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Transcript
Type I Diabetes
Diabetes
• Drinking heaps, urinating heaps
• Massive weight loss
– “Flesh melting into Urine”
– Diabetes = ‘Siphon’
• Death inevitable within weeks
• Sugar in urine
– Diabetes mellitus
• Sweet/organic breath
Root Cause
• -cell destruction
– Auto-immune attack
• Extent and time-course variable
– Appearance of symptoms varies
• Still functional -cells at time of diagnosis
What does Insulin do?
• Anabolic hormone
– Stimulates synthesis of macromolecules
– Inhibits catabolism
Glucose Uptake
• Insulin needed for GLUT-4 translocation
– Not GLUT-1 or GLUT-2
• So what is affected?
– Not basal or liver glucose transport
Glucose Disposal
• Lipogenesis
• Glycogenesis
• Key enzymes not stimulated
– Nowhere for glucose to go
• [G6P] rise inhibits glucose uptake
Protein Synthesis
• Little stimulus for protein formation
• Amino acids oxidised
Glycogenolysis
• Normally inhibited by insulin
Lipolysis
• Insulin inhibits lipolysis
– Decreases level of cAMP in fat cells
• Lack of insulin leads to uncontrolled fat
breakdown
– Lots of fatty acids released into blood
– And lots of glycerol
• Fatty acids will inhibit glucose oxidation
Proteolysis
• Hypoinsulinemia causes widespread
proteolysis
– Amino acids released into blood
Gluconeogenesis
• Insulin normally inhibits enzymes that
cause glucose production in the liver
• Now we have increased substrate supply
too…
– Lots of glycerol, amino acids, lactate
Ketone Bodies
• Massive supply of fatty acids to liver
• Removal of Krebs cycle intermediates for
gluconeogenesis
• So massive ketone body production
• Brain lowers use of glucose
So…
• Uncontrolled release of fatty acids, amin
acids and glycerol
• Inhibition of glucose storage and oxidation
everywhere
• Hepatic glucose production increases
• Ketone body production enormous
Acidosis
• Ketone bodies
• Lactate
• Fatty acids
• Severe drop in pH
• Ultimately fatal
Catabolic Meltdown
• “Starvation in the face of plenty”
• Hyperglycemia
– Glucose not disposed of
– Hepatic glucose production
Explaining Symptoms
• Drinking heaps, urinating heaps
– Hyperglycemia changes osmotic strength of blood
– Draws water out of tissues
– Unquenchable thirst
• Massive weight loss
– Uncontrolled lipolysis and proteolysis
• Sugar in urine
– Kidneys cannot reabsorb glucose when blood
[Glucose] > 10 mM
• Sweet/organic breath
– Spontaneous decarboxylation of ketone bodies to
acetone
Treatment
• Before 1920s… no treatment
• Banting & Best
– Dog pancreatic extracts
– Minus the digestive enzymes
– Leonard Thompson
• Aim to stabilize blood glucose
• But also to prevent lipolysis/proteolysis
Aims of Control
• Avoid prolonged hyperglycemia
– Very dangerous in the long run
• Glycosylated proteins
– Damage to capillaries, retina, kidney
• Polyol pathway
– Accumulation of sorbitol in nerve cells
Insulin Therapy
• Several types and blends available
–
–
–
–
Ultra-rapid – 10 min. immediately pre-meal
Short acting – 30 min
Intermediate – 1-2 hr – can take 6 h to peak
Long acting – 3 h to onset, lasts 24 h – Zn2+ core
• Mixtures – 70:30 long short
• Analogs - Structural modifications
–
–
–
–
–
Lispro – swap 28 & 29
Aspart – pro to asp at 28
glulisine- lys and glu at 3 & 29
glargline – replace A21 and add to arg
detemir – binds to albumin via fatty acid
Mooradian et al (2006) Narrative review: a rational approach to starting insulin therapy.
Ann Intern Med. 145(2):125-34
Monitoring
• Regular blood glucose readings
• Glycated hemoglobin - HbA1c
– to assess medium term diabetic control
– base changes in management of patients
• Red blood cell 120 day life span
• Aim for < 7.5%
– but note that hypoglycemia is much more dangerous
than hyperglycemia!!
Hypoglycemia Unawareness
• Impending hypoglycemia warning signs
– Sweating, trembling, irritability, dizziness…
• Better or worse in long term diabetics?