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Type 1 Diabetes
Diabetic Retinopathy fructose deposition in nerve cells, and increased inflammatory cytokines
Retinopathy is a progressive disease that begins with non-reversible leading to nerve degeneration.
microaneurysms and can lead to proliferative retinopathy. Diabetic
retinopathy is the leading cause of blindness, and leads to substantial One of the earliest signs of CAN is reduced response of the heart rate to
healthcare costs. The Wisconsin Epidemiologic Study of Diabetic respiration, referred to as low heart rate variability (HRV). Among 120
Retinopathy followed 995 patients with insulin-dependent diabetes for 25 patients with type 1 diabetes of 14 years’ duration on average, lower
years, and found a cumulative rate of retinopathy progression of 83%.
64
HRV was associated with higher levels of serum IL-6.
22
Additional
inflammatory markers, including CRP, TNF-α, fibrinogen, leptin,
Hyperglycemia has been established as a risk factor for retinopathy, and osteoprotegerin, soluble E-selectin, soluble VCAM (sVCAM), and soluble
intensive treatment in the DCCT reduced the incidence of retinopathy ICAM (sICAM), have been reported to be associated with both
by 76% among those without any evidence of retinopathy at symptomatic and asymptomatic neuropathy,
70
and higher levels of
randomization.
65
After a decade of follow-up in the EDIC study, those TNF-α receptors have been reported in patients with type 1 diabetes
patients who received intensive insulin therapy during the DCCT and neuropathy compared with patients with type 1 diabetes who are
experienced more than a 50% reduction in retinopathy progression, free from neuropathy.
33
Therefore, while hyperglycemia is a significant
despite the convergence of HbA
1c
in the DCCT treatment groups during risk factor for diabetic neuropathy, systemic inflammation also plays a
the follow-up.
18
The results of the DCCT and EDIC studies have clearly role in both central and peripheral neuropathy. Inflammation may
shown that hyperglycemia is a strong predictor of retinopathy incidence influence neuropathy through mediating the effect of elevated glucose
and progression, with an apparent ‘metabolic memory’ that continues to levels and through independent mechanisms leading to nerve damage.
reduce the risk for up to a decade after a return to moderate glycemic
control (mean HbA
1c
8%). Inflammation—The Common Thread of
Multiple Diabetic Complications?
In the EURODIAB Prospective Complications Study, a combined risk score Over the past few decades, our understanding of the role of hyperglycemia
using CRP, IL-6, and TNF-α levels was associated with the development of has expanded, and improved treatment has led to impressive strides in the
multiple complications of type 1 diabetes, including retinopathy.
48
An control of blood glucose levels. Improved glycemic control has been
additional cross-sectional study found that levels of TNF-α, IL-6, and definitely shown to reduce the complications of type 1 diabetes, including
VEGF were higher in 39 children with early evidence of retinopathy than retinopathy, nephropathy, and neuropathy, with more modest evidence for
in 163 children without retinopathy.
31
In addition to higher levels of decreased macrovascular disease. Despite these improvements, however,
TNF-α,
29
the relative levels of TNF-α and IL-12, a T-cell stimulator and anti- a significant risk of complications remains.
angiogensis cytokine, respectively, have been associated with the
presence of retinopathy in children with type 1 diabetes.
66
Increased systemic inflammation and altered fibrinolysis and coagulation
are commonly reported in patients with type 1 diabetes, and often
Neuropathy precede the development of complications. Cross-sectional associations
Diabetic neuropathy may develop in the peripheral and autonomic between inflammatory cytokines and markers of fibrinolysis with both
nervous system, leading to significant morbidity and increased mortality. microvascular and macrovascular complications have been found, and
One of the more serious manifestations of neuropathy in patients with there is clustering of complications among patients with type 1 diabetes,
type 1 diabetes is cardiac autonomic neuropathy (CAN). While symptoms suggesting common threads. Limited prospective data are available
of neuropathy are uncommon in childhood, the prevalence of linking inflammation with the development of early complications in the
asymptomatic neuropathy in adolescents was 57% in a study that pediatric population, so this remains an important area of investigation
carefully assessed patients using a series of electrophysiological for new biomarkers and predictors. n
evaluations
67
and 59% in a study of 80 youths between seven and 22 years
of age with at least three years of diabetes duration.
68
In the DCCT study,
Janet K Snell-Bergeon, PhD, MPH, is an Assistant
diabetic neuropathy prevalence was 46% in conventionally treated
Professor of Pediatrics at the Barbara Davis Center for
participants and 26% in intensively treated particpants.
69
In addition, Childhood Diabetes at the University of Colorado
neuropathy tends to occur in patients with other microvascular
Denver. She is a member of the American Heart
Association (AHA) and the American Diabetes
complications, including retinopathy and microalbuminuria. It is therefore
Association (ADA). Dr Snell-Bergeon completed an MPH
likely that common mechanisms underlie the development of subclinical at the Columbia School of Public Health in 1997, and
neuropathy, atherosclerosis, early renal disease, and retinopathy.
earned her PhD in epidemiology at the University of
Colorado Denver in 2007.
The etiology of diabetic neuropathy is poorly understood, and is likely
Dana Dabelea, MD, PhD, is an Associate Professor with
complex. Hyperglycemia is implicated in the development of autonomic
tenure in the Department of Epidemiology at Colorado
dysfunction and defects in peripheral nerve conduction, and improved
School of Public Health and Director of the Epidemiology
glycemic control reduces the risk of developing neuropathy.
69
However,
Doctoral Program at the University of Colorado Denver.
An expert in the area of pediatric diabetes epidemiology,
subclinical neuropathy is common even among youths with good
her experience also includes peri-natal and childhood
glycemic control from the time of their diabetes diagnosis.
68
Among
epidemiological studies with community-based and
potential biological mechanisms that have been proposed to cause
clinic-based sampling and longitudinal follow-up.
neuropathy independently of hyperglycemia are excess sorbitol and
88 US ENDOCRINOLOGY
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