Type 2 diabetes mellitus

• Microvascular complications (retina, kidney, nerve) relate to glycaemic exposure and duration.
• Macrovascular risk requires simultaneous blood pressure, lipid and antiplatelet management.
• Many patients are asymptomatic for years — complications may be present at diagnosis.

Metabolic / lifestyle

Adiposity (especially visceral), physical inactivity, energy-dense diet, sleep deprivation

Genetic

Strong polygenic predisposition; family history doubles risk; MODY as a monogenic mimic

Endocrine secondary causes

Cushing syndrome, acromegaly, phaeochromocytoma, hyperthyroidism

Pancreatic

Chronic pancreatitis, pancreatic cancer, haemochromatosis, cystic fibrosis

Drug-induced

Glucocorticoids, thiazides, atypical antipsychotics, protease inhibitors, calcineurin inhibitors

Autoimmune mimic

Latent autoimmune diabetes in adults — consider when lean, ketosis-prone or failing oral therapy quickly

• Over half a billion adults live with diabetes worldwide, more than 90% type 2.
• South Asian, African, Hispanic and Indigenous populations develop disease at lower BMI and younger age.
• Roughly a third to a half of cases remain undiagnosed depending on the health system.

• Overweight/obesity and central adiposity
• Age ≥ 35-40 years (earlier in high-risk ethnicities)
• First-degree family history
• Prediabetes (impaired fasting glucose, impaired glucose tolerance, HbA1c 5.7-6.4%)
• Gestational diabetes or macrosomic infant
• Polycystic ovary syndrome, non-alcoholic fatty liver disease
• Hypertension, dyslipidaemia, established ASCVD
• Obstructive sleep apnoea, glucocorticoid or antipsychotic exposure

1. 1Caloric excess and adiposity increase circulating free fatty acids and pro-inflammatory adipokines.
2. 2Lipid intermediates impair insulin receptor signalling in muscle and liver — insulin resistance.
3. 3Beta cells compensate with hyperinsulinaemia; this maintains normoglycaemia for years.
4. 4Glucolipotoxicity, amyloid deposition and endoplasmic reticulum stress cause progressive beta-cell dysfunction and loss of mass.
5. 5When secretion can no longer offset resistance, fasting and postprandial glucose rise.
6. 6Incretin defect, raised glucagon, increased renal glucose reabsorption and adipose lipolysis complete the multi-organ picture.

Normal physiology → mechanism → tissue change → clinical picture

1. 1Normal physiology: insulin suppresses hepatic glucose output and drives skeletal muscle glucose uptake through GLUT4.
2. 2Mechanism: receptor post-signalling defects blunt both actions; alpha-cell glucagon excess persists.
3. 3Tissue change: unrestrained gluconeogenesis, reduced peripheral disposal, ongoing lipolysis and hepatic steatosis.
4. 4Downstream injury: advanced glycation end-products, polyol and hexosamine flux, protein kinase C activation and oxidative stress damage endothelium.
5. 5Clinical manifestation: osmotic symptoms, then retinopathy, nephropathy, neuropathy and accelerated atherosclerosis.

Pancreas

Islet amyloid polypeptide deposition, reduced beta-cell mass, preserved islet architecture

Kidney

Mesangial expansion, glomerular basement membrane thickening, Kimmelstiel-Wilson nodules, arteriolar hyalinosis

Retina

Pericyte loss, microaneurysms, capillary occlusion, neovascularisation in proliferative disease

Nerve

Axonal degeneration with segmental demyelination, endoneurial microangiopathy

Vessels

Accelerated atherosclerosis, medial calcification, endothelial dysfunction

• Often asymptomatic and found on screening
• Polyuria, polydipsia, nocturia
• Unintentional weight loss when markedly hyperglycaemic
• Fatigue, blurred vision
• Recurrent candidal or skin infections, slow-healing wounds
• Distal burning or numbness suggesting established neuropathy

• Raised BMI and waist circumference; acanthosis nigricans and skin tags
• Hypertension
• Fundoscopy: microaneurysms, dot-blot haemorrhages, exudates, neovascularisation
• Feet: reduced 10 g monofilament sensation, absent ankle reflexes, deformity, ulceration, absent pulses
• Peripheral vascular disease and carotid bruits

1. 1Confirm hyperglycaemia with a laboratory test — two abnormal results, or one result with unequivocal symptoms.
2. 2Differentiate type 2 from type 1/LADA and secondary causes: age, phenotype, ketones, C-peptide, GAD antibodies where uncertain.
3. 3Stage complications at diagnosis: retinal screening, urine albumin-to-creatinine ratio, eGFR, foot examination, lipids, blood pressure.
4. 4Assess cardiovascular, renal and heart failure status because they determine drug choice.
5. 5Agree an individualised HbA1c target and set a review interval.

Fasting plasma glucose

≥ 7.0 mmol/L (126 mg/dL) after ≥ 8 h fast

2-h plasma glucose (75 g OGTT)

≥ 11.1 mmol/L (200 mg/dL)

HbA1c

≥ 6.5% (48 mmol/mol)

Random glucose

≥ 11.1 mmol/L with classic symptoms or hyperglycaemic crisis

Prediabetes

FPG 5.6-6.9 mmol/L, 2-h glucose 7.8-11.0 mmol/L, or HbA1c 5.7-6.4%

Initial

• Fasting glucose or HbA1c, urinalysis for ketones and glucose, lipid profile, renal function, liver enzymes, blood pressure.

Confirmatory

• Repeat confirmatory glycaemic test; C-peptide and GAD/IA-2 antibodies when the type is uncertain.

Complication staging

• Urine albumin-to-creatinine ratio, eGFR, dilated retinal photography, foot risk assessment, ECG where indicated.

Monitoring

• HbA1c every 3-6 months, annual ACR and eGFR, annual retinal and foot screening, lipids after treatment change.

Type 1 diabetes / LADA

Rule in: lean, rapid onset, ketosis, positive GAD, low C-peptide. Rule out: obesity with metabolic syndrome and preserved C-peptide.

MODY

Rule in: strong autosomal dominant family history, onset < 25 y, non-obese, negative antibodies. Rule out: insulin resistance features.

Steroid-induced hyperglycaemia

Rule in: temporal link to glucocorticoids, prominent post-lunch rise. Rule out: persistence long after withdrawal.

Pancreatogenic (type 3c)

Rule in: pancreatitis history, steatorrhoea, low faecal elastase. Rule out: normal pancreatic imaging and exocrine function.

Stress hyperglycaemia

Rule in: acute illness, normalises on recovery, normal HbA1c. Rule out: HbA1c ≥ 6.5%.

• Glycaemic: HbA1c bands, with individualised targets — typically < 7% (53 mmol/mol), relaxed to < 8% in frailty or limited life expectancy.
• Complication staging: retinopathy (none/mild/moderate/severe NPDR/proliferative), CKD by eGFR (G1-G5) and albuminuria (A1-A3), neuropathy severity, foot risk category.
• Cardiovascular risk category: primary prevention vs established ASCVD.

Foundation for every patient

• Structured education, nutrition therapy, 150 min/week activity, weight management (5-10% loss changes trajectory), smoking cessation, sleep and mental health support.

Pharmacologic sequencing

• Metformin as first-line pharmacotherapy for most patients without contraindication.
• With ASCVD or high risk: add GLP-1 receptor agonist or SGLT2 inhibitor with proven benefit.
• With heart failure or CKD: SGLT2 inhibitor first (with GLP-1 RA where albuminuria persists).
• Where weight is the priority: GLP-1 RA or dual GIP/GLP-1 agonist.
• Cost-constrained settings: sulfonylurea or pioglitazone as add-on with counselling on hypoglycaemia and fluid retention.

Insulin

• Basal insulin when HbA1c remains above target on combination therapy, catabolic features are present, or HbA1c > 10%.
• Add prandial insulin or switch to basal-bolus if postprandial excursions dominate.

Adjunct and organ protection

• Metabolic surgery for selected patients with BMI ≥ 35 kg/m² (≥ 32.5 in Asian populations) and inadequate control.
• Statin therapy, blood-pressure control with ACEi/ARB when albuminuric, aspirin only for secondary prevention.

Monitoring

• HbA1c at 3 months after each change, renal function 1-2 weeks after starting ACEi/ARB or SGLT2 inhibitor, weight, blood pressure, injection-site and hypoglycaemia review.

Linked drug entities

• metformin — first-line; hold in AKI and before contrast if eGFR is low
• empagliflozin — cardiorenal protection; watch euglycaemic ketoacidosis and genital mycotic infection
• insulin-glargine — basal insulin for persistent hyperglycaemia
• atorvastatin — cardiovascular risk reduction, indicated in most adults with diabetes over 40

Acute

• Hypoglycaemia (treatment-related), diabetic ketoacidosis, hyperosmolar hyperglycaemic state.

Microvascular

• Retinopathy and maculopathy, diabetic kidney disease, peripheral and autonomic neuropathy, foot ulceration and Charcot arthropathy.

Macrovascular

• Coronary disease, stroke, peripheral arterial disease, heart failure.

Other systems

• Non-alcoholic fatty liver disease, periodontal disease, depression, cognitive decline, sexual dysfunction, increased infection risk.

• Life expectancy reduction varies with age at diagnosis and risk-factor control; early multifactorial control substantially narrows the gap.
• Legacy effect: early intensive glycaemic control yields long-term microvascular and later macrovascular benefit.
• Remission is achievable with substantial weight loss, particularly within the first years after diagnosis.
• Albuminuria and reduced eGFR are the strongest predictors of cardiovascular death.

• Screen adults from 35 years, or earlier with overweight plus a risk factor; re-screen at least every 3 years.
• Intensive lifestyle programmes reduce progression from prediabetes by roughly half.
• Metformin can be considered in high-risk prediabetes, especially BMI ≥ 35, age < 60 or prior gestational diabetes.
• Postpartum screening after gestational diabetes at 4-12 weeks and lifelong periodic testing.

• HbA1c every 3 months until at target, then every 6 months.
• Annual: urine ACR, eGFR, lipids, foot examination, retinal screening, blood pressure at each visit.
• Review drug tolerability, hypoglycaemia episodes, vaccination status and mental health annually.
• Reassess treatment goals with ageing, frailty or new comorbidity.

Pregnancy

Stop most oral agents except metformin per local policy; insulin is standard; ACEi/ARB and statins contraindicated

Lactation

Metformin and insulin compatible; monitor for hypoglycaemia with reduced intake

Paediatrics/adolescents

More aggressive beta-cell decline; metformin plus lifestyle, GLP-1 RA options; screen for comorbidity early

Elderly / frail

Relax HbA1c targets, deprescribe sulfonylureas and complex insulin regimens, prioritise hypoglycaemia avoidance

CKD

Metformin down to eGFR 30 with dose reduction; SGLT2 inhibitors for kidney protection; adjust or avoid sulfonylureas

Liver disease

Pioglitazone may help steatohepatitis; avoid in decompensated disease; metformin generally safe without decompensation

Ramadan / fasting

Pre-fast risk stratification, dose restructuring, glucose monitoring education, break-fast criteria

• ADA Standards of Care in Diabetes (2025)
• National diabetes programme guidance applicable to your country

• SGLT2 inhibitor and GLP-1 receptor agonist outcome trials underpin the shift from glucose-centred to organ-protection prescribing.
• Dual incretin agonists deliver substantially greater weight and HbA1c reduction in trial populations.
• Remission trials show durable benefit is closely tied to sustained weight loss.

• ADA Standards of Care in Diabetes 2025 (guideline, USA).
• DrZep editorial summary, demo dataset v0.1.