Podcast Summary: Endocrine Feedback Loop

Episode: EFL066 - Islet Autoantibodies

Date: October 16, 2025
Host: Dr. Chase Hendrickson (Vanderbilt University)
Contributors: Dr. Steve Whitland (University of Rochester), Dr. Raghu Mirmira (University of Chicago)

Episode Overview

This episode of the Endocrine Feedback Loop centers on the clinical and research implications of a recent Journal of the Endocrine Society article:
“Prevalence of Islet Autoantibodies in Adults Without Diabetes.”

Prompted by the emergence of therapies (notably teplizumab) that may delay progression to type 1 diabetes, the discussion explores how frequently islet autoantibodies are found in adults with no known diabetes and the challenges of screening and interpreting these results—both clinically and for population health.

Key Discussion Points & Insights

Background: Type 1 Diabetes and Islet Autoantibodies

• Changing Demographics of Type 1 Diabetes

  • More adults than youth are now diagnosed with type 1 diabetes (~62% adults) ([02:31], Dr. Whitland).
  • Islet cell antibodies generally precede clinical type 1 diabetes.

• Natural History of Antibodies

  • Different antibodies predominate by age:
    • Insulin autoantibodies are more common in young children (often the first marker).
    • GAD65 autoantibodies appear first in older children and adults ([03:06], Dr. Mirmira).
  • Disease risk increases significantly with multiple autoantibody positivity, particularly within ten years in youth ([03:06]).

• Spectrum and Complexity

  • Some adults develop clinical type 1 diabetes without detectable autoantibodies, suggesting broader genetic and pathophysiological heterogeneity ([05:42]).

  "There's a spectrum of disease, and where does somebody fit along the spectrum from type one to type two? ... Many of these people can be ketosis prone ... perhaps they have a monogenic form or other genetic form of diabetes."
  —Dr. Raghu Mirmira [05:42]

• Gap in Knowledge

  • The prevalence and risk implications of single or multiple islet autoantibody positivity in adults—especially those without family history—are not fully characterized ([06:28]).

Study Design and Methods

• Study Framework

  • Cross-sectional study of >1,000 adults, mostly parents/guardians of children enrolled in a Colorado screening initiative (ASK/ASK ACT).
  • No selection or exclusion based on family history of type 1 diabetes; ~10% did have a relevant family history ([09:12], [13:01]).

• Autoantibody Screening

  • Measured insulin, GAD, IA2, and ZnT8 autoantibodies using both radio binding and electrochemiluminescence assays.
  • Positive screens required confirmation with a secondary test.

  "The radio binding assay ... picks up low affinity antibodies. Whereas the ECL [electrochemiluminescent] assay picks up high affinity antibodies... those that test positive for both are probably ones that have very real autoantibodies..."
  —Dr. Mirmira [14:52]

• Confounders Addressed

  • Race/ethnicity, family history, sex, assay method.

Results: Core Findings

• Demographics

  • 1,087 screened adults (mean age: 40.7); 75% female (in contrast to a slight male preponderance in T1D clinical cohorts) ([17:33]).

• Autoantibody Prevalence

  • Any insulin autoantibody: 3.86% (42/1,087).
  • Multiple autoantibodies: 0.55% (6/1,087).
    • Of these, 2 had a family history of T1D.
  • Single autoantibody (by both assays): 1.75% in adults vs. 0.59% in youth—about three times higher in adults ([17:33]-[21:43]).
  • Assay specificity: Most positives detected only by radio binding (i.e., possible low affinity, less clinically relevant).

• Progression to T1D

  • Only 2 confirmed cases of progression to type 1 diabetes among positive-screening adults.
  • Small numbers for multiple positivity limit broader conclusions about clinical risk.

• Additional Observations

  • GAD was the most commonly detected antibody.
  • Hispanic adults had increased likelihood of single antibody positivity.
  • First-degree relatives more likely to test positive for multiple autoantibodies.
  • No celiac-positive adults tested positive for islet autoantibodies ([17:33]–[21:43]).

Interpretation & Discussion

• Raw Prevalence Parity

  • Prevalence of multiple antibody positivity (defining preclinical stage 1 T1D) in adults was similar to youth.

  "The prevalence of multiple positive islet autoantibodies in these adults was 0.55%, which was similar to that from a matched sample of Colorado youth."
  —Dr. Hendrickson [21:45]

• Single vs. Multiple Antibody Significance

  • Adults are more likely to be single autoantibody positive, especially via only the radio binding assay—which may be less predictive of disease progression ([23:02], [25:35]).
  • Risk of progression in antibody-positive adults (especially without family history or a genetic risk locus) is unknown.

• Assay Implications

  • Single positives by radio binding may be less meaningful; double-positives (by both assay types) or multiple autoantibodies are higher risk.

• Race/Ethnicity & Family History

  • Hispanic status was associated with higher single-antibody positivity, though numbers are small.
  • Family history increases likelihood of finding antibodies, but most T1D occurs without known family history ([24:54], [13:01]).

• Antibody Fluidity

  • Antibody status is not always stable over time ("fluidity")—some individuals may convert from positive to negative or vice versa, muddying risk prediction.

  "There is this very well described phenomenon that people can test positive and then test negative. People can test positive for one antibody and then ... for a different antibody."
  —Dr. Mirmira [26:42]

• Limitations Identified

  • Cross-sectional design precludes incidence or progression rates.
  • Overrepresentation of females and adults aged 30–50.
  • Potential selection bias (via celiac/diabetes screening alongside, and potential self-selection).
  • Low proportion of initial positives returned for confirmation testing.
  • Limited generalizability to all U.S. adults or to men.
  • No HLA/genetic risk stratification ([27:25]).

Clinical Implications: Should Practice Change?

• Teplizumab Context

  • Recent therapies (e.g., teplizumab) shown to delay progression—but tested in stage 2: multiple antibody positive and abnormal glucose tolerance.
  • Screening implications: Identifying at-risk individuals (and deciding whom to treat) hinges on knowing both antibody status and glycemic stage ([31:03]).

  "What we don't know ... is in the context of those who have autoantibodies, what is their glycemic control look like? ... Without that information, we couldn't possibly determine who might be a candidate for therapy..."
  —Dr. Mirmira [31:03]

• Is Practice Ready to Change?

  • Both commentators agreed this study is a step forward but insufficient to alter practice.
  • Need for better long-term cohort studies to determine true predictive value of single or multiple antibodies in adults, optimal assay strategies, and role of genetic/risk factors ([33:26], [34:00]).

  "I don't think we have enough information. I think it's a good start. I think we need larger studies."
  —Dr. Whitland [33:26]

Notable Quotes & Memorable Moments

• On Population Screening & Selection Bias:

  "If you're saying, 'Hey, we're going to test you to see what your risk is for having type 1 diabetes,' there's a really good chance ... you're going to attract people who have a reason to be worried ... likely to have family history."
  —Dr. Hendrickson [09:12]

• On The Meaning of Single Positives

  "I've previously alluded to this. It really brings into question the importance of the radio finding assay in adults or the significance right with the importance."
  —Dr. Whitland [25:35]

• On The Complexity of Autoimmunity

  "We need to recognize ... islet autoimmunity may not be exclusive to type 1 diabetes. ... There is a complexity here that beta cells may be very, very central to the disease."
  —Dr. Mirmira [34:00]

Timestamps for Key Segments

• Natural History & Antibody Differences: [03:06] – [05:29]
• Design, Population, and Assays: [09:12] – [16:17]
• Results Breakdown: [17:33] – [21:43]
• Clinical Interpretation & Practice Implications: [21:45] – [34:40]
• Major Limitations: [27:25] – [29:36]
• Final Takeaways & What’s Next: [33:05] – [34:40]

Overall Takeaways

• Prevalence of islet autoantibody positivity (multiple antibodies, especially) is similar in adults and youth, at least in this selected Colorado cohort.
• Most T1D in adults still presents without known family history, posing challenges for screening.
• The clinical significance of isolated, especially low-affinity, antibody positivity in adults remains uncertain.
• Assay method matters: High affinity (ECL) positivity may be more predictive of disease, but broader studies needed.
• Practice is not poised to change yet—additional, larger, longitudinal cohort studies are needed to inform future screening, risk stratification, and intervention algorithms.