Type 2 Diabetes Mellitus
Summary
Type 2 Diabetes Mellitus (T2DM) is a metabolic disorder characterised by insulin resistance and progressive beta-cell dysfunction, leading to chronic hyperglycaemia. It accounts for 90% of all diabetes and is strongly associated with obesity, sedentary lifestyle, and genetic predisposition. T2DM is increasingly common, affecting over 450 million people worldwide. Complications include microvascular (retinopathy, nephropathy, neuropathy) and macrovascular (cardiovascular disease, stroke) disease. Modern management emphasises lifestyle intervention, glycaemic control, and cardio-renal protection with SGLT2 inhibitors and GLP-1 receptor agonists.
Key Facts
- Prevalence: 9-10% of adults globally; increasing
- UK Prevalence: 4.7 million people with diabetes (90% T2DM)
- Pathophysiology: Insulin resistance + progressive β-cell failure
- Complications: Microvascular and macrovascular
- Treatment Goal: HbA1c individualised (usually <48-58 mmol/mol)
- Remission Possible: With significant weight loss (15+ kg)
- Leading Cause: Blindness (working age), amputation, CKD in developed world
Clinical Pearls
High-Yield Points:
- Lifestyle modification can achieve remission in early disease
- SGLT2 inhibitors (flozins) have proven CV and renal benefit
- GLP-1 agonists (glutides) provide weight loss + CV benefit
- Screen for complications annually (eyes, feet, kidneys)
- Consider T2DM in young adults with obesity (not always T1DM)
- HbA1c target should be individualised (lower in young, higher in frail)
Why This Matters Clinically
T2DM is one of the most common conditions in medicine, encountered in every specialty. Its complications are preventable with good glycaemic and cardiovascular risk factor control. The therapeutic landscape has transformed with SGLT2 inhibitors and GLP-1 agonists, which offer benefits beyond glucose lowering. Every doctor should understand first-line management and when to escalate.
Prevalence and Incidence
| Metric | Value |
|---|---|
| Global Prevalence | 462 million (6.3%) |
| UK Prevalence | 4.7 million |
| Proportion of Diabetes | 90% |
| Annual New Diagnoses (UK) | ~200,000 |
Risk Factors
Non-Modifiable:
- Age (>40 years, or >25 in high-risk groups)
- Ethnicity (South Asian, Black African, Chinese - 2-4x risk)
- Family history (2-6x risk if first-degree relative)
- History of gestational diabetes
Drill Down: Ethnicity and Anatomy
The "Thin-Fat" Phenotype.
- South Asians: Often develop T2DM at BMI 22-25.
- Mechanism: Less subcutaneous storage capacity -> Fat spills into visceral organs (liver/pancreas) much earlier.
- Guideline: Screen at BMI >23 (not 25).
- Black African/Caribbean: Higher risk of T2DM but paradoxically lower visceral fat than Europeans. Mechanism unclear (Insulin hypersecretion?).
Modifiable:
- Obesity (especially central/visceral)
- Sedentary lifestyle
- Unhealthy diet
- Polycystic ovary syndrome
Core Defects
1. Insulin Resistance:
- Target tissues (muscle, liver, fat) respond poorly to insulin
- Compensatory hyperinsulinaemia initially
- Associated with visceral obesity, inflammation
2. Progressive β-Cell Dysfunction:
- β-cells fail to maintain compensatory insulin secretion
- Lipotoxicity and glucotoxicity worsen function
- β-cell mass progressively declines
3. Hepatic Glucose Overproduction:
- Failure to suppress gluconeogenesis
- Contributes to fasting hyperglycaemia
The Ominous Octet (DeFronzo)
Multiple organ defects contribute:
- Muscle insulin resistance
- Liver glucose overproduction
- Beta-cell dysfunction
- Fat cell lipolysis
- GI incretin dysfunction
- Alpha-cell glucagon excess
- Kidney glucose reabsorption
- Brain neurotransmitter dysfunction
Natural History
Prediabetes → Compensated insulin resistance → β-cell failure → Overt T2DM → Progressive insulin deficiency
Drill Down: The "Diabesity" Link
Fat is not inert stuffing. It is an angry endocrine organ.
- Adipokines: Visceral fat secretes pro-inflammatory cytokines (TNF-alpha, IL-6).
- Free Fatty Acids: Released into portal circulation -> Liver Fat (NAFLD) -> Hepatic Insulin Resistance.
- Ectopic Fat: Fat spills over into Pancreas (toxic to beta cells) and Muscle.
- Remission: Losing this specific "Internal Fat" allows the pancreas to wake up (Taylor Threshold Hypothesis).
Typical Presentation
Many are asymptomatic - diagnosed on screening
Classic Symptoms (if present):
Atypical/Late Presentations
Screening Indications
Structured Approach
General:
- BMI, waist circumference
- Acanthosis nigricans (insulin resistance marker)
Cardiovascular:
- Blood pressure
- Peripheral pulses
- Cardiac assessment
Feet (Critical):
- Inspection (ulcers, calluses, deformity)
- Pulses (dorsalis pedis, posterior tibial)
- Sensation (10g monofilament, vibration)
- Temperature
Eyes:
- Retinal screening (dilated fundoscopy or digital photography)
Diagnosis
| Test | Diagnostic Criteria |
|---|---|
| HbA1c | ≥48 mmol/mol (6.5%) |
| Fasting Glucose | ≥7.0 mmol/L |
| Random Glucose | ≥11.1 mmol/L + symptoms |
| OGTT 2h glucose | ≥11.1 mmol/L |
Repeat Confirmation: Needed if asymptomatic (single test insufficient)
Prediabetes
| Test | Prediabetes Range |
|---|---|
| HbA1c | 42-47 mmol/mol (6.0-6.4%) |
| Fasting Glucose (IFG) | 6.1-6.9 mmol/L |
| OGTT 2h (IGT) | 7.8-11.0 mmol/L |
Baseline and Annual Screening
| Investigation | Purpose |
|---|---|
| HbA1c | Glycaemic control |
| Renal function (U&Es, eGFR) | Nephropathy |
| Urine ACR | Microalbuminuria |
| Lipid profile | CV risk |
| LFTs | NAFLD, statin monitoring |
| Retinal screening | Retinopathy |
| Foot examination | Neuropathy, vascular |
Diabetes Types
| Type | Features |
|---|---|
| Type 1 | Autoimmune, insulin-dependent, younger onset |
| Type 2 | Insulin resistance, obesity-related, older onset |
| Gestational | During pregnancy |
| MODY | Monogenic, family history, young onset |
| Secondary | Steroids, pancreatitis, Cushing's |
HbA1c Targets (Individualised)
| Patient Group | Target |
|---|---|
| Diet/Metformin only | 48 mmol/mol (6.5%) |
| On medications with hypoglycaemia risk | 53 mmol/mol (7.0%) |
| Elderly/Frail | Higher targets acceptable |
Step 1: Lifestyle Intervention (All Patients)
- Weight loss: Target 5-10% (15kg+ for remission)
- Diet: Low glycaemic index, Mediterranean, calorie restriction
- Exercise: 150 minutes/week moderate intensity
- Smoking cessation, alcohol reduction
Step 2: First-Line Pharmacotherapy
Metformin:
- Start if HbA1c above target despite lifestyle
- Titrate to 2g/day (or max tolerated)
- Avoid if eGFR <30; reduce if eGFR 30-45
- Side effects: GI upset, B12 deficiency
Step 3: Second-Line (Add to Metformin)
Choice Based on Comorbidities (NICE):
| Condition | Preferred Agent |
|---|---|
| ASCVD (CVD) | SGLT2 inhibitor (empagliflozin, dapagliflozin) |
| Heart Failure | SGLT2 inhibitor |
| CKD with proteinuria | SGLT2 inhibitor then GLP-1 RA |
| Obesity | GLP-1 RA (semaglutide, liraglutide) |
| General | SGLT2i, GLP-1 RA, DPP-4i, or SU |
Key Drug Classes:
| Class | Examples | Benefits | Risks |
|---|---|---|---|
| SGLT2i | Empagliflozin, Dapagliflozin | CV benefit, renal protection, weight loss | Euglycaemic DKA, UTI, genital mycosis |
| GLP-1 RA | Semaglutide, Liraglutide, Dulaglutide | CV benefit, weight loss | GI upset, pancreatitis (rare) |
| DPP-4i | Sitagliptin, Linagliptin | Weight neutral, well tolerated | Modest efficacy |
| SU | Gliclazide, Glimepiride | Effective, cheap | Hypoglycaemia, weight gain |
Pharmacology Drill Down: The New Era
1. SGLT2 Inhibitors ("The Flozins")
- Mechanism: Blocks Sodium-Glucose Co-Transporter 2 in the kidney (PCT). Dumps glucose (and calories) into urine.
- Bonus: Osmotic diuresis lowers BP. Reducing preload helps Heart Failure.
- Rule: "Sick Day Rules" apply (Risk of Euglycaemic DKA). Stop if dehydrated/unwell.
2. GLP-1 Agonists ("The Glutides")
- Mechanism: Mimics Incretin.
- Brain: Satiety (Stop eating).
- Stomach: Slows emptying (Fullness).
- Pancreas: Boosts insulin (glucose-dependent).
- Potency: Tirzepatide (Twincretin: GLP-1 + GIP) provides surgical-level weight loss (>20%).
Step 4: Triple Therapy or Insulin
- Add third agent if dual therapy insufficient
- Consider insulin if:
- Symptomatic hyperglycaemia
- HbA1c >70 mmol/mol
- Contraindications to oral agents
Cardiovascular Risk Management
All Patients with T2DM:
- Statin (atorvastatin 20-40mg, higher if QRISK >10% or CVD)
- BP target: <140/90 (or <130/80 if CKD/CVD)
- ACE-I/ARB if albuminuria
- Consider aspirin if established CVD
Microvascular (Small Vessel)
| Complication | Screening | Management |
|---|---|---|
| Retinopathy | Annual retinal photo | Laser, anti-VEGF |
| Nephropathy | Annual ACR + eGFR | ACE-I/ARB, SGLT2i |
| Neuropathy | Annual foot exam | Foot care, manage pain |
Macrovascular (Large Vessel)
- Coronary artery disease (2-4x risk)
- Cerebrovascular disease
- Peripheral arterial disease
Diabetic Foot
Risk Factors: Neuropathy, PVD, deformity
Prevention: Annual review, footwear advice, podiatry
Management of Ulcer: MDT (diabetes, vascular, orthotics, wound care)
Drill Down: Obstructive Sleep Apnoea (OSA)
The dangerous partner.
- Prevalence: 50-80% of T2DM patients have OSA.
- Mechanism: Intermittent hypoxia worsens insulin resistance (Stress response).
- Screening: ASK about snoring and daytime sleepiness (Epworth Score).
- Treatment: CPAP improves glucose control.
Drill Down: MASLD (Fatty Liver)
Metabolic Dysfunction-Associated Steatotic Liver Disease.
- New Name: Replaces NAFLD to reduce stigma.
- Link: 70% of T2DM patients have Fatty Liver.
- Risk: Progression to Cirrhosis (NASH) and Hepatocellular Carcinoma.
- Screen: FIB-4 Score (Age, AST, ALT, Platelets).
Acute Complications
| Emergency | Features | Management |
|---|---|---|
| HHS | Severe hyperglycaemia, dehydration, osmolality >320 | IV fluids, insulin, K+ |
| Hypoglycaemia | Glucose <4 mmol/L | Oral glucose, glucagon, IV dextrose |
Drill Down: HHS Management
Hyperosmolar Hyperglycaemic State. The "Silent Killer".
- Mortality: 15-20% (Much higher than DKA).
- Pathophysiology: Enough insulin to stop ketones, but not enough to stop hyperglycaemia. Osmotic diuresis -> Profound Dehydration.
- Deficit: Patients are often 10-15 litres negative.
- Protocol:
- Fluids: 1L Saline stat. Aggressive rehydration is the primary treatment.
- Insulin: Fixed rate (0.05 u/kg/hr) ONLY if glucose isn't falling with fluids alone. (Insulin drives water into cells -> Circulatory collapse if given too early).
- Clotting: High risk of DVT/PE due to viscosity. Low Molecular Weight Heparin essential.
Life Expectancy
- Reduced by 6-7 years on average
- Better with good control of glucose and CV risk factors
Remission
- Possible with significant weight loss (15+ kg)
- DiRECT trial: 46% remission at 1 year with low-calorie diet
Drill Down: The DiRECT Remission Protocol
Putting the disease to sleep.
- Concept: A "crash restart" for the pancreas.
- Protocol:
- Total Diet Replacement: 825 kcal/day (Soups and shakes) for 12 weeks. Stop all drugs.
- Food Reintroduction: 2-8 weeks.
- Maintenance: Long term support.
- Results:
- Weight loss >15kg: 86% achieved remission.
- Duration: Benefits sustained at 5 years if weight kept off.
Socioeconomic Impact
- Deprivation: T2DM is twice as common in lowest income quintile.
- Food Environment: "Food Deserts" (easy access to ultra-processed food) drive the epidemic.
- Cost: Treating T2DM takes 10% of the entire NHS budget.
Psychology: The Stigma
It is not "Self-Inflicted".
- The Myth: "You ate yourself into this."
- The Reality: Genetics plays a stronger role in T2DM (80% heritability) than T1DM (40%). Your environment pulls the trigger.
- Mental Health: Depression is 2x more common in T2DM. Treat heavily.
Prognostic Factors
Poor Prognosis:
- Poor glycaemic control
- Existing complications
- Obesity
- Cardiovascular disease
Good Prognosis:
- Early diagnosis
- Lifestyle modification
- Target HbA1c achieved
- BP and lipid control
Key Guidelines
| Guideline | Organisation | Year |
|---|---|---|
| Type 2 Diabetes | NICE NG28 | 2015 (Updated 2022) |
| ADA/EASD Consensus | ADA/EASD | 2022 |
| CKD in Diabetes | KDIGO | 2022 |
Key Trials
- UKPDS: Intensive glucose control reduces microvascular complications
- EMPA-REG OUTCOME: Empagliflozin reduces CV death in T2DM
- DAPA-CKD: Dapagliflozin reduces CKD progression
- SUSTAIN-6, LEADER: GLP-1 RAs reduce CV events
- DiRECT: Weight loss can achieve remission
What is Type 2 Diabetes?
Type 2 diabetes happens when your body doesn't respond properly to insulin (a hormone that controls blood sugar) and can't make enough to compensate. This causes blood sugar levels to rise, which over time can damage your organs.
What causes it?
- Weight: Being overweight, especially around the middle
- Lifestyle: Not enough physical activity, unhealthy diet
- Genetics: It runs in families
- Age: More common as you get older
- Ethnicity: Higher risk in South Asian, Black, and Chinese populations
What are the symptoms?
Many people have no symptoms initially. When present:
- Passing urine more often
- Feeling thirsty
- Tiredness
- Blurred vision
- Frequent infections
How is it treated?
- Lifestyle changes - healthier eating, exercise, weight loss
- Tablets - Metformin first, then other medications
- Injections - GLP-1 (weight loss effect), insulin (if needed)
- Regular checks - eyes, feet, kidneys, heart
Can it be reversed?
Yes! With significant weight loss (about 15 kg), some people can put their diabetes into remission, especially if caught early.
-
NICE. Type 2 diabetes in adults: management (NG28). 2015 (Updated 2022). nice.org.uk
-
Davies MJ, et al. Management of Hyperglycemia in Type 2 Diabetes, 2022: A Consensus Report by ADA and EASD. Diabetes Care. 2022;45(11):2753-2786. PMID: 36148880
-
Zinman B, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME). N Engl J Med. 2015;373(22):2117-2128. PMID: 26378978
-
Lean MEJ, et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT). Lancet. 2018;391(10120):541-551. PMID: 29221645
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. It does not replace professional medical judgement.