What causes diabetes in young individuals?

Causes of Diabetes in Young Individuals

Diabetes in youth has two primary causes: autoimmune destruction of insulin-producing beta cells (type 1 diabetes) and insulin resistance combined with relative insulin deficiency (type 2 diabetes), with type 2 diabetes now rapidly increasing due to the obesity epidemic. 1

Type 1 Diabetes: Autoimmune Destruction

Type 1 diabetes results from autoimmune destruction of pancreatic beta cells in genetically predisposed individuals, triggered by environmental factors 2:

• Genetic predisposition: HLA-associated genetic susceptibility is clearly identified, though only a small percentage of genetically predisposed individuals actually develop the disease 2
• Environmental triggers: The rapid increase in type 1 diabetes incidence, particularly in children under 5 years, cannot be explained by genetics alone and points to environmental factors 2, 3
• Suspected environmental factors include:
  • Viral infections (enteroviruses, possibly rotavirus) 4
  • Early introduction of cow's milk proteins in infancy 1, 4
  • Vitamin D deficiency 2
  • Other dietary factors and toxins 2, 4

Critical point: Less than 10% of genetically susceptible individuals progress to clinical disease, demonstrating the crucial role of environmental modification 4

Type 2 Diabetes: The Emerging Epidemic in Youth

Type 2 diabetes in youth has increased dramatically over the past 20 years, with projections showing prevalence will quadruple in those under 20 years by 2060 1:

Primary Risk Factors:

• Obesity and excess adiposity: The most significant modifiable risk factor 1
• Physical inactivity and sedentary lifestyle: Direct contributor to insulin resistance 3, 5
• Family history of diabetes: Mediated by shared genetics, lifestyle, and environmental factors 1
• Female sex: Higher risk compared to males 1
• Maternal gestational diabetes: In utero exposure increases risk 1
• Adverse social determinants of health: Including low socioeconomic status 1
• Race/ethnicity: Disproportionately affects youth from historically marginalized communities and racial/ethnic minorities 1

Screening Criteria:

Screen youth after puberty onset or ≥10 years of age (whichever is earlier) if they have overweight (BMI ≥85th percentile) or obesity (BMI ≥95th percentile) PLUS one or more additional risk factors 1

Monogenic Diabetes: Rare but Important

A small fraction (<5%) of youth diabetes is caused by single gene defects 1:

• Neonatal diabetes: Occurs under 6 months of age; 80-85% have an identifiable monogenic cause, most commonly mutations in KCNJ11 or ABCC8 genes affecting the beta-cell KATP channel 1
• MODY (Maturity-Onset Diabetes of the Young): Characterized by autosomal dominant inheritance, onset before age 25, and impaired insulin secretion; most common form involves HNF1A mutations 1

All children diagnosed with diabetes in the first 6 months of life should have immediate genetic testing 1

Diagnostic Challenges: The Blurred Lines

The current obesity epidemic has made distinguishing diabetes types increasingly difficult 1:

• Overweight/obesity is now common in children with type 1 diabetes, complicating the clinical picture 1
• "Double diabetes" or "hybrid diabetes": Youth presenting with features of both types—obesity/insulin resistance AND positive autoantibodies to beta cells 3, 5
• Autoantibodies can be present in obese youth with clinical features suggesting type 2 diabetes 1
• DKA occurs in 11% of youth aged 10-19 years with type 2 diabetes at onset, further blurring diagnostic boundaries 1

Essential Diagnostic Step:

Children and adolescents with overweight or obesity being evaluated for type 2 diabetes should have diabetes-associated autoantibodies tested to exclude autoimmune type 1 diabetes 1

Unique Features of Youth-Onset Type 2 Diabetes

Type 2 diabetes in youth differs significantly from both type 1 diabetes and adult-onset type 2 diabetes 1:

• More rapidly progressive decline in beta-cell function compared to adults 1
• Accelerated development of complications: The TODAY study demonstrated that most individuals with youth-onset type 2 diabetes had microvascular complications by young adulthood 1
• Worse long-term outcomes: Higher morbidity and mortality compared to adult-onset disease 1

Other Causes

• Cystic fibrosis-related diabetes (CFRD): Occurs in approximately 20% of adolescents and 40-50% of adults with cystic fibrosis; insulin insufficiency is the primary defect 1
• Post-transplantation diabetes: Can develop after organ transplantation 1
• Obesity's role in type 1 diabetes: Obesity itself contributes to the development of type 1 diabetes in some individuals, further complicating the pathophysiology 1