What causes new-onset diabetes in individuals with no prior history of the disease?

Why New-Onset Diabetes Occurs

New-onset diabetes occurs through multiple distinct pathways: autoimmune destruction of pancreatic β-cells (type 1), progressive insulin resistance combined with β-cell dysfunction (type 2), specific genetic mutations affecting β-cell function or insulin action, drug-induced mechanisms (particularly checkpoint inhibitors), viral triggers (including SARS-CoV-2), and various secondary causes affecting pancreatic function.

Type 1 Diabetes: Autoimmune β-Cell Destruction

Autoimmune mechanisms are the primary cause of type 1 diabetes, involving:

• Genetic susceptibility through HLA-DR/DQ alleles that can be either predisposing or protective, establishing the foundation for autoimmune risk 1
• Environmental triggers that remain poorly defined but activate the autoimmune process in genetically susceptible individuals 1
• Progressive β-cell destruction marked by islet cell autoantibodies, insulin autoantibodies, GAD65 autoantibodies, and IA-2/IA-2β autoantibodies present in 85-90% of cases 1
• Variable destruction rates: rapid in children (often presenting with DKA), slower in adults (who may retain residual β-cell function for years) 1

Viral Triggers and COVID-19

Recent evidence highlights viral causation:

• Enteroviruses (particularly Coxsackievirus B) have long been associated with type 1 diabetes 1
• SARS-CoV-2 infection emerged as a significant trigger during the COVID-19 pandemic, with increased cases of hyperglycemia, DKA, and new diabetes 1
• Mechanisms of viral β-cell damage include direct virus-triggered β-cell death, immune-mediated loss, damage to surrounding exocrine cells, and the highly inflammatory cytokine storm 1
• The CoviDIAB global registry was established to characterize COVID-19-related diabetes pathogenesis 1

Drug-Induced Type 1 Diabetes

Checkpoint inhibitors represent an important iatrogenic cause:

• Patients with high-risk HLA haplotypes can develop checkpoint inhibitor-associated type 1 diabetes 1
• Risk cannot be predicted by family history or autoantibodies, requiring vigilant monitoring of all patients receiving these medications 1

Idiopathic Type 1 Diabetes

A minority of type 1 cases have no identifiable autoimmune markers:

• Permanent insulinopenia with DKA susceptibility but no evidence of β-cell autoimmunity 1
• Predominantly affects individuals of African or Asian ancestry 1
• Not HLA-associated and lacks immunological evidence for autoimmunity 1

Type 2 Diabetes: Insulin Resistance and β-Cell Failure

Type 2 diabetes accounts for 90-95% of all diabetes cases and involves a dual defect 1, 2:

Primary Pathophysiology

• Initial insulin resistance in peripheral tissues, particularly muscle and adipose tissue, requiring higher insulin levels to maintain normoglycemia 2, 3
• Progressive β-cell dysfunction that fails to compensate for insulin resistance, resulting in relative (not absolute) insulin deficiency 1, 3
• Chronic hyperglycemia further deteriorates both insulin sensitivity and secretion through glucotoxicity and lipotoxicity 3

Risk Factors and Causation

Genetic predisposition is substantial:

• Family history shows 74-100% frequency in first or second-degree relatives, though specific genes remain incompletely defined 2
• Complex polygenic inheritance involving multiple genes, unlike monogenic forms 4, 5

Environmental and lifestyle factors are critical:

• Obesity is present in most patients (BMI >85th percentile), causing significant insulin resistance 2
• Westernized lifestyle including decreased physical activity and increased calorie/fat intake strongly correlates with disease development 2, 6
• Age, prior gestational diabetes, hypertension, and dyslipidemia increase risk 1

Clinical Presentation Caveat

Type 2 diabetes frequently goes undiagnosed for years because hyperglycemia develops gradually and may not cause noticeable symptoms initially, yet patients remain at risk for both macrovascular and microvascular complications during this period 1, 2

Monogenic Diabetes: Specific Genetic Defects

Maturity-Onset Diabetes of the Young (MODY)

MODY represents monogenic β-cell dysfunction:

• Autosomal dominant inheritance with onset typically before age 25 years 1
• HNF1A mutations (chromosome 12) are most common, causing progressive insulin secretory defects with sulfonylurea sensitivity 1
• HNF4A mutations may present with large birth weight and transient neonatal hypoglycemia 1
• GCK mutations cause mild, stable hyperglycemia often requiring no treatment 1
• HNF1B mutations associate with renal cysts, genitourinary abnormalities, and pancreatic atrophy 1

Neonatal Diabetes

Diabetes occurring before 6 months of age is termed neonatal diabetes, with 80-85% having monogenic causes 1, 7:

• KCNJ11 and ABCC8 mutations (affecting KATP channels) are most common for permanent neonatal diabetes and respond to high-dose sulfonylureas instead of insulin 1, 7
• Transient neonatal diabetes most often involves chromosome 6q24 overexpression, recurs in 50% of cases, and may be treatable with non-insulin medications 1, 7
• INS gene mutations cause permanent diabetes requiring intensive insulin management 1, 7

Other Genetic Defects

• Mitochondrial DNA mutations (particularly position 3,243 tRNA leucine gene) cause diabetes with deafness 1
• Insulin receptor mutations cause syndromes ranging from hyperinsulinemia with modest hyperglycemia to severe diabetes with acanthosis nigricans 1
• Proinsulin conversion defects and mutant insulin molecules cause mild glucose intolerance with autosomal dominant inheritance 1

Hybrid and Heterogeneous Forms

Diabetes represents a spectrum rather than discrete categories:

• Latent autoimmune diabetes in adults (LADA) represents a hybrid form with features of both type 1 and type 2 diabetes 8
• Obesity modifies diabetes risk across types, accounting for increasing adolescent type 2 diabetes and complicating type 1 diagnosis 1, 8
• Both type 1 and type 2 diabetes result from gene-environment collisions, with rapid environmental changes (lifestyle factors) explaining increasing incidence 8, 5

Critical Clinical Implications

Accurate diagnosis determines treatment strategy:

• MODY diagnosis allows cost-effective therapy: no treatment for GCK-MODY, sulfonylureas for HNF1A/HNF4A-MODY 1
• KATP-related neonatal diabetes responds to oral sulfonylureas rather than insulin 1, 7
• Type 2 diabetes with severe insulinopenia may require insulin despite being non-autoimmune and carries higher DKA risk during stress 3
• Autoantibody testing should be considered in younger patients without traditional type 2 risk factors to exclude type 1 diabetes 3

The "missing heritability" problem means identified genetic variants explain only a small proportion of diabetes heritability, with rare variants, gene-environment interactions, and epigenetics likely contributing 5