Insulin - A Closer Look PDF

A CLOSER LOOK TO LINA ALKUFERAINI OUTLINE 1. Pancreas anatomy and physiology 2. Insulin production 3. Mechanism of action 4. Insulin resistance 5. Diabetes definition 6. Types, symptoms and complications 7. Tests and diagnosis...

A CLOSER LOOK TO LINA ALKUFERAINI OUTLINE 1. Pancreas anatomy and physiology 2. Insulin production 3. Mechanism of action 4. Insulin resistance 5. Diabetes definition 6. Types, symptoms and complications 7. Tests and diagnosis 8. Interpretation of results 9. Treatment INTRODUCTION  The pancreas is an organ of the digestive system and endocrine of vertebrates.  It is located in the upper abdomen behind the stomach, It lies next to the duodenum and just below the liver and gallbladder.  The pancreas is a mixed or heterocrine gland, it has both an endocrine and a digestive exocrine function.  99% of the pancreas is exocrine and 1% is endocrine. STRUCTURE  The pancreas is divided into 4 parts: head, neck, body, and tail.  The main pancreatic duct carries the pancreatic secretions joins with the bile duct to form the hepatopancreatic ampulla.  which opens into the descending part of the duodenum.  The sphincter of Oddi around the hepatopancreatic ampulla controls the flow of bile and pancreatic juice into the ampulla and inhibits reflux of duodenal substances into the ampulla.  FUNCTION  Endocrine function Exocrine function Is to make hormones that are Is to make digestive pancreatic juices from the acini released into the bloodstream from cells which are then secreted into the duodenum in Islets of Langerhans include : the small intestine, include : 1. Insulin 1. Amylase 2. Amylin 2. Lipase 3. Glucagon 3. Protease 4. Somatostatin 4. Trypsin and chymotrypsin 5. Ghrelin 6. Pancreatic Polypeptide (PP) BRIEFLY Hormone Function Amylin inhibits glucagon secretion, delays gastric emptying, and acts as a satiety agent Glucagon maintains blood glucose levels. Somatostatin inhibits the release of pancreatic hormones Ghrelin fat deposition and growth hormone release Pancreatic regulates pancreatic secretion activities by both endocrine and Polypeptide exocrine tissues (PP) Amylase digest starch into smaller molecules Lipase breaks down fats in food so they can be absorbed in the intestines Protease catalyses the hydrolysis of proteins INSULIN  Is a peptide hormone produced by beta cells of the pancreatic islets encoded in by the insulin (INS) gene located on chromosome 11.  It is the main anabolic hormone of the body. It regulates metabolism of carbohydrates, fats, and proteins.  Decreased or absent insulin activity results in diabetes, a condition of high blood sugar level (hyperglycaemia).  The human insulin protein is composed of 51 amino acids.  It is a heterodimer of an A-chain and a B-chain, which are linked together by di-sulfide bonds.  MECHANISM OF ACTION 1. Insulin acts by directly binding to its receptors on the plasma membranes of the cells. 2. These receptors are present on all the cells, but their density depends on the type of cells, with the maximum density being on the hepatic cells and adipocytes. 3. The insulin receptor is a heterotetrameric glycoprotein consisting of two subunits, the alpha and the beta subunits. 4. The extracellular alpha subunits have insulin binding sites. The beta subunits, which are transmembranous, have tyrosine kinase activity. 5. When insulin binds to the alpha subunits, it activates the tyrosine kinase activity in the beta subunit ( signal transduction process), which causes the translocation of glucose transporters from the cytoplasm to the cell's surface. 6. These glucose transporters allow the influx of glucose from the blood into the cell, thus reducing blood glucose levels.  Insulin causes the following effects in the cells: 1. Hepatic cells: Promotes glycogen synthesis, inhibits gluconeogenesis 2. Adipocytes: Promotes lipogenesis, inhibits lipolysis 3. Muscle cells: Promotes glycogenesis and protein synthesis, inhibits protein catabolism. 4. Pancreatic beta cells: Inhibits glucagon release. 5. Brain cells: Involved in appetite regulation.  INSULIN RESISTANCE  Insulin resistance is identified as the impaired biologic response of target tissues to insulin stimulation.  All tissues with insulin receptors can become insulin resistant, but the tissues that primarily drive insulin resistance are the liver, skeletal muscle, and adipose tissue.  Insulin resistance impairs glucose disposal, resulting in a compensatory increase in beta- cell insulin production and hyperinsulinemia.  Progression of insulin resistance can lead to metabolic syndrome, non-alcoholic fatty liver disease, and type 2 diabetes.  Insulin resistance is thought to precede the development of T2D by 10 to 15 years.  Insulin resistance also known as non-diabetic hyperglycaemia, or pre-diabetes. SYMPTOMS ETIOLOGY  The main cause of insulin resistance is not fully understood.  The etiologies of insulin resistance may be acquired, hereditary, or mixed.  The great majority of people fall have an acquired etiology.  The clinical presentation of insulin resistance is variable it depends on the duration of the condition, the level of beta- cell function, and the individual’s propensity for secondary illnesses due to insulin resistance. DIABETES  Is a group of common endocrine diseases characterized by sustained high blood sugar levels.  According to the WHO diabetes is classified to 6 main types are : 1. Type 1 Diabetes - Insulin Dependence. 2. Type 2 Diabetes - Insulin Resistance. 3. Type 3 Diabetes - Brain Diabetes. 4. Gestational Diabetes - During Pregnancy. 5. LADA - Latent Autoimmune Diabetes in Adults. 6. MODY- Maturity-onset diabetes of the young  LADA is a common hybrid disease because it combines features of both type 1 and type 2 diabetes , It is a slow-onset autoimmune disease characterized by an initial relative insulin deficiency  MODY refers to any of several hereditary forms of diabetes mellitus caused by mutations in an autosomal dominant gene disrupting insulin production  There are now at least 14 different known MODY mutations.  Type 3 diabetes mellitus responds to a chronic insulin resistance plus insulin deficiency state that is largely confined to the brain but ,can overlap with T2DM. DIABETES IN JORDAN TYPE 2  In fist degree insulin resistance turns to diabetes type 2 in the presence of excess calorie consumption, more insulin is required to traffic glucose into tissues.  This vicious cycle continues until pancreatic beta-cell activity can no longer adequately meet the insulin demand created by insulin resistance, resulting in hyperglycemia.  With a continued mismatch between insulin demand and insulin production, glycemic levels rise to those consistent with T2D.  Another main cause is the cells insulin receptors become less sensitive to insulin. It is not clear why but aging and increased levels of free fatty acids in the blood, which can cause cells to stop responding properly to insulin  It is the most common type worldwide.  TYPE 1  Type 1 diabetes is a condition in which immune system destroys insulin-making cells (beta cells) in the pancreas. That means body can't make enough insulin or any at all.  Because type 1 diabetes is often diagnosed in kids and young adults, it used to be called juvenile diabetes.  In the past, it was also called insulin- dependent diabetes.  It is the second common type of diabetes, type 1 diabetes affects 8% of people living with diabetes and type 2 diabetes affects 90% of people living with diabetes.  AUTOIMMUNE DIABETES Immune-mediated β-cell destruction begins when macrophages and dendritic cells present β-cell to naïve CD4 T cells through the MHC. Through cytokine signalling, CD4 helper T cells are activated, which in turn activates CD8 cytotoxic T cells directly responsible for causing β-cell death. Beta-cell destruction results in the release of additional intracellular antigens and allows antigen- presenting cells further access to typically sequestered auto-antigens. This activation leads to activation of additional autoreactive T cells through epitope spreading. Recently, another population of T cells, the Th17 cells, has been described. The pathogenic Th17 cells can cause the imbalance between T effectors that promote inflammation and T regulatory cells that controls it. COMMON SYMPTOMS  COMPLICATIONS  Most complications of diabetes are the result of problems with blood vessels.  Glucose levels that remain high over a long time cause both the small and large blood vessels to narrow.  The narrowing reduces blood flow to many parts of the body, leading to problems.  There are several causes of blood vessel narrowing: 1. Complex sugar-based substances build up in the walls of small blood vessels, causing them to thicken and leak. 2. Poor control of blood glucose levels causes the levels of fatty substances in the blood to rise, resulting DIAGNOSIS  INTERPRETATION  One used way to evaluate insulin resistance is the homeostatic model assessment for (HOMA-IR), based on fasting glucose and fasting insulin levels, is a widely utilized measure of insulin resistance.  IMPORTANT... !  Oral glucose tolerance test is considered more accurate than HOMA-IR score.  Oral glucose tolerance test with insulin or called (glucose insulin response test ) is considered the most accurate test for insulin resistance diagnosis.  If insulin level is 5 times greater the baseline it is a strong evidence of resistance.  Reactive hypoglycemia, sometimes called postprandial hypoglycemia, happens when blood sugar drops after a meal — usually within four hours after eating.  An extended glucose tolerance test may be conducted to detect cases of reactive hypoglycaemia or other abnormalities of glucose metabolism , samples are taken during 4 to 5 hours.  C peptide is secreted from the beta cells of islets of Langerhans when proinsulin is cleaved into insulin and C-peptide  So measuring the amount of C-peptide in the blood or urine can help determine the type of diabetes or how well diabetes treatments are working.  Fructose-amine is used instead of glycosylated A1C if the diabetic patient has hemoglobinopathy, thalassemia and Sickle cell disease.  The reflecting the average of glycaemic level over the preceding 2–3 weeks.  For type 1 diabetes 4 autoantibodies are markers of beta cell autoimmunity : 1. Islet cell antibodies (ICA, against cytoplasmic proteins in the beta cell) 2. Antibodies to glutamic acid decarboxylase (GAD-65). 3. Insulin autoantibodies (IAA). TREATMENT Depending on what type of diabetes, blood sugar monitoring, insulin and oral drugs may be part of treatment. Treatment for type 1 diabetes involves insulin injections or the use of an insulin pump, frequent blood sugar checks. Treatment of type 2 diabetes mostly involves lifestyle changes, monitoring of your blood sugar, along with oral diabetes drugs, insulin or both. Olive leaf extract comes from the leaves of an olive plant. It contains an active ingredient called oleuropein. Oleuropein reduces glucose concentration in the blood as well as lipid concentration. SUMMURY REFERENCES  StatPearls 1. Physiology, Pancreas - Suzan A. El Sayed; Sandeep Mukherjee-Last Update: May 1, 2023. 2. Anatomy, Abdomen and Pelvis, Pancreas - Saurabh S. Talathi; Ryan Zimmerman; Michael Young -Last Update: April 5, 2023. 3. Insulin - Sushmita Thota; Aelia Akbar-Last Update: July 10, 2023.  Autoimmunity: From Bench to Bedside  Chapter 29Autoimmune diabetes mellitus (Type 1A) - Andrés F. Echeverri and Gabriel J. Tobón.  International diabetes federation  https://idf.org/our-network/regions-and-members/middle-east-and-north-africa/members/jordan/