1. Pancreatic Alpha & Beta Cells Pancreatic Alpha & Beta Cells BCMP234 Cell of the Week Jessica Spinelli 02/01/16

2. Cnx.org “Anatomy and Physiology” Ch.23.6 Pancreatic Architecture

3. Pancreas: Exocrine & Endocrine Functions Secretion of “Pancreatic Juice” (1 Liter a day!) Cocktail: 1.Water 2.Salt 3.Inactive Proteases 4.Active amylases, lipases, nucleases 5.HCO 3 - **Buffer pH of blood before liver entry **Support digestion in the intestines Exocrine: Acinar Cells Endocrine: Islet Cells Cell Type Hormone Secreted α-Cell (15-20%) Glucagon β-Cell (65-80%) Insulin & Amylin γ-Cell (3- 10%) Somatostatin δ-Cell (3- 5%) Pancreatic Polypeptide ε-Cell (<1%) Ghrelin Function: Secretion of Hormones ***% composition by mass B. Ahren. Diabetologia (2000) 43: 393-410

4. Alpha Cells Glucagon-catabolic (Raise Blood Glucose ) Beta Cells Insulin-anabolic (Lower Blood Glucose) Alpha & Beta Cells Coordinate Blood Glucose Homeostasis Glycolysis, Gluconeogenesis & Glycogen metabolism with Dr. Michel

5. Beta Cells Store “Active” Insulin for Rapid Release during Hyperglycemia -Mature insulin bioaccumulates in beta cells for rapid release during hyperglycemia! -Proinsulin/insulin ratio is a marker of beta cell function Beta cell mass correlates with beta cell function Serum levels of C Peptide used for quantification of Beta Cell function! Alan J. Garber. Dia Care (2011) 34: 58-S263

6. Glucose Stimulates Insulin Secretion from Beta Cells Through Membrane Depolarization and Calcium Influx Maria-Luisa Lazo de la Vega-Monroy and Cristina Fernandez-Mejia (2011). Beta-Cell Function and Failure in Type 1 Diabetes, Type 1 Diabetes - Pathogenesis, Genetics and Immunotherapy, Prof. David Wagner (Ed.), ISBN: 978-953-307-362-0 Heightened glycolysis increases the ATP/ADP ratio K ATP channels are inhibited, causing β-cell membrane depolarization Calcium influx results in the mobilization of vesicles with “active” insulin to the membrane for secretion

7. Birnbaum,M.J. Nature 409, 672-673 Insulin Signaling is Systemically Diverse More to come week 3 with Dr. Burtner! Liver Cells Activate glycogen synthesis Inhibit gluconeogenesis mTOR activation (proliferation & protein synthesis) Heart, Muscle & Fat Cells Activate glycogen synthesis mTOR activation (proliferation & protein synthesis) GLUT4 mobilization to membrane (enhanced glucose consumption)

8. Diabetes: A Disease of Pancreatic Dysfunction Type 1: Lack of production of insulin by β-cells Caused by an autoimmune response to β-cells or physical damage to pancreas Type 2: Insulin resistance, lack of insulin secretion, excessive glucagon production Caused by obesity and genetic factors (More to come this week with Dr.Michel) Sulfonylureas Mechanism: inhibit K ATP channels Effect: Depolarization of β-cell membrane, inducing calcium influx and insulin secretion A solution for type two diabetes: Stimulate insulin secretion!!

9. Discussion Question What are the requirements for building a functional pancreatic Beta cell? 1. Synthesize, process, package and store insulin in secretory granules 2. Insulin secretion is sensitive to extracellular glucose concentration 3. Membrane depolarization and calcium sequestration mediate the secretion of insulin

10. Pagliuca, F. W., et al. (2014). Cell 159(2): 428-439.

11. Generating Functional Human β-Cells from Pluripotent Stem Cells ✔ The SC-β Cells produce insulin upon glucose challenge. 1. Is Insulin secretion sensitive to glucose concentration? 2. Is the insulin properly cleaved? ✔ C-Peptide cleavage and “active” insulin production ✔ Calcium influx coordinates with glucose stimulation (figure not shown) Pagliuca, F. W., et al. (2014). Cell 159(2): 428-439.

12. Generating Functional Human β-Cells from Pluripotent Stem Cells In vivo Activity? ✔ SC-β cells secrete insulin in vivo upon glucose stimulation Pagliuca, F. W., et al. (2014). Cell 159(2): 428-439.

13. Physiology & Regulation α-Cell Function Proglucagon Glucagon Packaging Secretory Vesicles α-cells synthesize, process and package glucagon for secretion! Positive regulators of glucagon secretion are poorly characterized…(Thesis Anyone?!?!) **Adrenaline activates glucagon secretion (Islets are highly innervated) Glucagon secretion is significantly controlled by negative regulators: **Insulin from β-cells induces the GABA receptor in α-cells to cause hyperpolarization of the membrane, blocking calcium influx and glucagon secretion. Intraislet Regulation of Glucagon Secretion Xu, E., et al. (2006). Cell Metab 3(1): 47-58.

14. Recall from Dr. Michel’s Lecture…Protein Kinase A regulates Fatty Acid Metabolism (Dr. Michel Lecture 2)

15. Similarly, Glucagon Stimulates PKA Activity to Regulate Glycogenolysis & Gluconeogenesis in Target Cells https://en.wikipedia.org/wiki/Glucagon#/media/File:Glucagon_Activation.png Glucagon Glucagon stimulates the Glucagon Receptor (GPCR) & Adenylate Cyclase activation increases intracellular cAMP Phosphorylation cascade by Protein Kinase A activates Glycogen Phosphorylase and inactivates Glycogen Synthase Summary Quesada, I. et al. Journal of Endocrinology (2008) 199, 5–19 Liver Cell

16. Small Molecule Induces Transcriptional Reprogramming of α-cells into β-cells BRD7552 Yuan, Y., et al. (2013). "A small-molecule inducer of PDX1 expression identified by high- throughput screening." Chem Biol 20(12): 1513-1522.

17. Summary: Pancreatic Alpha & Beta Cells The pancreas is an organ that has critical exocrine and endocrine functions α-cells & β-cells regulate blood glucose homeostasis through glucagon and insulin secretion Glucagon activates adenylate cyclase to increase cAMP, leading to inactivation of glycogen synthesis and enhanced gluconeogenesis. Insulin enhances glucose uptake (via GLUT4) in nonhepatic tissue and inhibits glucose secretion in the liver α- & β-cells store their peptide hormones in vesicles that require Ca +2 for mobilization to the membrane & secretion K ATP channels are critical for stimulating membrane depolarization to allow Ca +2 influx