FUNCTION/DYSFUNCTION OF ENDOCRINE PANCREAS

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FUNCTION/DYSFUNCTION OF ENDOCRINE PANCREAS
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Pancreas Anatomy

• Both exocrine, endocrine functions
• Exocrine
• Release alkaline fluid, enzs ? pancreatic duct
  ? small intestine
• Food breakdown, digestion
• Cells acinar cells

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Pancreatic Endocrine Cells

• Three endocrine cell types
• Regulate carbohydrate, fat, protein metabolism
• Secretory products
• Alpha glucagon
• Beta insulin
• Delta gastrin, somatostatin

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Insulin

• Synthd as pre-proinsulin
• Enz cleavage ? proinsulin, then further cleaved ?
  insulin
• Biolly active hormone released ? bloodstream
  insulin

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• http//upload.wikimedia.org/wikipedia/en/2/25/Insu
  linpath.png

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Endocrine Pancreas

• Synthesize, release hormones ? circulation
• Travel through bloodstream ? target tissues
  (especially liver and muscle)
• Bind specific receptors ? cell changes
  controlling metabolism

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Insulin Secrn Control

• Chemically
• Beta cells sensitive to concents glucose, amino
  acids in blood
• High glu, aas, fas ? ins secrn
• When would you expect these chemicals to be in
  high concentration?

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• Hormonally
• Beta cells sensitive to circulating hormones
• Stimn insulin release w/
• Cholecystokinin (from intest mucosa w/ eating ?
  incrd PKC activity)
• Gastrointest inhibitory peptide (GIP released
  w/ eating acts through ad cyclase)
• ACh from vagus nerve endings
• Inhibn insulin release w/
• a2 adrenergic agonists
• Adrenalin
• Somatostatin

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• Neurally
• Parasymp stimn ? insulin secrd
• Insulin secrn diminished by
• Decrd blood glucose
• Incrd blood insulin
• Sympathetic stimn

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Molecular Mechanism of Insulin Secretion

• Blood glucose incr
• Glu transported ? b cell through GLUT-2
• Glucokinase/hexokinase ? Glu-6-PO4
• ? Glycolysis ? TCA ? incrd ATP/ADP

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• High ATP/ADP ? inhibn K channel ? no K out of
  cell
• ? Depoln b cell membr
• ? Actn voltage gated Ca2 channels
• ? Incrd Ca into cell AND
• ? Incrd PKC activity ? incrd IP3 ? Ca2 reld
  from ER
• ? Incrd Ca2intracell
• ? Exocytosis insulin from intracell stores

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• Ins release biphasic in healthy indivs
• Init rapid phase
• Reflects release of stored hormone
• Slower, delayed phase
• Continued release of stored hormone release
  newly synthd hormone

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Insulin

• Transported through blood to target tissues
• Receptor binding at target cells
• Target cells have receptors embedded in cell
  membranes, specific for insulin
• When insulin binds its receptor on the target
  cell
• Acts as biochem signal to inside of the target
  cell
• Overall, cell metabolism is stimulated
• ? increased glucose uptake in the cell, and
• ? regulation of glucose breakdown within the
  cell, and
• ? regulation of protein and lipid metabolism
  within cell

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• http//cwx.prenhall.com/horton/medialib/media_port
  folio/text_images/FG11_14aC.JPG

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• http//www.endotext.org/diabetes/diabetes14/figure
  s14/figure2.jpg

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• http//www.emdbiosciences.com/sharedimages/calbioc
  hem/insulin_pathway.jpg

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• Overall blood glucose decrd
• Glu signaled to leave blood and enter
  metabolizing cells (with insulin action)
• NOTE Insulin does NOT
• Bind glucose and help excrete it out of the blood
• Break down glucose in the blood
• Signal increased excretion of glucose
• RATHER Insulin
• Goes to target cells and
• Signals them to take up glucose from the blood,
  and
• Metabolize the glucose they take up

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Disorder - Diabetes mellitus

• Group of glucose intolerance disorders
• Historical - weight loss and
• Excessive urination polyuria
• Excessive thirst polydipsia
• Excessive hunger polyphagia

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• Modern classifications
• IDDM - Insulin Dependent Diabetes Mellitus
• NIDDM - Non-Insulin Dependent Diabetes Mellitus
• GDM - Gestational Diabetes Mellitus

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IDDM ( Type I Diabetes)

• 10 of all DM in Western world
• Genetic, env assocns
• 10-15 have parent or sibling with disease
• Peak age of diagnosis 12 years
• Genetic/environmental/autoimmune factors destroy
  beta cells
• Believed abrupt onset
• Now immunomarkers, preclin symptoms discovered

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• Disequilibrium of hormones produced by islets of
  Lagerhans
• Ratio insulin/glucagon controls glu, fat metab
• Clinical
• Glucose in urine
• When insulin not present, glucose not taken up
  from blood at target cells ?
• Blood glucose very highly incrd ?
• Incrd glu filtered, excreted in urine
• Weight loss
• Patient eats, but nutrients not taken up by cells
  and/or not metabd properly
• Polyuria, polydipsia, pholyphagia

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• Ketoacidosis
• Fats metabd inappropriately ? accelerated
  acetyl-CoA prodn AND
• Decrd aerobic metab (decrd glu metab)
• ? Prodn acetoacetate b-hydroxybutyrate (acids)
  acetone (ketone body) prodd, reld to
  bloodstream
• ? Decreased blood pH
• ? Compensations for metabolic acidosis
• Hyperventn
• Renal compensations
• ? Acetone given off in breath

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Treatment

• Administer insulin
• Animal or human
• Cannot be given orally
• Protein, so broken down in digestive tract before
  absorption
• Patient must monitor own blood glucose concent
  and admin insulin with correct timing

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• Various insulin formns avail
• Ins lispro ins w/ lys/proline switched
• More rapid-acting, but avail shorter time
• Pts can inject immed before meal
• Ins glargine modd ins analog
• Forms micropreciptate in subcu tissue ? prolonged
  release
• Constant basal ins supply
• Ins preciptated w/ protamine or zinc ? slowly
  absorbed ins
• Varied dosing regimens, mixtures slow-, rapid
  release formulations

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• Control diet
• Carbohydrates should be 55-60 of total
  calories
• Fats lt30 of total calories
• Proteins 15-20 of total calories
• Monitor exercise
• Remember muscles are target tissue metab much
  glu
• Exercise may? irregular blood glu levels
• Pancreatic transplant so far not successful
• Experimental therapies not as successful as
  hoped

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NIDDM ( Type II Diabetes)

• More common than IDDM, often undiagnosed
• Slow onset
• Most common in those gt 40 years
• More children now diagnosed regularly
• May be genetic
• Obesity important
• Greatest risk factor
• Related to increased incidence in children

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• ? Insulin resistance in target cells
• See decrd b cell responsiveness ?
• Decrd insulin secrd by b cells
• Also abnormal glucagon secreted
• May be due to
• Abnormally functioning b cells, OR
• Decreased b cell mass, OR
• Combination of both, OR
• Target cell resistance to insulin
• Decrd insulin receptors on target cells, OR
• Target cells desensitized to insulin

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• Clinical
• Overweight, hyperlipidemia common (NOTE these
  are precursors, not symptoms)
• Recurrent infections
• Visual changes, others (explained below)

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• Treatment
• Weight loss
• Appropriate diet (see IDDM above)
• Exercise promotes weight loss
• Oral hypoglycemics or antihyperglycemics

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Oral Hypoglycemics

• Sulfonylureas
• Stim b cells to incr insulin secretion
• Bind subunit of ATP-sensitive K channels
• Block channels ? incrd depoln of b cell
  membranes
• ? Incrd Ca2 and incrd insulin released
• Work only when b cells are still functioning

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• 1st generation tolbutamide, tolazamide,
  acetohexamide, chlorpropamide
• 2nd generation glyburide, glipizide, glimepiride

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• Meglitinides
• Also bind ATP sensitive K channels BUT at site
  distinct from sulfonylureas

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• Metformin a biguanide
• Mech not completely understood
• Actn cAMP-dependent kinase ? incrd
  translocation GLUT4 to cell surface(?)
• Reduces hepatic gluconeogenesis
• Reduces LDLs and VLDLs
• Increases glu uptake, use in skeletal muscle and
  fat

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Antihyperglycemics

• Thiazolindinediones (glitazones)
• Max effect only 1-2 mos treatment
• Reduce hepatic glu output, incr glu uptake in
  muscle
• Less insulin needed

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• Bind nuclear receptor/transcription factor
  (PPAR-g) in adipocytes (also muscle, liver)
• ? Incrd synth of enzs, prots impt to insulin
  signalling
• Lipoprotein lipase
• FA transporter prot
• Adipocyte fa-binding prot
• GLUT 4
• Phosphoenolpyruvate carboxykinase
• Used in combination w/ sulfonylureas

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• a-Glucosidase Inhibitors
• Inhibit enzs that cleave complex CHs ?
  monosacchs
• Only monosacchs can be absorbed, so
• Delay CH absorption from intestine
• ? Decrd posprandial incr in blood glucose
• BUT gi disturbance side effects
• Often used in combination w/ other agents

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Gestational Diabetes

• Due to incrd hormone secrn during pregnancy
• Seen if patient has predisposition
• If previous or potential glucose intolerance has
  been noted
• Important - incrd mortality risk for mother,
  child

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Complications of Diabetes Mellitus

• Acute
• Hypoglycemia
• Rapid decrease in plasma glucose
• Insulin shock
• Neurogenic responses
• Probably due to decrd glucose to hypothalamus

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• Symptoms include
• Tachycardia, palpitations, tremor, pallor
• Headache, dizziness, confusion
• Visual changes
• Treatment
• Provide glucose (i.v. or subcu if unconscious)
• Observe for relapse

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• Ketoacidosis involves precipitating event (ex
  trauma, surgery, infection, stress)
• Increased hormones released w/ trauma ? increased
  glucose produced by the bodys cells
• Antagonizes the effects of any glucose present
  ?
• Incrd ketones in blood
• Acid/base imbalance
• Polyuria, dehydration
• Electrolyte disturbances
• Hyperventilation (Kussmauls)
• CNS effects
• Acetone on breath
• Treatment - low dose insulin

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• Chronic
• Neuropathies
• Nerve dysfunctions
• ? Slowing of nerve conduction
• See
• Degeneration of neurons ?
• Sensory, motor deficits ?
• Muscle atrophy, paresthesias
• Depression
• G.I. problems, as muscle motility decreased
• Sexual dysfunction

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• Chronic contd
• Microvascular disease -- chronic diabetes w/
  improper glucose metabolism ?
• Thickening of basement membrane of capillaries
• Particularly in eye and the kidney
• As the capillary changes ?
• Decrd tissue perfusion
• So ischemia ? hypoxia

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In the retina, weakening of the arterioles and
capillaries may result in the characteristic
appearance of intraretinal dot and blot
hemorrhages, exudates, intraretinal microvascular
abnormalities (IRMA) microaneurysms, edema and
cotton wool infarcts.
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• Microvascular disease contd
• In eye
• Retina is metabolically active
• Hypoxia a big problem (need lots of oxygen at a
  metabolically active tissue)
• See
• Retinal ischemia ?
• Formation of microaneurisms, hemorrhage, tissue
  infarct, retinal detachment
• In kidney
• Diabetes is most common cause of end-stage renal
  disease
• ? Injured glomeruli (glomerulosclerosis)

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• Glomerulus specialized capillary impt to filtrn
  
• If basement membr thickens, filtration ability
  changes. Body tries to overcome clogged filter
  over time. See
• Proteinuria (protein excrd into urine) ?
• Generalized body edema, hypertension
• Remember as body loses protein ? decreased COP
  ? vascular fluids now have even greater relative
  BHP ? fluids forced out toward tissues

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• Macrovascular disease
• Atherosclerosis
• Plaque formn incrs ?
• Incrd risk of
• Coronary artery disease, so incrd risk of
  myocardial infarction
• Congestive heart failure
• Infections
• Stroke
• Peripheral vascular disease
• Diabetic patients face problems with lower legs,
  feet may ? gangrene and amputation of limbs