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PY8.1-7 | Endocrine Physiology — SDL Guide (Part 3)

Type 1 vs Type 2 Diabetes: Pathophysiology

Type 1 Diabetes Mellitus (T1DM):
- Absolute insulin deficiency due to autoimmune destruction of β cells
- Without insulin: glucose cannot enter cells → hyperglycaemia; fat breakdown unchecked → ↑ ketone bodies (acetoacetate, β-hydroxybutyrate) → diabetic ketoacidosis (DKA)
- DKA: Kussmaul breathing (compensating metabolic acidosis), fruity breath (acetone), dehydration, hyperkalaemia initially (then hypokalaemia with insulin treatment)
- Treatment: insulin (exogenous replacement)

Type 2 Diabetes Mellitus (T2DM) — the epidemic:
- Insulin resistance (initially) + progressive β cell failure
- Mechanism of insulin resistance: ↑ visceral fat → free fatty acids + adipokines (resistin, TNF-α) → impair insulin signalling at post-receptor level (IRS-1 phosphorylation impaired)
- Initially: β cells compensate by secreting MORE insulin (hyperinsulinaemia). Blood glucose normal at the cost of high insulin.
- Eventually: β cells exhaust → insulin secretion falls → hyperglycaemia.
- T2DM is NOT associated with DKA (because residual insulin suppresses ketogenesis) but can develop hyperosmolar hyperglycaemic state (HHS) — extreme hyperglycaemia without ketosis.

Complications (long-term hyperglycaemia):
- Microvascular: Nephropathy, retinopathy, neuropathy — all from glycation of basement membranes and oxidative stress
- Macrovascular: Atherosclerosis → MI, stroke, PVD

Cross-subject link (BI): Advanced glycation end products (AGEs) that damage the GBM in diabetic nephropathy are the same biochemical products you studied in BI (non-enzymatic glycation of proteins).

Type 1 vs Type 2 Diabetes: Pathophysiology — Four-panel illustration showing T1DM autoimmune beta cell destruction with DKA pathway, T2DM insulin resistance progression to beta cell failure, micro- and macrovascular complications of diabetes, and HbA1c as a long-term glucose monitoring tool.

Flashcards

SELF-CHECK — : Glucose Homeostasis & Diabetes

A 16-year-old with T1DM misses his insulin injection for 24 hours. His blood gas shows pH 7.18, HCO₃⁻ 8 mEq/L, glucose 480 mg/dL. What is the primary mechanism causing the metabolic acidosis?

A. Excess lactic acid from anaerobic glycolysis

B. Renal failure causing inability to excrete H⁺

C. Unchecked lipolysis and ketogenesis due to absence of insulin, with glucagon driving ketone production

D. Hyperglycaemia directly acidifying the blood

Reveal Answer

Answer: C. Unchecked lipolysis and ketogenesis due to absence of insulin, with glucagon driving ketone production

A patient with T2DM has serum K⁺ of 6.2 mEq/L. The doctor gives insulin + glucose infusion. Why does insulin lower serum K⁺?

A. Insulin increases renal K⁺ excretion via aldosterone stimulation

B. Insulin activates Na-K-ATPase in muscle and fat cells, shifting K⁺ into cells

C. Insulin dilutes K⁺ by increasing blood volume

D. Insulin blocks K-ATP channels in the kidney

Reveal Answer

Answer: B. Insulin activates Na-K-ATPase in muscle and fat cells, shifting K⁺ into cells

Calcium Homeostasis: PTH, Vitamin D, and Calcitonin

Normal serum calcium: 8.5–10.5 mg/dL (or 2.1–2.6 mmol/L). About 50% is ionised (active); 40% protein-bound (to albumin — adjusts with albumin levels); 10% complexed.

Calcium is regulated by three hormones acting on three target organs (bone, kidney, gut):

PTH (Parathyroid Hormone) — the main defender against hypocalcaemia:
Released by chief cells of parathyroid glands when Ca²⁺ falls (sensed by calcium-sensing receptor, CaSR). PTH is the major short-term regulator.

Actions (all raise blood calcium):
- Bone: ↑ Osteoclast activity → bone resorption → releases Ca²⁺ and PO₄³⁻ into blood
- Kidney: ↑ Ca²⁺ reabsorption in DCT; ↓ phosphate reabsorption (phosphaturia); ↑ activation of Vitamin D (1α-hydroxylase in PCT)
- Gut: Indirect — via Vitamin D activation

Vitamin D (Calcitriol — 1,25-dihydroxycholecalciferol):
Activation pathway:
- Skin: UV light → 7-dehydrocholesterol → cholecalciferol (Vit D3)
- Liver: 25-hydroxylation → 25-OH Vit D3 (storage form; measured in blood tests)
- Kidney: 1α-hydroxylation (stimulated by PTH and hypophosphataemia) → 1,25-(OH)₂D₃ (calcitriol — active form)

Actions: ↑ Ca²⁺ and PO₄³⁻ absorption from gut (via TRPV6 channels); ↑ bone mineralisation; feedback inhibits PTH.

Calcitonin (from parafollicular C cells of thyroid):
Released when Ca²⁺ rises. Acts to LOWER calcium: ↓ osteoclast activity. Physiological role is MINOR in humans (people without calcitonin have normal Ca²⁺). Used pharmacologically (nasal calcitonin for Paget's disease, osteoporosis).

Cross-subject link (BI): Vitamin D activation cascade involves cytochrome P450 enzymes in liver and kidney — studied in BI enzyme biochemistry.

Calcium Homeostasis: PTH, Vitamin D, and Calcitonin — Four-panel illustration showing calcium homeostasis with three hormones and three target organs, PTH actions on bone-kidney-gut, the three-step vitamin D activation pathway from skin to kidney, and calcitonin from thyroid C cells.

Mark Words

Clinical Features of Calcium Disorders

Hypocalcaemia (Ca²⁺ < 8.5 mg/dL):
Causes: Hypoparathyroidism (post-thyroidectomy), Vit D deficiency (commonest in India), malabsorption, CKD (1α-hydroxylase impaired), hypomagnesaemia.

Clinical features — all due to increased neuronal excitability:
- Tetany: Involuntary carpopedal spasm (hand = obstetrician's hand)
- Trousseau's sign: Inflate BP cuff > systolic → carpal spasm within 3 minutes
- Chvostek's sign: Tap facial nerve anterior to ear → ipsilateral facial muscle twitch
- Perioral tingling, paraesthesias
- Severe: laryngospasm (stridor), seizures, prolonged QT on ECG → cardiac arrhythmia

Treatment: IV calcium gluconate (emergency), oral Vit D + calcium (maintenance), calcitriol in CKD.

Hypercalcaemia (Ca²⁺ > 10.5 mg/dL):
Causes (mnemonic: Bones, Stones, Moans, Groans, Psychic Overtones):
- Most common: Primary hyperparathyroidism (PTH adenoma), malignancy (bone mets, PTHrP-secreting tumours)

Clinical features:
- Bones: Osteitis fibrosa cystica (severe PTH → bone resorption)
- Stones: Renal calculi (hypercalciuria → calcium oxalate or phosphate stones)
- Moans: Abdominal pain, constipation, peptic ulcer (↑ gastric acid via gastrin)
- Groans: Polyuria/polydipsia (hypercalcaemia impairs ADH action in collecting duct)
- Psychic overtones: Depression, confusion, psychosis

Treatment: IV fluids + furosemide (loop diuretics increase renal Ca²⁺ excretion), bisphosphonates.

Clinical Features of Calcium Disorders — Four-panel illustration showing hypocalcaemia signs (Trousseau's, Chvostek's, tetany), causes of hypocalcaemia, hypercalcaemia features using the 'stones, bones, groans, moans' mnemonic, and hypercalcaemia causes and emergency treatment.