What we’re going to cover
• Basic glucose, insulin & pancreas physiology • Type 1 vs Type 2 • DKA • HONK • Hypoglycaemia • Long term complicaLons
What is diabetes mellitus?
• A group of disorders characterised by hyperglycaemia
• Insulin deficiency • Insulin resistance • … or both
An overview of glucose metabolism
Glucose Glucose-‐6-‐phosphate Glycogen
ACoA/Pyruvate Lactate
Kreb’s cycle
2 ATP
36 ATP
CO2 + H2O MITOCHONDRIA
CYTOPLASM
Glycolysis
Anaerobic (Cori)
PepLde hormones with opposing effects
Acts to decrease blood glucose ANABOLIC
Acts to increase blood glucose CATABOLIC 𝛂 cells 𝜷 cells
Insulin vs Glucagon
Release triggered by: 1. Metabolites e.g. ↑ glucose, ↑ FA, ↑AAs 2. Hormones -‐ ↑ gut hormones, adrenaline 3. Nerves -‐ PNS 4. Drugs -‐ sulphonylureas
AcLons: On glucose: ↑ rate of glucose uptake into cells ↓ glucose release from liver On fats: ↑ lipogenesis (adipose Lssue), ↓ lipolysis and β oxidaLon On proteins: ↓ proteolysis, ↑ protein synthesis
Insulin: mechanism of acLon
Insulin Receptor GLUT 4
IRS-‐1 PI3K
PDK1 PKB Uses PI3K as a second messenger
PKB s2mulates transloca2on of GLUT4 to the cell membrane
Type 1 vs Type 2
Type 1 Type 2
250,000 people 10% of diabetes
2.5 million people 90% of diabetes
Absolute insulin deficiency Insulin resistance
• HLA DR4 – linked to RA and SLE • 50% concordance in MZ twins • T-‐cell mediated destrucLon of beta cells
?autoimmune ?virally triggered – similar proteins on viral coat to those on beta cells, body alacks virus, body alacks beta cells
• Insulin binds to receptor but no increase in glucose transporters
• Glucose can’t get into the cell à high blood glucose • SLmulaLon of beta cells to produce more insulin à
hyperinsulinaemia Impaired glucose tolerance at this stage with post-‐prandial high glucose … Then aBer many years, decompensa2on of beta cells • Insulin levels drop to normal • Blood glucose very high à diagnosis of DM • Eventually beta cells become exhausted and there is
insulin deficiency as in T1DM
DKA
Lack of insulin Why? • Stress/infecLon
• Decreased insulin intake
glucose glucose
glucose
glucose glucose
glucose glucose glucose
glucose Lots of glucose in the bloodstream which can’t get into cells so
elevated blood glucose,
‘hyperglycaemia’
Cell
Cells shim to other substrates to produce energy: proteins
and lipids
Byproducts of this are faly acids à ketone bodies
Insulin is also a regulator of the Na+/K+ pump and exchange becomes abnormal • Intracellular K+ becomes low • Normal K+ levels in plasma as Lght control by kidneys • … but the enLre body has become hypokalaemic
• When you fix the situaLon and give insulin, K+ rapidly floods into the cells à paLent’s plasma suddenly becomes low in K+
• Therefore K+ is added to bags of fluid in treatment of DKA
glucose glucose
glucose glucose glucose glucose
Plasma glucose is above the renal threshold
OsmoFc diuresis and glycosuria
DehydraFon
Coma
Death Acidosis and Ketosis
Kussmaul breathing
ExhausFon
• 2-‐5% mortality • 60-‐90% mortality with cerebral oedema
PotenLally DKA?
• Polyuria • Polydipsia • Polyphagia + weight loss • Puking (N&V)
• Diuresis and dehydraLon • Dizziness • Dam – mental state changes
• KetoLc breath • Kussmaul breathing
• Abdo pain & cramps • Arrythmia + arrest
<3mmol/L or ++ in urine
<11.1mmol/L venous pH <7.3
Ketonaemia
Hyperglycaemia Acidaemia
Aims of treatment
• Fluids to correct dehydraFon – 0.9% saline – 40mmol K+ added to each bag to avoid hypokalaemia – Strict fluid balance: NG tube and catheter with fluid balance chart – Check electrolytes and glucose every hour
• Insulin – 0.1 units/kg intravenous insulin infusion (IVII) – Reduce glucose by 3mmol/L per hour, faster à increased risk cerebral oedema due to rapid changes in serum osmolality
• Introduce 10% glucose when BMs<14 – Need to keep the insulin going to switch off ketogenesis, but if you don’t add glucose the paLent will become hypoglycaemic
• Treat the underlying cause
HONK State
• Can develop due to the same reasons as DKA • More common in frail elderly • Extreme hyperglycaemia (>40) with serum hyperosmolarity (>340) • Hyperosmolarity leads to osmoLc shim of water into the intravascular compartment = severe
intracellular dehydraLon • OsmoLc diuresis with significant dehydraLon and altered mental state • Overt ketosis does not occur as low levels of insulin prevent lipolysis, but levels are insufficient to
reduce blood glucose
• Signs and symptoms: marked dehydraLon, weakness, confusion, neurological signs or seizures. Coma is rare, affecLng only 10%. If they are dehydrated, what signs might they have?
• ComplicaFons: thromboembolic events, infarcLon, DIC, cerebral oedema, mulLorgan failure • Overall mortality up to 30% -‐ slightly more than DKA as elderly populaLon
Plasma osmolality and anion gap
• Plasma osmolality is increased in DKA and HONK • Plasma osmolality = 2(Na + K) + Urea + Glucose – In DKA, usually >290 mOsm/kg – In HONK, usually >320 mOsm/kg
• Anion gap = (Na – Cl) + HCO3 – In DKA, usually >13 mmol/L
Hypoglycaemia
• Whipple’s triad: – Hypoglycaemia – Symptoms alributable to a low blood sugar level – ResoluLon of symptoms with correcLon of hypoglycaemia
• Usually a paLent on insulin or sulphonylureas • Symptoms: – SNS mediated 2.5-‐3: increased HR, sweaLng, pallor, fine tremor – Central ‘neuroglycopenia’ <2.5: blurred vision, slurred speech, disorientaLon, coma, cardiorespiratory arrest
Long term complicaLons
3 main pathways of pathology 1. Non-‐enzymaLc glycosylaLon i.e. direct toxicity of hyperglycaemia on cells • Directly related to poorly controlled blood glucose levels (increased levels = increased risk) • GlycosylaLon of collagen and proteins become ‘advanced glycosylaLon end products’ (AGE)
– Trap intersLLal proteins in blood vessels (eg. LDL) à atherogenesis – Trap albumin in renal vessels à thickened glycosylated basement membrane – AGE receptors cause release of cytokines à increased endothelial permeability and procoagulaLon
2. AcLvaLon of Protein Kinase C • Diacylglycerol (DAG) is a second messenger, hyperglycaemia increases synthesis • DAG and calcium ions acLvate PKC in cells • PKC acLvaLon has many downstream effects:
– Proangiogenic molecules e.g. vascular endothelial growth factor (VEGF) – ProfibroLc molecules e.g. transforming growth factor beta (TGFβ)
3. Polyol Pathway • In cells that do not require insulin for glucose uptake, hyperglycaemia causes increased intracellular glucose • Aldose reductase transforms it into sorbitol (a polyol), which is transformed into fructose • Increased intracellular osmolarity and water influx à cell oedema • Increased risk of oxidaLve stress (anLoxidant reserves are reduced with sorbitol metabolism)