What causes a patient to present with diabetes?

Causes of Diabetes Presentation in Patients

Diabetes presents due to either autoimmune destruction of pancreatic β-cells (type 1) or insulin resistance with relative insulin deficiency (type 2), with genetic and environmental factors playing crucial roles in both types. 1

Type 1 Diabetes (5-10% of cases)

Type 1 diabetes results from cellular-mediated autoimmune destruction of pancreatic β-cells, leading to absolute insulin deficiency and presenting with:

• Autoimmune markers: 85-90% of patients have detectable autoantibodies (islet cell, insulin, GAD65, tyrosine phosphatases IA-2 and IA-2β) at diagnosis 1
• Genetic factors: Strong HLA associations, particularly with DQA and DQB genes, influenced by DRB genes 1
• Variable β-cell destruction rate:
  • Rapid in children and infants (often presenting with ketoacidosis)
  • Slower in adults (may retain sufficient β-cell function to prevent ketoacidosis for years) 1

Clinical Presentation

• Often presents in childhood/adolescence but can occur at any age
• Patients rarely obese at presentation
• May present with ketoacidosis as first manifestation
• Associated with other autoimmune disorders (Graves' disease, Hashimoto's thyroiditis, Addison's disease, vitiligo, celiac sprue, pernicious anemia) 1, 2

Type 2 Diabetes (90-95% of cases)

Type 2 diabetes involves insulin resistance with relative (rather than absolute) insulin deficiency, characterized by:

• Defective insulin secretion: Insufficient to compensate for insulin resistance 1
• Multiple etiologies: No single cause identified, not related to autoimmune destruction 1
• Gradual onset: Often undiagnosed for years as hyperglycemia develops slowly 1

Risk Factors

• Age: Risk increases with age, screening recommended by age 35 1
• Obesity: Most patients are obese; abdominal fat distribution particularly significant 1
• Physical inactivity: Sedentary lifestyle increases risk 1, 3
• Genetic predisposition: Stronger family history component than type 1 1, 4
• Prior gestational diabetes: Women with history of GDM at higher risk 1, 3
• Comorbidities: Hypertension, dyslipidemia, polycystic ovary syndrome 1, 3
• Race/ethnicity: Higher risk in African American, Native American, Hispanic/Latino, and Asian American populations 1, 3

Other Specific Types of Diabetes

Genetic Defects of β-Cell Function

• Maturity-onset diabetes of the young (MODY): Early-onset hyperglycemia (before age 25), autosomal dominant inheritance 1
• Mitochondrial DNA mutations: Associated with diabetes and deafness 1

Idiopathic Diabetes

• Some patients have insulin deficiency without evidence of autoimmunity
• More common in African or Asian ancestry
• Strongly inherited but not HLA-associated 1

Drug-Induced Diabetes

• Medications that can precipitate diabetes:
  • Corticosteroids
  • Atypical antipsychotics
  • Thiazide diuretics
  • SGLT2 inhibitors (can precipitate DKA) 1, 5

Pathophysiological Mechanisms

• Type 1: T-cell mediated autoimmune destruction of β-cells 2
• Type 2: Combination of:
  • Insulin resistance
  • β-cell dysfunction/dedifferentiation
  • Mitochondrial dysfunction
  • Oxidative stress 6

Clinical Implications

• Early detection is crucial to prevent complications
• Type 2 diabetes often goes undiagnosed for years due to gradual symptom onset
• Even undiagnosed patients are at increased risk of developing macrovascular and microvascular complications 1
• Patients with type 1 diabetes should be screened for other autoimmune conditions, particularly thyroid disease 2

Understanding the specific etiology of a patient's diabetes is essential for appropriate management and prevention of complications that affect morbidity, mortality, and quality of life.