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Endocrine pancreas
1. Emperor Shahjan
● 1592-1666-
● Builder of the Taj Mahal
● Imprisoned by his son
● Chose lentils as his only diet in prison
2. Objectives
● Know the mechanisms of action of insulin and
glucagon
● Know how secretions of insulin/glucagon are
regulated
● Know effects of insulin on liver/muscle/ adipose
● Know effects of glucagon on liver and adipose
tissue
● Know control of lipid/sugar/protein metabolism
3. Anatomy of the pancreas
● Exocrine gland-secretes into duodenum
● Endocrine cells clustered into islets of
Langerhans all over the pancreas
● Endocrine cells secrete hormones into blood
● Close to 2 millions islets
6. Main embryological events
● Stomach, duodenum, biliary system, including
the gallbladder, liver and pancreas are derived
from related structures
● Dorsal/ventral pancreas enlarge
● Ventral pancreas and common bile duct rotate
● Two pancreatic ducts fuse
● Pancreatic/biliary secretions released thru
ventral pancreatic duct
7. Pancreas develops at 5 wk
gestations distal to stomach
Outpouchings of endodermal dudenal lining
8. Insulin, glucagon,
somatostanin and PP are secretions
● Endocrine cells are 2 % of total mass of
pancreas
● Alpha cells-peripherally located;secrete
glucagon
● Beta cells-centrally located
● D cells-somatostatin-inhibits insulin/glucagon
● F cells-pancreatic polypetide(PP)-affect
gastric/biliary secretion;GI tract; satiety
9. Origin and Structure of insulin
● May have originated I b years ago-simplest
unicellular eukaryotes(algae,diatoms)
● Made in Brokmann bodies of teleost fish
● Made as preprohormone(preproinsulin)
● Proinsulin(9 kD)- Insulin + C-peptide in golgi
● 51 amino acid AA- MW of 5.8 kD
● Composed of A and B chains linked by S-S
10. Origin and Structure of insulin
● May have originated I b years ago-simplest
unicellular eukaryotes(algae,diatoms)
● Made in Brokmann bodies of teleost fish
● Made as preprohormone(preproinsulin)
● Proinsulin(9 kD)- Insulin + C-peptide in golgi
● 51 amino acid AA- MW of 5.8 kD
● Composed of A and B chains linked by S-S
12. Membrane depolarization triggers
insulin release
● Stored in secretory vesicles in cytoplasm
● Calcium influx leads to exocytosis of vesicles
and release of insulin
● A t ½ of 5 minutes
● Broken down in liver mostly, some in kidney
13. Mechanism of action of insulin
●
Binds heterotetrameric receptor (2 α and 2 β
subunits)
●
Insulin binds extracellular α subunit
●
Δ conformation in cytoplasmic portion of
membrane-spanning β subunit that has tyrosine
kinase activity
● PO4
3-
of tyrosines in IRS-1 and other proteins
leads to Glut4 translocation
15. Functions of insulin-liver
●
↑Glut-4-mediated glucose uptake
●
↑glycogen synthesis; ↑glycolysis??
(pyruvate/TCA
●
↓glycogen synthetase kinase(GSK) and
promotes its dephosphorylation
● GSK inhibition in type 2 diabetes
●
↓gluconeogenesis (effect on enzymes)
●
↓amino acid influx;↑ peripheral protein synthesis
16. Functions of insulin-adipose tissue
●
↑ glucose uptake and triglyceride synthesis
●
↑ endothelial lipoprotein lipase to release free
fatty acids for uptake bt fat cells
●
↓lipolysis via inhibiting hormone-sensitive lipase
●
17. Functions of insulin-muscle
●
Glucose metabolism-↑glucose uptake and
glycogen synthesis(in non-exercising muslce)
●
Protein metabolism-↑ cellular amino acid
transport;↑ protein synthesis and ↓ protein
breakdown
18. Structure and properties of
glucagon
● Preprohormone;mature as 29 AA single chain
polypeptide
● Stored in cytoplasmic vesicles
● In intestinal L cells, proglucagon is cleaved into
glucagon-like peptide(GLP-1) (an incretin),
gastric inhibitory peptide(GIP)
● Has t ½ of 4-5 min;
20. Functions of glucagon-liver
●
↑ synthesis and release of glucose
●
↑ gluconeogenesis(upregulates enzymes) ;no
effect on amino acid uptake
●
↓glycogen synthase and ↑ glycogen
phosphorylase
21. Functions of glucagon-adipose
tissue
●
↑ fatty acid release by ↑ adipose cell hormone-
sensitive lipase
●
This effect is minor in lipolysis
●
Other hormones such as Epi, GH, and ACTH
may exert greater control
23. There exists a balance between
gluconeogenesis and lipogenesis
●
During hypoglycemia, glucagon↑ and
gluconeogenesis increases
●
Lipids are utilized and ketone bodies can form
●
During hyperglycemia,↑ insulin leads to
increased glucose uptakeand enhanced
lipogenesis
24. There exists a balance between
gluconeogenesis and lipogenesis
●
During hypoglycemia, glucagon↑ and
gluconeogenesis increases
●
Lipids are utilized and ketone bodies can form
●
During hyperglycemia,↑ insulin leads to
increased glucose uptakeand enhanced
lipogenesis
25. How are insulin and glucagon
secretion regulated?
● Pancreas acts as a homeostat
● Blood [Glu] exerts most important control
● High[Glu] in blood stimulates insulin secretion
and inhibits glucagon secretion
● Low [Glu] ????
● Amino acids increase glucose-induced insulin
secretion
● Amino acids increase glucagon secretion
26. How are insulin and glucagon
secretion regulated?
● Autonomic nervous system modulates
secretion- sympathetic Epi ↓ insulin and ↑
glucagon
● Autonomic nervous system modulates
secretion- parasympathetic ?? insulin and ??
glucagon
●
Hormones GH, glucagon, and cortisol ↑[insulin]
● Insulin inhibits glucagon secretion
27. Why does cortisol lead to increased
insulin secretion?
● Cortisol increases blood sugar levels through
gluconeogenesis
● Increased blood sugar levels lead to insulin
release
28. Together, insulin and glucagon
maintain glucose homeostasis
● Insulin-anabolic hormone
● Insulin enhances cell utilization/storage of
glucose
● Insulin promotes glycogen and fat/triglyceride
synthesis
● Insulin inhibits enzymes responsible for
glycogenolysis and gluconeogenesis
● Glucagon promotes fatty acid breakdown
29. gluconeogenic precursors are
lactate, glycerol, alanine and
glutamine.
● Other glucogenic AAs/TCA intermediates
(thru oxaloacetate)function in gluconeogenesis
