Diabetes -Insulin Discovered in 1921 by banting and Best Consist of a b chains linked by 2 disulfide bonds (plus additional disulfidein a +A=2lamino acids b=30 amino acids NHrs NHz NH NEI Gily-Ilou-val-Glu-Glu-Cy-Cy-Thr-Ser-llen-Cy-Ber-Leu-Try-Glu-Leu-Glu-Aap-Tyr-Cy-Asp 23456 8910111213141516171819/21 NH: NLa e-TyI-Thr-Pro-Lyg-Thr 1 8, 9, 10 and B so Phe-Val-Asp-Glu-His-Leu-Cy-Gly-Ser-His-Leu-Val-Glu-Ala-Len-Tyr-Leu-Val-Cy-Gly-Glu-Art-Gly-PI 12345078910112111516118102n222232425262228230A Al Sperm whale Rabbit Horse
Diabetes - Insulin ◼ Discovered in 1921 by Banting and Best ◼ Consist of A & B chains linked by 2 disulfide bonds (plus additional disulfide in A) ~ ~ A = 21amino acids B = 30 amino acids
Diabetes-Insulin proinsulin (synthesis, storage, secretion) B cel peptidases Produced within the pancreas by free C peptide Bcells islets of Langerhans insulin mrna is translated as a single chain precursor called preproinsulin removal of signal peptide during insertion into the endoplasmic reticulum generates proinsulin Within the endoplasmic reticulum, proinsulin is exposed Insulin dimer nsulin hexamer to several specific endopeptidases which excise the C peptide, thereby generating the mature form of insulin Stored as阝 granules
Diabetes – Insulin (synthesis, storage, secretion) Zn ◼ Produced within the pancreas by β cells → islets of Langerhans ◼ insulin mRNA is translated as a single chain precursor called preproinsulin ◼ removal of signal peptide during insertion into the endoplasmic reticulum generates proinsulin ◼ Within the endoplasmic reticulum, proinsulin is exposed to several specific endopeptidases which excise the C peptide, thereby generating the mature form of insulin ◼ Stored as β granules
Diabetes -Insulin (Biochemical role) The role of Insulin yrosine kinase receptors are the locks red blood cell in which the insulin bloodstream→ key fits Involved in signal B-adrenergic receptor transduction Extracellular (insulin hormone being Ist messenger) Epidermal growth Insulin receptor factor receptor
Diabetes – Insulin (Biochemical Role) -Tyrosine Kinase receptors are the locks in which the insulin key fits - Involved in signal transduction (insulin hormone being 1st messenger)
Diabetes -Insulin (Mechanism) Insulin Insulin binding site Outside 的 Membrane side ATP I yI Tyrosine kinase domain IRS-1 T IRS-1 ADP Insulin action
Diabetes – Insulin (Mechanism)
Insulin drug evolution Stage 1 Insulin was extracted from the glands of cows and pigs(1920s) Amino Acid substitutions A-Chain Position B-Chain Position Source/ ypes A8(0A21B2823(B30Ba B32 Ala Val Asn Pro Ly Ala Pork Thr IIc Asn Pro Ala Human Thr llc Asn Pro Lys Thr Stage 2 Convert pig insulin into human insulin by removing the one amino acid that distinguishes them and replacing it with the human version
Stage 1 Insulin was extracted from the glands of cows and pigs. (1920s) Stage 2 Convert pig insulin into human insulin by removing the one amino acid that distinguishes them and replacing it with the human version. Insulin drug evolution