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Diabetes and Oral hypoglycemic drugs
- 1. Monika Singh Assistant Professor PSIT, Kanpur
- 3. Pancreas – elongated tapered organ – lies behind stomach – connects with duodenum – small tube – pancreatic duct – narrow end – called tail – extends to left side of body towards spleen Types of pancreas Exocrine: Secrete – digestive enzymes – secreted into ducts network – joining main pancreatic duct – runs same length of pancreas Endocrine: Consists – islets of Langerhans – secretes hormones into bloodstream Types of pancreatic cells Alpha cells: Glucagon (15–20% of total islet cells) Beta cells: Insulin and amylin (65–80%) Delta cells: Somatostatin (3–10%) PP cells (gamma cells): Pancreatic polypeptide (3–5%), Vasoactive Intestinal Peptide (VIP) Epsilon cells: Ghrelin (<1%) PANCREAS
- 4. INSULINInsulin – anabolic hormone – discovered – 1921 – Banting – Best Two chain polypeptide – 51 amino acids – A chain – 21 amino acids – B chain – 30 amino acids Synthesized – β cells (pancreatic islets) – preproinsulin (110) – proinsulin (86) Golgi bodies – C pepetide & insulin – stored in vesicles – secreted into blood stream
- 5. MECHANISM OF GLUCOSE-STIMULATED INSULIN SECRETION (GSIS) Increased blood glucose uptake by pancreatic β-cells through GLUT2 Glucose oxidized to pyruvate via glycolysis Pyruvate oxidized by the PDHc results acetyl-CoA oxidized in TCA cycle increased ATP levels inhibits the KATP channel membrane depolarization influx of Ca2+ ions Insulin- containing vesicle migrates to plasma membrane release insulin into blood
- 6. MECHANISM OF ACTION OF INSULIN
- 8. DIABETES Diabetes – metabolic disorder – causing excessive – thirst & large amounts – urine production Diabetes : Diabetes mellitus – metabolic disorder – characterized by chronic hyperglycemia – disturbances – carbohydrate – fat – protein metabolism – defects in insulin secretion – insulin action – or both Diabetes insipidus (DI) – characterized – excessive thirst & severely dilute urine excretion (large amounts) – humans – neurological form – central DI (CDI) – arginine vasopressin (AVP) /anti-diuretic hormone (ADH) deficiency – second type – nephrogenic diabetes insipidus(NDI) – kidney or nephron dysfunction – caused – ADH insensitivity – kidneys or nephrons Diabetes mellitus Diabetes insipidus
- 9. Diabetes mellitus Classification Type-I diabetes/ IDDM (Insulin Dependent Diabetes Mellitus) Immune mediated Idiopathic Type-II diabetes / NIDDM (Non-Insulin Dependent Diabetes Mellitus) Gestational diabetes mellitus Other specific types Genetic defects of β-cell function Genetic defects in insulin action Diseases of the exocrine pancreas
- 10. TYPE-I DIABETES MELLITUS / IDDMType 1 Diabetes mellitus (T1D) – known – formerly – insulin-dependent diabetes – juvenile diabetes – diabetes mellitus form – results from autoimmune destruction – beta cells (pancreas) – producing insulin Characterized by hyperglycemic patients – absolute deficiency of the insulin hormone Lifelong insulin injections – require – survival Usually develops – children and adolescents (although can occur later in life) Patients are at increased risk of developing microvascular and macrovascular complications. Etiology: β cell destruction – pancreatic islets – Type 1A: Autoimmune antibodies – destroy β cells – detectable in blood – Type 1B: Idiopathic cause—no β cell antibody found Circulating insulin levels – low or very low – all type 1 cases – patients – more prone to ketoacidosis or coma – less common – low degree – genetic predisposition
- 12. TYPE-II DIABETES MELLITUS / NIDDM Formerly named – non-insulin-dependent diabetes mellitus (NIDDM) – over 90% cases – type-II DM Characterized by hyperglycemia – defect – pancreatic insulin secretion – insulin resistance Patients – higher risk – microvascular & macrovascular complications No loss or moderate reduction – β cell mass – insulin in circulation – low – normal or even high – no anti-β-cell antibody demonstrable – has high degree of genetic predisposition – generally has a late onset (past middle age) Etiology β cell gluco-receptor abnormality Down regulation – insulin receptor Excess hyperglycaemic hormone/ obesity
- 13. TREATMENT REGIMENDIABETES MELLITUS TYPE I / IDDM TYPE II / NIDDM Insulin injection Oral Hypoglycemic drugs Enhanced insulin secretion Sulfonylureas (KATP channel blockers) First generation: Tolbutamide Second generation: glibenclamide, glyburide, Glipizide Third generation: Glimeperide Meglitinide/phenylalanine analogue Repaglinide, nateglinide Glucagon-like peptide-1 (GLP-1) receptor agonists Exenatide, liraglutide Dipeptidyl peptidase-4 (DPP-4) inhibitors Sitagliptin, vildagliptin Overcome insulin resistance Biguanide (AMPK activator): Metformin Thiazolidinediones (PPARƔ activator): Pioglitazone α- glucosidase inhibitors: Miglitol, acarbose Amylin analogue: pramlintide Dopamin receptor-D2 receptor agonist: Bromocriptin Sodium-glucose cotransport-2 (SGLT-2): Dapagliflozin
- 14. MANAGEMENT OF DIABETES MELLITUS
- 15. SULFONYLUREAS (KATP CHANNEL BLOCKERS) Sulfonylureas – organic compounds – medicinal & agricultural use – antidiabetic drugs – type-II diabetes mellitus management First generation Tolbutamide Second generation Glipizide Gliclazide Glibenclamide Third generation Glimepiride Fourth generation (light-dependent) JB253 JB558
- 16. Stimulation of insulin release from the β-cells of the pancreas by blocking the ATP-sensitive K+ channels, resulting in depolarization and Ca2+ influx Reduction in hepatic glucose production Increase in peripheral insulin sensitivity Mechanisms of action
- 17. CLINICAL USES Diabetes Mellitus Type 2 (Higher Glucose Levels Than Recommended Hba1c Level >6.5%) Neonatal diabetes (rare) ADVANTAGES Long acting – duration of action ~ 24 hrs Lower incidence of hypoglycaemia. Complete gastrointestinal absorption Generally well tolerated SIDE EFFECTS Hypoglycemia Trembling or shaking Nervousness or anxiety Sweating, fatigue &tiredness Lightheadedness or dizziness Headache Fast heart rate or palpitations Weight gain Hyper-insulinemia Non specific side effects Headache Nausea Dizziness Weakness Hypersensitivity Anaphylaxis Angioedema Stevens-Johnsons syndrome
- 18. BIGUANIDE Class of drugs – function as oral antihyperglycemic drugs – for diabetes mellitus – or prediabetes treatment Metformin First-line medication for the treatment of type 2 diabetes Only currently available biguanide – classed as insulin sensitizer Decreases insulin resistance
- 19. PROPOSED MECHANISM OF ACTION Metformin – transported into hepatocytes – via OCT1 – inhibits mitochondrial respiratory chain (complex I) – resulting energy deficit production – balanced – reducing energy consumption in cell – reduced gluconeogenesis – in liver – (1) allosterically inhibit cAMP– PKA signalling – suppression of adenylate cyclase – (2) allosterically inhibit FBPase, gluconeogenic enzyme – (3) activates AMPK – causes gluconeogenesis inhibition & lipid/cholesterol synthesis – contributing longer term metabolic & therapeutic responses – drug
- 21. CLINICAL USES Type 2 diabetes mellitus Polycystic ovary syndrome/ Infertility Gestational diabetes Prediabetes ADVANTAGES Nonhypoglycaemia Weight loss promoting Modestly reduce hyperlipidemia Prevent diabetic macrovacsular & microvascular complications No acceleration of β- cell exhaution/ failure in type-II diabetes Can be combined – oral/ injectable antidiabetics SIDE EFFECTS Abdominal pain Anorexia Bloating Nausea Metallic taste Diarrhoea (mild) Tiredness Lactic acidosis Vitamin B12 deficiency (long term use) CONTRAINDICATIONS Renal disease Hepatic disease Acute myocardial infarction Severe infection Diabetic ketoacidosis Congestive heart failure history Alcohol abuse history
- 22. THIAZOLIDINEDIONE PIOGLITAZONE: Proposed Mechanism of Action Stimulates the nuclear receptor peroxisome proliferator- activated receptor gamma (PPAR- γ) and to a lesser extent PPAR-α ↑ insulin sensitivity in muscle and adipose tissue Inhibit hepatic gluconeogenesis
- 23. CLINICAL USES Diabetes mellitus type 2 (T2DM) Non-alcoholic steatohepatitis (fatty liver)- experimental ADVANTAGES Well tolerated Nonhypoglycaemia SIDE EFFECTS Edema Weight gain Headache Myalgia Anaemia (mild) Cardiovascular Fractures CONTRAINDICATED Liver diseases Congestive Heart Failure Pregnancy