Diabetes mellitus and its complications - type 2
Description
- Insulin resistance + progressive beta-cell failure
- Beta-cell mass already ~50% lost at diagnosis - hence progressive drug escalation
- Hyperglycaemia is the marker; the disease is cardio-reno-metabolic
- Modern therapy is chosen for organ protection, not only for HbA1c
Complications
- Microvascular - retinopathy, nephropathy, neuropathy (distal symmetric, autonomic, mononeuropathy, amyotrophy)
- Macrovascular - IHD, stroke, PAD
- Other - MASLD/MASH, OSA, foot ulcer/Charcot, infection, cognitive decline
- Microvascular risk tracks glycaemia; macrovascular risk tracks BP, lipids and smoking more than HbA1c
Look-alikes not to miss
| Clue | |
|---|---|
| LADA | Lean, GAD antibody positive, fails orals fast |
| MODY | Onset <25y, 3 generations, non-obese, no antibodies, no ketosis |
| Pancreatogenic (T3c) | Pancreatitis/CF/haemochromatosis; brittle, glucagon also lost |
| Steroid/antipsychotic-induced | Post-prandial predominant |
Epidemiology
- ~1.3 million Australians diagnosed; ~5-6% adults, plus large undiagnosed fraction
- ~85-90% of all diabetes
- Aboriginal and Torres Strait Islander peoples: 3-4x prevalence, onset a decade earlier, far higher ESKD and amputation rates
- Rising in youth - paediatric T2DM now outnumbers T1DM in some high-risk populations
- Risk: MZ twin concordance >70% (higher than T1DM), first-degree relative ~40% lifetime
- Polygenic; TCF7L2 the strongest common variant
Aetiopathogenesis
Core defects
- Insulin resistance - muscle (dec glucose uptake), liver (inc gluconeogenesis), adipose (inc lipolysis -> FFA -> lipotoxicity)
- Beta-cell failure - progressive, the determinant of whether diabetes appears at all
- Plus: dec incretin effect, inc glucagon (alpha cell), inc renal glucose reabsorption, CNS appetite dysregulation
- Visceral adiposity -> inflammatory adipokines, ectopic fat in liver and pancreas
- Twin-cycle hypothesis - explains remission with substantial weight loss
Complication mechanisms
- Hyperglycaemia -> polyol flux, AGEs, PKC activation, hexosamine pathway -> ROS, endothelial dysfunction
- VEGF drives proliferative retinopathy and macular oedema -> why anti-VEGF works
- Glomerular hyperfiltration -> mesangial expansion, GBM thickening, Kimmelstiel-Wilson nodules
- Diabetic dyslipidaemia: inc TG, dec HDL, small dense oxidisable LDL - atherogenic even when LDL count is unremarkable
MODY
- Autosomal dominant, monogenic beta-cell defect
| Gene | Phenotype | Treatment |
|---|---|---|
| GCK (MODY2) | Raised set-point for glucose-stimulated insulin release. Mild, stable, lifelong; no microvascular complications | None (except pregnancy) |
| HNF1A (MODY3) | Progressive secretory defect, glycosuria at normal glucose, micro- and macrovascular risk | Low-dose sulfonylurea |
| HNF4A (MODY1) | As HNF1A + macrosomia, neonatal hypoglycaemia | Low-dose sulfonylurea |
| HNF1B (MODY5) | Renal cysts, genital tract anomalies, pancreatic atrophy | Insulin |
Diagnosis
Thresholds
| Test | Diabetes | Intermediate |
|---|---|---|
| Fasting glucose | >=7.0 | IFG 6.1-6.9 |
| 2h post 75 g OGTT | >=11.1 | IGT 7.8-11.0 |
| HbA1c | >=6.5% (48 mmol/mol) | 6.0-6.4% high risk |
| Random | >=11.1 with symptoms |
- Asymptomatic -> two abnormal results (same or different tests) required
- HbA1c invalid in: haemoglobinopathy, haemolysis, recent transfusion, iron/B12 deficiency, ESKD, pregnancy
- Do not use HbA1c to diagnose acute-onset diabetes - it lags
Which type is it?
- GAD, IA-2, ZnT8 antibodies if lean, ketosis-prone, rapid oral failure, other autoimmunity
- C-peptide (paired with glucose) - low = insulin-deficient
- MODY criteria: onset <25y in >=1 affected relative, no ketosis, sustained control >2y without insulin, evidence of impaired secretion, antibody negative, C-peptide preserved
Screening
- AUSDRISK >=12, or age >=40 (>=18 if Aboriginal or Torres Strait Islander) - 3-yearly
Hyperosmolar hyperglycaemic state
- Glucose often >33, osm >320, minimal ketosis, pH >7.3
- Profound volume depletion, obtundation; mortality ~10-20%, higher than DKA
Management
1. Glycaemic target - individualised
- General HbA1c <=7% (53 mmol/mol)
- Tighter (<=6.5%) if young, short duration, no CVD, low hypoglycaemia risk
- Looser (<=8%) if elderly, frail, limited life expectancy, hypoglycaemia unawareness, established complications
- ACCORD vs UKPDS is the exam point
- UKPDS: intensive control from diagnosis -> fewer MIs and lower mortality at 10y despite convergence (legacy effect)
- ACCORD: aggressive target 6% in older, long-standing, high-risk patients -> excess mortality, stopped early**
- -> early and gradual, not late and aggressive
2. Choose agents by comorbidity, not by HbA1c alone
ADA 2026 / ADS 2026: cardiorenal and hepatic indications are independent of glycaemic need
| Comorbidity | Agent |
|---|---|
| HFrEF or HFpEF | SGLT2i |
| CKD (albuminuria) | SGLT2i, then finerenone; GLP-1 RA if eGFR permits |
| Established ASCVD | GLP-1 RA (or SGLT2i) |
| Obesity | Tirzepatide (GIP/GLP-1) > semaglutide |
| MASLD/MASH + obesity | Dual GIP/GLP-1 RA as adjunct to weight loss |
| HFpEF + obesity | Dual GIP/GLP-1 RA - now recommended for symptoms and HF events |
- Metformin remains the anchor for glucose control in most
- Avoid: eGFR <30, ketosis-prone, decompensated liver disease, pregnancy
- Withhold for contrast, sepsis, surgery, dehydration
- B12 deficiency with long-term use - check periodically
- AU PBS: GLP-1 RA subsidised only after inadequate response or intolerance to an SGLT2i; combination subsidy only where the SGLT2i is prescribed under the HF or CKD listing
- Sulfonylurea and insulin: effective, cheap, but cause hypoglycaemia and weight gain, and neither improves cardiovascular outcome
- DPP-4 inhibitors: weight-neutral, safe, outcome-neutral (saxagliptin inc HF admissions)
- Exenatide (EXSCEL) was neutral for MACE - GLP-1 cardiovascular benefit is not a class effect
3. Weight
- Weight loss is the only disease-modifying intervention - 15% loss -> remission in a substantial minority (DiRECT)
- Metabolic surgery if BMI >=35 (or >=30 with poor control); consider at BMI >=27.5 in South/East Asian populations
4. Cardiovascular risk - independent of glucose
- Statin for essentially all with T2DM aged >=40; high-intensity if established CVD
- BP target <130/80; ACEi or ARB first if albuminuric
- ACEi/ARB reduce proteinuria and slow GFR decline beyond their BP effect
- Smoking cessation, antiplatelet only for secondary prevention
5. Complication surveillance
- Retinal screening, ACR + eGFR, foot exam, lipids - see screening for complications
- Diabetic macular oedema / proliferative retinopathy -> intravitreal anti-VEGF (aflibercept, ranibizumab) +/- laser
HHS
- Fluid first and hardest (deficit often 8-10 L), slower correction than DKA
- Low-rate insulin infusion only after fluid started; VTE prophylaxis
- Falling osmolality too fast -> cerebral oedema
Associations
- Metabolic syndrome - central obesity, hypertension, dyslipidaemia, hyperuricaemia
- MASLD/MASH - up to 70%; leading cause of cirrhosis in this group
- OSA, PCOS, hypogonadism in men
- Depression, cognitive impairment and dementia
- Pancreatic, liver, colorectal, endometrial and breast cancer - modest excess
- Periodontal disease, frozen shoulder, Dupuytren, limited joint mobility
- Necrobiosis lipoidica, acanthosis nigricans, granuloma annulare, diabetic dermopathy
- Recurrent infection - candidiasis, emphysematous pyelonephritis, malignant otitis externa, mucormycosis
Natural history & complications
- Insulin resistance precedes diagnosis by 10-20y; ~half already have a complication at diagnosis
- Beta-cell function declines ~4%/yr -> most eventually need insulin
- Remission is possible with major weight loss, especially <6y duration
- Life expectancy reduced ~6 years; CVD is the commonest cause of death
- ~40% develop CKD; T2DM is the commonest cause of ESKD in Australia
- Foot ulceration -> ~85% of non-traumatic lower limb amputations
- Legacy effect cuts both ways - early control pays off decades later, early poor control is never fully recovered
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