Chapter 11: Risk Factors for Type 1 Diabetes

CHAPTER 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%¨C5%, 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¨C2-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¨C14 Years,

1950¨C2003

Finland

Sweden

Colorado

Germany

Poland

60

Incidence per 100,000 per year

The incidence of type 1 diabetes is

increasing worldwide, by 3%¨C5% 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%¨C5% 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¨C1

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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