10. Pancreatic Hormones

Cell Types of the Pancreas

• The Islets of Langerhans are ________ cells in the ___________ responsible for ____________ pancreatic hormones

• Alpha cells synthesize and secrete __________ and are the most ________

• Beta cells synthesize and secrete __________

• Delta cells synthesize and secrete ______________

• Epsilon cells synthesize and secrete __________

• PP/Gamma/F cells cells synthesize and secrete __________ _____________

• _____________ ___________ helps transmit __________ for release of pancreatic hormones

Cell Types of the Pancreas

• The Islets of Langerhans are endocrine cells in the pancreas responsible for secreting pancreatic hormones

• Alpha cells synthesize and secrete glucagon and are the most abundant

• Beta cells synthesize and secrete insulin

• Delta cells synthesize and secrete somatostatin

• Epsilon cells synthesize and secrete ghrelin

• PP/Gamma/F cells cells synthesize and secrete pancreatic polypeptides

• Autonomic Innervation helps transmit signalsfor release of pancreatic hormones

Insulin Overview

• Why is insulin important?

• What are its metabolic effects

• What is the structure of insulin

• Insulin is the most important hormone coordinating the use of fuels

• Insulin has anabolic (building) effects such as glycogenesis, fatty acid and protein synthesis

• The structure is composed of of 51 AA divided in A and B chains; The chains are held together by 2 disulfide bridges and another intramolecular disulfide bridge is found within the A chain

Insulin Synthesis

• What is is the process and what are the differences between the precursors and insulin?

• Where is insulin stored and how is it released when needed

• How is insulin degraded

• Why do we test for C-peptide and not for Insulin levels when we want to know how much insulin is being produced?

• In the RER: preproinsulin gets its N-terminal sequence cleaved and becomes proinsulin; In the Golgi A: proinsulin gets the C-peptide cleaved and becomes insulin

• Insulin is stored in the cytoplasm and is released by exocytosis

• Insulin is degraded by insulinase

• We test C-peptide because it has a longer-half life than insulin and is thus a better indicator

Insulin Regulation

• Stimulators

• Inhibitors

• Stimulators: Glucose (proportional relationship with insulin), Amino Acids (Fats too but not nearly as much), gastrointestinal hormones (hunger signals)

• Inhibitors: Scarcity of dietary fuels, Illness, Stress/Epinephrine

Insulin/Glucagon Secretion from the following starting molecules: mention low glucose and high glucose scenarios

• Glucose and Alanine

• Arginine

• TAG

Insulin during High Glucose

• Glucose and Alanine → Pyruvate → ATP → Depolarization of Ca2+ channels → exocytosis of insulin

• Arginine → Polarization of K+ channels → Depolarization of Ca2+ channels → exocytosis of insulin

• TAG → many ways to produce energy → ATP → Depolarization of Ca2+ channels → exocytosis

Glucagon during high glucose

• Blocks channels and does not exocytose glucagon

Insulin during Low Glucose

• Blocks channels and does not exocytose

Glucagon during Low Glucose (same effect as insulin during high glucose but i am not gonna write it again)

• Channels open up due to depolarization and it leads to glucagon exocytosis

• Insulin Mechanism of Action

• Insulin-dependent Transport of Glucose Mechanism

• What are the insulin-independent tissues

• Insulin Mechanism of Action

  1. Insulin binds tyrosine kinase receptor at the alpha subunit

  2. The binding causes autophosphorylation of the beta subunit of the tyrosine kinase

  3. Phosphorylated tyrosine kinase phosphorylates Insulin Receptor Substrates (IRS) → causes systemic effects

• Insulin-dependent Transport of Glucose Mechanism

  1. Insulin binding promotes recruitment of glucose transporters from storage pool

  2. Glucose transporters fuse with the membrane and let glucose pass through

  3. When insulin is absent they move out the cell membrane and return to the storage pool

• They are very niche organs such as the brain, then leukocytes, erythrocytes, lens and cornea of eye and liver

Insulin vs Blood Glucose levels Graph

• Insulin is only higher than glucose during the morning/breakfast → most important meal for regulating insulin

• The res of the day insulin and glucose should be almost equal

Glucagon Overview

• Why is glucagon important?

• What are its metabolic effects?

• What is the structure of glucagon?

• How is the synthesis of glucagon in comparison to insulin

• Because it opposes the effect of insulin during the fasting state by maintaining blood glucose levels

• Activates glycogenolysis, gluconeogenesis (only in liver, muscle does not have glucagon receptors), fatty acid oxidation and ketogenesis

• Glucagon is a a single polypeptide chain of 29 amino acids

• It is pretty much the same thing except the name changes to glucagon → preproglucagon and proglucagon

Glucagon Regulation

• Stimulants

• Inhibitors

• Stimulants:

  • Low blood glucose due to prolonged fasting (>2hrs)

  • Amino acids: also stimulate insulin but in this case availability of AA will allow gluconeogenesis to take place

  • Epinephrine, cortisol

• Inhibitors:

  • Elevated blood glucose

  • Ingestion of carb-rich meal

  • Insulin

Glucagon Mechanism of Action

1. Glucagon binds to G protein-coupled receptors on hepatocytes

   • Remember that muscle only has epinephrine receptors, not glucagon receptors

2. Glucagon binding activates adenyl cyclase

3. Adenyl cyclase causes a rise in AMP → cAMP

4. Rise in cAMP activates cAMP-dependent protein kinase

5. cAMP-dependent protein kinase phosphorylates enzymes that give various metabolic effects (glycogenolysis, gluconeogenesis, etc.)

Diabetes Mellitus

• Explain the Disease

  • What is the problem

  • What process acts to make up for it

  • What is degraded to make up for it

  • What enzyme activity is decreased and what are the consequences

• Symptoms

• Difference between Type I and Type II

• Diabetes causes tissues to not be able to use glucose

  • Gluconeogenesis and ketogenesis are higher than normal to try and make up

    • Metformin drug used to regulate -

  • Degradation of adipose into TAG and degradation of protein also present to try to make up

  • Lipoprotein Lipase is decreased because it requires insulin activation, therefore chylomicrons accumulate → Results in Dyslipidemia → elevated TAG, elevated cholesterol, etc.

• Symptoms:

  • Polyphagia: extreme hunger

  • Polydipsia: extreme thirst

  • Polyuria: frequent urination

• Type I:

  • autoimmune disease present from childhood

  • Destruction of beta cells, no insulin

  • Increased Ketogenesis may lead to ketoacidosis

• Type 2:

  • acquired, insulin secretion is normal but cells are resistant

  • Metformin drug used to regulate gluconeogenesis

Other hormonal involvement (don’t have to know specifics, just that there are other important hormones)

Ghrelin (from epsilon cells)→ Hunger signals

Somatostatin (from delta cells)

Gastrin, Secretin, CCK, GIP, GLP-1,GH, Cortisol