• Affects 10.5% of adults worldwide (2021) ^[1]
• Estimated 537 million adults living with DM globally (IDF Diabetes Atlas, 10th edition, 2021); projected to rise to 783 million by 2045
• ~90–95% of all DM is Type 2; ~5–10% is Type 1
• DM is a leading cause of blindness, end-stage renal disease, non-traumatic lower-limb amputation, and cardiovascular death worldwide

• Affects > 10% of HK adults ^[2]
• Prevalence is rising rapidly, particularly in younger age groups — driven by westernisation of diet, sedentary lifestyles, and the genetic susceptibility of East Asian populations to β-cell dysfunction at lower BMI
• T2DM accounts for ~95% of DM in HK; T1DM accounts for ~5% in Chinese populations (vs ~10% in Caucasians) ^[2]
• HK Chinese have a lower threshold for developing insulin resistance — metabolic consequences appear at lower BMI compared to Caucasians (hence a lower BMI cutoff for "overweight" in Asians: ≥ 23 kg/m²)

Genetic factors: ^[1][2]

• HLA-DR and HLA-DQ susceptibility haplotypes on chromosome 6 — these are the most important genetic determinants
  • 20% risk in HLA-identical twins ^[1]
  • 35% MZ twin concordance rate ^[2] (i.e., genetics is important but not sufficient — environment must play a role)
• Other genes, e.g. insulin gene (VNTR polymorphisms), CTLA-4, PTPN22 ^[1]

Environmental factors (exact nature uncertain, ?multi-hit action): ^[1]

• Viruses: Coxsackie B, mumps — proposed mechanism is molecular mimicry (viral antigens resemble β-cell antigens, triggering cross-reactive autoimmunity)
• Bovine serum albumin (BSA) in cow's milk in early infancy — ↑ risk of T1DM if cow's milk introduced early ^[2]
• Toxins: nitrosamines, coffee ^[2]

Immunological factors: ^[1][2]

• Hygiene hypothesis — reduced exposure to infections in early life may predispose to autoimmune disease
• Association with other autoimmune disorders: thyroid disease (Hashimoto's/Graves', 2–5%), coeliac disease, Addison's disease, pernicious anaemia, vitiligo ^[2]

Genetics: ^[2]

• MZ twin concordance rate = 70–90% (paradoxically higher than T1DM — strong genetic basis)
• Most genes associated with altered regulation of β-cell mass (not just insulin resistance)
• First-degree relative with DM is an important risk factor — 75% risk if both parents affected ^[2]

Modifiable risk factors:

• Obesity: 10× risk if BMI > 30 ^[2]
  • Central (visceral) obesity is the key driver — adipocytes release FFAs and pro-inflammatory adipokines → insulin resistance
  • In Asians, metabolic risk appears at lower BMI (overweight cutoff ≥ 23 kg/m²)
• Physical inactivity — ↓ AMPK activation → ↓ glucose uptake and ↓ FFA metabolism ^[2]
• Metabolic syndrome components: HTN, dyslipidaemia, PCOS, NAFLD ^[2]

Other risk factors:

• Previous pre-diabetes (IFG or IGT) ^[2]
• History of gestational diabetes ^[2]
• Age ≥ 45 years ^[2]
• Ethnicity (South Asian, Pacific Islander, Indigenous populations at higher risk)
• Medications: glucocorticoids, thiazides, atypical antipsychotics, immunosuppressants (e.g. tacrolimus)

The pancreas is a retroperitoneal organ lying posterior to the stomach, spanning from the C-loop of the duodenum (head) to the hilum of the spleen (tail). It has both exocrine (acinar cells producing digestive enzymes) and endocrine (islets of Langerhans) functions.

The islets constitute only ~1–2% of pancreatic mass but receive ~10–15% of pancreatic blood flow (reflecting their metabolic importance). Each islet contains ~3,000 endocrine cells:

Site: pancreatic islet β-cells (core) ^[2]

Process: ^[2]

1. Glucose entry: ↑ blood glucose → glucose enters β-cell via GLUT-2 transporters (GLUT-2 has a high Km — it acts as a "glucose sensor," only transporting significant glucose when blood levels are elevated)
2. Metabolism: Glucose undergoes glycolysis → ↑ ATP production
3. Channel closure: ↑ ATP → closure of ATP-sensitive K⁺ channels (K_ATP channels)
4. Depolarisation: K⁺ can no longer leave the cell → membrane depolarisation
5. Ca²⁺ influx: Depolarisation opens voltage-gated Ca²⁺ channels → Ca²⁺ influx
6. Exocytosis: Ca²⁺ triggers exocytosis of insulin-containing granules

Insulin is produced by cleaving C-peptide from proinsulin. ^[2] Therefore:

• C-peptide levels reflect endogenous insulin secretion — this is clinically critical because exogenous insulin injections do NOT contain C-peptide
• C-peptide measurement helps distinguish T1DM (↓ C-peptide) from T2DM (normal/↑ C-peptide, at least early on) and from factitious hypoglycaemia

Why C-peptide and not just measure insulin? Because in patients on insulin therapy, exogenous insulin would confound the measurement. C-peptide is released 1:1 with endogenous insulin, is not present in exogenous insulin preparations, and has a longer half-life — making it the ideal marker of residual β-cell function.

Critical to maintain normal blood levels of fuel molecules, i.e. glucose and fatty acids. ^[2]

Fed state (after a meal): ^[2]

• ↑ glucose → ↑ insulin secretion
  • ↑ tissue uptake of glucose (especially muscle and adipose tissue via GLUT-4)
  • ↑ hepatic uptake → glycogenesis (glucose → glycogen) and lipogenesis (glucose → fatty acids → triglycerides)
  • ↑ amino acid uptake → protein synthesis
• Net effect: anabolic — energy is stored

Fasting state (between meals): ^[2]

• ↓ glucose → ↓ insulin, ↑ glucagon, ↑ adrenaline
  • ↑ glycogenolysis (glycogen → glucose) in liver
  • ↑ gluconeogenesis (amino acids, lactate, glycerol → glucose) in liver
  • ↑ lipolysis (triglycerides → glycerol + free fatty acids)
  • ↑ ketogenesis (FFAs → ketone bodies in liver)
• Net effect: catabolic — energy stores are mobilised

Failure in any step of insulin secretion or action → diabetes ^[2]

Causes of DM: ^[1][2]

LADA: Latent Autoimmune Diabetes in Adults ^[1]

• Slow but progressive autoimmune β-cell destruction
• Years of marginal insulin secretion
• Presents like type 2 DM with difficult control
• Associated with other autoimmune diseases
• Non-obese
• Positive islet autoantibodies
• ?Type 1 DM (under debate) ^[1]

Think of LADA as "slowly burning" T1DM in adults. The immune attack on β-cells is more indolent, so patients initially look like T2DM (middle-aged, can be managed with oral drugs initially) but are actually autoimmune. Clues:

• Non-obese patient with "T2DM" who rapidly fails oral therapy
• Positive autoantibodies (especially anti-GAD)
• Other autoimmune conditions
• ↓ C-peptide over time

Monogenic diabetes, e.g. maturity-onset diabetes of the young (MODY) ^[1][2]

• MODY = Maturity-Onset Diabetes of the Young
  • Onset ≤ 25 years of age ^[1]
  • Autosomal dominant inheritance ^[1]
  • > 14 known genes; MODY 1/2/3 are most common ^[1]

• Other monogenic causes: MIDD (maternally inherited diabetes and deafness — mitochondrial), Wolfram syndrome (DIDMOAD) = Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, Deafness ^[2]

Secondary diabetes (may remit if underlying cause removed): ^[1][2]

All symptoms of DM can be derived from first principles if you understand two things:

1. Hyperglycaemia → osmotic effects + glycosuria
2. Insulin deficiency → inability to use/store fuel → catabolism

Workup for newly diagnosed DM — distinguishing T1 from T2: ^[2]

Note: considerable overlap may occur: ^[2]

• T2DM can present with marked weight loss and DKA and may be present in children
• T1DM can present insidiously and in an older age (i.e. LADA)

Definitive tests when unclear on diagnosis by clinical picture alone: ^[2]

• Auto-antibodies: anti-islet cell, anti-GAD (70–80%), anti-insulin (60–75%), anti-IA-2 (65–75%), anti-ZnT8 (70–80%)
• C-peptide: ↓ in T1DM, ↑/N in T2DM
• Glucagon stimulation test: inadequate stimulation of insulin secretion in T1DM

While I will cover DKA and HHS in detail in the management/complications section, it is worth mentioning the presenting features here:

Why does T1DM get DKA but T2DM gets HHS? In T1DM, absolute insulin deficiency means there is NO brake on lipolysis → massive FFA release → hepatic ketogenesis → ketoacidosis. In T2DM, there is still SOME residual insulin — enough to partially suppress lipolysis (so ketosis is minimal) but NOT enough to control glucose — so glucose climbs to extreme levels, causing severe osmotic diuresis and dehydration.

D/dx of polyuria + polydipsia: ^[4]

Polyuria as primary defect: urine output > water intake, ↑ plasma osmolality ^[4]

• Diabetes mellitus: a/w other hyperglycaemic symptoms ^[4] — glucose-driven osmotic diuresis
• Diabetes insipidus ^[4] — "insipidus" = tasteless (the urine has no sugar, unlike DM). Due to either ↓ ADH production (cranial DI) or ↓ renal response to ADH (nephrogenic DI) → inability to concentrate urine → massive water loss
• Chronic kidney disease ^[4] — loss of concentrating ability as nephrons are destroyed → obligatory polyuria
• Diuretics ^[4] — iatrogenic cause; always check the drug chart!
• Hypercalcaemia — Ca²⁺ antagonises ADH action at the collecting duct (nephrogenic DI-like effect) + causes nephrocalcinosis
• Hypokalaemia — impairs renal concentrating ability (↓ aquaporin-2 expression)

Excessive drinking as primary defect: water intake > urine output, ↓ plasma osmolality ^[4]

• Primary polydipsia: excessive drinking in patients with psychiatric disease or hypothalamic lesions ^[4] — the thirst drive is pathologically increased. Urine is appropriately dilute because the kidneys are working correctly to excrete the excess water.

How to distinguish these? The key discriminator is plasma osmolality and the paired urine osmolality:

• DM: ↑ plasma glucose, ↑ plasma osmolality, urine contains glucose
• DI: ↑ or high-normal plasma Na/osmolality, urine is inappropriately dilute (U/P ratio < 1)
• Primary polydipsia: ↓ plasma Na/osmolality, ↓ urine osmolality
• CKD: ↑ urea and creatinine, isosthenuria (urine osmolality fixed ~300 mOsm/kg)

When a patient presents with unexplained weight loss, DM is one cause — but the differential is wide:

Recurrent UTIs, vulvovaginal candidiasis, or skin infections can be the presenting complaint. The differential includes:

• Diabetes mellitus — glycosuria + immunodeficiency
• HIV/AIDS — check risk factors, offer HIV testing
• Primary immunodeficiency — rare, usually presents in childhood
• Structural urological abnormality — for recurrent UTIs specifically

Comparison of clinical, genetic, and immunologic features of type 1 and type 2 diabetes: ^[3]

LADA is the great mimicker — it masquerades as T2DM. Suspect LADA when:

• Non-obese patient diagnosed with "T2DM" ^[1]
• Difficult glycaemic control on oral agents — progressive deterioration suggesting β-cell failure ^[1]
• Other autoimmune diseases present (thyroid, vitiligo, coeliac) ^[1]
• Positive islet autoantibodies (especially anti-GAD) ^[1]
• Age typically 30–50 years

Monogenic diabetes — MODY: ^[1][2]

• Onset ≤ 25 years, autosomal dominant — strong FHx of early-onset DM across ≥ 3 generations
• Non-obese — unlike T2DM
• Negative autoantibodies — unlike T1DM
• Detectable C-peptide even years after diagnosis — unlike T1DM
• > 14 known genes; MODY 1/2/3 most common ^[1]
• Diagnosis: genetic testing ^[2]

Key distinguishing features:

Also note other causes of DM: ^[2]

Haemochromatosis deserves special mention as a cause of secondary DM in HK exams: ^[7]

• Diabetes mellitus in 50% of patients — due to progressive iron accumulation in pancreatic islets → β-cell destruction
• Known as "bronze diabetes" — combination of DM + leaden-grey skin pigmentation (from excessive melanin deposition)
• May have ↓ insulin requirement after phlebotomy ^[7] — because removing iron reduces ongoing β-cell damage
• Also causes: hepatomegaly/cirrhosis, dilated cardiomyopathy, arthropathy (MCP joints), hypogonadism

Chronic pancreatitis as a cause of DM: ^[6]

• Islets of Langerhans are relatively resistant to injury → usually affected last ^[6]
• DM from chronic pancreatitis is also insulin-dependent (like T1DM) but α-cells are also destroyed → associated with ↑↑ risk of hypoglycaemia ^[6] — this is a critical exam point. Why? Because glucagon (from α-cells) is the primary counter-regulatory hormone for hypoglycaemia. When both insulin-secreting β-cells AND glucagon-secreting α-cells are destroyed, the patient has no safety net against hypoglycaemia.
• Classical triad of chronic pancreatitis (late stage): pancreatic calcification + steatorrhoea + DM ^[6]

Diagnosis of Diabetes: WHO/IDF/ADA 2025 ^[3]

Based on Venous Plasma Glucose: ^[3]

Based on HbA1c: ^[3]

• HbA1c ≥ 6.5%
• Must be based on standardised HbA1c assays with stringent quality assurance ^[3]

Prediabetes (ADA) / Intermediate hyperglycaemia (WHO): ^[3]

By Glucose Criteria: ^[3]

By HbA1c Criteria: ^[3]

• ADA: 5.7–6.4%
• Canada/Europe: 6.0–6.4%
• WHO: no HbA1c criteria for pre-diabetes ^[3]

Pre-diabetes: ↑ risk of DM and macrovascular complications but no ↑ risk of microvascular complications ^[2]

Why does pre-diabetes matter? Because IGT/IFG carry an increased risk of developing diabetes and cardiovascular diseases ^[3]. Approximately 5–10% of people with pre-diabetes progress to frank DM per year. This is the window where lifestyle intervention (diet, exercise, weight loss) is most effective — the Diabetes Prevention Program (DPP) showed 58% reduction in progression to DM with lifestyle changes vs 31% with metformin.

GDM (gestational diabetes): ^[3]

• 14% of pregnancies globally (IDF Atlas 2022) ^[3]
• Transient diabetes / impaired glucose tolerance during pregnancy ^[3]
• Usually normal glucose tolerance after delivery ^[3]
• 50% DM on long-term follow-up ^[3]

GDM uses different diagnostic criteria (IADPSG / WHO 2013 criteria based on the HAPO study):

• Diagnosed by 75g OGTT at 24–28 weeks gestation
• ANY one of the following:
  • Fasting glucose ≥ 5.1 mmol/L
  • 1-hour glucose ≥ 10.0 mmol/L
  • 2-hour glucose ≥ 8.5 mmol/L

Note these thresholds are lower than for non-pregnant DM — because hyperglycaemia during pregnancy causes fetal macrosomia, birth complications, and neonatal hypoglycaemia at lower glucose levels.

HbA1c (glycated haemoglobin) reflects the average blood glucose over the preceding 2–3 months — because it measures the non-enzymatic glycation of haemoglobin, which is proportional to the ambient glucose concentration and the lifespan of the red blood cell (~120 days).

Advantages of HbA1c:

• No fasting required
• Less day-to-day variability than glucose measurements
• Not affected by acute stress
• Directly linked to complication risk

Limitations / caveats of HbA1c:

The Oral Glucose Tolerance Test (OGTT) is a dynamic test of how the body handles a standardised glucose load:

Procedure:

1. Patient fasts for ≥ 8 hours overnight
2. Fasting venous glucose is drawn
3. Patient drinks 75g anhydrous glucose dissolved in 250–300 mL water over 5 minutes
4. Venous glucose is drawn at 2 hours

When is OGTT specifically indicated?

• When fasting glucose and HbA1c are discordant or borderline
• Screening for GDM (24–28 weeks gestation)
• Diagnosis of IGT (cannot be diagnosed by fasting glucose alone — IGT specifically refers to the 2-hour post-load value)
• Post-transplant diabetes screening

Note that arterial glucose > venous glucose (due to tissue consumption) and plasma glucose > whole blood glucose (due to low glucose within RBC) ^[2]. This is why we specifically use venous plasma glucose for diagnosis — standardisation is key.

This is the aetiology workup — performed once DM is confirmed and the type is uncertain.

Why is C-peptide better than measuring insulin directly? Three reasons:

1. C-peptide is NOT present in exogenous insulin preparations — so it specifically reflects endogenous production
2. C-peptide has a longer half-life (~30 min vs ~5 min for insulin) — giving a more stable and reliable measurement
3. C-peptide is NOT cleared by the liver on first pass (unlike insulin, of which ~50% is extracted by the liver) — so peripheral C-peptide levels more accurately reflect total β-cell output

This workup assesses the metabolic state and screens for complications that may already be present at diagnosis — especially in T2DM where disease may have been subclinical for years.

A. Metabolic / Cardiovascular Risk Assessment

Diagnostic criteria of metabolic syndrome: presence of ≥ 3 of: ^[2]

1. Glucose intolerance or type 2 DM
2. Hypertension
3. Hypertriglyceridaemia
4. ↓ HDL-C
5. Central obesity

B. Microvascular Complication Screening

Complication screening: ^[9]

• Annual microvascular screen for all T2DM and T1DM ≥ 5 years from diagnosis or ≥ 10 years or at puberty ^[9]
• Involves: foot examination (including monofilament test), UACR, and dilated eye exam ^[9]

C. Other Baseline Investigations

D. Investigation for Secondary Causes (When Clinically Indicated)

Dietary management: integral part of therapy for all patients with diabetes ^[11]

General guidelines: ^[11]

• 30 kcal/kg ideal body weight per day, with adjustments depending on lifestyle and body weight ^[11]
• Aim at achieving normal body weight ^[11]
• Composition: ^[11][2]
  • 40–50% carbohydrates
  • 30% fat (< 7% saturated fat)
  • 20–30% protein
  • Fibre intake 20–35 g per day

Other dietary advice: ^[2]

• Personalised according to individual preference and culture
• Consistency of meal timing and quantity, especially if on insulin (to avoid hypoglycaemia and postprandial hyperglycaemia)
• Emphasis on ↑ fibre food, low-fat dairy products, and fresh fish
• Minimise high-energy food, especially those with high glycaemic index (GI) and glycaemic load (GL) ^[2]
• Hypocaloric diet for obese T2DM patients ^[2]

Glycaemic Index (GI) = a ranking of how quickly a carbohydrate-containing food raises blood glucose compared to pure glucose. Low-GI foods (< 55) cause a slower, steadier rise (e.g. legumes, whole grains). Glycaemic Load (GL) = GI × carbohydrate content per serving — a more practical measure of the actual glycaemic impact of a typical portion. ^[2]

Exercise: ^[2]

• 30–60 minutes moderate-intensity aerobic activity on most days of the week
• Resistance training ≥ 2 times per week
• Adequately but not excessively — especially if on insulin → risk of hypoglycaemia ^[2]

Weight management: ^[2]

• Dietician input, drug/operative treatment in severe cases
• Intensive clinician-supervised caloric restriction results in 46% remission at 1 year (DiRECT trial) ^[2]
• Alcohol in moderation (alcoholic beverages often also associated with caloric intake) ^[2]

Bariatric surgery for DM: ^[12]

• Indications in Asians: failed medical treatment + ^[12]
  • BMI ≥ 35
  • BMI ≥ 30 with T2DM
• Effect on metabolic syndrome: may achieve DM remission due to change in gut hormone levels (GLP-1) ^[12]
• ABCD score: Age, BMI, C-peptide, Duration of DM — total score = 10; score > 6 predicts DM remission after bariatric surgery ^[12]
• Contraindications: reversible causes (e.g. endocrine), psychiatric disorders, active substance abuse, non-compliance to medical care ^[12]

A. Biguanides — Metformin

B. Sulfonylureas (SUs)

C. Meglitinides (Glinides)

D. Thiazolidinediones (TZDs / Glitazones)

E. DPP-4 Inhibitors (Gliptins)

F. SGLT2 Inhibitors (Gliflozins)

G. GLP-1 Receptor Agonists (GLP-1 RAs)

H. Dual GIP/GLP-1 Receptor Agonists (Twincretins)

I. Alpha-Glucosidase Inhibitors

Forms of insulin: ^[2]

Insulin regimens: ^[2]

Initiation and titration (for T2DM starting basal insulin): ^[2]

• Start 10 IU/day or 0.1–0.2 IU/kg/day
• Titration: increase 2 IU every 3 days to reach fasting glucose target without hypoglycaemia
• For hypoglycaemia: determine cause; if no clear reason, lower dose by 10–20%

Assessing adequacy of basal insulin: ^[2]

• Consider clinical signals for overbasalisation and need for adjunctive therapy: basal dose > 0.5 IU/kg, elevated bedtime-to-morning or pre/postprandial differential, hypoglycaemia (aware or unaware), high variability

When basal insulin alone doesn't achieve target, the next step is:

1. Consider GLP-1 RA addition prior to prandial insulin ^[2] (weight benefit, lower hypo risk)
2. If GLP-1 RA not appropriate or already on it: add prandial insulin — usually one dose with the largest meal first, then stepwise additional injections
3. Full basal-bolus regimen as needed

T1DM: lifestyle measures + insulin ^[2]

• Basal-bolus is standard of care (multiple daily injections or insulin pump/CSII)
• Glycaemic control for T1DM: education important to match prandial insulin doses to carbohydrate intake, pre-meal H'stix, and anticipated physical activity ^[2]
• Consider CGM + insulin pump (closed-loop/hybrid closed-loop "artificial pancreas" systems) for improved control
• TFT ± anti-tTG IgA at diagnosis for concomitant autoimmune diseases ^[9]

• First-line: lifestyle modifications (diet + exercise)
• If targets not met: insulin is the preferred pharmacological agent (does not cross placenta)
• Metformin may be used in some guidelines as second-line (crosses placenta — long-term effects on fetus uncertain)
• Sulfonylureas: glibenclamide sometimes used but falling out of favour (neonatal hypoglycaemia)
• Postpartum: recheck glucose at 6–12 weeks (OGTT) — high risk of future T2DM (50% DM on long-term follow-up ^[3])

DKA is a life-threatening metabolic emergency characterised by the triad of:

1. Hyperglycaemia (usually > 14 mmol/L, but can be near-normal in "euglycaemic DKA")
2. Ketosis (↑ serum/urine ketones; β-hydroxybutyrate > 3.0 mmol/L)
3. Metabolic acidosis (pH < 7.3 and/or bicarbonate < 18 mmol/L)

Pathophysiology from first principles:

Absolute insulin deficiency (T1DM) or severe relative deficiency (stressed T2DM) → the body "thinks" it is starving:

• ↑ Counter-regulatory hormones (glucagon, cortisol, catecholamines, GH)
• Liver: ↑ gluconeogenesis + ↑ glycogenolysis → hyperglycaemia
• Adipose tissue: unopposed lipolysis → massive FFA release → FFAs transported to liver → hepatic β-oxidation → ketone body production (acetoacetate, β-hydroxybutyrate, acetone)
• Ketone bodies are organic acids → overwhelm blood buffering capacity → high-anion-gap metabolic acidosis (HAGMA)
• Hyperglycaemia → osmotic diuresis → severe dehydration + electrolyte loss (Na⁺, K⁺, PO₄³⁻, Mg²⁺)
• Total body K⁺ is DEPLETED (lost in urine) but serum K⁺ may be high/normal/low at presentation (acidosis drives K⁺ out of cells via H⁺/K⁺ exchange; insulin normally drives K⁺ into cells — without insulin, K⁺ stays extracellular)

Clinical features:

• Hyperglycaemic symptoms: polyuria, polydipsia, weakness
• Ketosis signs: nausea, vomiting, abdominal pain (thought to be due to ketone-mediated gastric stasis and mesenteric ischaemia), acetone (fruity) breath
• Metabolic acidosis: Kussmaul breathing (deep, rapid respiration — the respiratory system attempting to blow off CO₂ to compensate for metabolic acidosis)
• Dehydration: tachycardia, hypotension, dry mucous membranes, reduced skin turgor
• Altered consciousness: ranging from drowsiness to coma (related to hyperosmolality and cerebral dehydration)

Precipitants (the "5 I's"):

• Infection (most common)
• Insulin omission / non-compliance
• Infarction (MI, stroke)
• Intercurrent illness (surgery, trauma)
• Initial presentation (first diagnosis of T1DM)

Management principles:

1. Aggressive IV fluid resuscitation (0.9% NaCl initially — replace 5–8L deficit)
2. IV insulin infusion (fixed rate: 0.1 U/kg/h; DO NOT bolus)
3. Potassium replacement (critical — insulin drives K⁺ into cells; must check K⁺ before starting insulin; if K⁺ < 3.3 → replace K⁺ BEFORE starting insulin)
4. Monitor glucose hourly, VBG/electrolytes Q2–4h, fluid balance
5. Identify and treat precipitant (septic screen, ECG, CXR)
6. Bicarbonate: only if pH < 6.9 (controversial; routine use may worsen intracellular acidosis and hypoK)
7. Transition to SC insulin when: eating, pH > 7.3, bicarb > 18, ketones clearing — overlap SC and IV insulin by 1–2h

HHS is the typical acute emergency of T2DM — characterised by:

• Extreme hyperglycaemia (often > 33 mmol/L)
• Marked hyperosmolality (> 320 mOsm/kg)
• Profound dehydration (deficit often 8–12L)
• Minimal or NO ketosis (enough residual insulin to suppress lipolysis)

Why no ketosis in HHS? In T2DM, there is still some residual insulin — enough to prevent the massive lipolysis that drives ketogenesis, but NOT enough to control glucose. So glucose climbs to extreme levels, causing massive osmotic diuresis, while ketones remain low.

Clinical features:

• Develops insidiously over days to weeks (cf. DKA which develops over hours)
• Profound dehydration, altered consciousness (drowsiness → confusion → coma), seizures, focal neurological signs
• Mortality is HIGH (~15–20%, much higher than DKA) — largely because patients are often elderly with comorbidities, and the dehydration/hyperviscosity → thromboembolism risk

Management principles:

• IV fluids are the cornerstone (even more so than in DKA — the fluid deficit is greater)
• IV insulin at a lower rate initially (the glucose will drop substantially with rehydration alone; too-rapid insulin → precipitous osmolality drop → cerebral oedema)
• Thromboprophylaxis (LMWH) — hypercoagulability from dehydration/hyperviscosity
• Monitor and replace electrolytes

Clinical features: ^[2]

Adrenergic symptoms from ANS activity (usually occur first): ^[2]

• Palpitation, sweating, anxiety, tremor, tachycardia
• Note that threshold for awareness of hypoglycaemia varies between individuals and circumstances → especially note gradual ↓ awareness in recurrent hypoglycaemia (e.g. chronic DM) ^[2]

Neuroglycopenic symptoms from ↓ CNS activity due to hypoglycaemia (usually occur later): ^[2]

• Hunger sensation
• Periorbital and finger paraesthesia, seizures
• Focal weakness, ↓ sensation, clouding of vision
• ↓ Consciousness, drowsiness, coma ^[2]

Why do adrenergic symptoms come first? The sympathetic nervous system is activated at ~3.8 mmol/L as a counter-regulatory defence (adrenaline tries to raise glucose via glycogenolysis). Neuroglycopenic symptoms occur at ~2.8 mmol/L when brain glucose delivery falls below the threshold for normal neuronal function. In hypoglycaemia unawareness (common in long-standing T1DM with recurrent hypos), the adrenergic threshold shifts downward — the patient goes straight to neuroglycopenic symptoms without warning.

Diagnosis: confirmed by Whipple's triad: ^[2]

1. Symptoms compatible with hypoglycaemia
2. Low blood glucose coinciding with symptoms
3. Resolution of symptoms with correction of hypoglycaemia

Classification (ADA):

• Level 1: glucose < 3.9 mmol/L (alert value)
• Level 2: glucose < 3.0 mmol/L (clinically significant)
• Level 3: severe event requiring assistance from another person (regardless of glucose level)

Management: ^[2]

• Oral carbohydrates: sweet drink, early meal or snack, 15–20g oral glucose (especially if on acarbose)
• IV dextrose if unconscious or NPO: D50 40 mL IV stat followed by D10 drip
• IM glucagon if cannot obtain IV access: 1 mg IMI (avoided if suspected phaeochromocytoma)
• Monitoring: BG H'stix Q1–2h until stable ^[2]

Prevention: ^[2]

• Education to keep good balance between exercise, meals, and antidiabetic treatment
• Revise glycaemic target if frequent asymptomatic hypoglycaemia
• Consider pre-emptive glucagon prescription for those at risk of level 2–3 hypoglycaemia (ADA 2021)

Infections — pulmonary TB, urinary tract infection, others ^[1]

DM patients are immunocompromised due to:

• ↓ Neutrophil chemotaxis and phagocytosis (hyperglycaemia impairs the respiratory burst)
• ↓ T-cell function
• Glycosuria providing a culture medium for pathogens
• Microvascular disease → impaired tissue perfusion

Specific infections associated with DM:

• Pulmonary TB — HK has a high TB burden; DM increases TB risk 2–3× and TB may unmask undiagnosed DM. Marked weight loss suggests more severe diabetes or presence of TB ^[1]
• UTIs (including emphysematous cystitis/pyelonephritis)
• Skin/soft tissue infections — cellulitis, abscesses, necrotising fasciitis
• Rhinocerebral mucormycosis — aggressive fungal infection in poorly controlled DM/DKA; high mortality
• Malignant (necrotising) otitis externa — Pseudomonas in elderly diabetics; skull base osteomyelitis
• Emphysematous cholecystitis — gas-forming organisms in the gallbladder wall
• Fournier's gangrene — necrotising fasciitis of the perineum

Important ocular complications of diabetes mellitus: ^[11]

• Diabetic retinopathy (non-proliferative vs. proliferative)
• Diabetic macular oedema
• Neovascular glaucoma (growth of new vessels on iris extending to the angle of the anterior chamber, leading to high intraocular pressure and optic nerve degeneration)
• III, IV, VI nerve palsies
• Cataract

Prevalence: Retinopathy (90%) ^[2] — nearly all T1DM and ~60% of T2DM after 20 years

Pathogenesis: Hyperglycaemia → microvascular damage via all four pathways (polyol, AGEs, PKC, hexosamine) →

1. Pericyte loss (pericytes normally wrap around capillaries providing structural support — their loss leads to capillary weakness)
2. Basement membrane thickening (AGE cross-linking)
3. Microaneurysm formation (weak capillary walls balloon out — the earliest clinical sign)
4. Capillary occlusion → retinal ischaemia
5. Ischaemia → VEGF release → neovascularisation (new, fragile vessels that bleed easily)

Clinical features and course: ^[10]

• Asymptomatic: majority have no symptoms until very late stages ^[10]
• Visual loss: ^[10]
  • Insidious due to clinically significant macular oedema (CSME)
  • Acute due to vitreous haemorrhage (VH) or rubeotic glaucoma in PDR

Fundus findings: ^[10]

• Microangiopathy: microaneurysms, dot-and-blot haemorrhages
• Retinal exudation: hard exudates (lipid deposits from leaking capillaries — indicates macular oedema when close to macula! ^[10])
• Retinal ischaemia: cotton-wool spots (CWSs), venous beading, intraretinal microvascular abnormalities (IRMA) ^[10]
• Neovascularisation: disc, retina, iris (NVI), angle (NVA) ^[10]
• Complications of PDR: VH, posterior vitreous detachment (PVD), retinal detachment (RD), acute angle-closure glaucoma (AACG) ^[10]

Classification based on ETDRS: ^[10]

Course: ^[10]

• Onset: 3–5 years after diagnosis in T1DM; 4–7 years before diagnosis in T2DM (T2DM has subclinical hyperglycaemia for years before diagnosis)
• Worsens transiently with abruptly dropping blood sugar, cataract surgery, and during pregnancy ^[10]
• Presence of DR appears to be a marker of excess morbidity and mortality ^[10]

Management:

• Prevention: Good glycaemic control ^[11]; BP control; lipid management
• Monitoring: annual dilated fundoscopy; more frequent if NPDR detected
• PDR / high-risk NPDR: Panretinal photocoagulation (PRP) — laser destroys peripheral ischaemic retina, reducing VEGF drive for neovascularisation; prevention of drastic consequences — laser therapy ^[11]
• CSME / diabetic macular oedema: anti-VEGF intravitreal injections (ranibizumab, aflibercept, bevacizumab) — now first-line. Focal laser for refractory cases
• Ischaemic maculopathy: poorer visual prognosis; usually does NOT do PRP (↑↑ visual loss); benefit for anti-VEGF also less clear ^[10]
• Advanced PDR: vitrectomy for non-clearing VH or tractional retinal detachment

Prevalence: Nephropathy (30–40%) ^[2]

Pathogenesis: ^[2]

• Hyperglycaemia → ↑ ROS production → chronic damage to glomerular epithelium ^[2]
• Histology: ^[2]
  • Nodular glomerulosclerosis with Kimmelstiel-Wilson nodules (pathognomonic but not always present)
  • Diffuse glomerulosclerosis with ↑ mesangial matrix

Additional mechanisms:

• Haemodynamic: hyperglycaemia → afferent arteriolar dilation (via local mediators) → ↑ intraglomerular pressure → hyperfiltration → mechanical stretch damage to podocytes and mesangium → sclerosis
• Metabolic: AGEs cross-link GBM collagen → thickened, leaky basement membrane → proteinuria
• Inflammatory: ↑ TGF-β, angiotensin II → mesangial expansion and fibrosis

Clinical presentation: often associated with other microvascular complications (always in T1DM, ~70% in T2DM) ^[2]

• Onset: microalbuminuria develops 5–15 years after T1DM and 15–20 years after T2DM diagnosis ^[2]
• Albuminuria: slowly progressive from microalbuminuria (30–300 mg/day) to macroalbuminuria (> 300 mg/day) ^[2]
• Progressive CKD with gradual ↓ GFR ^[2]

Natural history:

Normal → Hyperfiltration → Microalbuminuria → Macroalbuminuria → ↓ GFR → ESRD
          (↑ GFR)         (UACR 3-30)         (UACR > 30)         (progressive)

Treatment of chronic complications — principles: ^[11]

1. Prevention — good glycaemic control ^[11]

2. Incipient (subclinical) stage — reversible (e.g. microalbuminuria): ^[11]

• Improve glycaemic control
• Treat other risk factors — BP, smoking
• Pharmacological intervention: ^[11]
  • Angiotensin converting enzyme inhibitor (ACEI)
  • Angiotensin II receptor blocker (ARB)
  • SGLT2 inhibitors / GLP-1 receptor agonists
  • Finerenone (non-steroidal aldosterone receptor antagonist) ^[11]

3. Overt complications: ^[11]

• Progression ↓ by: ↑ glycaemic control; risk factor management (hypertension, hyperlipidaemia, smoking)
• Specific: nephropathy — renin-angiotensin blockade (ACE inhibitors, ARB); SGLT2 inhibitors; GLP-1 receptor agonists; finerenone
• Symptomatic — dialysis / transplantation

Why ACEI/ARB? They dilate the efferent arteriole of the glomerulus → ↓ intraglomerular pressure → ↓ hyperfiltration → ↓ proteinuria → ↓ rate of GFR decline. They also reduce TGF-β and fibrosis. Indicated for ALL patients with DN regardless of BP.

Why SGLT2i? They restore tubuloglomerular feedback: ↑ Na delivery to macula densa → afferent arteriolar vasoconstriction → ↓ intraglomerular pressure. Additionally: ↓ inflammation, ↓ fibrosis, ↓ oxidative stress. CREDENCE and DAPA-CKD trials showed ~30–40% ↓ in CKD progression.

Why finerenone? Non-steroidal MRA that blocks aldosterone-mediated inflammation and fibrosis in the kidney and heart. FIDELIO-DKD and FIGARO-DKD trials showed ↓ CKD progression and ↓ CV events. Additive to ACEI/ARB and SGLT2i. Watch for hyperkalaemia.

Prevalence: Neuropathy (70–90%) ^[2]

Diabetic neuropathy is the most common complication of DM and takes many forms:

A. Distal Symmetrical Polyneuropathy (DSPN) — the most common form

• Pattern: Distal symmetrical sensorimotor ^[14] — "glove-and-stocking" distribution
• Fibre types affected: small fibres first (pain, temperature) → large fibres later (vibration, proprioception, motor)
• Pathophysiology: chronic hyperglycaemia → polyol pathway (sorbitol accumulation → Schwann cell osmotic damage) + AGE-mediated damage to vasa nervorum → nerve ischaemia + direct metabolic neuronal damage
• Symptoms: numbness, tingling, burning pain (worse at night), paraesthesiae in feet → progresses proximally
• Signs: ↓ vibration sense (128 Hz tuning fork), ↓ light touch (10g monofilament), ↓ ankle reflexes, ↓ proprioception
• Complications: diabetic foot (loss of protective sensation → unnoticed injury → ulceration → infection → amputation)
• Management:
  • Optimise glycaemic control (prevents progression)
  • Neuropathic pain: pregabalin/gabapentin (first-line); duloxetine/amitriptyline (alternatives)
  • Foot care: daily foot inspection, proper footwear, regular podiatry, avoid walking barefoot; prevention of drastic consequences — foot care ^[11]

B. Autonomic Neuropathy

C. Diabetic Mononeuropathy

Acute diabetic mononeuropathy: ^[2]

• Cause: likely ischaemic infarction of peripheral nerves ^[2]
• Site: most commonly CN III, CN VI, median and common peroneal palsies ^[2]
• Clinical presentation: acute onset, usually transient ^[2]
  • Ptosis and divergent squint (CN III) — typically pupil-sparing ^[2] (because the pupillary fibres travel on the outside of CN III and are spared in microvascular ischaemia; a compressive lesion like a PCA aneurysm DOES affect the pupil — this distinction is a classic exam question)
  • Lateral rectus palsy (CN VI)
  • Upper facial and eye pain (ocular)
  • Foot drop (peroneal nerve) ^[2]

D. Proximal Diabetic Neuropathy (Diabetic Amyotrophy)

Proximal diabetic neuropathy (diabetic amyotrophy, lumbosacral plexopathy): ^[2]

• Cause: likely ischaemic infarction of lumbosacral nerve roots and peripheral nerves ^[2]
• Site: asymmetrical, proximal, usually lower limbs ^[2]
• Clinical presentation: progressive, typically transient, lasting weeks to months ^[2]
  • Acute severe asymmetrical progressive proximal weakness and wasting
  • Hyperaesthesia and paraesthesia
  • Associated autonomic failure and weight loss ^[2]
• 60% with good functional recovery in 12–24 months but mild residual weakness may remain ^[2]