Title 35. INSULIN, INSULIN ANALOGUES AND ORAL HYPOGLYCEMIC AGENTS.pdf ✅

PHARMD GURU Page 1 INSULIN AND INSULIN ANALOGUES Diabetes mellitus (DM) is a clinical syndrome characterized by hyperglycaemia due to absolute or relative deficiency of insulin. Lack of insulin affects the metabolism of carbohydrate, protein and fat.  Type 1 DM: The aetiology is immunological or idiopathic. It appears when more than 90% of β-cells of pancreas are destroyed by an autoimmune process. The peak incidence is around 15 years. In type 1 DM, there is insulin deficiency. Insulin is essential for all patients with type 1 DM.  Type 2 DM: Genetic influence is much more powerful in type 2 DM. It is the commonest form of diabetes. Overeating, obesity, underactivity and ageing are the main risk factors. Type 2 DM is associated with increased hepatic production of glucose and resistance of target tissues to the action of insulin.  Hormones of pancreas: There are four types of cells in islets of Langerhans: β (B) - cells secrete insulin, α (A)-cells secrete glucagon, (D)-cells secrete somatostatin and F (PP)-cells secrete pancreatic polypeptide. INSULIN: Insulin was discovered by Banting and Best. Insulin is synthesized by the β-cells of pancreatic islets from a single-chain polypeptide precursor called preproinsulin, which is converted to proinsulin. Insulin is formed by the removal of C-peptide from INSULIN, INSULIN ANALOGUES AND ORAL HYPOGLYCEMIC AGENTS
PHARMD GURU Page 2 proinsulin by proteolysis. Insulin consists of two peptide chains called A and B (Fig. 9.19). These two chains are connected by two disulphide bridges. C-peptide (connecting peptide) can produce immunogenic reactions. REGULATION OF INSULIN SECRETION: Insulin secretion is regulated by chemical, neural and hormonal mechanisms. CHEMICAL: Glucose, amino acids and fatty acids in the blood stimulate β-cells and release insulin (Fig. 9.20). Ingestion of nutrients (carbohydrate/protein/fat) causes release of gut peptides (incretins) like GLP-1 (glucagon-like peptide) and GIP (glucose dependent insulinotropic polypeptide) which promote the secretion of insulin. Oral nutrients (including glucose) are more effective in stimulating incretin secretion as compared to their intravenous infusion. NEURAL: Both parasympathetic and sympathetic fibres supply the islet cells. Parasympathetic stimulation causes increase in insulin secretion and lowers raised blood glucose level. The islet cells have both α-adrenergic and β-adrenergic receptors. Adrenergic
PHARMD GURU Page 3 β2-stimulation increases insulin release and the blood glucose falls. Adrenergic α2- activation causes hyperglycaemia by inhibiting the release of insulin. HORMONAL: Counter-regulatory hormones like adrenaline, cortisol and glucagon promote glucose release from liver. Glucagon stimulates whereas somatostatin inhibits insulin release (Fig 9.21). ACTION OF INSULIN: Insulin has profound effects on the metabolism of carbohydrate, fat and protein. It facilitates the entry of glucose into all cells of the body. However, entry of glucose into RBCs, WBCs, liver and brain cells can occur independent of insulin. Exercise also facilitates entry of glucose into muscle cells without the need for insulin. 1. Insulin inhibits hepatic glycogenolysis and gluconeogenesis; inhibits lipolysis in adipose tissue. 2. Insulin enhances entry of amino acids into muscles and cells – promotes protein synthesis in muscle, lipogenesis, hepatic and muscle glycogenesis. 3. Insulin also promotes peripheral utilization of glucose and K+ uptake into the cells.
PHARMD GURU Page 4 MECHANISM OF ACTION OF INSULIN:  Insulin binds to specific receptors (tyrosine kinase receptor) present on the cell membrane. The receptor consists of two α and two β subunits (Fig. 9.23).  The α subunits are entirely extracellular, whereas the β subunits are transmembrane proteins with tyrosine kinase activity.  Binding of insulin to the α subunit activates tyrosine kinase activity of the β subunits resulting in phosphorylation of tyrosine residues of the receptor.  This results in a complex series of phosphorylation–dephosphorylation reactions, which promotes entry of glucose into the cell and mediates various actions of insulin.
PHARMD GURU Page 5 PHARMACOKINETICS: Insulin is destroyed by proteolytic enzymes in the gut, hence, not effective orally. Insulin is administered usually by subcutaneous (s.c.) route, but in emergencies, regular (soluble) insulin is given by i.v. route. After i.v. injection, soluble insulin is rapidly metabolized by the liver and kidney with a half-life of about 6 minutes. INSULIN PREPARATIONS: CONVENTIONAL INSULIN PREPARATIONS: 1. Bovine (beef) insulin: It differs from human insulin by three amino acid residues and is antigenic to man. 2. Porcine (pig) insulin: It differs from human insulin by only one amino acid residue and is less immunogenic than bovine insulin. These preparations are antigenic as they contain pancreatic proteins, proinsulin, etc. Hence, they are not used. MONOCOMPONENT INSULINS: Monocomponent insulins are purified insulins. They are less antigenic than conventional preparations, cause less insulin resistance and lipodystrophy at injection site, e.g. monocomponent porcine regular insulin, monocomponent porcine isophane insulin, etc. HUMAN INSULINS: They are produced by recombinant DNA technology using Escherichia coli or yeast. They have the same amino acid sequence as endogenous insulin. They are least immunogenic; insulin resistance and lipodystrophy at the site of injection are rare, e.g. human regular insulin and human NPH insulin. Purified human insulins are the commonly used insulin preparations.