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• Located partially behind stomach in
• Composed of both endocrine and exocrine
• Exocrine (acinar) cells secrete enzyme-rich
  juice that is ducted to duodenum
• Clusters of endocrine cells are scattered
  among exocrine cells
                        Endocrine pancreas
• “Islets of Langerhans”
• Two major populations of cells:
   – Alpha cells (glucagon)
   – Beta cells (insulin)
• Others:
   – D cells (somatostatin)
   – F cells (pancreatic polypeptide)
• Hormones signal in classic endocrine and
  paracrine manner

• Polypeptide:
  – Alpha chain (21 a.a.)
  – Beta chain (30 a.a.)
• Normally degraded within liver and kidneys
  by hepatic glutathione insulin
• Half-life is 5 minutes
• Released in response to elevated glucose levels
• Most important target tissues:
   – Hepatic cells
   – Muscle cells
   – Adipose tissue cells
• Enhances glucose uptake into cells (glucose
• Cells metabolize glucose and:
   – Store as glycogen
   – Used as energy substrate to synthesize proteins, fats
              Insulin: Effects on liver

• Enhances glucokinase activity
• Phosphorylates glucose > glucose-6-PO4
• Maintains diffusion gradient for glucose
• Activates glycogen synthetase
• Promotes formation of glycogen
   Insulin & Glycogen Synthetase
• GS is inactivate when phosphorylated
• 2 protein kinases can phosphorylate GS:
  – cAMP-dependent
  – cAMP-independent
• cAMP-dependent kinase relies on glucagon
  for activation
• Insulin inhibits cAMP-independent kinase
• Result: no phosphorylation > GS is active
            Insulin: Effects on fat cells
• Enhances glucose uptake and ultimately
  triglyceride production
• Glucose catabolized to glycerol
• Glycerol combined with free fatty acids to form
  triglycerides > stored
• Free fatty acids obtained from chylomicrons
   – Insulin causes endothelial cell release of lipoprotein
   – FFAs released from chylomicrons, taken up by fat cells
                       Insulin: Other effects

• Enhances presence of facilitated glucose transport
  (GLUT) proteins
   – In liver, fat, and muscle cells
• GLUT proteins form pores; allow polar sugars to
  cross lipid bilayer, move down [ ] gradient
• GLUT1 is constitutively expressed
   – “housekeeping glucose transporter”
   – Primary transporter exp’ed in liver
• Insulin enhances GLUT 1 gene expression
                Insulin effects, cont’d.

• GLUT 4 primarily expressed in muscle,
  adipose tissue
• GLUT4 initially resides in intracellular
• Insulin causes insertion into cell membrane
• Interesting side note: exercise also induces
  GLUT4 membrane insertion in muscle cells
                             Insulin receptors
• Figure 2.6
• Receptor is complex of two subunits:
   – alpha (extracellular; bind insulin)
   – beta (transmembrane protein; covalently linked to
• Insulin binds to receptor dimer
• Activation > autophosphorylation of beta subunit
• Acts as tyrosine kinase
                          Insulin receptor

• Target of receptor: insulin receptor substrate
  1 (IRS-1)
• IRS-1 generates secondary signals:
  – P13 kinase enhances glucose transport
  – Activates growth receptor-binding protein 2,
    which enhances glycogen synthesis

• Peptide (29 aa) produced by alpha cells
• Opposes insulin actions (hyperglycemic
• A catabolic factor
• Figure 8.3
• actions involve transmembrane receptor,
  cAMP pathway
                            Glucagon actions
• Stimulates hepatic glucose synthesis and release
• Glycogenolytic actions
• Role of phosphorylase a (Fig. 8.6)
• Inhibits glycogen formation (Fig. 8.7)
• Promotes conversion of amino acids and glycerol
  to glucose
• Lipolytic actions on fat cells:
    – Release of FFAs and glycerol
    – Can only occur when insulin is low
       Glucagon: Lipolytic actions

• Mobilization of triglycerides depends on
  lipase activity
• Lipase activated by glucagon (also
• cAMP-dependent kinase activates lipase >
  free fatty acid release
• Insulin can reverse (mechanisms unclear)
       Glucagon: Lipolytic actions,
• Glucagon inhibits lipogenesis (Fig. 8.8)
• Important enzyme for lipogenesis: acetyl CoA
• Acetyl CoA carboxylase inhibited via
• Two enzymes regulate its activity (cAMP-dep., -
  indep. Kinases)
• Glucagon > cAMP >> phos. of carboxylase >
  inhibition of lipogenesis
•   14 aa in length
•   Produced by D cells of islets
•   Juxtaposed to alpha, beta cells
•   Local, paracrine actions (inhibits glucagon,
    insulin, pancreatic polypeptide release)
•   Receptor inhibits cAMP levels in target cells
•   Release stimulated by ingestion of protein meal
•   Regulates movement of triglycerides from gut to
    internal environment
•   Lowers postprandial triglyceride levels
              Pancreatic polypeptide

• Produced by F cells
• Inhibits secretion of enzymes from acinar
• Secreted in response to ingestion of meal
• Conservation of digestive enzymes?
• Suppresses secretion of SST from D cells
                 Control of islet function
• Glucose is major metabolic substrate for brain
   – Can’t make, store, increase uptake of glucose
• Prevention / correction of hypoglycemia is critical
  to survival
• Most important / immediate regulator of islet
  function: glucose
   – Low glucose > glucagon release increases
   – Increase in glucose > insulin release increases
• Extreme hypoglycemia > release of epinephrine
  from adrenal medulla
                Autonomic control of
                       islet function

• Catecholamines of neural (ANS) and
  endocrine (adrenal) origin control islets
• Alpha and beta cells possess catecholamine
• High E, NE > beta adrenergic receptors >
  inhibition of insulin secretion
                   Autonomic control of
                   islet function, cont’d.

• Epinephrine inhibits insulin secretion:
  – Prevents glucose from being converted to
    glycogen, fat
  – Readily available to active tissues (brain,
• Epinephrine and norepinephrine stimulate
  glucagon secretion
  – Activates hepatic glucose production, release
          Insulin – glucagon feedback
• Intra-islet feedback loop?
• Elevated glucose > increased insulin secretion
• Insulin then inhibits glucagon production
• Only beta cells appear to possess “liver-type”
  glucose transporter
• Beta cells may then convey info to alpha cells
• Other supporting evidence : juvenile diabetes
    – No beta cells
    – Glucagon elevated even in presence of hyperglycemia
    – Elevated hepatic production of glucose
          Other factors that influence
                 glucose homeostasis
• Growth hormone is diabetogenic
• reduces sensitivity of peripheral tissues
   – Side effect > elevated insulin > further downregulation
     of receptors
• Acromegalics > insulin resistance
• Glucocorticoids:
   – increase hepatic gluconeogenesis
   – Catabolic action on muscle, fat
• Cushing’s syndrome leads to diabetes
                          Diabetes mellitus

• Hyperglycemia induced by:
  – Lack of insulin production
  – Insensitivity of target tissues to insulin
• Two types:
  – Type I (IDDM)
  – Type II (NIDDM) or maturity onset diabetes
             Type I Diabetes Mellitus

• Juvenile-onset diabetes
• Insulin deficiency
• Causes:
  – Viral-induced beta cell destruction
  – Cytotoxic autoantibodies to beta cells
• Abrupt onset of symptoms
• Almost always requires insulin therapy
            Type II Diabetes Mellitus

•   Accounts for 80% of cases of DM
•   Onset is during adulthood
•   Above-normal levels of insulin
•   Insensitivity of target tissues

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