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 – Zn 2+ 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 - HbA 1c –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?