What is the pathophysiology of type 1 diabetes mellitus and type 2 diabetes mellitus?

Pathophysiology of Diabetes Mellitus Type 1 and Type 2

Type 1 Diabetes Mellitus

Type 1 diabetes results from autoimmune destruction of pancreatic β-cells, leading to absolute insulin deficiency and complete dependence on exogenous insulin. 1, 2

Autoimmune Mechanism

• The pathogenesis involves T-cell-mediated destruction of insulin-producing β-cells in the pancreatic islets, occurring in genetically susceptible individuals 3, 4
• This autoimmune process is characterized by the presence of islet autoantibodies directed against insulin (IAA), glutamic acid decarboxylase 65 (GADA), insulinoma-associated antigen 2 (IA-2A), or zinc transporter 8 (ZnT8A) 1, 2
• The autoimmune attack progresses over months to years during which patients remain asymptomatic and euglycemic but test positive for relevant autoantibodies 3

Genetic Predisposition

• The HLA region on chromosome 6 represents the strongest genetic susceptibility factor, with specific HLA-DR and HLA-DQ alleles conferring increased risk 1
• HLA-DRB1*04:01,04:04, and 04:07 are susceptible alleles, while 04:03 and 04:06 subtypes are protective 1
• Multiple non-HLA loci also contribute to disease risk, including the variable nucleotide tandem repeat (VNTR) upstream from the insulin gene on chromosome 11q 1
• HLA-identical siblings of a proband have a 1 in 4 risk, while those with no shared haplotype have a 1 in 100 risk 1

Disease Progression

• Type 1 diabetes follows three distinct stages: Stage 1 (multiple islet autoantibodies with normoglycemia), Stage 2 (islet autoantibodies with dysglycemia), and Stage 3 (overt hyperglycemia with clinical symptoms) 1, 2, 5
• In children with two or more persistent islet autoantibodies, the risk of developing diabetes within 10 years is 70%, compared to only 15% with a single autoantibody 1
• Symptomatic hyperglycemia occurs only after a large percentage of β-cells have been destroyed, typically when 70-90% of β-cell mass is lost 3, 6
• Glucose and A1C levels may rise approximately 6 months before clinical diagnosis 1

Environmental Triggers

• Environmental factors such as viral infections, diet, and gut microbiome alterations interact with genetic susceptibility to trigger the autoimmune process 4
• Epigenetic influences represent a link between genetic susceptibility and environmental factors, potentially accounting for disease heterogeneity 4

Type 2 Diabetes Mellitus

Type 2 diabetes is caused by progressive loss of adequate β-cell insulin secretion occurring on the background of insulin resistance, representing a dual defect in glucose homeostasis. 1, 2

Insulin Resistance

• Peripheral tissues (muscle, liver, adipose) develop decreased sensitivity to insulin, requiring higher insulin levels to maintain normal glucose homeostasis 1
• Insulin resistance is frequently associated with metabolic syndrome, obesity, and other cardiovascular risk factors 1, 2

β-Cell Dysfunction

• The pancreatic β-cells initially compensate for insulin resistance by increasing insulin secretion, but over time undergo progressive functional decline 1, 2
• Pathways to β-cell dysfunction include genetic predisposition, epigenetic changes, inflammation, and metabolic stress (glucotoxicity and lipotoxicity) 2
• Unlike type 1 diabetes, this is a non-autoimmune process without islet autoantibodies 1

Progressive Nature

• Type 2 diabetes represents a continuum from normal glucose tolerance through impaired glucose tolerance to overt diabetes 1
• The degree of β-cell dysfunction becomes more pronounced over time, eventually requiring exogenous insulin therapy in many patients despite the absence of autoimmune destruction 1, 2
• The progressive loss of β-cell function explains why many patients initially controlled with lifestyle modifications and oral medications eventually require insulin 2

Genetic and Metabolic Factors

• Type 2 diabetes has strong genetic components distinct from type 1 diabetes, though the specific genes involved are more heterogeneous 1
• Metabolic stress from chronic hyperglycemia and elevated free fatty acids contributes to further β-cell deterioration (glucose toxicity and lipotoxicity) 2

Key Pathophysiological Distinctions

The fundamental difference is that type 1 diabetes involves autoimmune β-cell destruction leading to absolute insulin deficiency, while type 2 diabetes involves insulin resistance combined with relative insulin deficiency from progressive β-cell dysfunction. 1, 2

Clinical Implications

• Type 1 diabetes patients have absolute insulin deficiency and will develop diabetic ketoacidosis within hours to days without insulin replacement 1
• Type 2 diabetes patients retain some endogenous insulin production, which typically prevents ketoacidosis except under severe stress 1
• Misdiagnosis occurs in up to 40% of adults with new type 1 diabetes, often initially classified as type 2 diabetes due to older age at presentation 1, 5

Common Pitfalls

• The traditional paradigm that type 1 diabetes occurs only in children and type 2 only in adults is no longer accurate, as type 1 can present at any age (latent autoimmune diabetes in adults) and type 2 increasingly affects children and adolescents with obesity 2, 5
• Some patients exhibit features of both types, requiring individualized treatment approaches addressing both insulin deficiency and insulin resistance 5