Pancreas 2 2024 PDF

Cellular Biology & Homeostasis PANCREAS - part 2 VP 2024 Clara Camargo, DVM 1. Understand the synthesis and secretion of glucagon hormone 2. Describe the physiological actions of glucagon and understand the net effect on the glucose metabolism 3. Understand glucose homeostasis regarding insulin and...

Cellular Biology & Homeostasis PANCREAS - part 2 VP 2024 Clara Camargo, DVM 1. Understand the synthesis and secretion of glucagon hormone 2. Describe the physiological actions of glucagon and understand the net effect on the glucose metabolism 3. Understand glucose homeostasis regarding insulin and the counterregulatory hormones in target tissues 4. Define Diabetes mellitus type I and II 5. Correlate the main clinical signs of diabetes mellitus with the mechanism of action of insulin in target tissues 6. List the main functions of pancreatic somatostatin and polypeptide It is a polypeptide hormone produced in the pancreatic alpha cells Antagonistic relationship with insulin Immunostaining: red = glucagon antibody; blue = insulin antibody Synthesized: https://commons.wikimedia.org/wiki/File:Human_pancreatic_islet.jpg preprohormone → prohormone → hormone Similar structure/function between species Clearance Half-life 5-7 minutes (endogenous) Immunofluorescence staining: (A) glucagon (α cells, blue insulin (β cells, red); somatostatin (δ cells, green) https://www.proteinatlas.org/humanproteome/tissue/pancreas https://medschool.vanderbilt.edu/basic-sciences/2019/01/31/key-to-isletcell-differentiation/ Stimulated by a decreased glucose concentration in the blood plasma  When levels decline below a threshold (hypoglycemia) → threshold differs between species https://www.ncbi.nlm.nih.gov/books/NBK279127/figure/glucagon-physiology.F3/ Glucose enters cells via GLUT transporter Glucose is used to generate ATP Low glucose results in low intracellular ATP Low ATP levels close ATP-sensitive potassium channels Efflux of potassium is reduced → cell membrane changes Opens voltage-dependent Ca2+ channels https://www.ncbi.nlm.nih.gov/sites/books/NBK279127 Influx of Ca2+ is primary trigger for exocytosis of glucagon Glucagon receptor is a GPCR: 1. Glucagon binds to liver cell membrane receptor 2. G-protein is activated 3. Adenylyl cyclase converts ATP to cAMP 4. cAMP activates PKA 5. PKA phosphorylates several enzymes https://www.savemyexams.co.uk/a-level/biology/cie/22/revision-notes/14homeostasis/14-1-homeostasis-in-mammals/14-1-7-the-control-of-blood-glucose/ Physiological actions of glucagon is the opposite of the insulin  Main effect are centered in the liver and adipose tissue and greatly enhance the availability of glucose to the other organs of the body ↓ Glycolysis TAG → FFA + Glycerol Ingestion of carbohydrates, fat and protein GLUCOSE > 110 mg/dL INSULIN RELEASE Carbohydrates will be the main energy source for all cells GLUCOSE < 60 mg/dL Hepatic glycogenolysis (≈24h)* GLUCAGON AND EPINEPHRINE RELEASE Excess will be stored as GLYCOGEN and FAT CORTISOL AND GH RELEASE Gluconeogenesis (glycerol, AA, lactate) Reduced glucose intake → Fatty acids are used as primary energy source (except for the brain**) Hormones that oppose the action of insulin to prevent hypoglycemia Which hormones have insulin antagonistic effects?  Glucagon  Epinephrine/norepinephrine Acute response  Cortisol Chronic response  GH (growth hormone) Glucose Counterregulatory Responses to Hypoglycemia https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3755377/ https://www.researchgate.net/publication/322270151_The_Role_of_Glucag on_in_the_Pathophysiology_and_Treatment_of_Type_2_Diabetes Lack or deficiency of insulin produces a syndrome called Diabetes Mellitus Diabetes from the Greek means “Siphon - to pass through” Mellitus from the Latin means “sweet” Insulin deficiency can be absolute or relative Absolute = absence of insulin = TYPE 1 DIABETES Relative = insulin resistance = TYPE 2 DIABETES Caracterized by permanent hypoinsulinemia  Absolute deficiency  No increase in endogenous insulin after stimulation;  Patient is insulin-dependent → to maintain control of glycemia, avoid ketoacidosis and survival  Common in dogs (95% of the cases)  Auto-immune disease, obesity, genetics, pancreatitis are risk factors Insulin deficiency causes blood glucose to increase The glucose uptake from insulinsensitive tissues (muscle and adipose tissue – GLUT 4) will be compromised Common findings on uncontrolled diabetic dogs caused by hyperglycemic state PPP Polyuria Polydipsia PUPD Polyphagia INSULIN DEFICIENCY HYPERGLYCEMIA GLYCOSURIA Renal tubular reabsorption threshold for glucose (FYI) Dogs: 180-200 mg/dL POLYURIA Cats: 280-290 mg/dL (diabetic cats ≈ 200 mg/dL) Horses: 160-180 mg/dL Cattle: 100-140 mg/dL POLYDIPSIA  Catabolism of protein increases, and protein synthesis is severely reduced  Lipolysis increases Hyperlipidemia https://www.semanticscholar.org/paper/Lipidmetabolism-and-hyperlipidemia-in-dogs.-XenoulisSteiner/785a7cbd1ed0672ac21854700a052d64f29 28eb1/figure/1 Insulin deficiency causes lipolysis of stored fat and release FFA + glycerol  The enzyme Hormone-Sensitive-Lipase (HSL) is strongly activated Hydrolysis of stored triglycerides → Releasing large amounts of FFA and glycerol in the blood  FFA will be used as a source of energy in the absence of glucose (except the brain)  Increased ketone bodies synthesis  Excess FFA will be converted into phospholipids and cholesterol (in the liver)  Triglycerides will be formed at the same time in the liver (can lead to non-alcoholic fatty liver disease)  Lipidemia (an increase in blood lipids) is expected in diabetic patient INSULIN DEFICIENCY (ABSOLUTE OR RELATIVE) COMPROMISED GLUCOSE TRANSPORT FOR MUSCLE AND ADIPOSE TISSUE HYPERGLYCEMIA GLUCAGON HEPATIC GLUCONEOGENESIS AMINO ACIDS AND GLYCEROL IN THE BLOOD PROTEIN AND FAT CATABOLISM INSULIN DEFICIENCY HYPERGLYCEMIA GLYCOSURIA WEIGHT LOSS POLYURIA POLIPHAGIA POLYDIPSIA The most common long-term complication (mainly in dogs) Altered osmotic relationship in the lens induced by accumulation of SORBITOL and GALACTITOL Reduction of glucose by the enzyme Aldose Reductase in the lens → produce alcohols Alcohols are potent hydrophilic agents → causing influx of water (osmosis) into the lens Swelling and rupture of the lens fibers → opacity  Caracterized by the resistance to the metabolic effects of insulin  Relative deficiency  It is a combination of impaired insulin action in liver, muscle and adipose tissue (insulin resistance) and beta cell failure  Common in cats (80% of the cases)  Obesity (metabolic syndrome) and islet amyloidosis are big risk factors For diabetes to develop, there must have a beta cell dysfunction Healthy beta cell can adapt to obesity and insulin resistance by increasing insulin secretion Amylin (or Islet Amyloid Polypeptide – IAPP) It is a polipeptide produced and secreted by beta cells with insulin secretion  Increases satiety, decreases gastric empty and reduces glucagon production When amylin agregates it forms the amyloid The amyloid deposition within the pancreatic islets is called amyloidosis The deposition is toxic to beta cell and leads to beta cell dysfunction Glucotoxicity progressive impairment in insulin secretion due to chronic exposure to high glucose levels Clinical remission can occur depending on beta cell dysfunction: Irreversible damage: AMYLOIDOSIS Reversible damage: GLUCOTOXICITY One of the most common chronic complications Hyperglycemia leads to nerve injury  In Schawnn cells and axons of myelinated fibers  Microvascular abnormalities Pathogenesis is not completely understood  Studies in cats are scarse FYI Clinical signs range from very mild to severe      Limb weakness Difficulty to jump Base-narrow gait Ataxia Muscle atrophy in pelvic limbs     Plantigrade posture (may progress to front limb) Postural reaction deficits Decreased tendon reflexes Irritability when feet are touched Produced by delta cells In the same way as other protein hormones Inhibitory actions  Decreases motility and secretory activity of GI tract  Inhibits secretion of all endocrine cell types of the Islet of Langerhans Glucagon is more affected than insulin 20% 70% 05% 05% Cunningham's Textbook of Veterinary Physiology, 6th Edition Produced by F or PP cells Secretion is stimulated by GI hormones, vagal stimulation and protein ingestion Inhibition occurs through somatostatin Effects on the GI tract Decrease gut motility and gastric emptying Inhibits secretion of pancreatic digestive enzymes and the contraction of the gall bladder 20% 70% 05% 05% Cunningham's Textbook of Veterinary Physiology, 6th Edition