Diabetes Lecture 16 BMS2002 PDF

Diabetes Lecture 16 BMS2002 Dr Alessio Iannetti 1  Join the Vevox session Go to vevox.app Enter the session ID: 103-704-338 Or scan the QR code Learning outcomes At the end of this lecture students will be able to: Explain and differentiate the pathogenesi...

Diabetes Lecture 16 BMS2002 Dr Alessio Iannetti 1  Join the Vevox session Go to vevox.app Enter the session ID: 103-704-338 Or scan the QR code Learning outcomes At the end of this lecture students will be able to: Explain and differentiate the pathogenesis of Diabetes 1 and diabetes 2 from insurgence to the complications Describe the insulin-resistance mechanisms Provide an account for the current therapeutic options and mechanism of action of drugs Suggested readings: Robbins and Cotran. Pathologic basis of disease, 8th edition, 1130-1144 Berne and Levi. Physiology, 7th edition, 698-708 Paerson. Human Physiology, 6th edition, 753-764 Rang and Dale. Pharmacology, 8th edition, 386-392 Diabetes.org.uk 3 Diabetes mellitus – inability to regulate blood glucose Blood [glucose] normally ~ 5mM; diabetes > 7 mM – even larger defect after glucose ingestion Sugar in urine is important symptom  4 A brief history… - 1550 B.C. In India physicians noted that diabetic urine attracted ants (Madhumeha or honey urine) - 100 A.D. Aretaeus the Cappodocian used the term “diabetes” used by the Greeks, means “to syphon” - 400 A.D. Sushruta (Indian physician), discovered type 1 and type 2 diabetes - 1798 Term “Diabetes mellitus” - by John Rollo, the King’s doctor, Mellitus - Latin for honey - 1889 Joseph von Mering and Oskar Minkowski (German) 1889 - Joseph von Mering and Oskar Minkowski (German) removed the pancreas from dogs Dogs became diabetic, Oskar Minkowski 1858–1931 however, failed to purify / identify insulin - 1921 Banting and Best isolated insulin and discovered insulin deficiency caused diabetes Banting and Best started a series of experiments in 1920 where they showed that the removal of the pancreas from dogs results in diabetes Banting and Best were able to purify an extract from the pancreas that reversed diabetes Lab books were already in use Banting and Best lab and note book Page shows key experiment with dog 408, administration of Isletin (original name for insulin) caused a drop in blood glucose 1922 - Leonard Thompson (14), received insulin treatment - weighed only 64 pounds, lived to 27 Diabetes mellitus – inability to regulate blood glucose High or low [glucose] both cause acute symptoms Chronic high [glucose] damages almost all tissues (blood vessels, eyes, kidneys, nerves) Untreated type 1 diabetes leads to body wasting –very serious disease Before 1923 treatment basically starvation – post diagnosis survival < 5 years Insulin therapy revolutionised treatment One of most significant advances of 20th century However....diabetes is a very complex disease that still causes many clinical problems  Diabetes mellitus – inability to regulate blood glucose High or low [glucose] both cause acute symptoms Chronic high [glucose] damages 1 Insulin 0 9 almost all tissues (blood vessels, 8 eyes, kidneys, nerves) 7 Untreated type 1 diabetes leads to 6 body wasting –very serious disease Glucose 5 Before 1923 treatment basically (mM) 4 Safe starvation – post diagnosis survival < Range 5 years 3 2 Insulin therapy revolutionised 1 treatment 0 Glucagon One of most significant advances of 0 1 2 3 4 5 6 20th century 7 8 9 10 However....diabetes is a very complex Time (units of seconds, minutes, hours or years, doesn't matter) disease that still causes many clinical problems Pathogenesis of type 1 vs Type 2 Diabetes Type 1 diabetes Type 2 diabetes Caused by a failure of insulin Caused by insulin resistance secretion in tissues Characterised by very Insulin present in circulation low/absent [insulin] and but [glucose] remains high [glucose] elevated Has sudden onset Has gradual onset Usually develops early in life Usually develops later in life Sometimes referred to as It is the most common form of juvenile diabetes – and is becoming Relatively rare (~5% of much more common diabetes) Associated very strongly with obesity  Type 1 diabetes pathogenesis Type 1 diabetes is caused by destruction of β cells Involves an autoimmune Environmental factors Genetic predisposition mechanism (CD8 cytotoxic T cells mediated) Autoimmune destruction Total failure of insulin secretion of  cells Evidence of hereditary tendency although environmental factors crucial (viral infections, autoimmune disorders) Severe insulin deficiency However can develop spontaneously in absence of family history or environmental trigger Hyperglycemia  Pathogenesis Diabetes 1 Insulin-dependent diabetes mellitus – -cells of pancreas destroyed by cytotoxic CD8 T cells reactive against peptides of insulin and of other specific proteins which are complexed with MHC molecules and recognized by cytotoxic T limphocytes (CTL) Genetics HLA-DR3 and DR4 are associated with type 1 diabetes DR4-DQ8 haplotype for Caucasians Peptide/MHC complexes https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10566625/ In Caucasoid populations many patients have a substitution of Asp57 to Val/Ala/Ser in the HLA-DQ β1 chain https://www.ncbi.nlm.nih.gov/pmc/art icles/PMC3253030/  Symptoms of type 1 diabetes Promotes uptake and storage of glucose (mainly liver / skeletal muscle) Promotes metabolic utilisation of glucose and so “spares” fatty Insulin acid Promotes storage of excess energy as fat Promotes synthesis of new protein  Symptoms of type 1 diabetes In diabetes Due to lack of insulin Promotes uptake Tissues cannot and storage of accumulate and glucose (mainly liver store glucose / skeletal muscle) Promotes metabolic Tissues cannot utilisation of glucose use glucose as and so “spares” fatty Insulin acid metabolic fuel Body cannot Promotes storage of store excess excess energy as fat energy as fat Reduced Promotes synthesis synthesis of of new protein protein Hyperglycemia Weight loss Symptoms from hyperglycaemia High [Glucose] enters glomerular filtrate and overwhelms glucose absorbing capacity of proximal convoluted tubule Increased fluid osmolarity in tubules More water is secreted from cells into the proximal convoluted tubule causes increased urine flow – diuresis Water reabsorption is reduced Dehydratation, excessive urine production and thirst  Lack of insulin effects and ketoacidosis No Insulin Glucose not utilized as metabolic fuel by Proteins tissues Fatty acids Rapid weight loss Ketone bodies pH Metabolic acidosis Acidotic coma Type 1 diabetes therapy Promotes uptake Tissues cannot and storage of accumulate and glucose (mainly liver store glucose / skeletal muscle) Promotes metabolic Tissues cannot utilisation of glucose use glucose as and so “spares” fatty Insulin acid metabolic fuel Body cannot Promotes storage of store excess excess energy as fat energy as fat Reduced Promotes synthesis synthesis of of new protein protein Type 1 diabetes therapy Promotes uptake and storage of glucose (mainly liver / skeletal muscle) Promotes metabolic utilisation of glucose Insulin and so “spares” fatty acid Promotes storage of excess energy as fat Promotes synthesis of new protein  The aim of insulin therapy is to artificially regulate blood glucose Ins. Ins. Ins. Ins. Patient monitors their own blood sugar levels with a pump and regulates the amount of carbohydrate in their diet In collaboration with health care workers develops a protocol to match insulin injection / food consumption and thus obtain control over blood glucose levels However, in practise good control over [glucose] is hard to achieve Most patients with diabetes eventually develop long term complications Glycosylated haemoglobin can be used to predict glucose values of the past 6-8 weeks and to monitor the long term control Problems with repeatedly injecting insulin Exogenous insulin into general circulation – natural insulin portal circulation A major effects of insulin is to promote the deposition of fat Cells close to site of insulin injection exposed to high [insulin] If same site used again and again will promote deposition of fat around injection site (lipohypertrophy) Also clinically important as leads to unpredictable rate of insulin absorption This could lead to poor glycemic control and patients could experience hyper/hypoglycemic events Important to change site frequently to avoid this Forms of insulin used for therapy Animal insulin (porcine/bovine) Human insulin Human insulin analogue  Human insulin Soluble insulin - Rapid and short lived - Used intravenously in emergency treatment of hyperglycemic emergencies only (e.g. chetoacidosis) Isophane insulin - Tends to form precipitates. Intermediate acting Insulin zinc suspension - Tends to form precipitates. Long acting  Insulin analogues Insulin Lispro - A modified insulin (analogue) obtained by switching a Lys28 and Pro29 - Very rapid and very short lived. Normally taken from patients before a meal Insulin glargine & detemir - Glargine: A modified insulin (analogue) obtained by mutating Asn21 in Gly and by adding 2 Arg at the end of the B chain. Long-acting. - Detemir: A modified insulin (analogue) obtained by mutating Thr 30 (deletion) - Long-acting. Normally taken by patients before a meal in combination with a short-acting form - Forms a micro-precipitate at the physiological pH of subcutaneous tissue - Slowly absorbed Targeting the autoimmune reaction in diabetes 1 Teplizumab 27  ##/## Join at: vevox.app ID: XXX-XXX-XXX Question slide Which of the following is NOT a feature of type 1 diabetes? sudden on-set ##.##% develops early in life ##.##% rare ##.##% caused by a failure of insulin secretion ##.##% caused by peripheral insulin-resistance ##.##%  ##/## Join at: vevox.app ID: XXX-XXX-XXX Results slide Which of the following is NOT a feature of type 1 diabetes? sudden on-set ##.##% develops early in life ##.##% rare ##.##% caused by a failure of insulin secretion ##.##% caused by peripheral insulin-resistance ##.##% RESULTS SLIDE ##/## Join at: vevox.app ID: XXX-XXX-XXX Question slide Which cell is responsible for the autoimmune reaction that destroys the beta cells of pancreas in type 1 diabetes? B cell ##.##% CD4 T helper cell ##.##% CD8 T cell ##.##% Treg cell ##.##% Macrophage ##.##%  ##/## Join at: vevox.app ID: XXX-XXX-XXX Results slide Which cell is responsible for the autoimmune reaction that destroys the beta cells of pancreas in type 1 B cell diabetes? ##.##% CD4 T helper cell ##.##% CD8 T cell ##.##% Treg cell ##.##% Macrophage RESULTS SLIDE ##.##% ##/## Join at: vevox.app ID: XXX-XXX-XXX Question slide Which of the following combinations of insulin forms would be routinely used to control glycaemia? Lispro + soluble insulin ##.##% Zinc suspension + Glargine ##.##% Soluble insulin + Glargine ##.##% Lispro + Detemir ##.##%  ##/## Join at: vevox.app ID: XXX-XXX-XXX Results slide Which of the following combinations of insulin forms would be routinely used to control glycaemia? Lispro + soluble insulin ##.##% Zinc suspension + Glargine ##.##% Soluble insulin + Glargine ##.##% Lispro + Detemir ##.##% RESULTS SLIDE  Type 2 diabetes 1. Genetic and environmental predisposition - Life style - Bad dietary habits - Obesity 2. Insulin resistance Glucose uptake - Insulin pathway defects 3. Hyperinsulinemia - β cells try to compensate for peripheral resistance - Normal glucose levels can be maintained for years 4. β cells failure and hypoinsulinemia - β cells become “exhausted” and cannot keep up with the peripheral demand of insulin - Insulin secretion decrease 5. Diabetes - Hyperglicemia develops Taken from Robbins - Total failure of insulin secretion - Exhausted Beta cells may convert to Alpha cells Obesity and insulin resistance More than 80% of patients present visceral obesity Free fatty acids (FFAs) - Lead to insulin resistance in muscle and liver. - When in excess they are transformed in second messenger DAG - DAG activate PKC, which phosphorylate IRS-1 on Ser residues - This attenuates Insulin Receptor signalling pathway Taken from: Shetty And Kumari “Fatty Acids and their role in type 2 Diabetes” Exp Ther Med 2021 Obesity and insulin resistance More than 80% of patients present visceral obesity Adipokines - Released by adipocytes - Pro-hyperglicemic or anti-hyperglicemic adipokines - Adiponectin is anti-hyperglicemic, because improves insulin sensitivity by activating AMPK, enzyme promoting lipolysis in liver and muscle - Adiponectin expression is reduced in obesity - Also activates IRS1/2 improving insulin signalling and GLUT4 improving glucose uptake - AMPK activators can be used in therapy (metformin) Taken from:Achari AE& Jain S. Adiponectin a therapeutic target for obesity, diabetes and endothelial dysfunction. Int J Mol Sci 2018 Obesity and insulin resistance More than 80% of patients present visceral obesity PPARγ - Nuclear receptor involved in adipocyte differentiation - Also expressed in liver and muscle - Promotes secretion of anti-hyperglicemic adipokines - Mutations/Post-translational modifications associated with diabetes (e.g Ser273 phosphorylation) - Agonists used in therapy Current knowledge of how phosphorylation of PPARγ is linked to T2DM. Taken from: Frkic R, Richter K, Bruning J The therapeutic potential of inhibiting PPARγ phosphorylation to treat type 2 Diabetes. JBC reviews, 2021 Obesity and insulin resistance More than 80% of patients present visceral obesity Inflammation - Adipocytes overexpress certain cytokines (IL-1/IL-6) - Cytokines activate JAK-STAT signalling - Promoting SOCS expression - SOCS3 compete for binding to phosphotyrosine residues attenuating insulin signalling Taken from: Yin Y, Liu W, Dai Y SOCS3 and its role in associated diseases. Human immunology, 2015 Obesity and insulin resistance More than 80% of patients present visceral obesity Free fatty acids (FFAs) - Lead to insulin resistance in muscle and liver. - When in excess they are transformed in second messenger DAG - DAG activate PKC which phosphorylate IRS-1 - This attenuates Insulin Receptor signal Adipokines - Released by adipocytes - Pro-hyperglicemic or anti-hyperglicemic adipokines - Adiponectin is anti-hyperglicemic, because improves insulin sensitivity by activating AMPK, enzyme promoting lipolysis in liver and muscle - Adiponectin expression is reduced in obesity - AMPK activators can be used in therapy (metformin) PPARγ - Nuclear receptor involved in adipocyte differentiation - Promotes secretion of anti-hyperglicemic adipokines - Mutations/Post-translational modifications (P-Ser273) can cause diabetes - Agonists used in therapy Inflammation - Adipocytes overexpress IL-6 and IL-1 which impair insulin signalling via JAK- STAT-SOCS pathway - Experimental reduction of cytokines improve insulin sensitivity Type 2 diabetes therapy -beginning- Diet/Excercise - Initially, weight loss / exercise can reverse the development of dia betes an d resto re normal sensitivity to insulin Type 2 diabetes therapy -during disease- Thiazolidinediones – e.g. (Pioglitazone) - Agonist of nuclear receptor PPAR-γ - Promotes expression and secretion of anti- hyperglycemic adipokines (so increase lipolysis) - Increase hypoglycemic action of insulin by sensitizing cells to its action - Collectively reduce insulin-resistance in liver and other peripheral tissues Metformin - Suppress glucose release from liver - Activate AMPK - increase lipolysis in liver and muscles and therefore improving insulin receptor signalling - Suppress glucose release from liver - Useful in obese type 2 patients Type 2 diabetes therapy -during disease- Sulphonylurea Sulphonylureas (e.g. Gliclazide) - Bind to sulphonylurea receptors expressed on membranes of β cells - Block ATP-sensitive K + channels in β cells - K + accumulates inside cells - β cells depolarize - Ca++ channels open and allow insulin secretion by exocitosis Insulin - Once disease fully developed Type 2 diabetes therapy -new drugs under research- Selective β3 agonists - β3 adrenoreceptors control lipolysis in fat cells - Under development - Potentially important for treating obese patients with type 2 diabetes α2 adrenoreceptor antagonists - Increase insulin secretion Type 2 diabetes therapy -new drugs under research- Selective β3 agonists - β3 adrenoreceptors control lipolysis in fat cells - Under development - Potentially important for treating obese patients with type 2 diabetes α2 adrenoreceptor antagonists - Increase insulin secretion GLP-1 (Glucagon like peptides) SGLT-2 inhibitors (Sodium- receptor agonists glucose co-transporter - Increase insulin secretion from Beta - Increase excretion of glucose in cells urine - Pro-survival effect on Beta cells Lower blood glucose and blood - Promote weight loss (loss of appetite) pressure - Renoprotective - Induce ketogenesis Type 2 diabetes therapy -new strategy under research- Alpha-cells reprogramming - Reprogramming alpha-cells in insulin producing cells - In mice MafA and Pdx1 overexpression experimentally showed to convert Alpha to Beta cells Taken from: Saleh M, Gittes G, Prasadan K. Alpha to Beta cells transdifferentiation for treatment of Diabetes, Biochem Soc Trans, 2021 Long term consequences of diabetes Causes of the long term consequences of diabetes - ROS generation - Causes of the long term consequences of diabetes - AGEs generation - Long term consequences of diabetes -AGE’s effects on blood vessels- AGE’s crosslink with collagen The basal membrane of the endothelium thickens The thickened endothelium traps LDL and IgGs Oxidation, complement activation and inflammation Blood vessel damage Effects of the damage to the blood vessels 51  ##/## Join at: vevox.app ID: XXX-XXX-XXX Question slide Put in the correct order the following events leading to type 2 Diabetes Hyperinsulinemia Retinopathy Hyperglicaemia Beta cells failure Obesity/sedentary style of life ##/## Join at: vevox.app ID: XXX-XXX-XXX Results slide Put in the correct order the following events leading to type 2 Diabetes Correct order: 1. Obesity/sedentary style of life 2. Hyperinsulinemia 3. Beta cells failure 4. Hyperglicaemia 5. Retinopathy RESULTS SLIDE Correct responses:  ##/## Join at: vevox.app ID: XXX-XXX-XXX Question slide Which of the following molecules can lead to insulin resistance in type 2 diabetes? 2 right answers AMPK ##.##% Adiponectin ##.##% IL-1 ##.##% DAG ##.##% PKA ##.##%  ##/## Join at: vevox.app ID: XXX-XXX-XXX Results slide Which of the following molecules can lead to insulin resistance in type 2 diabetes? 2 right answers AMPK ##.##% Adiponectin ##.##% IL-1 ##.##% DAG ##.##% PKA ##.##% RESULTS SLIDE ##/## Join at: vevox.app ID: XXX-XXX-XXX Question slide Which of the following drugs work by improving insulin secretion from the Beta cells of the pancreas? 2 right answers Pioglitazone ##.##% SGLT-2 inhibitors ##.##% GLP-1 agonists ##.##% Gliclazide ##.##% Metformin ##.##%  ##/## Join at: vevox.app ID: XXX-XXX-XXX Results slide Which of the following drugs work by improving insulin secretion from the Beta cells of the pancreas? 2 right Pioglitazone answers ##.##% SGLT-2 inhibitors ##.##% GLP-1 agonists ##.##% Gliclazide ##.##% Metformin ##.##% RESULTS SLIDE