In an adult with newly diagnosed diabetes and laboratory results showing positive anti‑GAD‑65 (glutamic acid decarboxylase‑65) antibodies, negative IA‑2 (insulinoma‑associated protein 2) antibodies, negative ZnT8 (zinc transporter 8) antibodies, and elevated C‑peptide, what is the most likely diagnosis and recommended initial management?

Diagnosis: Latent Autoimmune Diabetes in Adults (LADA)

This adult has latent autoimmune diabetes in adults (LADA), characterized by positive anti-GAD-65 antibodies indicating ongoing autoimmune β-cell destruction, with currently preserved C-peptide demonstrating residual β-cell function that will inevitably progress to insulin dependence. 1

Diagnostic Interpretation

Antibody Profile Analysis

• Positive GAD-65 antibodies confirm autoimmune etiology, as GAD is the most frequently positive marker in adult-onset autoimmune diabetes, detected in approximately 70-80% of LADA cases 1, 2
• The negative IA-2 and ZnT8 antibodies indicate single-antibody positivity, which carries a lower but still clinically significant risk of progression compared to multiple antibody positivity 1, 2
• Single positive GAD antibody confers approximately 15% risk of progression to insulin dependence within 10 years in normoglycemic individuals, but this risk is substantially higher when diabetes is already present 1
• GAD-positive patients with elevated C-peptide represent LADA, a slowly progressive form of autoimmune diabetes that bridges type 1 and type 2 phenotypes 1, 3

C-Peptide Significance

• Elevated C-peptide (>600 pmol/L or >1.8 ng/mL) indicates preserved β-cell function at this time, distinguishing LADA from classic type 1 diabetes 1
• However, the presence of GAD antibodies predicts inevitable β-cell failure, with 92% of GAD-positive young adults requiring insulin within 3 years 4
• Patients with GAD-positive diabetes typically progress to insulin dependence within 3-5 years, markedly faster than antibody-negative type 2 diabetes 1

Immediate Management Plan

Confirm and Complete Diagnostic Workup

• Repeat GAD antibody measurement in an accredited laboratory with quality-control programs to confirm the initial finding 4, 2
• Order ZnT8 antibody testing to complete risk stratification, as adding ZnT8 increases diagnostic sensitivity and multiple antibodies dramatically increase progression risk 1, 2
• Perform oral glucose tolerance test (OGTT) if not already done to establish current glycemic status and stage the disease 4
• Measure HbA1c, lipid profile, and albumin-to-creatinine ratio to assess baseline glycemic control and cardiovascular/kidney risk 4

Insulin Therapy Initiation

• Begin insulin therapy now rather than waiting for complete β-cell failure, as GAD positivity indicates ongoing autoimmune destruction that will lead to absolute insulin deficiency 4
• Start with basal insulin (e.g., insulin glargine) at 0.2-0.3 units/kg/day 4
• Add prandial rapid-acting insulin (e.g., insulin aspart) at 0.05-0.1 units/kg/meal three times daily as part of a basal-bolus regimen 4
• Insulin analogs are strongly preferred over human insulins to minimize hypoglycemia risk 4

Adjunctive Pharmacotherapy

• Continue or initiate metformin as adjunctive therapy, as it provides comparable efficacy in lean individuals with autoimmune diabetes and offers ongoing metabolic benefits 4
• Consider GLP-1 receptor agonists as an alternative when immediate insulin intensification is not feasible; when combined with insulin they enhance efficacy and improve treatment durability 4

Glucose Monitoring

• Implement self-monitoring of blood glucose 4+ times daily or continuous glucose monitoring (CGM), with CGM strongly preferred 4
• Target glucose range of 5-10 mmol/L (90-180 mg/dL) with HbA1c target <7.0% 4
• Consider hybrid closed-loop (automated insulin delivery) systems once insulin therapy is established 4

Patient Education Priorities

• Teach carbohydrate counting and how to match mealtime insulin doses to carbohydrate intake 4
• Instruct on hypoglycemia recognition and treatment with glucagon 4
• Educate on sick day management and ketone monitoring 4

Screening for Associated Autoimmune Conditions

• Screen for celiac disease with tissue transglutaminase antibodies (tTG) and document normal serum IgA levels 4
• Screen for thyroid disease with TSH and thyroid peroxidase antibodies, as autoimmune thyroid disease commonly coexists with autoimmune diabetes 1, 5
• Screen for adrenal insufficiency in symptomatic individuals by measuring morning cortisol 4

Specialist Referral

• Urgent endocrinology consultation for initial insulin regimen optimization, diabetes technology assessment (CGM, insulin pump), and comprehensive autoimmune screening 4
• Consider referral to specialized diabetes center for evaluation and potential enrollment in clinical trials 2

Monitoring and Follow-Up

• Check HbA1c every 3 months until target achieved, then at least every 6 months 4
• Reassess treatment regimen every 3-6 months and adjust according to glycemic control, hypoglycemia frequency, and β-cell function 4
• Monitor for development of additional autoimmune conditions given the established autoimmune predisposition 4

Critical Pitfalls to Avoid

• Do not delay insulin therapy based on preserved C-peptide; oral agents alone are inadequate for autoimmune diabetes, and waiting for complete β-cell failure increases risk of diabetic ketoacidosis 4
• Do not use sliding scale insulin alone or rely solely on basal insulin without prandial coverage, as this is insufficient for progressive autoimmune diabetes 4
• Avoid overbasalization (basal insulin >0.5 units/kg/day without prandial insulin), as this signals inadequate treatment intensification 4
• Do not repeat autoantibody testing to monitor disease activity, as antibodies may disappear at the clinical stage and have no role in routine management 1, 2

Prognosis

• Patients with GAD-positive diabetes will develop absolute insulin deficiency requiring lifelong insulin therapy 4
• Early insulin initiation may preserve quality of life, reduce complications, and potentially slow β-cell loss 4
• The presence of high GAD antibody levels indicates ongoing autoimmune β-cell destruction that will inevitably lead to insulin dependence despite currently preserved C-peptide 4