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?