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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?
