosis factor-α
Complications of Type 1 Diabetes
[TNF-α]) may induce the production of pro-inflammatory cytokines in
the pancreatic islet cells, leading to beta-cell apoptosis and eventual
CVD Renal Disease Retinopathy Neuropathy
insulin deficiency, as suggested by animal studies.
36
IL-6 X
21,22,48
X
21,48
X
21,31,48
X
22
TNF-α X
21,48
X
21,30,48
X
21,29–31,63
X
22,70
In a study involving 35 children with poorly controlled type 1 diabetes
CRP X
21,24,47–50
X
21,48
X
21,31,48
X
70
and 30 age- and sex-matched controls, levels of pro-inflammatory
TNF-α RI + II X
22,33
cytokines IL-6 and TNF-α were significantly increased only among
sICAM-1 X
21
X
21
X
21
X
70
children with less than a year’s duration of type 1 diabetes, while levels
sVCAM-1 X
21
X
21
X
21
X
70
of the chemokine IL-8 were significantly increased among all children
E-selectin X
21
X
21
X
21
VEGF X
58,71
X
31
with type 1 diabetes compared with controls.
37
C-reactive protein (CRP),
IL-12 X
66 an acute-phase protein that indicates systemic inflammation, was also
IL-1β X
50 reported to be increased among children with type 1 diabetes relative to
Uric acid X
63
X
60,61
controls in this study, although the difference was not significant.
37
Fibrinogen X
70
PAI-1, t-PA X
35
X
35,72
X
34,35
X
35
Among a group of 27 children with type 1 diabetes of varying duration
and 25 healthy controls studied by Dogan et al. in Turkey, higher levelsCRP = C-reactive protein; CVD = cardiovascular disease; IL = interleukin;
PAI-1 = plasminogen activator inhibitor type 1; sICAM-1 = soluble intercellular
of pro-inflammatory cytokines IL-1β and TNF-α, but lower levels of
adhesion molecule-1; sVCAM-1 = soluble vascular cell adhesion molecule-1;
IL-2 and IL-6, were reported among children with long-standingTNF = tumor necrosis factor; t-PA = tissue plasminogen activator;
VEGF = vascular endothelial growth factor.
diabetes, as well as among those who were newly diagnosed, both
before and after treatment was initiated.
38
Increased levels of
Therefore, while hyperglycemia is a well-recognized risk factor for the inflammation (IL-1β, IL-4, and IL-6) were reported among 22 children
development of microvascular complications of type 1 diabetes, and has with hyperglycemia, but short-term improvement in glycemic control
also been associated with the development of macrovascular disease,
16,19
using intravenous insulin infusion did not reduce levels of these
improved glycemic control alone does not completely remove the risk cytokines.
39
These study results suggest that improved glycemic
of complications in patients with type 1 diabetes.
20
Furthermore, most control may not be sufficient to treat the increased inflammation in
adults and children with type 1 diabetes are unable to achieve the pediatric patients with type 1 diabetes.
optimal glycemic control that would be needed to reduce complications
further. As a result, investigators have searched for additional biomarkers In a study of 553 children with type 1 diabetes and 215 non-diabetic control
that might provide a common thread between renal disease, retinopathy, children who participated in the SEARCH for Diabetes in Youth
neuropathy, and cardiovascular disease (see Table 1). case–control study, levels of IL-6 and fibrinogen were significantly higher in
youths with type 1 diabetes than in non-diabetic youths, independent of
Low-grade Systemic Inflammation levels of hyperglycemia and body mass index (BMI).
40
In addition, levels of
and Fibrinolysis CRP were significantly higher among youths with type 1 diabetes who
Tissue damage in type 1 diabetes has been linked to abnormalities in were normal weight compared with non-diabetic youths who were normal
the inflammatory cytokine system as well as altered fibrinolysis and weight. Increased levels of inflammatory markers were associated with
coagulation.
21
Increased pro-inflammatory cytokines and acute-phase adverse lipid levels, suggesting that increased inflammation may influence
proteins have been reported to be associated with cardiovascular cardiovascular risk through promoting an atherogenic lipid profile.
disease,
22–24
and have also been implicated in the development of
diabetic nephropathy,
25–28
diabetic retinopathy,
29–32
and neuropathy.
33
Macrovascular Disease
Increased fibrinolytic capacity and coagulation factors have been CAD remains the most common cause of death for patients with type 1
associated with peripheral arterial disease, microalbuminuria, diabetes. Young adults with type 1 diabetes are at dramatically increased
retinopathy,
34
and neuropathy.
35
Therefore, in addition to the risk for CAD death, which is generally rare among individuals less than 40
established role of chronic hyperglycemia in the development of years of age in the non-diabetic population.
9
Annually, up to 2% of young
multiple complications of type 1 diabetes, increased inflammation adults with type 1 diabetes develop CAD.
41,42
By their mid-40s, over 70% of
and altered fibrinolysis may provide additional common threads in men and 50% of women with type 1 diabetes develop coronary artery
the development of diabetes complications. If this is the case, the calcification
43
—a marker of significant atherosclerotic plaque burden.
detection of excess inflammation and altered fibrinolysis may allow Autopsy studies have demonstrated that fatty streaks are present even
for the earlier prediction of diabetes complications, particularly among children,
11,12
and the extent of coronary artery plaque during
among children with type 1 diabetes, before complications typically childhood and adolescence correlates with risk factors such as cholesterol
become clinically apparent. and obesity.
44
Risk factors for CAD track from childhood to adulthood, and
so the identification of children with increased CAD risk factors presents
Inflammation in Pediatric Patients with an opportunity for primary prevention.
Type 1 Diabetes
Type 1 diabetes is an autoimmune disease characterized by a shift While cardiovascular events typically do not occur until at least the third
towards a T helper 1 (Th1) subset of T-cells. Th1 cytokine products decade of life even among patients with type 1 diabetes,
9
vascular
86 US ENDOCRINOLOGY
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