Pro-Insulin

Physiology and Biochemistry of Insulin Glucagon Dr. Mohammed Kalimi And

Release of Insulin ↑ Blood glucose ↑ Glucose transport into β cells of pancreas ↑ Glucose transporter proteins ↑ Glucose oxidation ↑ ATP production Closure of potassium channels ↑ Intracellular calcium ↑ Release of insulin by exocytosis

Diabetes Mellitus ↑ Plasma glucose Large amount of sweet urine Boils and tendency to die in coma

1889: Minkowsky: Presence of hypoglycemic factor in pancreas 1922: Benting and Best- Discovery of insulin 1959: Sanger: Chemical analysis of insulin (51 amino acids peptide)  1967: Steiner: Proinsulin 1977: Rosalyn Yalow: Development of Radio Immuno Assay (RIA)

Human insulin production by recombinant DNA technique Down regulation of insulin receptor Insulin receptor has intrinsic tyrosine phospho kinase activity Insulin pumps (including nasal spray) Stem cell research

Insulin release ↑ Blood glucose (hyperglycemia) ↑ Plasma amino acids (lysine, arginine) Diet Vagus stimulation: acetylcholine Sulfonylureas (hypoglycemic agent) GIP and GLP-1 (glucagon-like peptide I)

Insulin Inhibition Somatostatin Catecholamines Fasting Exercise Leptin

↑Insulin  Glucose  Amino acids  FFA  Ketoacids ↑ Glucose transport, FFA transport, Amino acids transport ↑ Cell growth (RNA, DNA and protein synthesis), Differentiation

Insulin Mechanism Insulin – Receptor Complex  p- IRS   PI-3 kinase G-Ras MAPK Gene Expression

Excess Insulin Tumors of β cells Hypoglycemia during fasting Fasting releases catecholamines Rapid heart rate, sweating, hunger and nervousness Coma, brain damage

Primary Diabetes Type I (Juvenile) Type II (Adult onset) Diabetes during pregnancy

Diabetes Type I 10% of all people Thin, young, ketosis prone Acute onset often with ketosis Sensitivity to exogenous insulin Destruction of pacreatic β cells

Symptoms of Type I Diabetes Increased Hunger Increased Thirst Frequent Urination Fatique Weight Loss (negative nitrogen balance)

Type II Diabetes Adult , often linked with obesity, hypertension, dyslipidemia, aging sedentary life style or genomic predisposition Defects in insulin secretion and action (defective insulin receptor or post receptor defect) Increased glucose output from the liver

Symptoms and complications of Type II Diabetes Peripheral insulin resistance Increased hunger (polyphagia), Increased thirst (polydispia), frequent urination Frequent infections, cataract and blindness, numbness or tingling in hands and feet ( amputations), neuropathy, retinopathy and vascular diseases Problems with pregnancy Impotence

Secondary Diabetes Thyrotoxicosis Acromegaly Cushing’s syndrome Destruction of pancreas

Contributions of diabetogenic hormones Effects of hypophysectomy  Plasma ACTH and glucocorticoid secretion,symptoms of diabetes Effects of pituitary extracts and glucocorticoids,↑ symptoms of diabetes

Methods of Inducing Diabetes Anti-insulin serum Alloxan and Streptozotocin Pancreatectomy Viral infection (coxsackie, mumps)

Glucagon ↑ Glycogenolysis ↑ Gluconeogenesis ↑ Lipolysis

Blood Glucagon Insulin ↑ Glucose  Glucose ↑ FFA  FFA ↑ Ketoacids  Ketoacids  Aminoacids  Aminoacids

Glucagon Release Hypoglycemia ↑ Plasma amino acids Stress and exercise

Glucagon Inhibition Somatostatin Insulin ↑ Blood glucose (hyperglycemia) ↑ Blood FFA

Tumors of α Cells Excess Glucagon Levels Weight loss ↑ Plasma glucose, FFA, and ketoacids and  Plasma amino acids

Somatostatin Release ↑ Plasma glucose, amino acids, FFA and GI hormones