Chapter 11: Risk Factors for Type 1 Diabetes
嚜澧HAPTER 11
RISK FACTORS FOR TYPE 1 DIABETES
Marian Rewers, MD, PhD, Lars C. Stene, PhD, and Jill M. Norris, MPH, PhD
Dr. Marian Rewers is Professor of Pediatrics and Medicine at the Barbara Davis Center for Childhood Diabetes, University of Colorado
School of Medicine, Aurora, CO. Dr. Lars C. Stene is Senior Scientist at the Department of Child Health, Norwegian Institute of Public Health,
Oslo, Norway. Dr. Jill M. Norris is Professor of Epidemiology at the Colorado School of Public Health, University of Colorado, Aurora, CO.
SUMMARY
The incidence of type 1 diabetes is increasing at an annual rate of 3%每5%, which suggests a major environmental exposure has changed,
by either the gradual introduction of a susceptibility factor or the removal of a protective factor, during the past 60 or more years.
Outbreaks and seasonality of type 1 diabetes may suggest an infectious cause, perhaps related to increasing sanitation and loss of herd
immunity. Early childhood diet and environmental toxins are also of interest.
Prospective studies following high-risk children from birth to development of the subclinical phase of the disease (islet autoimmunity)
and diabetes have been the most reliable source of information regarding risk factors for type 1 diabetes. Prenatal and early postnatal exposures appear to be critical, as the incidence of islet autoimmunity peaks in the second year of life. Among the infectious
agents, enteroviral infections (particularly if they are persistent and acquired in early childhood) have gained most interest. Early leads
suggesting the role of cow*s milk exposure in the initiation of islet autoimmunity have not been confirmed by large prospective studies
and a large randomized clinical trial. While numerous studies have reported 1.5每2-fold increases in the risk of islet autoimmunity or
type 1 diabetes with various components of early childhood diet and infectious exposures, none of the associations appears particularly
strong or universal across different populations.
In the United States, 1 in 300 children and adolescents develop type 1 diabetes by age 20 years, but 1 in 40 offspring of mothers with
type 1 diabetes and 1 in 15 offspring of fathers with type 1 diabetes develop type 1 diabetes. The disease is likely caused by the interplay of genetic and environmental factors. Systematic investigation of gene-environment interactions in large, prospectively followed
cohorts of young children may help to identify and fully characterize modifiable risk factors and design trials to fully evaluate the strongest candidate triggers of autoimmunity.
INTRODUCTION
Received in final form December 27, 2015.
FIGURE 11.1. Incidence of Type 1 Diabetes Per 100,000 Per Year in Children Age 0每14 Years,
1950每2003
Finland
Sweden
Colorado
Germany
Poland
60
Incidence per 100,000 per year
The incidence of type 1 diabetes is
increasing worldwide, by 3%每5% annually
(1), with rates doubling every 20 years
(2,3). The rising incidence, outbreaks (4),
and a seasonal pattern (5) may suggest
that infectious agents play a role in the
pathogenesis. However, the incidence has
been increasing since at least the 1950s
(Figure 11.1) (2,3,6,7,8,9,10,11). Such a
secular trend is unlikely to result from a
new infectious agent; however, similar to
the polio model (12), an ※old§ microbe
could express its diabetogenic effect due
to increasing hygiene and decreasing herd
immunity. Changes in early childhood
diet have also been implicated, as type
1 diabetes has increased the most in the
youngest children. Prospective studies
(13,14,15) following high-risk children from
birth have made important inroads into
the understanding of the role of infectious
45
30
15
0
1950
1960
1970
1980
1990
2000
Type 1 diabetes incidence is increasing 3%每5% per year and has doubled every 20 years.
SOURCE: Reference 11. Data for Finland are from the Finnish National Public Health Institute (3); data for Sweden
are from the Swedish Childhood Diabetes Registry (6); data for Colorado are from the Colorado IDDM Registry,
the Barbara Davis Center for Childhood Diabetes, and SEARCH for Diabetes in Youth (2,7); data for Germany are a
compilation of two reports (8,9); data for Poland are from seven regional registries (10).
11每1
DIABETES IN AMERICA, 3rd Edition
and dietary factors in type 1 diabetes.
Prospective studies have defined two
major steps in the pathogenesis of type
1 diabetes (Figure 11.2). Seroconversion
to positivity for one or more islet autoantibodies (to insulin, glutamic acid
decarboxylase [GAD], insulinoma antigen
2 [IA-2], or zinc transporter 8 [ZnT8])
marks the development of islet autoimmunity. Approximately 70% of children
positive for two or more of these autoantibodies develop diabetes in 10 years
following the appearance of the first autoantibody (16). In contrast, most children
persistently positive for only one islet autoantibody do not progress to diabetes (16).
Data suggest that a variety of exposures
may trigger islet autoimmunity, promote
progression to clinical diabetes, or affect
both of these steps.
Most of the existing data concerning risk
factors for islet autoimmunity and type
1 diabetes have come from a handful of
prospective studies that have sometimes
generated inconsistent results. While the
large international prospective cohort
study (The Environmental Determinants of
FIGURE 11.2. Two-Step Model of Type 1 Diabetes Development and Potential Role of
Environmental Factors
TRIGGERS:
virus? diet?
PROMOTERS:
virus? diet?
Islet autoimmunity (IA):
Genetic
susceptibility
PERSISTENT autoantibodies
to insulin, GAD, IA-2, or ZnT8
Clinical
Diabetes
GAD, glutamic acid decarboxylase; IA-2, insulinoma antigen 2; ZnT8, zinc transporter 8.
SOURCE: Original figure constructed by M. Rewers.
Diabetes in the Young [TEDDY]) will likely
reconcile some of the inconsistencies,
randomized clinical trials of risk factor
modifications will provide the ultimate test.
Type 1 diabetes is caused by the interplay
of genetic and environmental factors.
The genetics of type 1 diabetes is
reviewed in depth in Chapter 12 Genetics
of Type 1 Diabetes and only briefly
summarized in the following section.
In this chapter, infectious, dietary, and
other environmental factors are reviewed
in detail, as well as potential gene-environment interactions in type 1 diabetes
etiology.
GENETIC FACTORS
FAMILY HISTORY OF
TYPE 1 DIABETES
In the United States, approximately 1 in
300 children and adolescents develop
type 1 diabetes by age 20 years (Table
11.1) (2,17). The risk is increased to about
1 in 40 in offspring of mothers with type 1
diabetes and 1 in 15 in offspring of fathers
affected by type 1 diabetes; the reason
for this difference may have an epigenetic origin. The risk to siblings of type 1
diabetes individuals ranges from 1 in 12
to 1 in 35 (18,19). The risk is significantly
higher in siblings of individuals diagnosed
at age ................
................
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