Diabetes, a rising epidemic

Diabetes mellitus is a lifelong disease of high levels of sugar in the blood. Diabetes affects over 20 million Americans. Over 40 million Americans have prediabetes and the incidence of this disease is increasing every year. The disease is characterized by any combination of the pancreas dysfunction (not making enough insulin), cells’ inability to respond to insulin normally, and the body’s inability to move sugar into the fat, liver, and muscle cells for energy storage. There are three types of diabetes:

Type I: can occur at any age, but most often diagnosed in young children, teens or young adults. This is an autoimmune disease characterized by the immune system T lymphocytes destroying the beta cells (insulin secretors) of the pancreatic islet.

Type II: is generally adult-onset and makes up the majority of diabetics. There is an increasing incidence of the onset of Type II in young children, teens, and young adults because of an increasingly high rate of obesity.

Gestational diabetes: high blood sugar of the mother developing during pregnancy

Diabetes can be tested by urine analysis for high blood content, fasting blood glucose test, hemoglobin A1c, and an oral glucose tolerance test.

The autoimmune response is detectable in type I diabetes (T1D) by screening for autoantibodies. Autoantibodies are detectable pre-diagnosis in the months or years preceding clinical disease. Studies by various labs around the world indicate that the disease can be diagnosed by the presence of two or more of the autoantibodies (some are beta cell specific) to glutamate decarboxylase (GAD65), insulin, islet antigen (IA-2) and zinc transporter 8 (ZnT8). These are biomarkers or indicators of beta cell destruction. T-lymphocytes mediate the beta cell destruction. They receive signals from antigen presenting cells, such as dendritic cells and macrohpages and receive help from B-lmphocytes to initiate a complete immunological response. This results in impairment of beta cell function, progressive destruction of beta cells, and consequently the development of T1D. Throughout progression of disease these autoantigens undergo epitope spreading, leading to an increase in antigenic determinants.

Thus the goal of many studies is to understand the etiology of T1D and design methods to intervene the immunological response before disease onset. Autoantigens thus far identified include GAD65, insulin, IA-2, ZnT8, Chromagranin A, and Insulin amyloid peptide (IAPP).

ZnT8 was recently discovered in the lab of John Hutton of the Barbara Davis Diabetes Center and is a major target of humoral and cell-mediated autoimmunity. ZnT8, like insulin and islet-specific glucose 6 phosphatase related protein (IGRP) are found in the pancreatic beta cell and is more restricted in its tissue distribution than other autoantigens. Goals in the lab include ZnT8 autoantibody prevalence (wildtype and polymorphisms have been identified), antibody titer, epitope specificity pre and post-diabetes onset, relationship to C-peptide responses, and effects on insulin secretion and beta cell function. From an immunological point of view, we are interested in specificity of T cell and B cell responses and identifying specific T cell and B cell clones.

http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002194/

Skyler JS. Immune intervention for type 1 diabetes mellitus. Int J Clin Pract Suppl. 2011, (170):61-70.

Wenzlau JM, Walter M, Gardner TJ, Frisch LM, Yu L, Eisenbarth GS, Ziegler AG, Davidson HW, Hutton JC. Kinetics of the post-onset decline in zinc transporter 8 autoantibodies in type 1 diabetic human subjects. J Clin Endocrinol Metab. 2010, 95(10):4712-9.