Pancreas 1 2024.pdf

Cellular Biology & Homeostasis PANCREAS - part 1 VP 2024 Clara Camargo, DVM 1. Describe the location of the pancreas and its exocrine and endocrine functions 2. Describe the islets of Langerhans: list the 4 types of cells and hormones produced 3. Understand the structure of insulin, and the differen...

Cellular Biology & Homeostasis PANCREAS - part 1 VP 2024 Clara Camargo, DVM 1. Describe the location of the pancreas and its exocrine and endocrine functions 2. Describe the islets of Langerhans: list the 4 types of cells and hormones produced 3. Understand the structure of insulin, and the differences between species 4. Explain insulin synthesis and secretion, and the biphasic kinetics (acute and chronic phase) 5. Understand the insulin-receptor interaction and the net effect of insulin on the metabolism 6. Describe the effects of insulin on the three main target tissues (muscle, adipose tissue and liver) 7. Understand insulin metabolic clearance  Glandular organ, in the abdominal cavity  Two lobes, one behind the stomach, the other in apposition to the proximal duodenum https://veteriankey.com/pancreas-4/ https://todaysveterinarypractice.com/soft-tissue-surgery/a-guide-to-exploratory-laparotomy/ EXOCRINE PANCREAS Acinar cells Acinar cells and duct cells Secrete digestive enzymes into the Duct lumen of duodenum Islets of Langerhans ENDOCRINE PANCREAS 4 types of cells – organized in islets Secrete hormones into the blood Acinar cells Involved in endocrine function (glucose metabolism) 2-3% of the pancreas http://medcell.org/histology/digestive_organs_lab/pancreas.php Acini exocrine function Delta cell secretes somatostatin Alpha cell secretes glucagon F cell Beta cell secretes insulin secretes pancreatic polypeptide 4 cell types producing 4 hormones (all polypeptides)  Alpha α cells (20%) – Glucagon  Beta β cells (>70%) – Insulin Immunostaining: red = glucagon antibody; blue = insulin antibody https://commons.wikimedia.org/wiki/File:Human_pancreatic_islet.jpg  Delta δ cells (D cells) (5%) – Somatostatin  F cells (PP cells, γ cells) (< 5%) – Pancreatic Polypeptide The hormones above are involved in glucose metabolism and the regulation of blood glucose levels Immunofluorescence staining: (A) glucagon (α cells, blue insulin (β cells, red); somatostatin (δ cells, green) https://medschool.vanderbilt.edu/basic-sciences/2019/01/31/key-to-islet-cell-differentiation/ All pancreatic hormones are polypeptides  Insulin, Glucagon, Somatostatin, Pancreatic Polypeptide Circulate unbound in the blood  Hydrophilic Short half-life ≤ 30 minutes Bind to cell surface receptors PRE-PROHORMONE → PROHORMONE → HORMONE Insulin → a polypeptide hormone produced by pancreatic beta cells in response to hyperglycemia Active insulin - two peptide chains: alpha connected by disulfide bridges beta https://teachmephysiology.com/endocrine-system/pancreas/insulin/ α signal 1. Synthesized as preproinsulin within the rER 2. The signal sequence (pink) is removed in the ER to form proinsulin β 3. Proinsulin → Golgi apparatus → packaged into C vesicles → cleavage of C-peptide (mature vesicle) http://parts.igem.org/Part:BBa_K2117003 FYI C-peptide test measures the amount of C-peptide in the blood or urine.  It can help differentiate Type 1 or Type 2 diabetes  Helps evaluate the efficacy of treatment  Determine if the pancreas is synthesizing insulin C-peptide https://pdb101.rcsb.org/motm/14 https://teachmephysiology.com/endocrine-system/pancreas/insulin/ Differences in amino acid sequences between species are small: Cattle, sheep, horses, dogs and whales differ only in positions 8, 9 and 10 of the alpha chain Porcine insulin differs from human insulin by 1 amino acid Bovine insulin differs from cat insulin by 1 amino acid Porcine insulin differs from cat insulin by 3 amino acids Human insulin differs from cat insulin by 4 amino acids Porcine and canine insulin are exactly the same https://pdb101.rcsb.org/motm/14 Several variables dictate insulin release:  nutritional  paracrine  neural  endocrine Secretagogue A substance that stimulates secretion of another substance The importance of the secretagogues depends on the natural diet and nutritional status of the species Glucose → important for omnivores Amino acids → important for carnivores https://www.diabetesincontrol.com/handbook-of-diabetes-4th-editionexcerpt-4-normal-physiology-of-insulin-secretion-and-action/ Fatty acids → also stimulate insulin release in humans How is insulin secreted from beta cells? An increase in blood glucose concentration leads to insulin secretion and production Hyperglycemia → High ECF [glucose] X Beta cells have a glucose transporter (GLUT2 - insulin independent) in the membrane surface Allows glucose to diffuse into the cell (towards the 2 1 concentration gradient) Extracellular fluid glucose concentration directly affects glucose concentration inside beta cells Pancreatic beta cell https://commons.wikimedia.org/wiki/File:Glucose-insulin-release.svg The secretion of insulin follows biphasic kinetics: ACUTE PHASE  secretion of pre-synthesized insulin CHRONIC PHASE  Synthesis and secretion of insulin Cunningham's Textbook of Veterinary Physiology, 6th Edition FYI Dynamics of insulin secretion and the clinical implications for obesity and diabetes https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3104758/ After secretion from beta cells, insulin binds to specific membrane receptors on target tissues: RTK Receptor Tyrosine Kinase https://www.drawittoknowit.com/course/cell-biology/receptors/receptor-types/1124/receptor-tyrosine-kinases Insulin facilitates glucose entry into cells by increasing the number of specific GLUCOSE TRANSPORTERS (GLUT4) in the cell membrane Pearson Education  There are different types of GLUTs  GLUT4 is the only insulin sensitive  Muscle and adipose tissue requires https://www.researchgate.net/publication/336374126_Hepatitis_C_ virus_infection_genotypes_and_mechanism_of_insulin_resistance insulin to take glucose into the cells GLUT4 x exercise Resistance exercise can stimulate translocation of GLUT 4 to muscle membrane, increasing glucose uptake by the cell The net effect of insulin is to lower blood concentration of glucose, fatty acids, and amino acids 1. Facilitating glucose entry into cells 2. Promoting intracellular conversion of these compounds to their storage forms: Glucose → Glycogen Fatty acids → Triglycerides Amino acids → Proteins Compound  storage form ANABOLIC EFFECT Smooth, striated and cardiac muscle:  Stimulates glycogen synthesis enzymes  Promoting storage of glucose molecules in the form of glycogen Glycogenesis the process of storing excess glucose as glycogen for use by the body later Promotes the use of glucose as fuel source  Reduces fatty acid beta oxidation In the absence of insulin muscle rely more on fatty acids as fuel source Enhances amino acid uptake and promotes muscle growth (protein synthesis) Increase glucose uptake by adipocytes:  Stimulates Dihydroxyacetone phosphate (DHAP) pathway → Glycerol synthesis  Stimulates glycolysis → formation of pyruvate → Acetyl CoA → Fatty acid synthesis Glycerol + Fatty acids = Triacylglycerol (TAG) → storage in adipocytes ↑ LIPOGENESIS Insulin inhibits lipolysis Lipolysis - the process of breaking down of triglycerides into fatty acids and glycerol Promotes fatty acid synthesis in hepatocytes  Stimulates incorporation of those fatty acids and triglycerides into lipoprotein–bound vesicles such as VLDL for transport to adipocytes Stimulates glycogen synthesis (glycogenesis) and glycolysis (ATP production) Decrease gluconeogenesis and glycogenolysis Decrease synthesis of ketone bodies Gluconeogenesis - the process of producing glucose from Glycogenolysis - the process of non-carbohydrate substrates (amino acids, glycerol, lactate) breaking down glycogen into glucose Most important insulin-sensitive tissues: Carbohydrate metabolism Lipid metabolism Protein metabolism + glycogen synthesis - glycogenolysis - gluconeogenesis + glucose transport GLUT 4 + glycogen synthesis - glycogenolysis + lipogenesis - lipolysis - ketone bodies synthesis - gluconeogenesis + glucose transport GLUT 4 + lipogenesis - lipolysis + amino acid uptake + protein synthesis - protein degradation Insulin is metabolized mainly by the liver and excreted by the kidneys In the liver, specific enzymes reduce the disulfide bonds → inactive A and B chains Chains are subjected to protease activity → reduce them to peptides and amino acids Insulin Clearance Half-life 10 min Picture source: drug discovery news