Antibody testing for autoimmune endocrine disease - diabetes mellitus, type 1

The five islet autoantibodies

Antibody	Target	Comment
GAD65	Glutamic acid decarboxylase 65	Most persistent into adulthood - the single best test in an adult; also the LADA marker
IA-2 (ICA512)	Islet antigen 2, a tyrosine phosphatase	Later appearance, predicts faster progression
ZnT8	Zinc transporter 8 (SLC30A8)	*The most beta-cell specific*; catches ~25% of otherwise antibody-negative cases
IAA	Insulin autoantibody	First to appear in young children; uninterpretable once exogenous insulin has been given for >1-2 weeks
ICA	Islet cell cytoplasm (immunofluorescence)	Historic; superseded by the specific assays

~95% of new-onset type 1 diabetes has >=1 antibody; ~5-10% are antibody-negative
- Antibody-negative does not exclude T1DM - reconsider MODY, ketosis-prone T2DM, pancreatic disease

Stage	Autoantibodies	Glycaemia	Symptoms
1	>=2	Normal	None
2	>=2	Dysglycaemia (impaired fasting/OGTT, or rising HbA1c)	None
3	>=2	Overt hyperglycaemia	Yes

*Type 1 diabetes now begins at stage 1, not at symptom onset* - the staging exists because there is now something to do about stage 2

Incidence in Australia ~20-25 per 100,000 children/year and rising; peaks at 5-7 years and around puberty
>50% of new type 1 diabetes is diagnosed in adults - it is not a paediatric disease
Lifetime risk: general population ~0.4%; sibling ~6-7%; offspring of an affected father ~6%, of an affected mother ~2%; monozygotic twin ~50-70%
Number of antibodies drives risk: 1 antibody ~15% at 10 years; >=2 antibodies -> ~70% by 10 years and ~85-100% lifetime progression to stage 3
LADA accounts for ~5-10% of adults labelled type 2 diabetes

T-cell-mediated destruction of beta cells - the antibodies are markers, not the effectors
- CD8+ cytotoxic T cells cause the killing; insulitis on histology
Genetic: ~50% of risk from HLA class II - DR3-DQ2 and DR4-DQ8 (highest in the DR3/DR4 heterozygote); protective *DQB10602**
- Non-HLA: INS VNTR, PTPN22, CTLA-4, IL2RA
Environmental triggers proposed: enteroviral infection, early cow's milk exposure, vitamin D status, gut microbiome
- None established; none actionable
Order of antibody appearance in children: IAA or GAD first (usually before age 3), then IA-2 and ZnT8

Distinguishing type 1 from type 2 in an adult who is lean, has a personal or family history of autoimmunity, poor response to oral agents, or early insulin requirement
Suspected LADA
Distinguishing type 1 from MODY (MODY is antibody-negative with preserved C-peptide and a strong 3-generation family history)
Screening relatives of a proband (research or trial context)
*Not needed in a classic paediatric presentation with DKA* - the diagnosis is clinical

	Antibodies	C-peptide
Type 1	Positive	Low/undetectable (after honeymoon)
LADA	GAD positive	Initially preserved, falls over years
Type 2	Negative	High or normal
MODY	Negative	Preserved with low insulin requirement, family history in 3 generations
Ketosis-prone T2DM	Negative	Recovers after the acute episode

C-peptide is only interpretable with a simultaneous glucose (must be >4 mmol/L)
A random non-fasting C-peptide >600-700 pmol/L more than 3-5 years after diagnosis effectively excludes type 1

LADA

Latent autoimmune diabetes in adults: adult onset, GAD (and/or ZnT8) positive, initially non-insulin-requiring, progresses to insulin over months to years
Working criteria: age >30, positive islet antibody, no insulin requirement for the first 6 months
Often misdiagnosed and treated as type 2 until secondary failure - the antibody is what prevents that

TSH + TPO antibodies annually
Coeliac serology (tTG-IgA with total IgA) at diagnosis and periodically
21-hydroxylase antibodies only if adrenal insufficiency is suspected
- *Falling insulin requirement or unexplained recurrent hypoglycaemia in T1DM = look for Addison's or coeliac disease*

Insulin from diagnosis: basal-bolus analogue regimen or insulin pump / automated insulin delivery (hybrid closed loop)
CGM for essentially everyone - time in range >70%, time below range <4%
Structured education, carbohydrate counting, sick day rules, hypoglycaemia and driving advice
Metformin, sulfonylureas and DPP-4 inhibitors have no role; SGLT2 inhibitors carry a substantial euglycaemic DKA risk in T1DM

Teplizumab (anti-CD3 monoclonal) delays progression from stage 2 to stage 3 by a median of ~2 years
- 14-day IV course; transient lymphopenia, rash, cytokine release
- Approved in the US; not PBS-listed in Australia - Australian access is through trials or special access
Otherwise: metabolic monitoring (HbA1c and OGTT every 6 months), DKA-prevention education

Autoantibody screening of first-degree relatives reduces presentation in DKA from ~40% to <5% - the strongest argument for screening
Repeat glucose/HbA1c monitoring; education about symptoms

LADA

Start insulin early rather than exhausting oral agents - beta-cell reserve is finite
Avoid sulfonylureas (accelerate beta-cell failure in this group)
Treat as type 1 once C-peptide is low

Autoimmune thyroid disease (~20%), coeliac disease (~5-10%), Addison's disease, pernicious anaemia, vitiligo, alopecia areata
APS-2 - Addison's + thyroid + T1DM
IPEX (FOXP3) - neonatal diabetes with enteropathy
APS-1 (AIRE)
Checkpoint inhibitor therapy -> fulminant, antibody-variable, insulin-dependent diabetes (often presents in DKA with a near-normal HbA1c)
Down and Turner syndromes
Cystic fibrosis-related diabetes - antibody-negative, a distinct entity

Antibody-positive stage 1 -> stage 3 over years; the number of antibodies, young age at seroconversion, and IA-2/ZnT8 positivity all accelerate it
Honeymoon phase after diagnosis - transient partial remission with low insulin requirement; does not mean the diagnosis was wrong
Antibody titres fall over time - GAD persists longest, IAA becomes uninterpretable on insulin
- A negative antibody panel 20 years after diagnosis does not retrospectively exclude type 1
Residual C-peptide is protective - less hypoglycaemia, less variability, fewer complications
Lifelong insulin dependence; long-term outcome driven by glycaemic control, cardiovascular risk factors and hypoglycaemia burden

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