Insulin and Diabetes Part 2

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

1. Chronic
2. Elevated plasma glucose levels
3. Due to defects in insulin secretion and/or insulin action

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

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

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

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

Nota:

• Really good paper alert!! F. Giacco and M. Brownlee, Oxidative Stress and Diabetic Complications, 2010

1. Increased glucose
   1. Increased AGE precursors
      1. Intracellular protein glycation
      2. Abnormal interaction with matrix proteins and integrins (matrix receptors)
         1. Signal for intracellular transducers
            1. Altered gene expression
2. Production of modified AGE plasma proteins
   1. Bind to RAGE (AGE receptors)
      1. Increased production of ROS
         1. NF-kappaB activation
            1. Changes to gene expression
      2. Altered function of AGE plasma proteins changes signal for intracellular transducers
         1. Altered gene expression

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

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