Type 1 Diabetes—Reaping the Rewards of a Targeted Research Investment

Judith E. Fradkin; Julie A. Wallace; Beena Akolkar; Griffin P. Rodgers

Disclosures

Diabetes. 2016;65(2):307-313. 

In This Article

Elucidating the Causes of Type 1 Diabetes

Type 1 diabetes arises through an interaction between genetic predisposition and environmental factors. The HLA region on chromosome 6p21.3 is by far the strongest genetic determinant for type 1 diabetes, accounting for about 50% of the genetic risk. Through the SDP-funded international Type 1 Diabetes Genetics Consortium (T1DGC) more than 50 additional chromosomal regions have been identified that harbor loci that confer low to moderate risk of developing type 1 diabetes.[17] This effort has made type 1 diabetes rare among polygeneic diseases in that more than 80% of the genetic risk is accounted for by known loci. Building on this success, SDP funds will support research to elucidate the specific genes and mechanisms involved, providing potential new therapeutic targets. Already an SDP-supported study found that Clec16a, a type 1 diabetes susceptibility gene, is required for normal glucose-stimulated insulin release.[18] The diabetogenic single nucleotide polymorphism reduces insulin secretion in humans, and pancreatic deletion of Clec16a alters mitochondria in islets and induces β-cell endoplasmic reticulum stress. This work uncovered an important role for mitophagy in β-cell function and a pathway that could be a therapeutic target for type 1 diabetes prevention.

New impetus for identifying environmental determinants of type 1 diabetes has come from the SEARCH study. With SDP support, the SEARCH study reported the first national surveillance data on rates of childhood diabetes. The study found that the prevalence of type 1 diabetes in people under age 20 years rose by 21% between 2001 and 2009, and the incidence of childhood type 1 diabetes increased on average 2.7% annually.[19] This increase is nearly as rapid as that seen in northern Europe and without evidence of the plateau seen after 2005 in Europe. This suggests that an environmental factor(s) contributes to disease risk. Identifying dietary, infectious, or other environmental triggers or protective factors is critical to understanding the disease process and to developing prevention strategies.

Soon after the inception of the SDP, the NIH launched The Environmental Determinants of Diabetes in the Young (TEDDY) study to identify such triggers or protective factors.[20] The availability of tests for genetic risk and assays to measure onset of autoimmunity made such a study possible. Capitalizing on this opportunity, 450,000 newborns were screened to identify and enroll over 8,000 at high genetic risk for type 1 diabetes. Participants are developing autoimmunity and type 1 diabetes at the rates predicted, with follow-up planned through age 15 years. Detailed information on diet, infections, and other environmental exposures are being analyzed. Recently, TEDDY launched case-control studies probing some of the over 2.7 million biological samples collected to date with state-of-the-art genomic, metabolomic, and proteomic technology to answer critical questions about disease etiology. It also provides an unparalleled resource to study the development of the human microbiome from birth through childhood. The detailed information collected in the study has already shed light on the pathogenesis of celiac disease, a more common condition that shares risk genes with type 1 diabetes.[21]

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