2008A11 Outline the physiological consequences of diabetic ketoacidosis.

Definition

·   Life-threatening acute metabolic complication of type 1 diabetes mellitus

Pathophysiology

·   Absolute or near insulin deficiency

o Missed doses

o Sudden ↑ insulin resistance e.g. acute illness

·   ↓↓ peripheral glucose uptake

·   Cells metabolise alternative substrates

·   Hence ↑[glucose], ↑[ketones], ↑anion gap metabolic acidosis (HAGMA)

Hormone profile

·   ↓ insulin

·   ↑ glucagon, cortisol, catecholamines

Metabolic pathways

·   ↑[glucose]

o ↓GLUT-4 -> ↓uptake into skeletal muscle and fat

o ↓glycolysis

o ↑gluconeogenesis from glycerol/lactate/pyruvate/amino acids (liver > kidney)

o ↑glycogenolysis, ↓glycogenolysis (liver, skeletal muscle)

·   ↑[lipids]

o ↑Hormone-sensitive lipase activity

·   ↑[ketones]

o ↑ratio acetyl-CoA : oxaloacetate -> ↑ketogenesis

Fluid

·   ↑Osmolarity (due to ↑glucose more than ↑ketones)

·   ↓Blood volume, cellular dehydration (due to osmotic diuresis)

·   ↑RAAS (early ↓due to ↑NaCl at macula densa, late ↑ due to ↓afferent arteriolar stretch)

·   ↓ADH early if ↑osmolality (sensitive ±1-3%), ↑ADH late if ↓blood volume (sensitive ±10%), ↓mAP

Electrolytes

·   Dilutional ↓[Na⁺]

o ↓1mmol/L for each +1mmol/L ↑[glucose]

·   ↑[K⁺]

o ↓ insulin-mediated cell uptake, ↑K⁺/H⁺ exchange)

o Note global K+ depletion due to urinary loss (osmotic diuresis -> ↑ROMK activity)

·   ↑[Ca²⁺]

o ↑ H⁺/Ca²⁺ exchange with bone

Acid-base

·   Ketoacids -> HAGMA

·   Lactic acid -> HAGMA (if ↓blood volume -> ↓tissue pO₂ -> ↑anaerobic metabolism)

Renal

·   Initial ↑ urine output

o Transport maximum of 375mg/min exceeded at BSL >10mmol/L

o Hyper-osmolar urine, osmotic diuresis

·   Later ↓ urine output

o Due to ↓blood volume -> mAP <70mmHg -> ↓ GFR

o ±ARF, anuria, ATN

·   ↑Gluconeogenesis

Cardiovascular

·   Heart:

o Acidosis: ↓ inotropy, arrhythmia, arrest (predominates if pH <7.2)

o SNS: ↑ inotropy, ↑ HR (predominates if pH >7.2)

·   ↓Blood volume -> ↓ preload -> ↓ cardiac output -> ↓ mAP

·   Vessels:

o Acidosis: systemic dilatation, pulmonary constriction

o SNS: systemic + pulmonary constriction

Respiratory

·   Acidosis: systemic dilatation, pulmonary constriction, right shift OHDC

·   SNS: systemic + pulmonary constriction

Central nervous system

·   Acidosis -> ↑SNS output

·   Glucose supply preserved by constitutive GLUT1