LADA - Latent Autoimmune Diabetes in Adults

What Is LADA?

• Older age at diagnosis (typically >30 years)
• Presence of pancreatic autoantibodies
• No absolute insulin requirement at diagnosis (unlike classic T1DM)

• Textbook of Family Medicine 9e, p. 985

Pathophysiology

Diagnostic Criteria (LADA Triad)

When to Screen for LADA

1. Age <50 years
2. Acute symptoms of hyperglycemia
3. BMI <25 kg/m²
4. Personal history of autoimmune disease
5. Family history of autoimmune disease

• Washington Manual of Medical Therapeutics, p. 895

LADA vs. T1DM vs. T2DM

• Textbook of Family Medicine 9e, Table 34-21

Clinical Presentation

• Present with mild-to-moderate hyperglycemia that initially responds to oral agents
• Are initially misclassified as T2DM
• Fail oral antidiabetic drugs faster than true T2DM patients (within months to a few years)
• Are non-obese (or have a lower BMI than typical T2D)
• May have other autoimmune conditions (autoimmune thyroid disease, celiac disease, Addison disease)

Treatment

1. Preserve residual beta-cell function (reduce autoimmune attack via beta-cell "rest")
2. Prevent progression to absolute insulin deficiency
3. Reduce DKA risk

Practical approach:

• Metformin may be used initially as adjunct therapy (reduces insulin resistance)
• Sulfonylureas should be avoided - they stimulate beta cells, accelerate destruction, and worsen long-term outcomes in LADA
• Insulin therapy (basal +/- bolus) - transition is inevitable; earlier may be better
• GLP-1 receptor agonists and SGLT-2 inhibitors are under study and may provide metabolic benefit
• Vitamin D supplementation has theoretical immunomodulatory benefit and may slow progression

Complications

• Microvascular complications (retinopathy, nephropathy, neuropathy) - risk may actually exceed T2DM after ~9 years of follow-up
• Cardiovascular disease (2-4x increased risk vs. euglycemic individuals)
• DKA - becomes a risk as beta-cell function declines
• Other autoimmune conditions - higher prevalence of autoimmune thyroid disease and others

Recent Evidence (PubMed, 2025)

Summary

Endocrine Causes of Diabetes (Endocrinopathies)

• Harrison's Principles of Internal Medicine 22E, Table 4.15-1
• Goodman & Gilman's Pharmacological Basis of Therapeutics

The 7 Classic Endocrine Causes

1. Acromegaly (Growth Hormone Excess)

"Excessive growth hormone secretion associated with acromegaly may lead to insulin resistance, compensatory increases in insulin secretion, and ultimately type 2 diabetes mellitus."

• Guyton and Hall Textbook of Medical Physiology

2. Cushing's Syndrome (Cortisol Excess)

"Clinical features of Cushing syndrome include visceral and truncal obesity, muscle weakness, insulin resistance/type 2 diabetes, hypertension, abdominal striae, moon face."

• Sabiston Textbook of Surgery

3. Glucagonoma (Glucagon Excess)

4. Pheochromocytoma (Catecholamine Excess)

5. Hyperthyroidism (Thyroid Hormone Excess)

6. Somatostatinoma (Somatostatin Excess)

"Inhibition of insulin secretion by somatostatin causes diabetes in over a third of patients. The severity of glucose intolerance varies..."

• Yamada's Textbook of Gastroenterology

7. Aldosteronoma / Primary Hyperaldosteronism (Conn's Syndrome)

Summary Table

Key Clinical Point

• Presents with features of an underlying endocrine syndrome
• Is unusually difficult to control
• Occurs in a young, non-obese patient without family history of T1D or T2D
• Resolves after treatment of the primary condition

• Harrison's Principles of Internal Medicine 22E
• Henry's Clinical Diagnosis and Management by Laboratory Methods
• Goodman & Gilman's Pharmacological Basis of Therapeutics

Types of Diabetes Mellitus

• Textbook of Family Medicine 9e, p. 940
• Harrison's Principles of Internal Medicine 22E, Table 4.15-1

TYPE 1 - Type 1 Diabetes Mellitus (T1DM)

Pathophysiology

• Autoimmune destruction of pancreatic beta cells in the islets of Langerhans
• Leads to absolute insulin deficiency
• Genetically susceptible individuals (HLA-DR3, HLA-DR4) + environmental trigger (enteroviruses)
• Prediabetes period (gradual beta-cell destruction) can last months to decades
• First-phase insulin response to IV glucose is lost early

Two Subtypes

Key Features

• Typically onset in childhood/adolescence (can occur at any age)
• Lean body habitus
• Prone to diabetic ketoacidosis (DKA)
• C-peptide very low or absent
• Requires lifelong insulin for survival
• Associated other autoimmune diseases: thyroid disease (15-30%), celiac disease (4-9%), Addison disease (0.5%)
• LADA = slow-onset T1DM in adults (see separate discussion)
• Henry's Clinical Diagnosis and Management by Laboratory Methods

TYPE 2 - Type 2 Diabetes Mellitus (T2DM)

Pathophysiology

• Dual defect: peripheral insulin resistance + progressive beta-cell secretory failure
• Genetically predisposed individuals → chronic progressive disease
• Insulin resistance in muscle, liver, and fat → compensatory hyperinsulinemia → eventual beta-cell exhaustion
• C-peptide is detectable (patients are not absolutely insulin deficient initially)

Risk Factors

• Obesity (especially upper-body/visceral adiposity)
• Sedentary lifestyle
• Family history of T2DM
• Age >40 years
• Ethnicity (African American, Latino, Native American, Asian, Pacific Islander)
• Impaired glucose tolerance (IGT) or impaired fasting glucose (IFG)
• History of gestational diabetes
• Hypertension, dyslipidemia (metabolic syndrome)

Key Features

• Insidious onset; often asymptomatic early
• Usually no DKA (unless severe stress/illness)
• May initially be managed with lifestyle + oral agents
• Insulin eventually required as beta-cell function declines
• Autoantibodies typically absent
• Berek & Novak's Gynecology, Table 22-7

TYPE 3 - Gestational Diabetes Mellitus (GDM)

Definition

Pathophysiology

• Placental hormones (human placental lactogen, progesterone, cortisol) create progressive insulin resistance, especially in the 3rd trimester
• Women with insufficient beta-cell reserve to compensate develop GDM

Key Features

• Affects ~6-8% of pregnancies in the USA
• Risk factors: obesity, family history of T2DM, previous GDM, polycystic ovary syndrome
• Most women return to normal glucose tolerance postpartum
• 35-60% risk of developing T2DM within 10-20 years
• Children of GDM mothers have increased risk of metabolic syndrome and T2DM
• ADA recommends lifelong screening every 3 years post-GDM
• Creasy & Resnik's Maternal-Fetal Medicine
• Harrison's Principles of Internal Medicine 22E

TYPE 4 - Other Specific Types of Diabetes

A. Genetic Defects of Beta-Cell Function - MODY (Maturity-Onset Diabetes of the Young)

• Autosomal dominant; onset typically <25 years
• Beta-cell dysfunction without autoantibodies; no obesity
• 14 known MODY types (mutations in different genes):

• Often misdiagnosed as T1DM or T2DM
• Many respond well to sulfonylureas rather than insulin

B. Genetic Defects in Insulin Action

• Type A insulin resistance, leprechaunism (Donohue syndrome), Rabson-Mendenhall syndrome, lipodystrophy syndromes
• Caused by mutations in the insulin receptor gene (INSR)

C. Diseases of the Exocrine Pancreas

• Pancreatitis (chronic), pancreatectomy, pancreatic neoplasia, cystic fibrosis, hemochromatosis, fibrocalculous pancreatopathy
• Also called Type 3c diabetes

D. Endocrinopathies

• Acromegaly (GH excess)
• Cushing's syndrome (cortisol excess)
• Glucagonoma
• Pheochromocytoma (catecholamine excess)
• Hyperthyroidism
• Somatostatinoma
• Aldosteronoma

E. Drug- or Chemical-Induced

• Glucocorticoids, calcineurin/mTOR inhibitors (transplant drugs), atypical antipsychotics, thiazides, statins, PCSK9 inhibitors, pentamidine, nicotinic acid, HIV antiretrovirals, diazoxide, beta-adrenergic agonists

F. Infections

• Congenital rubella, cytomegalovirus (CMV), coxsackievirus

G. Uncommon Immune-Mediated Forms

• "Stiff-person" syndrome (anti-GAD antibodies)
• Anti-insulin receptor antibodies
• Immune checkpoint inhibitor therapy (cancer treatment)

H. Other Genetic Syndromes

• Wolfram syndrome, Down syndrome, Klinefelter syndrome, Turner syndrome, Friedreich's ataxia, Huntington's chorea, myotonic dystrophy, Prader-Willi syndrome, porphyria
• Henry's Clinical Diagnosis and Management by Laboratory Methods
• Goodman & Gilman's Pharmacological Basis of Therapeutics

Summary at a Glance