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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?