ARCS1150 Digestion & Blood Glucose PDF

Discovery and Translational Science Department Leeds Institute of Cardiovascular And Metabolic Medicine DIGESTION & BLOOD GLUCOSE ARCS 1150 Dr Cédric Duval [email protected] AIM & LEARNING OUTCOMES Aim: To enable you to...

Discovery and Translational Science Department Leeds Institute of Cardiovascular And Metabolic Medicine DIGESTION & BLOOD GLUCOSE ARCS 1150 Dr Cédric Duval [email protected] AIM & LEARNING OUTCOMES Aim: To enable you to understand the role of the gastro-intestinal system in maintaining homeostasis. Learning outcomes: Label a diagram of the gastrointestinal tract (GIT). Name the tissue layers that make up the GIT wall. Describe the mechanical and chemical processes of digestion. Outline the function of the liver. Outline the role of bile in fat digestion. Describe the structure and function of the large bowel. Describe how blood glucose is regulated by pancreatic hormones. Explain the differences between type-1 and type-2 diabetes mellitus. RELEVANCE TO YOUR COURSES Audiology: ABSTRACT: Inflammatory bowel disease (IBD) is a multisystemic disease. The ear is a rare but recognized site of extraintestinal manifestations of IBD. In external ear, the more common manifestations of IBD are pyoderma gangrenosum, metastatic Crohn’s disease and relapsing polychondritis and the treatment includes corticosteroids and anti-TNF agents. Sensorineural hearing loss (SNHL) is the most common ear disease in IBD and especially in patients with ulcerative colitis. In most cases of IBD patients with SNHL, the hearing loss is attributable to autoimmune inner ear disease (AIED). Diagnosis of AIED is based on clinical presentation, the demonstration of a progressive sensorineural hearing loss in periodic audiological tests, a response to immunosuppressive drugs and exclusion of other causes of SNHL. The only diagnostic test that is available for clinical use is the Otoblot test (Western blot for antibodies against 68 kD protein-inner ear antigens). Initial therapy is usually steroids, with a step up to anti-TNF-a therapy and cochlear implantations with failure of treatment. Furthermore, Cogan's syndrome, a chronic disease characterized by deafness, vertigo keratitis and aortitis, has been associated with IBD and mainly with Crohn's disease. RELEVANCE TO YOUR COURSES Audiology: ABSTRACT: Diabetes mellitus (DM) is a major disease threatening human health and its incidence is increasing year on year. As a chronic complication of DM, hearing loss mostly occurs undetectably. However, the mechanism of this diabetes-related hearing loss (DRHL) remains unclear and there is no effective clinical treatment. Studies of animal or human pathology show that DM causes damage to the blood vessels, spiral ganglion neurons, afferent nerve fibers, the organ of Corti, and the stria vascularis of the inner ear. In recent years, more advances in pathological research have revealed the possible mechanism of DRHL. In addition, a large number of clinical studies suggest that the duration and severity of DM are closely related to the incidence and severity of DRHL. This review focuses on the relationship between DM and hearing loss. The clinical audiological characteristics of diabetic patients, risk factors for DRHL, typical pathology, and potential interventions of DRHL are summarized. This will help reveal the pathogenesis and intervention approaches for DRHL. RELEVANCE TO YOUR COURSES Cardiac Physiology: ABSTRACT: The heart and the gut seem to be two organs that do not have much in common. However, there is an obvious and clinically relevant impact of gut functions on the absorption of drugs and oral therapies on the one hand. On the other hand, the gut determines the quantity of nutrient uptake and plays a central role in metabolic diseases. Patients with inflammatory bowel diseases appear to have a higher risk for coronary heart disease despite a lower prevalence of ‘classical’ risk factors, indicating additional links between the gut and the heart. However, they certainly have a ‘leaky’ intestinal barrier associated with increased permeability for bacterial wall products. An impaired intestinal barrier function will be followed by bacterial translocation and presence of bacterial products in the circulation, which can contribute to atherosclerosis and chronic heart failure (CHF) as recent data indicate. Impaired cardiac function in CHF vice versa impacts intestinal microcirculation leading to a barrier defect of the intestinal mucosa and increased bacterial translocation. These pathways and the most recent insights into the impact of the gut on acute and chronic heart disease will be discussed in this review. RELEVANCE TO YOUR COURSES Cardiac Physiology: ABSTRACT: Type 2 diabetes is one of the most relevant risk factors for heart failure, the prevalence of which is increasing worldwide. The aim of the review is to highlight the current perspectives of the pathophysiology of heart failure as it pertains to type 2 diabetes. This review summarizes the proposed mechanistic bases, explaining the myocardial damage induced by diabetes-related stressors and other risk factors, i.e., cardiomyopathy in type 2 diabetes. We highlight the complex pathology of individuals with type 2 diabetes, including the relationship with chronic kidney disease, metabolic alterations, and heart failure. We also discuss the current criteria used for heart failure diagnosis and the gold standard screening tools for individuals with type 2 diabetes. Currently approved pharmacological therapies with primary use in type 2 diabetes and heart failure, and the treatment-guiding role of NT-proBNP are also presented. Finally, the influence of the presence of type 2 diabetes as well as heart failure on COVID-19 severity is briefly discussed. FUNCTIONS OF THE DIGESTIVE SYSTEM “The primary function of the digestive system is to transfer nutrients (after modifying them), water, and electrolytes from the food we eat into the body’s internal environment” Sherwood L. 1993 FUNCTIONS OF THE DIGESTIVE SYSTEM Ingestion Digestion Mechanical Chemical Absorption Elimination ORGANISATION THE GASTROINTESTINAL TRACT Gastrointestinal tract (GI tract) Continuous tube extending from the mouth to the anus (mouth, oral cavity, oropharynx, esophagus, stomach, small intestine, large intestine, rectum, anus) Accessory structures Teeth, tongue, salivary glands, liver, gallbladder, pancreas HISTOLOGY OF THE GASTROINTESTINAL TRACT 4 tissue layers Mucosa Submucosa Muscularis Serosa / Peritoneum MUCOSA In direct contact with GI contents Specialised for secretion by glands & absorption (passage into blood) Good blood supply Pulled into folds SUBMUCOSA Autonomic nerve network (plexus) MUSCULARIS 2 layers - circular & longitudinal - smooth muscle Nerve plexus runs between the two muscle layers SEROSA Serous membrane - “tough” protective GI Tract below diaphragm, serosa called peritoneum Peritoneum also covers wall of peritoneal cavity HOW DOES THE SEROSA WORKS? INGESTION The oral cavity allows food to enter the digestive tract. It is where mastication (chewing) occurs, and the resulting food bolus is swallowed. MOUTH & ORAL CAVITY Food enters the GI tract by ingestion. Food is broken down by mechanical digestion, using mastication. One chemical digestive process occur where amylase enzyme in saliva breaks down polysaccharide into disaccharides. The tongue, made of skeletal muscle, manipulates the food during mastication. It also contains taste buds to detect taste sensations. Food particles are mixed with saliva during mastication, resulting in a moist lump called bolus for easier passage into the pharynx. DIGESTION MECHANICAL Muscular movement of the digestive tract (mainly in the oral cavity and stomach) physically break down food into smaller particles. CHEMICAL Hydrolysis reactions aided by enzymes (mainly in the stomach and small intestine) chemically break down food particles into nutrient molecules, small enough to be absorbed. TEETH Adapted for mechanical digestion (mastication) in the oral cavity. 20 deciduous or primary teeth before the age of 6. By age 7, 32 permanent or secondary teeth are developed & are divided into 4 types: Incisors (for cutting) Canines (for tearing) Premolars (for crushing) Molars (for grinding) These teeth follow the human dental formula of 2-1-2-3. SALIVARY GLANDS 3 pairs of salivary glands called parotid, submandibular, and sublingual gland secrete most of the saliva in the oral cavity, using salivary ducts. Saliva helps moisten the food during mastication, dissolve the food in forming the bolus, and help cleanse the teeth. Saliva consists of 99.5% water, the remaining 0.5% is dissolved substances including amylase enzyme (for chemically digesting carbohydrate), bicarbonate ion (HCO3-; maintains pH of saliva at 6.5-7.5), and many electrolytes. PERISTALTIS & SEGMENTATION STOMACH A pouch-like organ primarily designed for food storage (for 2-4 hours), some mechanical and chemical digestion also occur. Contains two sphincters at both ends to regulate food movement - cardiac sphincter near the esophagus, and pyloric sphincter near the small intestine. Divided into 4 regions: cardiac stomach (or Cardia), fundic stomach (or Fundus), body of stomach , and pyloric stomach (or Pylorus). Contain thick folds called rugae at its layer, for providing larger surface area for expansion, secretion , digestion, and some absorption. GASTRIC SECRETORY CELLS Chief cells: Secrete pepsinogen (an inactive enzyme). Parietal cells: Secrete hydrochloric acid (HCl) and "intrinsic factor" (which helps absorption of vitamin B12 in the intestines). Mucous cells: Secrete mucus and alkaline substances to help neutralize HCl in the gastric juice. G cells: Secrete a hormone called gastrin, which stimulates the parietal cells and overall gastric secretion. CHEMICAL DIGESTION IN THE STOMACH Carbohydrate digestion is continued with gastric amylase, resulting in disaccharides. Protein digestion begins with pepsin (activation of pepsinogen by HCl), resulting in peptides (small chains of protein). Lipid digestion begins with gastric lipases which can only break down certain lipids such as butterfat , resulting in fatty acids. Absorption in the stomach is limited, where only small and fat soluble substances can be absorbed - water, alcohol, aspirin, and certain drugs. The result of all these mixing, chemical digestion, secretion, and absorption is a yellowish paste called chyme, which will be passed on to the small intestine. PANCREAS Pancreas: most pancreatic enzymes are produced as inactivate molecules, or zymogens, so that the risk of self-digestion within the pancreas is minimized. More than 98% of the pancreas mass is devoted to its exocrine function: the secretion of pancreatic juice by the pancreatic acini and their ductile cells. Ductile cells produce Sodium bicarbonate which helps neutralize the acidic gastric contents. Acinar cells of the exocrine pancreas produce a variety of digestive enzymes to break down food substances into smaller absorbable molecules. Only 2% of pancreas mass is devoted to the islets of langerham, which produce insulin and glucagon, hormones that regulate blood sugar and carbohydrate metabolism. MAJOR PANCREATIC ENZYMES Pancreatic amylase: digest polysaccharides into disaccharides. Pancreatic lipases: digest triglycerides into fatty acids. Pancreatic nucleases: digest nucleic acids into nucleotides. Pancreatic proteinases (secreted in their inactive forms): digest peptides into amino acids. Trypsinogen is activated by enterokinase (secreted by duodenum) into trypsin, which in turn activates the other 3 enzymes: - chymotrypsinogen becomes chymotrypsin. - proaminopeptidase becomes aminopeptidase. - Procarboxypeptidase becomes carboxypeptidase. GALLBLADDER A small sac located on the inferior, visceral surface of the liver. Stores and concentrates bile secreted by the liver. Bile: Water (97%), bile salts, … Bile salt anions: hydrophilic on one side, hydrophobic on the other à Aggregate around droplets of lipids to form micelles (small fat particules). Micelles increase surface area for actions of pancreatic lipase. SMALL INTESTINE Divided into duodenum, jejunum and ileum. Secretes: Watery fluids to help moving chime to villi. Digestive enzymes located on surface of microvilli: - Maltase, Sucrase, Lactase. - Peptidases. - Lipases. - Nucleases. - Enterokinase. ABSORPTION Passage of the end-products (nutrients) of chemical digestion from the digestive tract into blood or lymph for distribution to tissue cells. SMALL INTESTINE MODE OF ABSORPTION ABSORPTION OF AMINO ACIDS ABSORPTION OF SUGAR ABSORPTION OF FAT CIRCULATION OF NUTRIENTS IN THE BLOODSTREAM Products of digestion are absorbed into the capillaries within the villi of the small intestine. Digested food molecules then travel through hepatic portal veins to the liver. The liver monitors blood contents. Hepatic veins deliver blood and nutrients to the circulatory system. MACROSCOPIC ANATOMY OF THE LIVER MICROSCOPIC ANATOMY OF THE LIVER Products of digestion are absorbed into the capillaries within the villi of the small intestine. Digested food molecules then travel through hepatic portal veins to the liver. The liver monitors blood contents. Hepatic veins deliver blood and nutrients to the circulatory system. FUNCTIONS OF THE LIVER Important in carbohydrate metabolism where hepatic cells conduct glycogenesis (converting glucose into glycogen), and glycogenolysis (breaking glycogen down to glucose). Also is critical in lipid metabolism where hepatic cells produce bile (for fat emulsification), oxidize fatty acids, synthesize various forms of lipids, and convert glucose to fatty acids (lipogenesis). Other functions of the liver include: -Storage of glycogen, iron, and vitamins A,D,B12. -Contains phagocytes to destroy damaged erythrocytes and foreign substances, using phagocytosis. -Detoxifies harmful substances in the blood. -Serves as a blood reservoir (contains 7% of blood volume). ABSORPTION IN THE LARGE INTESTINE Reabsorption of salts. Reabsorption of water. ELIMINATION Undigested material will be released through the rectum and anus by defecation. DEFECATION BLOOD GLUCOSE REGULATION – THE PANCREAS Accessory digestive organ with both exocrine and endocrine functions. Exocrine function: important in digestion as it secretes a broad spectrum of enzymes. Endocrine function: release of hormones insulin and glucagon. BLOOD GLUCOSE REGULATION – THE PANCREAS Exocrine functions Pancreatic tissue contains numerous ‘acini’. Acini: clusters of secretory cells which secrete pancreatic juice into the duodenum via the main pancreatic duct, they contain a broad spectrum of enzymes (proteases, lipases and nucleases). BLOOD GLUCOSE REGULATION – THE PANCREAS Endocrine functions Secretion of hormones from the pancreatic islets of Langerhans: - Insulin, β-cells (↓ blood glucose) - Glucagon, ⍺-cells (↑ glucose) Both play important role in blood glucose regulation. BLOOD GLUCOSE REGULATION – INSULIN After a meal, when exogenous blood glucose levels are high: Pancreatic β-cells release insulin into the blood … … triggering glucose uptake into insulin-dependent cells as well as to promote glycogenesis … … and leading to a return of the blood glucose (and insulin) to normal levels. BLOOD GLUCOSE REGULATION – GLUCAGON When blood glucose levels are low: Pancreatic ⍺-cells release glucagon into the blood … … triggering glucose release into the blood by liver glycogenolysis and gluconeogenesis* … … and leading to a return of the blood glucose (and glucagon) to normal levels. * Synthesis of glucose from lactic acid and other sources (i.e. amino acids) BLOOD GLUCOSE REGULATION – INSULIN/GLUCAGON BALANCE Maintenance of blood glucose levels is a constant balancing act between the release of insulin and glucagon. Failure of the body to regulate blood sugar, via the actions of insulin, is detrimental to health à Diabetes Mellitus. 2 TYPES OF DIABETES MELLITUS Type 1 Diabetes (T1DM): Autoimmune attack on the pancreatic β- cells à Loss of insulin production. Treatment: Injection of insulin to regulate blood glucose levels. Type 2 Diabetes (T2DM): Associated with obesity and now considered a global epidemic. Characterised by insulin resistance (individuals no longer responds appropriately to the effects of insulin despite its production). Treatment: Eating well, moving more, weight loss. Metformin (tablet), insulin (+ medication that ↓ blood sugar levels), other types of diabetes medicine. Weight loss surgery. INSULIN RESISTANCE Insulin resistance has a profound effect on the vascular system affecting multiple organs: - Premature aging of the vascular system with a reduction of the vasoactive signalling molecule nitric oxide and premature vascular disease. - Predisposition to atherosclerosis and peripheral vascular disease. - Increased risk of developing an acute cardiovascular event (MI / IS) and less likely to survive those. Reducing blood sugar levels are insufficient to restore vascular health and so we are looking to progress the current therapeutic approach and improve the cardiovascular risk of T2DM. LEARNING OUTCOMES ü Label a diagram of the gastrointestinal tract (GIT). ü Name the tissue layers that make up the GIT wall. ü Describe the mechanical and chemical processes of digestion. ü Outline the function of the liver. ü Outline the role of bile in fat digestion. ü Describe the structure and function of the large bowel. ü Describe how blood glucose is regulated by pancreatic hormones. ü Explain the differences between type-1 and type-2 diabetes mellitus.