T2DM/Pancreatic Hormones

T2DM/Pancreatic Hormones Sunday, February 25, 2024 11:49 PM 1. Discuss the primary differences between Types I and II Diabetes Mellitus. Type 1 Type 2 • • • • 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. Childhood • Adults, occasionally adolescents Insulin is NOT present, insulin-dependent • Insulin is present, but tissues do not respond Autoimmune disease • Main cause: Obesity Main cause: absolute deficiency of pancreatic β • Insulin resistance cell secretion • Deficiency of pancreatic β cell response to • Treated w/ insulin glucose • Treated w/ lifestyle management w/ or w/o oral antidiabetic drugs, may progress to require insulin Identify whether Type 1 or Type 2 DM is more linked to genetics. ○ Type 2 DM Identify the site of adipose tissue deposition that is most closely linked to insulin resistance ○ Visceral Identify the consequences of lipid accumulation in the liver ○ Insulin resistance ○ Liver inflammation ○ Liver dysfunction Define “Ectopic Fat” and why it is important. ○ Ectopic Fat: abnormal accumulation of fat in locations where fat is not typically stored ○ Importance: preventing and managing metabolic disorders, cardiovascular diseases, and other health complications associated with abnormal fat distribution Identify the two most important incretins. ○ GLP-1: glucagon-like peptide-1 ○ GIP: glucose-dependent insulinotropic peptide Describe the incretin effect and how it is affected by DM Type 2. ○ Incretins are GI hormones that regulate blood glucose along with insulin ▪ Encoded by glucagon gene → differential cleavage of pro-glucagon in α cells vs. GI tract (L-cells) ○ Type 2 DM does not get incretin effect ▪ ↑ GLP-1 post-prandial = ↓ effect in T2DM Describe the relative impacts of diet and exercise versus drugs on A1C lowering. ○ Diet + exercise has higher A1C lowering ability than any of the drugs (3%) Identify the role played by Adenosine Monophosphate Activated Protein Kinase (AMPK) in glucose uptake. ○ AMPK pathway activated during exercise ○ Activation leads to: ▪ Cellular uptake of glucose (↑) ▪ Biogenesis of GLUT4 + translocation to plasma membrane ▪ Transcriptional activation of hexokinase gene ▪ Β-oxidation of fatty acids (breaking down stored fat to produce ATP) ▪ Inhibition of cholesterol synthesis Define “Secretagogues”. ○ Secretagogues: substance that causes another substance to be secreted Name the two classes of Insulin Secretagogues. Explain the mechanism of action of Sulfonylureas. I Classes of Insulin Secretagogues ○ Sulfonylureas Meglitinides MOA Insulin release from pancreatic β cells = ↓ insulin hepatic clearance = ↓ serum glucagon concentration Similar to sulfonylureas (insulin release) - SUR on K(ATP) channel 13. Name the two components that comprise the K-ATP channel in cells ○ SUR (Sulfonylurea Receptor) ○ Kir6.2 14. Explain the importance of mutations to SUR1 as a genetic link for Type 2 DM. ○ Encoded by ABCC8 gene and mutations responsible for congenital hyperinsulinism and susceptibility to DM2 15. Identify the general chemical structure of the Sulfonylureas. 16. State how the potency of the First and Second generation Sulfonylureas compare. ○ Second generation is more potent up to 100x = administer lower dose ○ In first generation, half-life depends on R1 group attached to benzene (ex. Cl at R1 = ↑ half-life) ○ In second generation, more extensive substitution on R1 group = higher affinity for SUR 17. Explain why displacement of Sulfonylureas from plasma proteins by other drugs is important. ○ Displacement of sulfonylureas from plasma proteins by other drugs → ▪ Increased free drug concentrations ▪ Potentially resulting in enhanced pharmacological effects ▪ Increased risk of adverse reactions, particularly hypoglycemia 18. Explain why the Meglitinides can be used in patients with sulfur allergies while Sulfonylureas can’t. ○ Patients may be hypersensitive to sulfonylureas due to the presence of sulfur in the chemical structure ○ Meglitinides is the benzoic acid derivative of the non-sulfonylurea moiety of glyburide 19. Identify the chemical structure of Metformin. NAMIEneHsia 20. Identify the difference in Hypoglycemic and Antihyperglycemic drugs. ○ Hypoglycemic drugs: lower blood glucose levels ○ Antihyperglycemic drugs: lower elevated blood glucose levels 21. Identify the sites of action of the Biguanides. ○ Liver ○ Muscle ○ Adipose tissues ○ Intestine 22. Name the only Biguanide drug approved for use in the US. ○ Metformin 23. Describe the mechanism of action of Metformin. 24. Describe the pharmacokinetics of Metformin. 25. Identify the primary adverse effects of Metformin. insult boassensitig to improve t to ofglucoseinliver moreeffectivetoIverBf MOA 26. 27. 28. 29. 30. 31. PK Adverse Effects Metformin Activation of AMP-activated protein • Absorbed from intestines w/ • C/I in pts w/ renal, hepatic disease, kinase (AMPK) bioavailability of 50-60% alcoholism, or conditions predisposing to • Direct stimulation of glycolysis (fasting) tissue hypoxia and history of lactic acid in tissues w/ ↑ glucose • Onset within days • Lactic uptake by liver is ↓ w/ metformin removal from blood • Max: up to 2 weeks • Lactate = substrate for hepatic • ↑ insulin sensitivity of tissues • NOT protein bound = not gluconeogenesis ○ = ↓ insulin resistance metabolized • Common SE: GI related (~20%) • ↓ hepatic gluconeogenesis • Excreted by kidneys by tubular • Slows glucose absorption from secretion (~90% as active drug) GI tract w/ ↑ conversion of glucose to lactate by enterocytes • Inhibition of glucagon-induced elevation of cyclic adenosine monophosphate (cAMP) • ↓ plasma glucagon levels Describe the effects of Thiazolidinediones on insulin resistance and insulin secretion. ○ Enhance target tissue insulin sensitivity and reduce insulin resistance (insulin sensitizers) ○ Does not affect insulin secretion improve Explain the mechanism of action of the Thiazolidinediones. responsive insuin efficantly glucose ○ Activation of genes involved w/ glucose and lipid metabolism mediated through peroxisome proliferator activated receptor gamma (PPARγ) - transcription factor ▪ Ligands bind to PPARγ (steroid receptor) found in muscle fat/liver-regulating glucose or lipid metabolism ○ Increase glucose uptake and metabolism in muscles and adipose tissues = ↑ insulin sensitivity absorption Explain the mechanism of action of Alpha-glucosidase inhibitors. ○ Competitive inhibition of intestinal α-glucosidase slowdown digestion ○ Modulate postprandial digestion + absorption of starch and disaccharides ○ ↑ reduction in post-prandial glucose level Identify the location of synthesis of endogenous Incretins. ○ GI tract (L-cells) Name the enzyme that degrades GLP-1 and GIP. ○ DPP-4 = dipeptidyl peptidase 4 Identify the primary effects of GLP-1 in the body. ○ Blood levels are low during fasting and rise after a meal ○ Acts on G-protein coupled receptors on α (inhibits glucagon secretion) + β (stimulate glucagon secretion) cells ▪ ↑ insulin, ↓ glucagon secretion ▪ In stomach = delays gastric emptying ▪ Hypothalamus = ↓ appetite To To De insulinsensitiveinbots ccan aus to more toenter anow ofcarbinstead and meals after preventBSP help the ○ 32. Describe the mechanism of action of the GLP-agonists. ○ In T2DM, post-prandial rise in GLP-1 ↓ = ↓ phase 2 response (phase 1 missing in T2DM) 33. Name the GLP-1 agonists on the market. ○ Exenatide (Byetta, Bydureon) ○ Lixisenatide (Adlyxin) ○ Liraglutide (Victoza) ○ Semaglutide (Ozempic) ○ Dulaglutide (Trulicity) 34. Describe the mechanism of action of DDP-4 Inhibitors ○ DPP-4 ▪ A serine protease expressed as ectoenzyme on vascular endothelial cells, on the surface of T lymphocytes, and in a circulating form ▪ Selectively cleaves 2 amino acids from peptides (GLP-1 and GIP), which have proline or alanine in 2nd position. ○ DPP-4 inhibitors ▪ Inhibit enzyme DPP-4 that degrades incretin hormones ▪ ↑ circulating levels of endogenous GLP-1 • ↑ glucose mediated insulin secretion • ↓ glucagon level 35. Name the available DDP-4 inhibitors. ○ Sitagliptin (Januvia) ○ Saxagliptin (Onglyza) ○ Linagliptin (Tradjenta) ○ Alogliptin (Nessina) 36. Compare and contrast the DDP-4 Inhibitors and the GLP-1 analogs I roadenEPI DPPIB Big so Inhibitoppytop0 regulateByod DPP-4 Inhibitors 37. 38. • Small molecule drug • Protein drugs, injectables • NOT a peptide • EXCEPT semaglutide PO • Physiologic levels of GLP-1 (preserved) • Supraphysiologic levels of GLP-1 • Moderate A1c reduction • More potent in A1c reduction • Neutral in ASCVD risk reduction • ↓ ASCVD risk – CV mortality • Saxa - ↑ HF • Exenatide, lixisenatide • Immune modulation • Immunogenicity + attenuation of response • ADRs • ADRs: GI-related • URIs • Weight loss induces (not all agents) • Angioedema • Improve or maintain β cell mass • SJS reported • Useful to ↓ acute GVHD • Weight neutral • Can be administers in renal failure (Lina) Describe the function of Amylin ○ 37 amino acid protein packaged w/ insulin in secretory granules of pancreatic β cell ▪ Co-secreted w/ insulin following a meal (insulin + amylin complement each other) Explain the mechanism of action of Amylinomimetic agents. ○ Mimics action of amylin (given w/ insulin) ○ ↓ gastric emptying ○ Suppresses glucagon release ○ ↓ food intake Name the only amylinomimetic drug available. protein ○ Pramlintide (Symlin) Describe the mechanism of action of SGLT-2 inhibitors risk 39. 40. GLP-1 Analogs sat no BI backtoblond glyose inking th glucosein one ABS ○ ↑ urinary excretion of glucose preventing reabsorption of glucose ○ Inhibits SGLT-2 (symporter w/ 14-transmembrane α-helices) → allow excretion of glucose thru urine ○ Glucose and phlorizin binds to TM4 41. Name the SGLT-2 inhibitors available. ○ Canagliflozin (Invokana) ○ Dapagliflozin (Farxiga) ○ Empagliflozin (Jardiance) glucoside ○ Ertugliflozin (Steglatro) 42. Explain how the commercially available SGLT-2 inhibitors differ chemically from Phlorizin. ○ Phlorizin – a glycoside isolated from bark of apple tree ○ SLGT-2 inhibitors – synthetic compounds designed specifically to target the SGLT-2 transporter 43. Compare the A1C lowering capacity of the major classes of DM drugs. tree from aInsulin exercise 2Distad Linomimatie 3Amy 44. Identify the characteristics of Gestational Diabetes. ○ Gestational diabetes: ↑ blood glucose in mother → extra glucose to baby → causes baby to put on extra weight ○ Placenta + placental hormones may create insulin resistance ○ Hypertension, preeclampsia ○ Risks to infant • Damage to shoulder, brachial plexus injury • Hypoglycemia after birth • Breathing problems, jaundice, and still birth ○ Preferred treatment: diet + exercise, if uncontrolled → insulin • Metformin + SU ○ Risk factors: • Smoking • Overweight, obese • PCOS T2DM: Medications Class First-Gen Sulfonylureas • ½ life depends on R1 group Generic Tolbutamide Brand Orinase, Tol-tab Chlorpropamide Tolazamide Second-Gen Sulfonylureas • Higher affinity for SUR ○ Give lower dose Glyburide/Glibenclamide USAN/BAN Diabeta, Glynase, Micronase Glipizide Glucotrol Glimepiride Insulin secretagogues (Meglitinides) Biguanides Repaglinide Prandin Nateglinide Starlix Metformin Glucophage Thiazolidinediones (TZDs) Short-acting GLP-1 receptor agonists (SQ) • Incretin hormones Pioglitazone Actos Rosiglitazone Avandia Exenatide Byetta Lixisenatide Adlyxin Liraglutide Victoza Long-acting GLP-1 receptor agonists Exenatide LAR Bydureon (SQ) • Incretin hormones Dulaglutide Trulicity Semaglutide Ozempic Semaglutide (PO) Rybelsus Sitagliptin Januvia Saxagliptin Onglyza Alogliptin Nesina Linagliptin Tradjenta Amylinomimetic Pramlintide Symlin SGLT-2 • A1c lowering: <1% • High plasma protein binding • Metabolism: Hepatic glucuronidation Canagliflozin Invokana Empagliflozin Jardiance Dapagliflozin Farxiga Ertugliflozin Steglatro DPP-4 Inhibitors (PO)