L21 Diabetes

• Diabetes Mellitus


  Thomas Willis (1621-1675) in Oxford noted the sweet taste of urine, which he suggested came from the blood - doctors had to subsequently resort to tasting the urine of patients for sweetness in order to detect the disease
• Diabetes Mellitus


  In 1766 Mathew Dobson proved that the sweet taste of diabetic urine was due to sugar. He made the crucial observation of the excess of sugar in blood

  
• Experiment on a diabetic dog

  1. The dog's blood sugar rose

  2. It became thirsty, drank lots of water, and urinated more often

  3. It became weaker and weaker

  4. A pancreatic extract was injected into the diabetic dog

  5. Its blood glucose level dropped, and it seemed healthier and stronger

  6. By giving the diabetic dog a few injections a day, Banting and Best could keep it healthy and free of symptoms

  
• Pancreas


  Both an exocrine & endocrine gland
• Exocrine pancreas


  • ~99% of pancreatic mass
  • Secretes into duct
  • Empties directly into duodenum or via common bile duct
  • 2.5 L/day
• Endocrine pancreas


  • ~1% of pancreatic mass
  • Islets of Langerhans: α cells (68%): insulin, β cells (20%): glucagon, δ cells (10%): somatostatin, PP cells (2%): VIP

  
• Insulin release


  1. Increased uptake of glucose by β-cells, via insulin-independent transport protein GLUT-2

  2. Immediate release of insulin from stores

  3. Also provoked by amino acids, intestinal hormones, sulphonylureas

  4. Increased synthesis of insulin

  5. Stimulates extra GLUT-4 on cell membrane-insulin-dependent glucose transporter

  
• Type I Diabetes


  Insulin Deficiency, Absolute Lack
• Type II Diabetes


  Insulin Resistance, Relative Lack
• Disturbed Glucose Homeostasis
• Diabetes Diagnosis


  • Measure sugar, measure sugar attached to Hb
  • Insulin and c-peptide levels. Levels of these will be low or normal with type 1 diabetes but high with type 2 diabetes
  • Antibody levels. People with newly diagnosed type 1 diabetes will often have high levels of antibodies against certain proteins found in the pancreas
• Type I Diabetes Presentation

  • Often young and slim, presents acutely
  • Silent (asymptomatic) discovery - Diagnosed before onset of symptoms
  • Presents with polyuria, polydipsia, weight loss, hyperglycaemia & ketonaemia, ketonuria
  • Diabetic ketoacidosis (DKA) - Second most common presentation - Polyuria, polydipsia, weight loss, etc + fruity breath, neurological symptoms, vomiting
  • Hypoglycaemia (when treated) - Drug insulin-induced

  
• Type II Diabetes Presentation

  • Often older and obese, Usually presents insidiously
  • Polyuria, polydipsia
  • May be diagnosed as part of a check-up or with chronic complications
  • Hyperosmolar hyperglycaemic state - Prolonged hyperglycaemic diuresis leads to severe dehydration & coma - Residual insulin prevents lipolysis & ketoacidosis - Insidious onset often leads to delayed treatment - Higher mortality rate than DKA
  • Hypoglycaemia (when treated) - Drug insulin-induced, Metformin, sulfonylurea, acarbose, glitazone
• Diabetes is a significant cause of mortality
• Causes of mortality in 2015

  • 5.0 million from diabetes
  • 1.5 million from HIV/AIDS
  • 1.5 million from tuberculosis
  • 0.6 million from malaria

  
• Diabetes caused 1,910,364 total deaths in the Western Pacific Region in 2015

  
• Differences between Type 1 and Type 2 Diabetes

  • Differ in inheritance, pathogenesis, insulin response, but share long-term complications
• Vascular complications of diabetes

  • Macrovascular: Atherosclerosis- promotion, younger, females, mortality from MI and CVA higher, metabolic syndrome
  • Peripheral vascular disease- ulcers, gangrene
  • Microvascular Disease- capillary basement membrane thickening, glycation of proteins, platelet aggregation, & impaired fibrinolysis: Nephropathy, Retinopathy, Neuropathy
• Obesity leads to chronic inflammation
• Non-Enzymatic Glycation


  • Attachment of glucose to amino groups of proteins is non-degradable
  • Degree related to hyperglycaemia
  • Glycated haemoglobin HbA1C: measure of diabetic control
  • Advanced glycation end products (AGE) bind to a particular receptor- and can affect properties of proteins (Vessels= AGE receptor= RAGE)

  
• Effects of AGEs


  • Release of cytokines and growth factors , including transforming growth factor-β (TGF-β), which leads to deposition of excess basement membrane material, and vascular endothelial growth factor (VEGF), implicated in diabetic retinopathy
  • Generation of reactive oxygen species (ROS) in endothelial cells
  • Increased procoagulant activity of endothelial cells and macrophages
  • Enhanced proliferation of vascular smooth muscle cells and synthesis of extracellular matrix
  • In addition to receptor-mediated effects, AGEs can directly cross-link extracellular matrix proteins
• Activation of Protein Kinase C (PKC)

  1. Calcium enters the cell when glucose and insulin bind

  2. This triggers the PKC pathway- signal transduction cascades: VEGF is produced (stimulates new blood vessels), Vasodilator NO reduced, TGF-beta stimulated to induce extra matrix and basement membrane material to be laid down, Reduced fibrinolysis, More pro-inflammatory cytokines, hypertension, hyperglycemia, and activation of the renin-angiotensin system may be induced by the same pathway

  3. Ruboxistaurin- PKC inhibitor- Good, so far for retinopathy and nephropathy

  4. And Bevacizumab as an anti-VEGF

  
• Disturbance of polyol pathway

  1. Nerves, lenses, kidney, blood vessels- non-insulin dependant

  2. Increased intracellular glucose -> glucose metabolized to sorbitol and fructose: Osmotic stress, Decreased NADPH and antioxidant ability- susceptible to oxidative damage, Nerves 'glucose neurotoxicity'

  
• Diabetic Nephropathy


  • Common site for complications-one of leading causes of renal failure
  • 30% of type I diabetics
  • 20% of deaths in diabetics < 40 yr
  • Several anatomical compartments of the kidney involved
  • Several mechanisms involved
• Hypertension


  • Accelerates atherosclerosis
  • Accelerates hyaline arteriolosclerosis
  • Diabetes accelerates atherosclerosis and hypertension
• Macrovascular changes in diabetic nephropathy

  • Accelerated atherosclerosis - stroke, MI, gangrene of lower limbs
  • Hyaline arteriolosclerosis - Associated with hypertension, it is worse in diabetics - Hyaline thickened arterioles- narrowing the lumen
• Microvascular changes in diabetic nephropathy

  • Diabetic microangiopathy - Thickening of basement membranes of arterioles and capillaries: which are also more leaky - Leads to ischaemia - Accumulation of type IV collagen - Nephropathy, neuropathy
• Diabetic Nephropathy


  • Big vessel disease from atherosclerosis at the renal artery ostium, L>R
  • Nodular glomerulosclerosis- Kimmelstiel-Wilson nodules
  • Nodular and diffuse glomerulosclerosis
  • Hyaline arteriolosclerosis- Glassy pink homogenous thickening of the vessel walls, Intimal and medial thickening, Results in luminal narrowing, and ischaemia
• Tubular changes in diabetic nephropathy

  • Wipeout!
• Infectious problems in diabetes

  • All types of Urinary tract infections are more frequent
  • UTI are more severe and carry worse outcomes in patients with diabetes
  • Renal abscesses occur far more frequently in diabetic patients
  • Pyelonephritis occurs more frequently in the diabetic than non-diabetic

  
• Reasons for increased infections in diabetes

  • Diabetics more often have asymptomatic bacteruria (bacteria in the urine)
  • High kidney/urine glucose contents favour bacterial growth
  • Defective host innate and adaptive immunity - Hyperglycaemia causes neutrophils dysfunction by increasing intracellular calcium levels and interfering with actin and thus diapedesis and phagocytosis, Blood vessels don't dilate well allowing for immune cell influx
  • Autonomic neuropathy leads to incomplete bladder emptying- thus the flushing mechanism is lost and bacteria keep growing
• Infectious complications in diabetic nephropathy

  • Acute pyelonephritis
  • Papillary Necrosis- One special pattern of acute pyelonephritis, necrotizing papillitis (or papillary necrosis), is much more prevalent in diabetics than in nondiabetics
  • Chronic pyelonephritis
• Drug Induced Nephropathy


  • Penicillins, diuretics, NSAIDS, etc
  • Type I (IgE) or IV (T-cell) mediated hypersensitivity
  • Tubulointerstitial nephritis
• Types of diabetic neuropathy

  • Symmetrical peripheral neuropathy - Sensorimotor problems contribute to tissue damage especially in feet, 50% have clinical symptoms after 25 yrs, Sensory axons are more severely affected than motor axons, resulting in a clinical presentation dominated by paresthesias and numbness. Features of both axonal and demyelinating injury
  • Autonomic neuropathy - Bladder problems, infection, kidney infection
  • Lumbosacral radiculopathy (diabetic amyotrophy) - Usually manifests with asymmetric pain, numbness, weakness, and muscle atrophy that typically starts in one lower extremity and may spread to the other
• Diabetic Retinopathy


  • Fourth commonest cause of blindness
  • Retinopathy: capillary changes, BM changes, microaneurysms, haemorrhage, nonperfusion, new vessels
  • Cataracts: AGE role
  • Glaucoma: elevated intraocular pressure - nerve damage
• The better the glucose control, the better the outcome, probably for the small vessel disease at least, but the effect on large vessel disease is unclear