FRCA Notes

Physiology of Diabetes Mellitus

Curriculum

The curriculum asks for knowledge on "...regulation of plasma glucose" as well as "endocrine abnormalities of significance to anaesthesia e.g. diabetes mellitus"

Resources

  • Diabetes mellitus is a group of disorders characterised by hyperglycaemia, due to defects in insulin secretion, insulin action or both
  • This page covers the underlying physiology; classification, diagnosis and peri-operative management are covered on the diabetes mellitus page
  • Understanding the pathophysiology explains the acute complications seen peri-operatively: hyperglycaemia, ketoacidosis and hypoglycaemia

  • Plasma glucose is normally kept between ~4 and 7mmol/L by the balance of insulin and the counter-regulatory hormones (see insulin physiology)
  • The brain is an obligate glucose user in the fed state, consuming ~120g/day

Fed state

  • ↑ insulin and ↓ glucagon
  • Glucose is taken up by muscle and adipose tissue and stored as glycogen and triglyceride
  • Hepatic glucose output is suppressed

Fasted state

  • ↓ insulin and ↑ glucagon
  • Hepatic glycogenolysis maintains glucose for the first ~24hrs, after which gluconeogenesis predominates (from lactate, glycerol and amino acids)
  • Lipolysis releases free fatty acids, which are used by muscle and converted to ketones by the liver
  • In prolonged starvation the brain adapts to use ketones, sparing muscle protein
  • Low insulin levels are still present, which restrain lipolysis and ketogenesis; physiological starvation ketosis is therefore mild and does not cause acidosis

  • Autoimmune T-cell mediated destruction of pancreatic β-cells, leading to absolute insulin deficiency
  • Associated with autoantibodies (e.g. GAD, islet cell, insulin antibodies) and HLA-DR3/DR4
  • Hyperglycaemia develops once ~80-90% of β-cell mass is lost
  • Typically presents in childhood or early adulthood, but can occur at any age (including latent autoimmune diabetes in adults, LADA)

  • Without insulin, there is unopposed glucagon action:
    • Uncontrolled hepatic glucose output despite hyperglycaemia
    • Unrestrained lipolysis and ketogenesis
    • Patients are therefore prone to diabetic ketoacidosis
  • Patients require lifelong insulin; insulin must never be completely withheld, even when fasted

  • A progressive disorder of insulin resistance combined with relative insulin deficiency
  • Strong genetic predisposition, with obesity, inactivity and ageing as the main environmental factors
  • Often occurs as part of the metabolic syndrome: central obesity, hypertension, dyslipidaemia and insulin resistance

Insulin resistance

  • Reduced response of muscle, liver and adipose tissue to insulin, due to post-receptor signalling defects
  • Visceral adipose tissue releases free fatty acids and inflammatory cytokines (e.g. TNF-α, IL-6) which impair insulin signalling ('lipotoxicity')
  • In the liver this causes failure to suppress gluconeogenesis, driving fasting hyperglycaemia
  • In muscle there is reduced GLUT4 translocation and glucose uptake, driving post-prandial hyperglycaemia

β-cell dysfunction

  • Initially, β-cells compensate by increasing insulin secretion
  • Over time, β-cell function progressively declines owing to genetic factors, glucotoxicity, lipotoxicity and amyloid deposition
  • Diabetes develops when secretion can no longer overcome resistance; by diagnosis, ~50% of β-cell function may be lost
  • There is also a reduced incretin effect and inappropriately high glucagon secretion

Consequences

  • Some endogenous insulin persists, which is usually enough to suppress ketogenesis
  • Severe hyperglycaemia therefore tends to cause the hyperosmolar hyperglycaemic state (HHS) rather than DKA, although DKA can occur
  • The progressive nature explains why treatment typically escalates over time, often eventually requiring insulin

  • Ketogenesis is driven by a low insulin:glucagon ratio
  • Insulin deficiency removes inhibition of hormone-sensitive lipase, releasing free fatty acids from adipose tissue
  • In the liver, glucagon reduces malonyl-CoA levels, which removes inhibition of carnitine palmitoyltransferase-1 (CPT-1)
    • Fatty acids are transported into mitochondria for β-oxidation to acetyl-CoA
    • Excess acetyl-CoA is converted to the ketone bodies acetoacetate and β-hydroxybutyrate; acetone forms by spontaneous decarboxylation

  • Ketone bodies are strong acids that dissociate at physiological pH, causing a high anion gap metabolic acidosis
  • β-hydroxybutyrate predominates in DKA, which is why blood ketone meters measure it (see glucose and ketone meters)

  • Euglycaemic ketoacidosis occurs when the insulin:glucagon ratio falls without marked hyperglycaemia, classically with SGLT2 inhibitors, starvation, pregnancy or alcohol

Acute

  • Once the renal threshold (~10mmol/L) is exceeded, glycosuria causes an osmotic diuresis (see renal glucose handling)
    • Dehydration and loss of Na+, K+, Mg2+ and phosphate
  • Raised plasma osmolality shifts water from the intracellular to the extracellular compartment, diluting plasma sodium
    • Corrected Na+ = measured Na+ + (glucose - 5.5) ÷ 3.5
  • Impaired neutrophil function, increasing infection risk

Chronic

  • Sustained hyperglycaemia damages tissues that take up glucose independently of insulin, such as nerves, retina, renal glomeruli and endothelium
  • Mechanisms include:
    • Non-enzymatic glycation of proteins, forming advanced glycation end-products that stiffen collagen and damage vessels
    • The polyol pathway: aldose reductase converts glucose to sorbitol, causing osmotic and oxidative cell injury
    • Protein kinase C activation and oxidative stress
  • These underlie microvascular (retinopathy, nephropathy, neuropathy) and macrovascular complications, as well as stiff joint syndrome

HbA1c

  • Glycated haemoglobin forms in proportion to the average plasma glucose over the lifespan of the red cell
  • It therefore reflects glycaemic control over the preceding ~2-3 months
  • Unreliable where red cell lifespan is altered e.g. haemolysis, recent transfusion, haemoglobinopathies, pregnancy, iron deficiency

  • Surgery and critical illness trigger release of catecholamines, cortisol, glucagon and growth hormone, with inflammatory cytokines
  • The result is a catabolic, insulin-resistant state:
    • ↑ hepatic glycogenolysis and gluconeogenesis
    • ↓ peripheral glucose uptake
    • Relative suppression of insulin secretion by catecholamines
  • Hyperglycaemia can therefore occur even in patients without diabetes ('stress hyperglycaemia')
  • In patients with diabetes, the magnitude of the response increases insulin requirements and the risk of DKA or HHS

  • The response is proportional to the extent of surgical injury, and may be attenuated by minimally invasive surgery and regional anaesthesia
  • Dexamethasone, fasting and omission of usual medication further disturb glycaemic control peri-operatively