Pathophysiology
I-8. Pathogenesis of Type 1 diabetes mellitus
1型糖尿病の発症機序
Diabetes — General
- A metabolic disease characterized by deficient insulin action, diagnosed mainly by raised blood glucose; risks lifelong organ dysfunction/tissue damage.
- Prediabetes: milder metabolic derangement (mild glucose elevation), common before T2DM.
Diagnostic criteria (DM)
- Classic hyperglycemic symptoms (polyuria, polydipsia, polyphagia) + abnormal glucose test: fasting ≥7.0 mmol/L (126 mg/dL) or random ≥11.1 mmol/L (200 mg/dL).
- Two abnormal glucose tests on two occasions.
- HbA1c ≥ 6.5% (≈48 mmol/L).
Symptoms at presentation
- The 3 P’s (polyuria, polydipsia, polyphagia) from severe hyperglycemia — develop acutely in T1DM due to severe insulin deficiency.
- Infection signs (fatigue, anorexia); ketosis (nausea, vomiting, abdominal pain); hyperosmolarity (blurry vision from lens swelling, altered consciousness).
- In T2DM: longer history of mild hyperglycemia; infections (pruritus vulvae, balanitis), or CV/neuropathic presentations (MI, stroke, paresthesia).
Type 1 Diabetes Mellitus
Insulin-dependent (IDDM), juvenile onset:
- 5–10% of diabetics; childhood onset (peak 10–14 yrs); normal body weight + weight loss; acute, severe onset; ketosis/ketoacidosis; absolute insulin deficiency; autoimmune β-cell destruction.
Genetic & Environmental Factors
- Genetic: certain HLA haplotypes (DR3, DR4-DQ8) ↑ risk; monozygotic twin concordance 35–50%.
- Environmental triggers (promote immune cross-reactivity): viral infections (enterovirus, Coxsackievirus B4); nutritional factors (infant complementary feeding), gut microbiome.
Natural History
Classic 1987 model
- Genetic predisposition →
- precipitating event (Coxsackievirus) →
- autoantibodies → β-cells die (no C-peptide) →
- progressive loss of insulin release (normal → overt diabetes). (An oversimplification.)
Staged model (insulitis progression)
- Stage 1 — ongoing autoimmunity against β-cells:
- Environmental trigger (enterovirus, Coxsackievirus B) attacks β-cells.
- Innate immunity: inflammation/antiviral response maintains low-grade persistent infection.
- Adaptive immunity (genetic): T-cells slowly kill β-cells; autoantibodies present as markers only (early sign).
- Insulitis — inflammation of the islets of Langerhans.
- Stage 2 — dysglycemia (hard to detect).
- Stage 3 — overt diabetes.
Absolute Insulin Deficiency — Diagnostic Implications
- β-cells are killed by CD8⁺ cytotoxic T-cells; islet autoantibodies (seroconversion) mark the ongoing immune reaction.
- Risk can be assessed via autoantibody testing: ≥2 autoantibodies → ~70% chance of developing T1DM.
- Do not use C-peptide to diagnose diabetes.
- Glucose tests: fasting (8–12 h) ≥7.0 mmol/L; random ≥11.1 mmol/L.
- HbA1c: hemoglobin irreversibly glycosylated in proportion to glucose; reflects ~RBC lifespan (4 months).
Treatment & Prevention
- Focus on early phases (autoimmune destruction started, overt diabetes not yet present) to slow progression.
- Prevention: vitamin supplementation in pregnancy, breastfeeding 4+ months, stepwise complementary feeding; healthy lifestyle, avoid stress/childhood obesity.
- Future: Coxsackievirus B (serotypes 1–6) as major precipitants; vaccines protective in preclinical models (not yet in clinical trials).
一問一答
▶What are the diagnostic criteria for diabetes?
Classic symptoms + abnormal glucose (fasting ≥7.0 mmol/L or random ≥11.1 mmol/L), or two abnormal glucose tests on two occasions, or HbA1c ≥6.5%.
▶What are the defining features of Type 1 diabetes mellitus?
5–10% of diabetics, childhood onset (peak 10–14 yrs), normal weight with weight loss, acute severe onset, ketosis/ketoacidosis, absolute insulin deficiency from autoimmune β-cell destruction.
▶What genetic factors predispose to T1DM?
Certain HLA haplotypes (DR3, DR4-DQ8) increase risk, with monozygotic twin concordance of 35–50%.
▶What is diabetes mellitus?
A metabolic disease characterized by deficient insulin action, diagnosed mainly by raised blood glucose, that risks lifelong organ dysfunction/tissue damage.
▶What are the "3 P's" of diabetes and why do they occur?
Polyuria, polydipsia, polyphagia — from severe hyperglycemia; they develop acutely in T1DM due to severe insulin deficiency.
▶What environmental triggers are linked to T1DM?
Viral infections (enterovirus, Coxsackievirus B4), nutritional factors (infant complementary feeding), and the gut microbiome — promoting immune cross-reactivity.
▶What is insulitis?
Inflammation of the islets of Langerhans, occurring during the ongoing autoimmune attack on β-cells (Stage 1 of T1DM).
▶What are the three stages of the staged model of T1DM?
Stage 1: ongoing autoimmunity (insulitis, normoglycemia); Stage 2: dysglycemia (hard to detect); Stage 3: overt diabetes.
▶Which immune cells kill β-cells in T1DM, and what is the role of autoantibodies?
CD8⁺ cytotoxic T-cells kill β-cells; islet autoantibodies are present as markers only (an early sign), not the killers.
▶How is T1DM risk assessed using autoantibodies?
Having ≥2 islet autoantibodies confers about a 70% chance of developing T1DM.
▶Why should C-peptide not be used to diagnose diabetes?
It reflects endogenous insulin secretion but is not a diagnostic criterion; diagnosis relies on glucose tests and HbA1c.
▶What does HbA1c measure and over what time period?
Hemoglobin irreversibly glycosylated in proportion to glucose, reflecting average glucose over roughly the RBC lifespan (~4 months).
▶What symptoms beyond the 3 P's can appear at T1DM presentation?
Infection signs (fatigue, anorexia), ketosis (nausea, vomiting, abdominal pain), and hyperosmolarity (blurry vision from lens swelling, altered consciousness).
▶What is the classic 1987 model of T1DM natural history?
Genetic predisposition → precipitating event (Coxsackievirus) → autoantibodies + β-cell death (no C-peptide) → progressive loss of insulin release to overt diabetes (now seen as an oversimplification).
▶What is prediabetes?
A milder metabolic derangement with mild glucose elevation, commonly preceding T2DM.
▶How does innate immunity contribute to early T1DM?
An inflammatory/antiviral response to the trigger (e.g., enterovirus) maintains a low-grade persistent infection that fuels the adaptive attack on β-cells.
▶What preventive measures may reduce T1DM risk?
Vitamin supplementation in pregnancy, breastfeeding 4+ months, stepwise complementary feeding, a healthy lifestyle, and avoiding stress/childhood obesity.
▶Why is the early phase of T1DM the target for treatment/prevention?
Intervening after autoimmune destruction begins but before overt diabetes can slow progression to clinical disease.
▶What is a promising future preventive strategy for T1DM?
Vaccines against Coxsackievirus B (serotypes 1–6), which are protective in preclinical models (not yet in clinical trials).
▶How does the presentation of T2DM differ from T1DM?
T2DM has a longer history of mild hyperglycemia and may present with infections (pruritus vulvae, balanitis) or cardiovascular/neuropathic events (MI, stroke, paresthesia), rather than acute severe symptoms.