What are the secondary causes of diabetes?

Secondary Causes of Diabetes

Secondary causes of diabetes include diseases of the exocrine pancreas, endocrinopathies, drug-induced diabetes, genetic defects in β-cell function or insulin action, and infections that can lead to hyperglycemia requiring clinical intervention. 1

Diseases of the Exocrine Pancreas

• Pancreatitis (acute or chronic): Extensive pancreatic damage is typically required to cause diabetes
• Pancreatic cancer: Notably, even small adenocarcinomas can cause diabetes, suggesting mechanisms beyond simple β-cell mass reduction
• Trauma to the pancreas
• Pancreatectomy: Surgical removal of pancreatic tissue
• Cystic fibrosis: When extensive enough to damage β-cells
• Hemochromatosis: Iron overload damages pancreatic tissue
• Fibrocalculous pancreatopathy: Characterized by abdominal pain radiating to the back and pancreatic calcifications 1

Endocrinopathies

Hormones that antagonize insulin action can cause diabetes when present in excess:

• Acromegaly (excess growth hormone)
• Cushing's syndrome (excess cortisol)
• Glucagonoma (excess glucagon)
• Pheochromocytoma (excess epinephrine)
• Somatostatinoma (inhibits insulin secretion)
• Aldosteronoma (hypokalemia can inhibit insulin secretion)

Hyperglycemia typically resolves when the hormone excess is corrected. These generally occur in individuals with preexisting defects in insulin secretion. 1

Drug or Chemical-Induced Diabetes

Many medications can impair insulin secretion or action:

• Glucocorticoids: High-dose steroids are among the most common causes of drug-induced diabetes 2, 3

• Antipsychotics: Particularly second-generation agents like clozapine, olanzapine, and quetiapine 4, 3

• Cardiovascular drugs: Including statins, beta-blockers, and thiazide diuretics 2, 5

• Antiretroviral therapy: Particularly protease inhibitors 2, 3

• Immunosuppressants: Including mTOR inhibitors and post-transplant medications 2

• Other medications:

  • Diazoxide (antihypertensive)
  • Nicotinic acid
  • β-interferon
  • Tyrosine kinase inhibitors
  • Immune checkpoint inhibitors 1, 2, 3

• Toxins: Such as Vacor (rat poison) and intravenous pentamidine can permanently destroy pancreatic β-cells 1

Genetic Defects

Genetic Defects in β-cell Function

• Maturity-onset diabetes of the young (MODY): Characterized by onset before age 25, autosomal dominant inheritance, and impaired insulin secretion with minimal insulin resistance

  • HNF-1α mutations (chromosome 12) - most common form
  • Glucokinase mutations (chromosome 7p) - affects the "glucose sensor" of β-cells
  • Other transcription factor mutations: HNF-4α, HNF-1β, IPF-1, NeuroD1 1

• Mitochondrial DNA mutations: Associated with diabetes and deafness, most commonly at position 3,243 in the tRNA leucine gene 1

• Proinsulin conversion defects: Rare autosomal dominant traits causing mild glucose intolerance 1

Genetic Defects in Insulin Action

• Insulin receptor mutations: Ranging from hyperinsulinemia with modest hyperglycemia to severe diabetes
• Type A insulin resistance: Often with acanthosis nigricans; women may have virilization and polycystic ovaries
• Leprechaunism: Pediatric syndrome with characteristic facial features, usually fatal in infancy
• Rabson-Mendenhall syndrome: Associated with abnormalities of teeth, nails, and pineal gland hyperplasia 1

Infections

• Congenital rubella: Associated with β-cell destruction
• Certain viruses: Have been linked to β-cell damage 1

Uncommon Forms of Immune-Mediated Diabetes

• Stiff-man syndrome: Autoimmune disorder of the central nervous system with high titers of GAD autoantibodies; approximately one-third develop diabetes
• Anti-insulin receptor antibodies: Can cause diabetes by blocking insulin binding or occasionally act as insulin agonists 1

Genetic Syndromes Associated with Diabetes

• Down syndrome
• Klinefelter syndrome
• Turner syndrome
• Wolfram syndrome: Autosomal recessive disorder with insulin-deficient diabetes, diabetes insipidus, hypogonadism, optic atrophy, and neural deafness 1

Clinical Considerations

When evaluating for secondary causes of diabetes:

1. Assess for clinical features suggesting specific etiologies (e.g., cushingoid features, acromegalic features)
2. Review medication history thoroughly
3. Consider genetic testing in young patients with atypical presentations
4. Evaluate for pancreatic disease with appropriate imaging when indicated
5. Screen for endocrine disorders when clinically suspected

Management Approach

The management of secondary diabetes should focus on:

1. Treating the underlying cause when possible (e.g., removing the offending drug, treating the endocrinopathy)
2. Standard diabetes care including lifestyle modifications and appropriate glucose-lowering medications
3. Regular monitoring of glucose levels, especially when starting medications with known diabetogenic effects

For drug-induced diabetes specifically, consider decreasing the dose or selecting alternative treatments when possible 2.