U1iii: Outline physiological consequences of inability to produce insulin
Insulin Summary
- Polypeptide Hormone
- Stored + synthesised by β cells of pancreas
- Ca2+ required for exocytosis & release
- Released when BSL > 6mmol/L
- Binds Insulin Receptor A subunits
- Activates TK
- Autophosphorylation of receptor
- Alters intracellular gene transcription
- Major ANABOLIC HORMONE
Lack of Insulin
- Blood glucose tightly regulated by:
- Insulin → anabolic, ↓BSL
- Glucagon → catabolic, ↑BSL
- Lack of insulin alters ratio Insulin : Glucagon
↓ Insulin
- Inability of cells to transport glucose intracellularly (↓GLUT-4, glucokinase)
- Inability to store glycogen (↓glycogen synthase)
- Inability to convert glucose → TAGs (↓lipoprotein lipase)
- Inability to utilise glucose via glycolysis (↓phosphofructokinase)
↑ Glucagon
- ↑Gluconeogenesis: ↑Acetyl CoA, glycerol, α-acids → glucose
- ↑Glycogenolysis
- ↑Lipolysis: ↑HORMONE SENSITIVE LIPASE (inhibited by Insulin)
- Breaks stored TAGs
- Release glycerol + FFA → circulation
- ↑β-oxidation FFA → Acetyl CoA
- Acetyl CoA → Kreb’s → ATP
- Excess Acetyl CoA → ketogenesis
- ↑Protein breakdown: α-acids → gluconeogenesis → glucose
Physiological Consequences
Hyperglycaemia + Hypovolaemia
- Ingested CHO + gluconeogenesis = ↑BSL
- Exceeds kidney TMAX glucose (180mg/dL)
- Glucosuria
- Osmotic diuresis → hypovolaemia
Hypovolaemia
- Osmoreceptors → ↑ADH, thirst
- Baroreceptors → ↑ outflow, ↑RAAS
Electrolyte Derangement
- Osmotic diuresis → ↓Na/↓K reabsorption
- Dilutional hyponatraemia → ECF osmotic shift from ↑BSL, exacerbated by polydipsia
- ↓insulin → ↑K extracellularly
- ↓Na+ = confusion, seizures
- ↑K+ = arrhythmias
Anaerobic Metabolism & Acidosis
- HORMONE SENSITIVE LIPASE → strongly activated
- Hydrolyses TAGs → FFAs + Glycerol
- FFA become 1° E substrate (except in brain) – β-oxidation
- Ketones = freely diffusible
- Alternative E. source for brain
- Excess Acetyl CoA/extreme starvation = ↑ketone production
Acetyl CoA + Acetyl CoA
↓
Acetoacetyl CoA
↓
HMG CoA
↓
Acetoacetate
↓
β – hydroxybutarate (1° ketone in blood)
↓
Freely diffusible
↓
Oxidised back to Acetoacetyl CoA which enters Kreb’s
- If ketones produced faster than they’re used → then broken down to CO2 + acetone → exhaled
- β-hydroxybutarate & acetone = anions of strong acids
- Acetoacetic acid & β-hydroxybuteric acid
- Production > buffering capacity → ↓↓↓pH
- ↑anaerobic metabolism by inability of cells to utilise fuels → Pyruvate → lactate → ↓↓↓pH
↓ pH
- RESP = ↑MV → hypocarbia → R) shift ODC
- CVS = mass symp. activation = ↑HR ↑SVR
- Heart → ↓FoC, arrhythmias
- CVS = mass symp. activation = ↑HR ↑SVR
- ELECTROLYTE
- ↑K+ ECF 2° H+/K+ exchange
- ↓total body K+ 2° hyperosmolar diuresis
- ↑Ca2+ plasma 2° H+/Ca2+ exchange bone
- ELECTROLYTE
- CNS = coma