Insulin and Diabetes Part 2

Insulin and Diabetes Part 2

1. Symptoms of no/low insulin

   • Decreased anabolism
     • Hyperglycaemia
       • Fatigue
       • Glucosuria
         • Osmotic diuresis
           • Polydipsis (thirst)
           • Water and salt depletion
             • untreated
   • Increased catabolism
     • Increased glycogenolysis, gluconeogenesis an lipolysis
       • Wasting/weight loss
       • Hyperketonaemia and acidosis
         • Vasodilation
           • Hypotension and hypothermia
         • Diabetic ketoacidosis
           • Fatal if

2. Definition

   • Chronic
   • Elevated plasma glucose levels
   • Due to defects in insulin secretion and/or insulin action

3. Complications

   • Short-term
     • Hypoglycaemia
     • Diabetic ketoacidosis
     • Lactic acidosis
     • Diabetic coma
   • Long-term
     • Retinopathy
       • Aneurysms and haemorrhages in retina
     • Nephropathy
       • Nodular scarring (sclerosis)
         • Blood vessels are compressed/distorted
     • Neuropathy
       • Blood vessels around nerves become diseased and retract
         • Nerves shrivel
     • Cardiovascular disease - atherosclerosis
       • Increased fatty acids, triglycerides, VLDL, remnant particles and oxidised LDL particles (also small, dense LDL)
         • Decreased HDL
         • Postprandial (post-meal) hyperlipidemia
     • (Increased risk for pancreatic cancer?)
     • Ulceration
     • Dermatopathy

4. Type 1 Diabetes

   • Insulin dependent diabetes mellitus (IDDM)
   • Can occur in adulthood but usually presents earlier
   • Incidence - 1:250 people
     • 3% increase in incidence each year
   • Due to autoimmune destruction of beta cells
   • Genetic and environmental causes
   • Evidence for autoimmune disease
     • T-lymphocyte infiltration of islet (insulitis)
     • Islet cell antibodies (ICAs)
       • Insulin
       • Glutamic acid decarboxylase (GAD)
     • Strong genetic association with HLA loci on MHC Class II
     • Associated with other autoimmune diseases (e.g. Hashimoto's thyroiditis)
     • Possible triggers for autoimmune disease
       • Beta cell apoptosis
         • Triggered by environmental factor (e.g. virus)
       • Molecular mimicry
         • Immune response to antigen with beta cell structural similarity
       • Bystander activation
         • Islet inflammation (due to viral infection)
           • Stimulates beta cell specific T cells
   • Prevention and Therapy
     • Prevention with immunosuppression
       • Anti-CD3 antibodies
     • Treatment
       • Insulin
       • Islet transplantation

5. Type 2 Diabetes

   • Occurs in adults <45 years
     • 1 in 20 people
   • Accounts for 90-95% of diabetes
   • Defects in both secretion activation and secretion
   • Genetic component
     • 100% concordance in monozygotic twins
     • Frequent in particular ethnic groups
   • Environmental component
     • Associated with sedentary lifestyle and high fat diet
   • Non-insulin dependent diabetes mellitus (NIDDM)
   • Impaired glucose tolerance

6. Hyperglycaemia and the Polyol Pathway

   • Reactive oxygen species form toxic aldehydes
     • Converted into inactive alcohols via aldose reductase AND NADPH to NADP+
   • Increased glucose converted into sorbitol
     • Becomes fructose via SDH and NAD+ to NADH
     • Via NADPH to NADP+
       • Converts oxidised GSSG to reduced GSH via glutathione reductase
   • Decreased NAD+ and increased sorbitol
     • Sorbitol causes osmotic stress

7. Hyperglycaemia and AGE Precursors

   • Really good paper alert!! F. Giacco and M. Brownlee, Oxidative Stress and Diabetic Complications, 2010
   • Increased glucose
     • Increased AGE precursors
       • Intracellular protein glycation
       • Abnormal interaction with matrix proteins and integrins (matrix receptors)
         • Signal for intracellular transducers
           • Altered gene expression
   • Production of modified AGE plasma proteins
     • Bind to RAGE (AGE receptors)
       • Increased production of ROS
         • NF-kappaB activation
           • Changes to gene expression
       • Altered function of AGE plasma proteins changes signal for intracellular transducers
         • Altered gene expression

8. Hyperglycaemia and PKC

   • Increased glucose causes increased DAG and increased PKC (beta and delta isoforms)
     • Blood flow-abnormalities
       • Decreased eNOS
       • Increased ET-1
     • Vascular permeability and angiogenesis
       • Increased VEGF
     • Capillary occlusion
       • Increased TGF-beta causing increased collagen and fibronectin
     • Pro-inflammatory gene expression
       • Increased NF-kappaB
     • Vascular occlusion
       • Increased PAI-1 causing decreased fibrinolysis
     • Multiple other effects
       • Increased NAD(P)H oxidases causing increased ROS

9. Hyperglycaemia and the Hexosamine Pathway

   • Increased glucose - becomes glucose-6-phosphate and then fructose-6-phosphate
     • Converted to glucoseamine-6-phosphate (instead of following glycolytic pathway)
       • Converted into UDPGIcNAc (UDP-N-acetylglucoseamine)
         • Addition of O-GlcNAc and (PO4)2- to serine and threonine residues at transcription factor sites (e.g. Sp1)
           • Increased production of TGF-beta1 and PAI-1 (plasminogen activator inhibitor-1)
       • Via GFAT (Glutamine:Fructose-6-phosphate aminotransferase) - inhibited by azaserine/AS-GFAT (antisense)