"A chronic disorder characterised by raised blood glucose levels, secondary to a complete or relative lack of insulin. Affects 10.5% adults worldwide in 2021." ^[1]

• Complete lack → Type 1 (autoimmune β-cell destruction)
• Relative lack → Type 2 (combination of insulin resistance + progressive β-cell failure)
• The word "relative" is important: in early Type 2, the pancreas may actually produce more insulin than normal, but it's not enough to overcome the resistance.

Asymptomatic – 50% – incidental glycosuria or hyperglycaemia. ^[1]

This is a critical exam point: half of DM patients are asymptomatic at diagnosis. They are found incidentally on routine blood tests.

Diagnosis based on venous plasma glucose OR HbA1c: ^[1]

Why venous plasma glucose? Arterial glucose > venous (tissues consume glucose), and plasma glucose > whole blood (RBCs have lower glucose concentration). The standard is venous plasma. ^[2]

IFG and IGT carry an increased risk of developing diabetes and cardiovascular diseases. ^[1]

Why two different IFG cut-offs? WHO uses 6.1, ADA uses 5.6. The ADA lowered their cut-off because the lower threshold identifies more people at risk, but this comes at the cost of lower specificity. For exams, know both but default to the one asked about.

Non-enzymatic glycosylation of N-terminal valine of Hb β-chain. Clinically used as an objective index of overall blood glucose control in the preceding 2–3 months. ^[1]

From first principles: Glucose attaches non-enzymatically to the N-terminal valine of the haemoglobin β-chain throughout the 120-day lifespan of a red blood cell. The more glucose in the blood over time, the higher the percentage of haemoglobin that becomes glycated. This gives you a weighted average of blood glucose over ~2–3 months (more recent weeks contribute more).

Objective index of overall blood glucose control in the preceding 1–3 weeks. Correct for serum albumin level (if < 3.0 mmol/L). ^[1]

Why does this exist? Fructosamine = glycosylated serum proteins (mainly albumin, which has a half-life of ~20 days). It's useful when HbA1c is unreliable (haemoglobinopathies, haemolytic anaemia, pregnancy). You must correct for low albumin because hypoalbuminaemia artificially lowers fructosamine regardless of glycaemic control.

Cluster of metabolic disorders linked by insulin resistance & associated with accelerated atherosclerosis. Diagnosis: presence of ≥ 3 of the following: ^[1]

Why does insulin resistance cause all of these? Insulin resistance means cells (especially muscle, liver, fat) respond poorly to insulin. The pancreas compensates by producing more insulin (hyperinsulinaemia). This hyperinsulinaemia promotes sodium retention (→ hypertension), stimulates hepatic VLDL production (→ hypertriglyceridaemia, ↓ HDL), and fails to suppress hepatic gluconeogenesis (→ hyperglycaemia). Central (visceral) adiposity is particularly metabolically active and drives the inflammatory milieu.

Type 1: β-cell destruction, mostly autoimmune in etiology: life-long insulin dependency. Type 2: reduced insulin secretion & sensitivity: diet ± oral drugs ± insulin. ^[1]

Other Specific Types:

Prediabetes; DM in first-degree relatives; History of GDM; Age over 35; Obesity, hypertension, dyslipidaemia. ^[1]

Type 1 diabetes occurs as a result of islet cell destruction, immunologically mediated. ^[1]

Three pillars:

a) Genetic factors:

• Chromosome 6: HLA-DR and HLA-DQ susceptibility genes
• 20% risk in HLA-identical twins
• Other genes: insulin gene (VNTR polymorphism on chromosome 11)
• Population-specific: Type 1 is rarer in Chinese (5%) vs Caucasians (10-20%)

b) Environmental factors:

• Exact nature uncertain, likely multi-hit
• Viruses: Coxsackie B, mumps → molecular mimicry or direct β-cell damage
• Cow's milk protein in infancy (controversial)

c) Immunological factors (evidence):

a) Presence of islet autoantibodies (GAD; IA2; ZnT8; insulin) at onset ^[1] b) Cell-mediated autoimmunity vs islet cells at autopsy ^[1] c) Increased remission/β-cell preservation after immunosuppressants (Cyclosporin/anti-TNF-α) ^[1] d) Teplizumab (anti-CD3 antibody targeting T-cells) delayed onset of T1DM by 2 years in asymptomatic at-risk relatives (Herold et al, NEJM 2019) – FDA-approved Jan 2023 ^[1]

The pathophysiology of type 2 diabetes includes three main defects: ^[1]

1. Insulin resistance (peripheral – muscle and fat): ↓ glucose uptake
2. Insulin resistance (hepatic): ↑ hepatic glucose output (gluconeogenesis + glycogenolysis)
3. Insulin deficiency (pancreas): Progressive β-cell failure + excess glucagon from α-cells

The natural history cascade:

Genes + Environment (obesity, physical inactivity, excessive food) → Insulin resistance → Compensatory hyperinsulinaemia with normal glucose tolerance → β-cell decompensation → IGT → Progressive β-cell decline → Hypoinsulinaemia with increasing hyperglycaemia → T2DM ^[1]

Key concept – Glucotoxicity and Lipotoxicity:

Decline is accelerated by glucotoxicity & lipotoxicity. ^[1]

• Glucotoxicity: Chronic hyperglycaemia itself damages β-cells (oxidative stress, ER stress) and worsens insulin resistance → vicious cycle
• Lipotoxicity: Elevated free fatty acids from visceral adiposity are toxic to β-cells and impair insulin signalling in muscle/liver

Diabetic ketoacidosis ± coma; Hyperosmolar nonketotic coma; Infections – pulmonary TB, UTI, others. ^[1]

Must exclude PRECIPITATING FACTORS: Infection; operation; trauma; severe emotional stress; MI; stroke (especially in the elderly); Drug administration e.g. steroid. ^[1]

The "6 Is" mnemonic from senior notes: ^[3]

• Insulin deficiency (missed doses, T1DM)
• Infection (chest, UTI)
• Inflammation (pancreatitis)
• Infarct (silent MI – always get ECG!)
• Iatrogenic (steroids, antipsychotics, SGLT2 inhibitors)
• Ingestion (methamphetamine, cocaine)

1. First manifestation of undiagnosed Type 1 diabetes. 2. Inadequate insulin treatment in known Type 1 diabetic patients. ^[1]

Acute insulin deficiency leads to unrestrained lipolysis, ↑ free fatty acids, excess hepatic ketone production and metabolic acidosis. ^[1]

From first principles:

1. Without insulin → no glucose entry into cells → cells "starve"
2. Counter-regulatory hormones surge (glucagon, cortisol, catecholamines, GH)
3. Hyperglycaemia pathway: ↑ gluconeogenesis + ↑ glycogenolysis (liver) + ↓ peripheral glucose uptake → blood glucose soars
4. Ketosis pathway: Insulin deficiency removes the brake on hormone-sensitive lipase → unrestrained lipolysis → ↑ free fatty acids flood the liver → β-oxidation → acetyl-CoA → overwhelms Krebs cycle capacity → shunted into ketogenesis → acetoacetate, β-hydroxybutyrate, acetone
5. These ketoacids are strong organic acids → consume bicarbonate → high anion gap metabolic acidosis (HAGMA)
6. Hyperglycaemia → osmotic diuresis → dehydration + electrolyte losses

Insulin deficiency also causes impaired tubular sodium reabsorption. Net result: serum sodium and potassium usually normal on admission. ^[1]

Hypokalaemia becomes evident after rehydration and insulin therapy (insulin-stimulated glucose transport into cell is accompanied by inward K+ shift). ^[1]

Why is K+ "normal" on admission but actually depleted?

• Osmotic diuresis → K+ lost in urine (total body K+ deficit)
• BUT: Insulin deficiency → K+ stays extracellular (no insulin-driven K+ uptake); acidosis → H⁺/K⁺ exchange pushes K+ out of cells
• So serum K+ looks normal or even high, masking a profound total body deficit
• When you give insulin → K+ rushes back into cells → serum K+ plummets → potentially fatal hypokalaemia with arrhythmias

Pseudohyponatraemia in DKA: Severe hyperglycaemia draws water out of cells osmotically → dilutes serum sodium. The "corrected sodium" is calculated by adding 1.6 mmol/L to the measured Na+ for every 5.6 mmol/L (100 mg/dL) increase in glucose above normal. ^[3]

1. Replace salt and water deficit – IV normal saline + K+ supplement (guided by serum K & renal function). ^[1] 2. Insulin – low dose (5–10 u/h) by continuous IV infusion. ↓ rate when blood glucose < 13 mmol/L. ^[1] 3. Correct acidosis – pH rises with rehydration and insulin. Bicarbonate infusion if pH < 7.0. ^[1] 4. Identify and treat the cause of DKA. ^[1] 5. Monitoring of clinical response, BP, pulse, urine output; CVP and ECG as indicated. ^[1] 6. Emergency measures/care of the unconscious patient. ^[1]

Step-by-step rationale:

1. Fluids first: These patients are typically 5–10 L fluid-depleted. Normal saline (0.9% NaCl) is first-line. Fluid alone begins to lower glucose (dilution + improved renal perfusion → glucosuria).
2. Insulin infusion (NOT bolus): Low-dose continuous IV insulin (5–10 units/hour) is safe and effective. The key goal of insulin is not just to lower glucose – it's to suppress ketogenesis. When glucose drops below 13 mmol/L, add 5% dextrose to the IV fluids and reduce insulin rate (but don't stop it – you still need to suppress ketones).
3. Potassium: Add K+ to IV fluids once K+ is confirmed < 5.5 mmol/L. Check K+ hourly initially.
4. Bicarbonate: Only if pH < 7.0 (severe acidosis impairs cardiac contractility and catecholamine response). Over-aggressive bicarb can cause paradoxical CNS acidosis, hypokalaemia, and rebound alkalosis.
5. Find the trigger: Blood cultures, urine culture, CXR, ECG (silent MI), drug history.
6. Monitor: Hourly glucose, 2-hourly K+ and blood gas until stable. Fluid balance chart. Consider CVP line in elderly/cardiac patients.

Ketosis usually absent (just sufficient insulin to suppress lipolysis and ketogenesis; severe hyperosmolality may ↓ lipolysis). ^[1]

In Type 2 DM, there is still some residual insulin secretion. This small amount of insulin is enough to prevent the massive unrestrained lipolysis that drives ketogenesis – but it's not enough to prevent hyperglycaemia. Additionally, hyperosmolality itself inhibits lipolysis through unknown mechanisms.

Severe hyperglycaemia and dehydration; severe hyperosmolality; depression of sensorium (when serum osmolality > 340 mmol/L) with lack of thirst response; high mortality. ^[1]

Why high mortality? Patients with HHS are typically elderly, present late (insidious onset over days to weeks), and are profoundly dehydrated (water deficit often 10–15 L). They may have reduced thirst perception and may be on diuretics, worsening dehydration. The severe hyperosmolality directly causes altered consciousness.

Effective serum osmolality = 2[Na⁺] + [Glucose] (all in mmol/L). Normal ~275–300. HHS: typically > 320.

Same as for DKA except: ^[1] 1. Less insulin required. 2. Water deficit more severe. 3. Fluid replacement guided by CVP or pulmonary wedge pressure monitoring (especially elderly/cardiac/renal disease). 4. If Na⁺ > 150 mmol/L, use ½ normal saline. 5. Thrombosis is more common especially in Caucasians with hyperosmolality: clinical vigilance required.

Why ½ normal saline? When Na⁺ is very high (> 150), giving isotonic (0.9%) saline would be relatively hypotonic to the patient's serum anyway, but switching to 0.45% saline provides more free water to correct the hyperosmolality and hypernatraemia more effectively. However, initial resuscitation should still use 0.9% NS to restore circulating volume.

Why thrombosis? Severe dehydration and hyperviscosity create a prothrombotic state → risk of DVT, PE, mesenteric ischaemia, stroke.

Too much sulphonylurea or insulin; too little carbohydrate; too much exercise; exclude renal impairment. ^[1]

Why renal impairment? The kidney is responsible for ~30% of insulin clearance. In CKD, insulin half-life is prolonged → accumulates → hypoglycaemia. Also, renal gluconeogenesis (which contributes ~20% of fasting glucose production) is impaired. Furthermore, sulphonylureas and their active metabolites are renally excreted.

Adrenergic: palpitation, sweating, tremor. Neuroglycopenic: hunger, restlessness, anxiety, numbness in fingers and around mouth, altered consciousness, drowsiness, coma. ^[1]

Why two categories? When glucose drops, the body first releases adrenaline/noradrenaline (adrenergic response – this is the "warning system"). If glucose continues to drop, the brain itself is starved of fuel (neuroglycopenia – this is the "danger zone"). In long-standing diabetes, patients may lose the adrenergic warning signs (hypoglycaemia unawareness) and present directly with neuroglycopenic symptoms.

Early meal or snack; sweet drinks, glucose tablets; intramuscular glucagon (1 mg); intravenous glucose. ^[1]

Up to 15 days recording. Detection of hypoglycaemia unawareness; nocturnal hypoglycaemia and Somogyi phenomenon; post-prandial hyperglycaemia. ^[1]

Somogyi phenomenon: Nocturnal hypoglycaemia → counter-regulatory hormone surge → rebound morning hyperglycaemia. Without CGM, you might see the morning high glucose and incorrectly increase the evening insulin dose, worsening the problem.

Treatment targets (CGM): Time in Range (TIR: 3.9–10 mmol/L) ≥ 70%; High (> 10) < 25%; Very high (> 14) < 5%; Hypoglycaemia (< 3.9) < 4%; Serious hypoglycaemia (< 3.0) < 1%. ^[1]

Less than 7% in general. Individualization of treatment goals. Greater risk of hypoglycaemia at extremes of age. Less stringent target if multiple co-morbidities or short life expectancy. ^[1]

Increasing prevalence due to obesity. Majority onset at 10–14 years; often asymptomatic (76% in HK). More rapid deterioration of β-cell function and earlier development of complications than adult-onset T2D. ^[1]

This is an alarming point: childhood-onset T2DM is more aggressive than adult-onset T2DM, with faster β-cell decline and earlier complications.

Use GLP1-RA or SGLT2 inhibitors as additional therapy to metformin. Basal or basal-bolus insulin analogs if glycaemic target not reached; CGMS. ^[1]

HK new-onset T1:T2 = 1.3:1. Basal-bolus insulin analogs; use of pump recommended; CGMS. Target HbA1c ≤ 7%; ≤ 6.5% if on pump (ADA 2025). ^[1]

DCCT: Benefits of good control (pump or multiple injections): ^[1]

• Primary prevention: retinopathy ↓ 53%, microalbuminuria ↓ 10%
• Secondary prevention: retinopathy progression ↓ 70%, microalbuminuria ↓ 70%
• Faster motor and sensory nerve conduction velocities
• Lower total cholesterol levels
• BUT: Intensive therapy associated with 2–4 fold ↑ in severe hypoglycaemia

Take-home: Good glycaemic control dramatically reduces microvascular complications, but the trade-off is increased hypoglycaemia risk. This is why individualisation of targets is crucial.

T1DM: Screen if (1) ≥ 5 years from diagnosis or (2) ≥ 2 years from diagnosis AND ≥ 10 years old. ^[1] T2DM: Start complication screening at diagnosis (HK: dyslipidaemia 35.3%, hypertension 22.5%, microalbuminuria 12.8% at diagnosis). ^[1]

Why screen T2DM at diagnosis? Because T2DM has typically been present for years before clinical diagnosis (insidious onset), so complications may already be established.

Annual thyroid dysfunction screening in T1DM (3–5% patients may have autoimmune thyroid disease). ^[1]

Why? Type 1 DM is an autoimmune disease. Autoimmune conditions cluster together (polyglandular autoimmune syndrome). Always screen for autoimmune thyroiditis, coeliac disease, and Addison's disease in T1DM patients.