Pancreas

1
Pancreas

• Located partially behind stomach in abdomen
• Composed of both endocrine and exocrine tissue
• Exocrine (acinar) cells secrete enzyme-rich juice
  that is ducted to duodenum
• Clusters of endocrine cells are scattered among
  exocrine cells

2
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

3
Insulin

• Polypeptide
• Alpha chain (21 a.a.)
• Beta chain (30 a.a.)
• Normally degraded within liver and kidneys by
  hepatic glutathione insulin dehydrogenase
• Half-life is 5 minutes

4
Insulin

• Released in response to elevated glucose levels
• Most important target tissues
• Hepatic cells
• Muscle cells
• Adipose tissue cells
• Enhances glucose uptake into cells (glucose
  transporter)
• Cells metabolize glucose and
• Store as glycogen
• Used as energy substrate to synthesize proteins,
  fats

5
Insulin Effects on liver

• Enhances glucokinase activity
• Phosphorylates glucose gt glucose-6-PO4
• Maintains diffusion gradient for glucose entry
• Activates glycogen synthetase
• Promotes formation of glycogen

6
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 gt GS is active

7
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 gt stored
• Free fatty acids obtained from chylomicrons
• Insulin causes endothelial cell release of
  lipoprotein lipases
• FFAs released from chylomicrons, taken up by fat
  cells

8
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 exped in liver
• Insulin enhances GLUT 1 gene expression

9
Insulin effects, contd.

• GLUT 4 primarily expressed in muscle, adipose
  tissue
• GLUT4 initially resides in intracellular vesicles
• Insulin causes insertion into cell membrane
• Interesting side note exercise also induces
  GLUT4 membrane insertion in muscle cells

10
Insulin receptors

• Figure 2.6
• Receptor is complex of two subunits
• alpha (extracellular bind insulin)
• beta (transmembrane protein covalently linked to
  alpha)
• Insulin binds to receptor dimer
• Activation gt autophosphorylation of beta subunit
  tail
• Acts as tyrosine kinase

11
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

12
Glucagon

• Peptide (29 aa) produced by alpha cells
• Opposes insulin actions (hyperglycemic factor)
• A catabolic factor
• Figure 8.3
• actions involve transmembrane receptor, cAMP
  pathway

13
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

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Glucagon Lipolytic actions

• Mobilization of triglycerides depends on lipase
  activity
• Lipase activated by glucagon (also
  catecholamines)
• cAMP-dependent kinase activates lipase gt free
  fatty acid release
• Insulin can reverse (mechanisms unclear)

15
Glucagon Lipolytic actions, contd.

• Glucagon inhibits lipogenesis (Fig. 8.8)
• Important enzyme for lipogenesis acetyl CoA
  carboxylase
• Acetyl CoA carboxylase inhibited via
  phosphorylation
• Two enzymes regulate its activity (cAMP-dep.,
  -indep. Kinases)
• Glucagon gt cAMP gtgt phos. of carboxylase gt
  inhibition of lipogenesis

16
Somatostatin

• 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

17
Pancreatic polypeptide

• Produced by F cells
• Inhibits secretion of enzymes from acinar cells
• Secreted in response to ingestion of meal
• Conservation of digestive enzymes?
• Suppresses secretion of SST from D cells

18
Control of islet function

• Glucose is major metabolic substrate for brain
• Cant make, store, increase uptake of glucose
• Prevention / correction of hypoglycemia is
  critical to survival
• Most important / immediate regulator of islet
  function glucose
• Low glucose gt glucagon release increases
• Increase in glucose gt insulin release increases
• Extreme hypoglycemia gt release of epinephrine
  from adrenal medulla

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Autonomic control of islet function

• Catecholamines of neural (ANS) and endocrine
  (adrenal) origin control islets
• Alpha and beta cells possess catecholamine
  receptors
• High E, NE gt beta adrenergic receptors gt
  inhibition of insulin secretion

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Autonomic control ofislet function, contd.

• Epinephrine inhibits insulin secretion
• Prevents glucose from being converted to
  glycogen, fat
• Readily available to active tissues (brain,
  muscles)
• Epinephrine and norepinephrine stimulate glucagon
  secretion
• Activates hepatic glucose production, release

21
Insulin glucagon feedback

• Intra-islet feedback loop?
• Elevated glucose gt 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

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Other factors that influence glucose homeostasis

• Growth hormone is diabetogenic
• reduces sensitivity of peripheral tissues
• Side effect gt elevated insulin gt further
  downregulation of receptors
• Acromegalics gt insulin resistance
• Glucocorticoids
• increase hepatic gluconeogenesis
• Catabolic action on muscle, fat
• Cushings syndrome leads to diabetes

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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

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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

25
Type II Diabetes Mellitus

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