Type 2 Diabetes Mellitus

Type 2 Diabetes Mellitus (T2DM) accounts for approximately 90% of diabetes cases in the UK. It is a heterogeneous condition where the primary defects are insulin resistance (the body's tissues fail to respond adequately to insulin) and relative insulin deficiency (the pancreas cannot secrete enough insulin to overcome the resistance). Risk factors include increasing age, obesity (particularly visceral adiposity), physical inactivity, and ethnicity (higher risk in South Asian, African-Caribbean, and Black African populations). Unlike T1DM, the onset is often insidious, and patients may remain asymptomatic for years, often presenting with complications such as foot ulcers or visual loss. Diagnosis is typically made using HbA1c (≥ 48 mmol/mol or 6.5%) or fasting glucose (≥ 7.0 mmol/L). If the patient is asymptomatic, two elevated tests are required on separate days. A key feature of T2DM is its association with 'Metabolic Syndrome', involving hypertension, dyslipidaemia, and obesity, which collectively increase the risk of macrovascular events. Management is stepwise, moving from lifestyle changes to Metformin, then adding agents like SGLT2 inhibitors (particularly in those with heart failure or CKD), DPP-4 inhibitors, Pioglitazone, or GLP-1 analogues. The UKPDS trial highlighted that intensive glycaemic control significantly reduces microvascular complications.

The pathogenesis of T2DM is multifactorial. Insulin resistance occurs when normal circulating levels of insulin produce a subnormal biological response. In obesity, adipocytes release non-esterified fatty acids (NEFAs), inflammatory cytokines (IL-6, TNF-alpha), and resistin, which interfere with insulin signalling pathways (PI3-kinase) in skeletal muscle and the liver. Initially, the pancreas compensates through hyperinsulinaemia to maintain normoglycaemia (Pre-diabetes). Over time, beta-cells begin to fail due to 'glucotoxicity', 'lipotoxicity', and amyloid deposition (amylin). This results in impaired glucose tolerance and eventually clinical diabetes. Furthermore, there is an 'Incretin effect' deficiency; the hormones GLP-1 and GIP produced by the gut in response to food are reduced or their action is impaired. The kidneys also play a role through increased expression of SGLT2 transporters in the proximal tubule, which increases glucose reabsorption despite systemic hyperglycaemia.

Presenting symptoms include polyuria, polydipsia, and blurred vision (due to osmotic changes in the lens). Recurrent infections, such as candidiasis (thrush) or skin infections, are common. Physical signs may include acanthosis nigricans (hyperpigmented, velvety skin folds in the neck or axilla), which is a clinical marker of severe insulin resistance. Chronic complications mirror T1DM: microvascular (retinopathy, nephropathy, neuropathy) and macrovascular (MI, Stroke, PAD). T2DM is a major risk factor for Non-Alcoholic Fatty Liver Disease (NAFLD). In extreme hyperglycaemia without significant ketosis, T2DM patients can develop Hyperosmolar Hyperglycaemic State (HHS), representing a medical emergency with high mortality.

Diagnosis: HbA1c (gold standard for non-pregnant adults); Fasting plasma glucose; Oral Glucose Tolerance Test (OGTT) - mainly used in pregnancy or if HbA1c is unreliable. Baseline bloods: Renal function (U&Es, eGFR), Liver Function Tests, Lipid profile, Urine ACR. NICE recommends assessing cardiovascular risk using the QRISK3 tool (though all T2DM patients are considered high risk).

**Conservative:** Weight loss (5-10%), smoking cessation, exercise (150 mins/week moderate intensity), dietary modification (low glycaemic index, high fibre).

**Medical — NICE NG28 (2023 update):**
**Phase 1:** Metformin (titrate to 500mg-1g BD). If Metformin is contraindicated or not tolerated, use a DPP-4i, SGLT2i, or Sulfonylurea based on individual factors.

**Intensification — add a second agent based on clinical profile:**
- **SGLT2 inhibitors** (Dapagliflozin/Empagliflozin): Add early if established CVD, Heart Failure, or CKD with ACR >3mg/mmol. Significant CV and renal outcome benefits beyond glucose lowering.
- **GLP-1 Receptor Agonists** (e.g. Semaglutide sc weekly, Liraglutide): Preferred intensification option where weight loss is a priority or BMI ≥35 kg/m², or in those with established atherosclerotic CVD (major CV benefit demonstrated in LEADER, SUSTAIN-6 trials). Semaglutide (Ozempic/Rybelsus) is the preferred agent for many patients. Tirzepatide (GLP-1/GIP dual agonist) approved by MHRA 2023 — significant weight loss and HbA1c reduction; NICE technology appraisal ongoing.
- **DPP-4 inhibitors** (e.g. Sitagliptin): Weight-neutral, low hypoglycaemia risk; use if SGLT2i/GLP-1 RA not suitable.
- **Sulfonylureas** (e.g. Gliclazide): Effective but cause weight gain and hypoglycaemia — use when cost or injection aversion is a factor.

**Phase 3:** Triple therapy or initiation of insulin (typically basal insulin first). Review ongoing GLP-1 RA if starting insulin — can be continued but reassess individually.

**Surgery:** Bariatric surgery recommended for BMI >35 kg/m² with recent-onset T2DM, or BMI 30-35 in certain ethnic groups; can achieve remission in up to 50-80% at 1 year.