Insulin and Diabetes Part 1

Chronic Symptoms of Diabetes
1. Retinopathy - most common cause of blindness in people of working age
2. Macrovascular Disease - 2/3 x increased risk of heart disease or stroke
3. Foot Problems - 15% develop foot ulcers, 5-15% of them require amputation
4. Erectile Dysfunction - can affect up to 50% of men
5. Nephropathy - 16% of patients needing renal replacement therapy have diabetes
Pancreas
1. Exocrine tissue
  1. Alkaline fluid with digestive enzymes
    1. Small intestine
2. Endocrine tissue
  1. Produce insulin and glucagon
    1. Regulates blood glucose
3. 1-2% of total pancreas mass is Islets of Langerhans
  1. Surrounded by rings of acinar cells which coat fine branches of the pancreatic duct
  2. Include multiple cell types
    1. Alpha (A) cells
      1. Secrete glucagon
      2. Found in islet mantle (periphery)
      3. Common in splenic lobe (tail end)
    2. Beta (B) cells
      1. Secrete insulin (and IAPP/amylin - involved in glycemic regulation)
      2. Make up 60-80% of islet endocrine cells
      3. Primarily in islet medulla (core)
    3. Delta (D) cells
      1. Secrete somatostatin
      2. Make up 5% of islet cells
    4. PP (F) cells
      1. Secret pancreatic polypeptide
      2. Found in islet mantle (periphery)
      3. Common in duodenal lobe (head end)
  3. Islet blood flow
    1. Islets have a rich blood supply
    2. Arterioles ender islet peripheries at breaks and emerge at beta cell-rich regions in the islet core
      1. Coalesce into collecting venules outside of islet
    3. Blood flow is BAD (beta-alpha-delta)
  4. Islet cell interactions
    1. Intra-islet interactions
      1. Via circulation within the islet
    2. Paracrine actions
      1. Between neighbouring cells via interstitial space
    3. Gap junctions
      1. Ions and small molecules (>1000 Da) pass directly between cells
  5. Islet innervation
    1. Richly innervated by autonomic system
    2. Parasympathetic
      1. Via vagus nerve
      2. Transmitters - acetylcholine and neuropeptides (VIP - vasoactive intestinal peptide)
    3. Sympathetic
      1. Via coeliac ganglion
      2. Transmitters - Noradrenaline and neuropeptides (NPY)
      3. Neurohormonal (adrenal)
  6. Islet Hormones
    1. Somatastatin
      1. Found in hypothalamus, gut, stomach and islets
      2. Major islet form SS-14
      3. Released in response to nutrients
      4. Has inhibitory actions on most tissues
    2. Islet amyloid polypeptide (IAPP/amylin)
      1. Co-secreted with insulin (1:1 molecular ratio)
      2. May inhibit gastric emptying - decreases appetite
      3. Forms islet amyloid deposits in type 2 diabetes
    3. Pancreatic polypeptide
      1. Vagus nerve activation stimulates release
      2. May inhibit pancreatic exocrine secretions
Insulin
1. 6 kDa peptide
  1. Made of 2 chains - A chain and B chain
    1. Linked by disulphide bonds
2. Formation
  1. Proteolysis converts preproinsulin to proinsulin
    1. Release of a signal peptide
  2. Proinsulin
    1. 9 kDa
    2. Synthesised in beta cells
    3. Proinsulin contains A and B chains and C peptide
  3. 2 routes - same but in opposite directions
    1. Proinsulin is split between arginine 32 and 33 to give Split 32, 33 proinsulin
      1. By PC3 (type-I) endopeptidase
      2. Arg 31 and 32 removed to give Des 31,32 proinsulin
        By carboxypeptidse-H
        Split and Arg 64 and 65 removed to give insulin and C peptide
        By PC2 endopeptidase and carboxypeptidase-H
    2. Proinsulin is split between arginine 65 and 66 to give split 65, 66 proinsulin
      1. By PC2 (type-II) endopeptidase
      2. Arg 64 and 65 removed to give Des 64, 65 proinsulin
        Carboxypeptidase-H
        Split and Arg 31 and 32 removed to give insulin and C peptide
        By PC3 endopeptidase and carboxypeptidase-H
3. Regulation
  1. Major stimulus is glucose
  2. Other agents - neural, hormonal, nutrient
    1. Most neural and hormonal stimulators and glucose dependent
  3. Neural Stimulation
    1. Parasympathetic
      1. Neurotransmitters - Ach, VIP
        Stimulate insulin secretion
    2. Sympathetic
      1. Neurotransmitters - Adrenaline, Noradrenaline
        Inhibits insulin secretion
        Alpha adrenergic
  4. Hormonal
    1. Incretins (GI hormones) released from the gut following food ingestion
      1. GIP (gastric inhibitory polypeptide) - stimulatory
      2. GLP-1 (glucagon-like peptide-1) - stimulatory
      3. Somatastatin-28 from gut - inhibitory
    2. Islet hormones (paracrine?)
      1. Glucagon - stimulatory
      2. Somatostatin - inhibitory
  5. Nutrient Control
    1. Glucose - stimulatory
      1. Transported into beta-cell by GLUT-2
        Undergoes glycolysis (glucokinase has low affinity but high specificity for glucose)
        Change in ATP:ADP inhibits ATP K+ channels
        Decrease in K+ efflux depolarises cell
        Voltage-depended calcium channel opens
        Ca2+ release (100-500 nM) into cell
        Insulin release by exocytosis
    2. Leucine and arginine - stimulatory
    3. Free fatty acids - stimulatory
  6. Neurotransmitters and hormones act via specific receptors which activate different intracellular pathways
    1. Activation is weak in the absence of glucose
      1. Activation is very strong in the presence of glucose (and Ca2+) - synergistic
    2. Ach binds to receptor - Gq and PLC bind
      1. PIP2 becomes IP3 and DAG
        IP3 stimulates ER which causes Ca2+ release
        Ca2+ and DAG cause increase of PKCs (and Ca2+ increases CaMKs)
        Increase of trafficking
        Exocytosis of insulin
    3. GIP and GLP-1 (7-36) bind to receptor - Gs and AC bind
      1. ATP converted to cAMP
        Increase of PKAs
        proteins
Glucagon
1. Single chain, 39 amino acid peptide - 3845 kDa
2. Has a large precursor - proglucagon
3. Involved in tissue-specific processing
  1. Glucagon is found in islet alpha cells (PC2)
  2. GLP-1 (7-36) and GLP-2 found in intestinal endocrine cells (PC1/3)
4. Main site of action is liver
  1. Increased hepatic output by glycogenolysis and gluconeogenesis
  2. Increased blood glucose
5. Regulation
  1. Neural
    1. Parasympathetic and sympathetic stimulate glucagon release
  2. Hormonal
    1. GI hormones
      1. Cholecystokinin (CCK) and GIP - stimulatory
      2. GLP-1 (7-36) and somatostatin - inhibitory
    2. Islet hormones
      1. Insulin - inhibitory (via islet circulation)
      2. Somatostatin - inhibitory (via paracrine action)
  3. Nutritional
    1. Low glucose - stimulation
    2. Arginine - stimulation
    3. Fatty acids - inhibition
Biological Action of Insulin
1. Anabolic - energy storage
2. Has a critical role in growth and development
3. Major target tissues - muscle, fat, liver
4. Glucose uptake in muscle and adipose tissue
  1. Insulin binds to insulin receptor, causing receptor phosphorylation
    1. Stimulates GLUT-4 containing vesicle to move to the cell surface
      1. Glucose enters cell via GLUT-4 receptors
        In muscle - glucose is used as energy/stored as glycogen
        In adipocyte - glucose is stored as fat (glycolysis provides glycerol for triglyceride synthesis)
        Alpha-glycerophosphate becomes glycerol (and free fatty acids) which forms triglycerides
        Inhibition of hormone sensitive lipase (which hydrolyses triglycerides into free fatty acids)
        Stimulation of fatty acid synthesis from glucose
        Liver glycogen reaches 5-6%
        Stimulation of lipoprotein lipase (on capillary wall in fat tissue)
5. Glucose metabolism
  1. Insulin
    1. Stimulation
      1. Glucose-1-phosphate to glycogen
      2. Glucose to glucose-6-phosphate
      3. Fructose-6-phosphate to fructose-1,6-bisphosphate
      4. Phosphoenolpyruvate
    2. Inhibition
      1. Glycogen to glucose-1-phosphate
      2. Fructose-1,6-bisphosphate to fructose-6-phosphate
      3. Pyruvate to oxaloacetate
  2. Glycogen
    1. Stimulation
      1. Glycogen to glucose-6-phosphate
      2. Pyruvate to oxaloacetate
      3. Oxaloacetate to phosphoenolpyruvate
    2. Inhibition
      1. Phosphoenolpyruvate to pyruvate
6. Carbohydrate metabolism in liver
  1. Stimulation of glycogen synthesis (glucose storage)
  2. Stimulation of glycolysis (phosphorylation of glucose kinase, trapping glucose in cell and stimulating glucose uptake)
  3. Inhibition of glycogenolysis
  4. Inhibition of gluconeogenesis
7. Inhibition - gluconeogenesis, glucogenolysis, lipolysis, ketogenesis, proteolysis
8. Stimulation - Glucose uptake (in muscle/adipose), glycolysis, glycogen synthesis, protein synthesis, uptake of ions (K+ and PO4-3)
Insulin Receptor
1. Glycoprotein
2. 2 alpha and 2 beta subunits
  1. Alpha subunits (MW 135K) are extracellular - joined by disulfide bonds
  2. Beta subunits (MW 95K) span cell membrane
  3. Each beta subunit bound to alpha subunit by a disulphide bond
3. Tyrosine kinase
4. Insulin binds - phosphorylation of tyrosine on beta subunit
  1. Growth signal - Shc phosphorylation
    1. Ras-MAPK pathway
      1. Cell proliferation
      2. Protein synthesis
  2. Metabolic signal
    1. Phosphorylation of IRS family proteins (IRS-1/-2/-3/-4
      1. Cascade of serine and tyrosine phosphorylation/dephosphorylation (involving PI3K)
        Protein synthesis
        Glycogen synthesis
        Lipid metabolism
        Glucose uptake (via GLUT-4 translocation)

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