Scientists Reveal How Genetic Mutations May Cause Type 1 Diabetes

Scientists from The Scripps Research Institute have provided an answer to the 40-year-old mystery of how certain genetic mutations lead to Type 1 diabetes. This new molecular understanding could lead to novel therapies for Type 1 diabetes and other autoimmune diseases.

The study was published in an advanced, online issue of the Journal of Clinical Investigation on April 19, 2010, and will appear in the May print edition of the journal.

“People have been looking for the mechanism linking HLA and autoimmunity for 40 years,” said Scripps Research Professor Luc Teyton, who led the study with Scripps Research Professor Ian Wilson. “This study provides a big leap forward in understanding and suggests a critical new target to intervene in type 1 diabetes.”

Teyton notes that his lab has been trying to solve the mystery of autoimmune mechanisms and related conditions like celiac disease for some 25 years.

A Life-Threatening Condition

This new study focuses on Type 1, or insulin-dependent diabetes, a rapidly progressive disease of the young that leads to high blood sugar, coma, and death if not treated with replacement insulin.

Type 1 diabetes occurs when the body’s immune system attacks insulin-producing β cells in the pancreas. Without insulin, the glucose in the bloodstream increases dramatically; early symptoms are unusual thirst, increased output of urine, fatigue, and unusual hunger accompanied by weight loss.

Currently, the only therapy available is to compensate for the destruction of the body’s insulin-producing cells by injecting insulin on an ongoing basis.

While genes predispose people to many different types of diseases in many different ways, specific genetic variations are an especially strong predictor of the development of type 1 diabetes. Three genetic variations in particular (HLA-DQ2, HLA-DQ8, and HLA-DR0405)—all located in the region of the genome called HLA for “human leukocyte antigen”—are known to dramatically increase risk of coming down with the condition.

These three genes encode molecules that present peptides (protein fragments) to the body’s T cells. T cells then determine whether the peptide being presented is dangerous and needs to be eliminated from the body—as in the case of foreign invaders such as bacteria or viruses—or whether the peptide is “self,” part of the host and something the immune system needs to leave alone. However, in the context of type 1 diabetes, T cells aggressively attack the body’s own cells.

The scientists wanted to know on a molecular level how mutations in the immune surveillance machinery could lead to type 1 diabetes.

“We were interested in trying to understand why certain MHC molecules (which are molecules in mice analogous to HLA molecules in humans) are linked to autoimmune disease, particularly type 1 diabetes,” said Research Associate Adam Corper of the Wilson lab, who was first author of the paper with Kenji Yoshida of the Teyton lab. “In particular, we wanted to know why a single residue at position 57 on the β chain of HLA molecules seems to be linked to the disease.”