PA31.{5,7} | Diabetes Mellitus & Pancreatic Cancer — Summary & Reflection

REFLECT

Before moving to pancreatic cancer, pause and consolidate:

1. A 16-year-old presents in DKA. You understand the mechanism — absolute insulin deficiency, lipolysis, ketogenesis, metabolic acidosis. You also know to check potassium before starting insulin. What else from the pathogenesis do you want to check on admission that tells you the underlying autoimmune process is still active vs burnt out?

1. A 45-year-old obese patient is told 'you are pre-diabetic — your FPG is 6.2 mmol/L'. Based on what you have just read about the natural history of T2DM, what is happening at the level of the islets right now? What are the therapeutic implications of intervening at this stage?

1. Your memory aid for KW nodules: Construct one sentence linking the mechanism (mesangial matrix expansion from AGE-driven type IV collagen overproduction) to the morphology (PAS-positive peripheral nodules) to the clinical consequence (nephrotic syndrome → ESRD). Write it in your own words.

KEY TAKEAWAYS

Diabetes Mellitus — key synthesis points:

• Classification: T1DM (autoimmune, absolute insulin deficiency, HLA-DR3/DR4, insulitis) vs T2DM (insulin resistance + progressive β-cell failure, islet amyloid/IAPP, obesity/metabolic syndrome) vs MODY (monogenic, AD) vs secondary vs gestational.

• Diagnosis: Any one of — FPG ≥7.0 mmol/L, 2hPG in OGTT ≥11.1 mmol/L, HbA1c ≥6.5%/48 mmol/mol, or random glucose ≥11.1 mmol/L with symptoms; confirmed on second occasion if asymptomatic.

• Acute complications: DKA (T1DM, absolute deficiency → ketosis + acidosis + hyperglycaemia) vs HHS (T2DM elderly, relative deficiency → extreme hyperosmolality, no ketosis).

• Chronic complication pathology:
• Microangiopathy mechanism: AGEs, polyol pathway, PKC, hexosamine pathway → basement membrane thickening
• Nephropathy: KW nodular glomerulosclerosis (PAS-positive mesangial nodules), efferent arteriolar hyalinosis (pathognomonic)
• Retinopathy: Dot/blot haemorrhages → hard exudates → cotton-wool spots → neovascularisation (proliferative, VEGF-driven)
• Neuropathy: Distal sensorimotor polyneuropathy; sorbitol in Schwann cells; autonomic neuropathy
• Macrovascular: Accelerated diffuse atherosclerosis (CAD, PAD, stroke)
• Diabetic foot: Neuropathy + ischaemia + infection → ulceration → amputation

Pancreatic ductal adenocarcinoma — key synthesis points:

• Risk factors: Smoking (strongest modifiable), chronic pancreatitis, T2DM, obesity, BRCA2 hereditary

• Molecular sequence: KRAS (>90%, earliest) → p16 loss (95%) → TP53 mutation (70%) → SMAD4 deletion (55%, predicts metastasis)

• PanIN precursor: PanIN-1 → PanIN-2 → PanIN-3 → PDAC; 5–10 year window

• Morphology: Head>body>tail; firm, grey-white, stellate, desmoplastic; ductal glands with perineural invasion; double duct sign

• Clinical triad (head): Painless obstructive jaundice + Courvoisier's sign + back/epigastric pain

• Paraneoplastics: Trousseau's migratory thrombophlebitis, new-onset DM, depression

• Tumour marker: CA19-9 (monitoring + recurrence; not diagnostic alone; absent in Lewis-negative patients)

• Metastasis: Liver (portal) > lungs > peritoneum; perineural spread; regional lymph nodes

• Prognosis: <10% 5-year survival; <20% resectable at diagnosis — one of the most lethal solid tumours.