Endocrine System IV: Growth Hormone, Insulin, and Glucagon Lecture Notes PDF

ENDOCRINE SYSTEM IV: IMPORTANCE OF GROWTH HORMONE, INSULIN AND GLUCAGON ANSC 3080 G. Bedecarrats  Learning Objectives  Describe the roles of growth hormone (GH)  Understand the regulation of GH secretion  Describe the roles of insulin and glucagon  Understand the regulat...

ENDOCRINE SYSTEM IV: IMPORTANCE OF GROWTH HORMONE, INSULIN AND GLUCAGON ANSC 3080 G. Bedecarrats  Learning Objectives  Describe the roles of growth hormone (GH)  Understand the regulation of GH secretion  Describe the roles of insulin and glucagon  Understand the regulation of insulin and glucagon secretion  GROWTH HORMONE  Growth hormone (somatotropin; GH) originates from cells of the anterior pituitary  Promotes tissue and body growth in young animals, especially longitudinal growth until skeleton is complete  In adult, GH mainly controls metabolism  During fetal life, GH does not stimulate growth; this role is played by Insulin Like Growth Factors (IGF1 and 2)  Protein sequence differs a lot between species (poor cross reactivity)  GH secretion is regulated by hypothalamic neurohormones: GHRH stimulates GH GHIH (somatostatin) inhibits GH  GH stimulates IGF1 production by the liver. In turn, IGF1 stimulates cartilage and bone growth and milk production  GH regulates lipid and protein metabolism  GH receptor is a member of the interleukin (cytokine) family  Regulation of GH Secretion  Very precise dual regulation by hypothalamic GHRH and GHIH  Hypothalamus receives information from external stimuli and nutrients in the blood: Follows a circadian pattern,  during sleep High amino acid and low glucose content in plasma both  GH secretion (high protein diet, long fasting) Exercising and stress also  GH secretion Sex steroids  GH secretion = burst of growth at puberty IGF1 responsible for negative feed back on GH secretion  Direct Effects of Growth Hormone  GH affects most cells of the body  GH has a short half life (around 20 min)  GH is an anabolic hormone: like insulin GH promotes synthesis of protein  GH is also a catabolic hormone: conversely to insulin GH stimulates lipolysis and reduces lipogenesis in adipose tissue (important during fasting and at night).  Lipolysis  fatty acid production. In addition, GH decreases glucose utilization in most tissues. As a result GH increases glucose concentration in blood.  Indirect roles of GH via IGFs  GH stimulates synthesis of IGF1 and its binding proteins in the liver. Small amounts also locally produced in muscle and adipose tissue.  IGF1 is a polypeptide chain with a sequence similar in human, porcine and bovine. Bound to carrier proteins its half life is much longer than GH.  It acts via its own tyrosine kinase receptors.  IGF1 stimulates chondrocytes (cartilage cells) proliferation to increase bone growth  IGF1 stimulates satellite cells in muscle (muscle fibre growth)  IGF1 stimulates amino acid uptake and protein synthesis  GH and Lactation  No major role in mammary gland development  Effects of GH on milk production are mainly mediated via metabolism, and partitioning nutrients to the mammary gland for milk synthesis  Insulin normally directs nutrient towards lipogenesis in adipose tissue. GH has the opposite effect.  Bovine GH (bST) can boost milk production by 10 and 40% in early and late lactation, respectively.  Major concern for humans: infant can absorb GH and IGF in the gut, IGF1 has similar sequence in bovine and human  GH Pathologies Overproduction of GH: Rare in animals  Before puberty (before skeleton formed): gigantism (increased longitudinal growth)  After puberty (no more longitudinal growth): acromegaly, increased bone width and density, diabetes  In old dogs and cats: can be due to pituitary tumor Lack of GH production: Dwarfism  Mostly genetic defects of GH or GH receptor genes, can be treated by injection of recombinant GH and IGF1  In dogs, dwarfs keep their puppy coat for a long time. Lack of IGF1 action on hair follicle differentiation.  INSULIN and GLUCAGON  Pancreas is an endocrine and exocrine gland  Endocrine pancreas = islets of Langerhans (scattered through the pancreas)  In islets:  cells (70%) secrete insulin,  cells (20%) secrete glucagon  Insulin and glucagon have opposite effects on glucose metabolism  Synthesis and Secretion Insulin:  Produced as a preprohormone, converted to proinsulin  Before secretion, converted to active insulin by removing a connecting (C)-peptide  After secretion, circulates free (half life of 5-8 min), and is degraded in target cells or in liver Glucagon:  29 AA peptide produced as a preprohormone rapidly converted to active glucagon.  After secretion, circulates free (half life of 5 min), and is metabolized in the liver and kidney FYI Pre-Proinsulin SH SH COOH SH SH Signal Sequence SH SH HN 2 Proinsulin S S COOH COOH S S S S HN 2 Connecting Peptide S S Insulin HN COOH 2 S S S S HN COOH 2  Actions of Insulin  Insulin is the major anabolic hormone of the body  Through its tyrosine kinase receptor, insulin leads to the upregulation of membrane glucose transporters  CELLULAR UPTAKE OF GLUCOSE in muscles and adipose tissue  Insulin stimulates incorporation of glucose in energy storage molecules: glycogen in liver and muscle, and triglycerides in adipose tissue  Insulin also promotes the uptake of amino acids  The overall effects will lead to a decrease in blood glucose and amino acid levels.  Actions of Glucagon  Glucagon has opposite effect to insulin  Through its G-protein coupled receptor glucagon activates enzyme responsible for glycogenolysis  release of glucose from glycogen by the liver  Glucagon also stimulates gluconeogenesis in the liver (synthesis of glucose)  Glucagon stimulates release of fatty acids from triglycerides in adipose tissue. Regulation of Insulin and Glucagon Secretion  The major mechanism of regulation of insulin and glucagon is the blood glucose concentration  To a lesser extent amino acid concentration  Role of the autonomic nervous system: During meals, parasympathetic activates insulin secretion Sympathetic inhibits insulin secretion and stimulates glucagon release = “stress hyperglycemia”  Insulin and Diabetes Mellitus  Diabetes = hyperglycemia. When blood levels exceed kidney reabsorption capacity  glycosuria  increase osmolarity of urine  increase in urine volume (diabetes), sweet (mellitus)  In insulin-dependent diabetes, the insulin secretion is impaired = Type I  In insulin-independent diabetes, insulin secretion normal but tissues are insensitive = Type II  In animals, only observed in cats and dogs. Mainly due to inflammation of pancreas  In humans:  Type I = mainly autoimmune disorder destroying -cells  Type II = insulin receptor or signal transduction defect