Diabetes Mellitus Expanded Evaluation

Introduction

Hi, I’m Matt Binnicker, the Director of Clinical Virology and Vice Chair of Practice in the Department of Laboratory Medicine and Pathology at Mayo Clinic. Did you know that more than 29 million Americans live with diabetes, and it remains one of the leading causes of death in the United States? Well, because of the significance of this disease, it’s important that we identify patients as early as possible, and in this month’s Hot Topic, my colleague, Dr. Andrew McKeon, will provide you with valuable information regarding the utility of antibody testing for the diagnosis of type 1 diabetes. I hope you enjoy this month’s Hot Topic, and I want to personally thank you for allowing Mayo Medical Laboratories the opportunity to be a partner in your patients’ healthcare.

In this Hot Topic presentation, I am going to discuss the diabetes mellitus evaluation in serum, which has been updated to include the Zinc Transporter 8 Antibody (ZnT8 Ab).

My name is Dr. Andrew McKeon.  I am a Co-Director of the Neuroimmunology Lab and Professor of Neurology, Associate Professor of Laboratory Medicine and Pathology at Mayo Clinic in Rochester, Minnesota.  Although we are primarily a neuroimmunology lab, we also have a long-standing commitment to serological diagnoses in type 1 diabetes.

Disclosures

Here are here are my disclosures.

Objective

The objective of this presentation is to describe the utility of antibody testing for the diagnosis of type 1 diabetes mellitus and to review the Mayo Clinic diabetes mellitus evaluation of serum, including the newly added Zinc Transporter 8 Antibody.

DM1

Type 1 diabetes mellitus or type 1 diabetes accounts for most juvenile-onset diabetes mellitus and some adult cases.  Antibodies can be detected in these patients to make a diagnosis and can even be detected in some patients before they become symptomatic, particularly in patients who are relatives of those with diabetes mellitus.  This testing was traditionally done by an immunofluorescence assay by looking for an antibody binding to human pancreas, but this had relatively limited sensitivity.

Four Antigens Recognized

Nowadays, 4 specific antigens are recognized, and antibodies targeting these antigens can be tested for in clinical laboratories to make a diagnosis of type 1 diabetes.  These include glutamic acid decarboxylase, 65 kilodalton isoform (also known as GAD65 antibody), insulin; insulinoma-associated protein 2 or IA-2, Zinc Transporter 8. These antibody tests have all been validated internationally as being sensitive and specific for type 1 diabetes.

How Are Abs Detected?

How are the antibodies detected?  Well in various labs, mainly people use either immunoprecipitation assays or ELISA assays.  At Mayo Clinic, for GAD65, insulin, and IA-2 antibodies, we use immunoprecipitation assays; while for Zinc Transporter 8 Antibodies, we use an ELISA assay.  These antibody tests should be positive in patients with type 1 diabetes and should be negative in patients with other diabetes type, most commonly type 2 diabetes due to insulin resistance.

Orderable as…

These antibodies are orderable as individual antibodies, GAD65, insulin, IA-2, Zinc Transporter 8, or as a profile where all 4 antibodies are tested for.

Utility

Now onto a little bit about utility.  These antibodies are detectable in most patients with type 1 diabetes.  At least 1 of them shall be detectable in over 90% of patients with type 1 diabetes.  Most patients have 3 or 4 of these antibodies detectable.  They can aid in the distinction of type 1 diabetes, autoimmune diabetes from type 2 diabetes.  These antibody tests can also aid in the stratification of patients with gestational diabetes for future diabetes risk; meaning that if a woman becomes diabetic or hyperglycemic during pregnancy, what are the chances of the patient, after pregnancy when the diabetes should resolve, may eventually go on to develop diabetes or have persisting diabetes after pregnancy.  This testing may also aid in risk assessment in close relatives of those with type 1 diabetes.

Adults: Distinguishing DM1 & DM2

These autoantibody tests also have utility in adults with diabetes.  Autoimmune type 1 diabetes in adults may appear like juvenile type 1 diabetes and lean patients with rapid weight loss, but also may mimic type 2 diabetes and may be slowly progressive, such as those with latent autoimmune diabetes of adulthood.  However, antibody-positive patients, overall, tend to be leaner than the average adult diabetic.  These patients are more likely to require insulin therapy and to require it sooner than patients with typical type 2 diabetes and very often have a higher HbA1C at presentation.

Children, Young Adults: Diabetes of Uncertain Type

The utility of this antibody testing in children is very useful for distinguishing type 1 diabetes, which is the most common type, from diabetes of other types in children.  This is particularly true in those children that are overweight, present in ketoacidosis, and when the clinician is trying to figure out is this maturity-onset diabetes of the young versus autoimmune type 1 diabetes.

Gestational Diabetes

Among pregnant patients, antibody positivity will predict future development of diabetes outside of pregnancy; and the more antibodies that are positive, the greater the risk.  For example, if there are more than 2 antibodies positive, approximately 60% of those patients will develop type 1 diabetes within 2 years of the pregnancy where gestational diabetes developed.

Predicting Type 1 Diabetes

Then also the antibody testing can be useful in trying to predict the onset of diabetes of autoimmune type in first-degree relatives of those with autoimmune diabetes.  The more antibodies that are positive in these patients, the higher the risk of developing type 1 diabetes within 5 years.  As you can see, this would stretch from 2% for 1 antibody positive up to about 70% for those with 4 antibodies positive.

Diabetes Mellitus Evaluation

Just to recap on the evaluation itself, each antibody is orderable individually; but in our comprehensive diabetes mellitus evaluation, all 4 antibodies are tested for in all circumstances.

Conclusions

In conclusion, serum antibody testing for type 1 diabetes can aid: distinction of autoimmune type 1 diabetes from type 2 diabetes, prediction of future insulin needs, prediction of diabetes after gestational diabetes, and prediction of risk for type 1 diabetes among close relatives of patients with type 1 diabetes.

Here are some references.  Thank you very much for your attention.