MPP II 3.6 - ENDOCRINE PANCREAS PHYSIOLOGY

• The endocrine pancreas secretes glucagon, insulin, and somatostatin
• The exocrine pancreas secretes digestive enzymes and HCO3-
• The exocrine pancreas digests food and liberates energy substrates for absorption
• The endocrine pancreas regulates the availability of energy substrates like glucose, fatty acids, amino acids, and ketone bodies

Islet Cells

• Alpha cells are generally located near the periphery and produce glucagon
• Beta cells are the most numerous cell type in the islet, located in the center, and produce amylin and insulin
• Delta cells are located between beta and alpha cells and produce somatostatin
• F Cells display a delta cell-like distribution, are not numerous (~1%), and produce pancreatic polypeptide

Vascular Supply and Innervation

• Afferent blood vessels penetrate nearly to the center of the islet before branching out and returning to the surface
• Delta cells release somatostatin locally to decrease glucagon and insulin secretion
• Arrangement to islets is consistent with paracrine involvement in regulating islet secretion
• The sympathetic and parasympathetic nervous systems innervate the pancreas
• The parasympathetic nervous system takes up and stores energy and increases insulin secretion
• The sympathetic nervous system increases energy release, glucagon secretion and decreases insulin secretion

Glucagon

• Glucagon is a small (29 aa) peptide hormone synthesized by alpha cells
• Glucagon is formed by proteolytic cleavage of proglucagon
• It has a short half-life of 5-10 minutes
• Glucagon mobilizes and makes energy substrates available for tissues during times of stress or between meals
• The primary target is the liver, but there are secondary targets

Glucagon Targets

• The targets of glucagon are the heart, brain, pancreas, adipose tissue, liver, kidney and intestines
• Glucagon targets the liver to increase glycogenolysis, which is the breakdown of glycogen
• Glucagon stimulates glycogen phosphorylase and glucose-6-phosphatase and inhibits glycogen synthase, which leads to liver glycogen breakdown
• Glucagon stimulates glucose synthesis from noncarbohydrate sources (lipids and proteins)

Adipocytes

• Glucagon targets adipocytes
• Glucagon breaks down triglycerides, called lipolysis, in order to produce glycerol and free fatty acids
• Lipolysis is mediated by hormone-sensitive lipase (HSL) which supports lipid metabolism by increasing plasma FFA

Ketogenesis

• Ketone bodies form in the liver as a result of incomplete oxidation of FFA

Increased Secretion of Glucagon

• Cholecystokinin (CCK) and high blood concentrations of amino acids stimulate glucagon secretion
• The sympathetic nervous system increases glucagon during stressful events
• Glucagon increases the availability of blood glucose, fatty acids, and ketone bodies

Decreased Secretion of Glucagon

• Decreased secretion of glucagon happens with increased somatostatin
• Glucagon-like peptide 1(GLP-1) decreases glucagon secretion

Glucagon-Like Peptides

• When glucagon is secreted, two other inactive fragments are secreted in the pancreas as well, including GLP1 and GLP2
• The active forms of GLP are appropriately secreted from the intestinal cells and have extra amino acid sequences attached

Insulin

• Proinsulin is broken down into insulin and C-peptide
• Insulin is made up of two peptide chains, with a half-life of 3-8 minutes
• 50% of insulin is degraded by the liver during first pass, and the kidneys and peripheral tissues contribute to degradation

Insulin Synthesis

• Transcription and processing of the insulin gene product results in the production of a full length mRNA that encodes preproinsulin
• In the ER, as preproinsulin is synthesized the leader sequence is cleaved forming proinsulin
• In the Golgi, proinsulin is packaged into secretory granules
• Proteases in the granule cleave the proinsulin in two spots, excising the C peptide and forming insulin consisting of two peptide chains (designated A and B)

Insulin Actions

• C peptide has no biological action, but is used as a marker of insulin secretion
• Approximately 50% of secreted insulin in the portal blood is removed in a first pass through the liver
• C peptide is not extracted by the liver and provides a quantitative measure of insulin secretion
• C peptide is eventually excreted in the urine and measurements of C peptide reflect the amount of insulin made

Insulin Function

• Insulin lowers blood glucose levels and targets the liver, skeletal muscle, and adipose tissues
• Insulin works to promote the uptake of glucose, FA, glycerol, ketone bodies and AA

Insulin Action in the Liver

• Promotes glycogen synthesis
• Inhibits gluconeogenesis
• Promotes protein and lipid synthesis
• Inhibits ketogenesis

Insulin Action in the Muscles

• Promotes glucose and amino acid uptake
• Promotes glycogen and protein synthesis
• Inhibits protein catabolism and release of gluconeogenic amino acids
• Promotes K+ uptake

Insulin Action in Adipose Tissue

• Promotes glucose uptake and fatty acid and glycerol phosphate synthesis
• Promotes triglyceride deposition
• Activates lipoprotein lipase
• Inhibits hormone-sensitive lipase
• Promotes K+ uptake

Cellular Effects

• Insulin binds tyrosine kinase receptors which activates docking proteins like Insulin Receptor Substrate (IRS)
• Downstream phosphorylation then results in various cellular effects

Glucose Uptake in the liver and muscle

• Increases glucose uptake by upregulating and inserting GLUT4
• Stimulates the conversion of glucose to G-6-P by targeting glucokinase "hexokinase IV”
• Promotes glycogen formation by stimulating glycogen synthase and inhibiting glycogen phosphorylase
• Promotes CoA formation by stimulating phosphofructosekinase (PFK) and dehydrogenase complex

Insulin Secretion

• Insulin secretion is increased with increased blood glucose, FA, and AA
• GLP-1, CCK, acetylcholine, and PNS stimulation either increase cytosolic Ca++ or activate PKA
• Insulin secretion is decreased with decreased blood glucose, and increased somatostatin from adjacent islet cells
• Sympathetic nervous system stimulation also decreases insulin secretion