Diabetes mellitus and its complications - type 1
Description
- T-cell mediated destruction of pancreatic beta cells -> absolute insulin deficiency, ketosis-prone
Staging - now the organising framework
| Stage | Antibodies | Glycaemia | Symptoms |
|---|---|---|---|
| 1 | >=2 islet autoantibodies | Normal | No |
| 2 | >=2 | Dysglycaemic | No |
| 3 | >=2 | Diabetic range | Yes |
| 4 | Established | Long-standing |
- Stage 1-2 are diagnosable disease, not risk - and now treatable
- Near-100% lifetime progression from stage 1 to clinical disease
Phases of clinical disease
- Preclinical autoimmunity -> clinical onset -> honeymoon remission (partial recovery of residual beta cells, months to ~2y) -> established
- Residual C-peptide, even tiny, means less hypoglycaemia and fewer complications - worth preserving
Epidemiology
- ~130,000 Australians; ~10% of all diabetes
- Peak onset bimodal - 5-7y and around puberty; ~half present as adults
- Highest incidence globally in Finland, Sardinia; Australia mid-high
- Risk: general population ~0.4%; sibling ~6%; MZ twin ~50%, DZ ~10%
- Concordance is lower than T2DM - environment matters more
- ~85% have no family history
Aetiopathogenesis
Genetics
- HLA class II (DR3-DQ2, DR4-DQ8) accounts for ~50% of genetic risk - the dominant locus
- DQB1\0602 is strongly protective*
- Non-HLA: INS VNTR, PTPN22, CTLA4, IL2RA
- Monogenic mimics/associations
- IPEX - FOXP3, X-linked - loss of Tregs; enteropathy, eczema, endocrinopathy, neonatal diabetes
- APS-1 (APECED) - AIRE, AR - candidiasis + hypoparathyroidism + Addison
Triggers
- Enterovirus (coxsackie B), early cow's milk/gluten exposure, vitamin D, microbiome - all associations, none proven causal
- Immune checkpoint inhibitors -> fulminant T1DM
- Rapid, often ketoacidotic at onset, C-peptide undetectable, antibodies frequently negative
- Irreversible - unlike most other irAEs, steroids do not rescue it
Mechanism
- Insulitis: autoreactive CD8 T cells + CD4 help, IFN-gamma, IL-1beta -> beta-cell apoptosis
- Antibodies (GAD65, IA-2, ZnT8, insulin) are markers, not effectors
- Alpha cells survive -> glucagon response to hypoglycaemia lost early, adrenaline response lost later -> hypoglycaemia unawareness
Diagnosis
Clinical
- Polyuria, polydipsia, weight loss, fatigue over weeks; ~30% present in DKA
- Distinguishing from T2DM: lean, young, ketosis, rapid symptoms, other autoimmunity
- But obesity does not exclude T1DM, and adult-onset is common (LADA)
Confirming type
- Islet autoantibodies: GAD65, IA-2, ZnT8, insulin (IAA) - >=2 positive is strongly confirmatory
- ~5-10% antibody-negative at diagnosis - consider MODY if also C-peptide preserved and family history
- C-peptide with paired glucose - low/undetectable after ~3-5y duration confirms; unhelpful in the honeymoon
Screening for presymptomatic disease
- Offer autoantibody screening to first-degree relatives and those with known genetic risk
- >=2 antibodies -> refer for metabolic staging (OGTT), education, and consideration of disease-modifying therapy
- Rationale: prevents DKA at presentation and opens a treatment window
DKA
- Glucose >11 (or known diabetes) + ketonaemia >=3.0 mmol/L (or ketonuria >=2+) + bicarbonate <15 or pH <7.3
- Anion gap raised; effective osmolality guides the neurological picture
- *Euglycaemic DKA - SGLT2i (used off-label in T1DM), pregnancy, starvation, alcohol. Glucose can be normal - check ketones, not glucose*
Management
Insulin - everyone, for life
- Total daily dose ~0.5-1.0 units/kg/day, ~50% basal / 50% prandial
- Multiple daily injections - long-acting basal (glargine U100/U300, degludec) + rapid analogue with meals (aspart, lispro, glulisine, faster aspart)
- Automated insulin delivery (pump + CGM + algorithm) is now the standard of care
- 2026 ADA: offer CGM, pump and AID early, including at diagnosis - no requirement for a C-peptide level, antibody result, or minimum duration of insulin therapy
- Twice-daily premixed regimens now reserved for adherence or resource limitation
- Carbohydrate counting with an insulin:carbohydrate ratio and correction factor
- Insulin requirement falls in the honeymoon - do not mistake it for resolution
Glucose targets
- HbA1c <=7% (53 mmol/mol) for most, individualised
- CGM: time in range 3.9-10.0 mmol/L >70%, time below 3.9 <4%, time below 3.0 <1%
- Time in range and hypoglycaemia exposure now matter as much as HbA1c
Disease modification
- Teplizumab (anti-CD3) in stage 2 - delays progression to clinical diabetes by a median ~2 years
- Not TGA-registered in Australia - specialist/trial access
Hypoglycaemia
- Conscious: 15 g rapid carbohydrate, repeat at 15 min
- Impaired: IM glucagon or IV 50% dextrose; nasal glucagon available
- Impaired awareness -> relax targets, structured education (DAFNE), CGM with alarms, restore awareness by strict hypoglycaemia avoidance for weeks
- Driving: check glucose before, >5 to drive
Sick day rules
- Never omit basal insulin
- Check glucose and ketones 2-4 hourly, maintain fluid and carbohydrate
- Hyperglycaemic + ketotic but not unwell: give an extra 10% of total daily dose as rapid-acting insulin, recheck 1-2 hourly, repeat while ketones >=1.0 mmol/L
DKA
- Fluid first: 0.9% saline, then correct deficit over 24-48h
- Fixed-rate insulin infusion 0.1 units/kg/hr - do not titrate to glucose; add 5-10% dextrose once glucose <14 and continue insulin until the gap closes and ketones <0.6
- Potassium: falls precipitously with insulin. Replace if K <5.5, hold insulin if K <3.3
- Continue long-acting basal insulin throughout - prevents rebound ketosis
- Bicarbonate only if pH <6.9; treat the precipitant
- Cerebral oedema - children, over-rapid osmolar correction
Glycaemic control - the evidence
- DCCT: intensive control -> less retinopathy, albuminuria, neuropathy; macrovascular only a trend
- EDIC follow-up: after control converged, the early-intensive group retained a 57% relative reduction in severe cardiovascular events - *metabolic memory*
- -> microvascular benefit is immediate, macrovascular benefit takes decades and depends on what you did early
Adjuncts and other care
- Statin from age 40 (earlier with risk factors); ACEi/ARB for albuminuria or hypertension
- Metformin, SGLT2i and GLP-1 RA are not standard - SGLT2i carries a real euglycaemic DKA risk in T1DM
Associations
- Autoimmune thyroid disease (Hashimoto or Graves) - commonest; screen TSH at diagnosis and periodically
- Coeliac disease - 5-10%; screen with tTG-IgA + total IgA
- Addison disease, autoimmune gastritis and pernicious anaemia, vitiligo, alopecia areata
- Rheumatoid arthritis, SLE
- APS-2 (Addison + T1DM + autoimmune thyroid); APS-1 (AIRE)
- Eating disorders - insulin omission for weight control ("diabulimia"), markedly raises DKA and complication rates
- Necrobiosis lipoidica; limited joint mobility (prayer sign)
Natural history & complications
- Lifelong insulin dependence; honeymoon in ~50%, always temporary
- Long-term complications: retinopathy, nephropathy, neuropathy, IHD, PAD
- Retinopathy in most after 20y; nephropathy in ~30%
- Life expectancy still reduced by ~10 years, narrowing with modern technology
- Leading causes of death: cardiovascular disease; DKA and hypoglycaemia in the young
- Complication risk is set by cumulative glycaemic exposure - the first decade counts disproportionately
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