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Transcript
Hormones affect glucose levels ¾ Insulin ¾ Glucagon ¾ Epinephrine ¾ Norepinephrine ¾ Cortisol ¾ Growth hormone ¾ GIP Blood sugar homeostasis ¾NO Or Hypoglycemia Hyperglycemia Endocrine Pancreas • The pancreas is both an endocrine and an exocrine gland • Houses the islets of Langerhans – Secretion of glucagon and insulin – Cells • • • • Alpha—glucagon Beta—insulin Delta—somatostatin and gastrin F cells—pancreatic polypeptide Endocrine Pancreas Endocrine Pancreas • Insulin – Synthesized from proinsulin – Secretion is promoted by increased blood glucose levels – Facilitates the rate of glucose uptake into the cells of the body – Anabolic hormone • Synthesis of proteins, lipids, and nucleic acids Endocrine Pancreas • Glucagon • Secretion is promoted by decreased blood glucose levels – Stimulates glycogenolysis, gluconeogenesis, and lipolysis • Somatostatin – Possible involvement in regulating alpha and beta cell secretions C peptide Proinsulin Ca2+-dependent endopeptidases PC2 (PC3) Insulin MW 5808 A Chain B Chain PC3 Insulin metabolism • Secreted into portal circulation • 50% of degradation in liver • 50% of degradation in other target tissues and kidney • Enzymatic degradation follows receptormediated endocytosis • Plasma half-life: 3 - 5 min. – Circulates as free monomer – Distribution volume approximates that of the extracellular fluid Effects of insulin: molecular & cellular Metabolic and mitogenic Regulation of glucose transport and metabolism Regulation of lipid metabolism Regulation of transcription of other genes Regulation of insulin secretion Na+ GLUT2 K+ KIR K+ Na+ K+ Vm K+ - Ca2+ Ca2+ Pancreatic ß cell Ca2+ Ca2+ Insulin granules Voltage-gated Ca2+ channel Basal insulin secretion Pacemaker ß cells Na+ GLUT2 K+ KIR K+ Na+ Signal K+ Vm K+ Ca2+ Ca2+ Pancreatic ß cell Ca2+ Ca2+ Insulin granules Voltage-gated Ca2+ channel Glucose-stimulated insulin secretion ß cell integrates input from various metabolites, Glucose hormones and Na+ GLUT2 Glucokinase Km= 7-9 mM KIR K+ Na+ - K+ ATP Pancreatic ß cell neurotransmitters K+ Vm K+ Ca2+ Ca2+ IP3 cAMP Insulin granules Ca2+ Ca2+ Voltage-gated Ca2+ channel Insulin : mechanism of action Cell-surface receptors: α subunits contain insulin binding sites plasma membrane β subunits have tyrosine kinase activity Insulin receptor signaling Insulin binding to α subunit regulates β subunit activity Insulin GLUT4 autophosphorylation of β subunit PO4 IRS-1 + ATP IRS-1PO4 GLUT4 ⇑ tyr kinase activity phosphorylation of other substrates activation of phosphoinositide 3-kinase Glucose transporter translocation to plasma membrane Insulin receptor signaling Insulin binding to α subunit regulates β subunit activity Insulin GLUT4 autophosphorylation of β subunit ⇑ tyr kinase activity phosphorylation of other substrates phosphorylation of MAP kinase PO4 IRS-1 + ATP IRS-1PO4 e.g. ↑GLUT expression MAPK MAPKPO4 + ATP Transcriptional regulation Protein synthesis, proliferation & differentiation Insulin receptor signaling Insulin binding to α subunit regulates β subunit activity Insulin GLUT4 autophosphorylation of β subunit PO4 IRS-1 + ATP IRS-1PO4 Glycogen deposition ⇓+ ⇑ tyr kinase activity phosphorylation of other substrates phosphorylation of MAP kinase protein phosphatase-1 ⇓+ glycoge n synthas e ⇓- phosphoryla se kinase ⇓- phosphorylas e Effects of insulin: Liver Stimulates Inhibits glycogen synthesis glycogenolysis triglyceride synthesis ketogenesis gluconeogenesis Skeletal Muscle glucose uptake protein synthesis glycogen synthesis Adipose protein degradation glycogenolysis tissue glucose uptake triglyceride storage Promotes anabolic processes lipolysis Inhibits catabolic processes Abnormalities due to insulin deficiency • Hyperglycemia – Underutilization of glucose – Overproduction of glucose • Increased lipolysis • Acidosis - Increased conversion of fatty acids to ketoacids (acetoacetic and β-hydroxybutyric) • Increased plasma triglycerides and LDL; decreased HDL • Osmotic diuresis, plasma hyperosmolarity, dehydration, hypovolemia, polydipsia • Depletion of intracellular and whole-body K+ Endocrine Pancreas Actions of Insulin (anabolic hormone/hormone of feasting) • Insulin affects Liver. Muscle, Adipose • Increases glucose uptake in all cells EXCEPT: CNS, RBCs, Kidney tubules, intestinal mucosa, B-cells of Pancreas Effects of Insulin on Carb. metabolism • Insulin lowers blood glucose A. Increase uptake of glucose most tissues especially muscle and fat by increasing transporters (GLUT 4) Increases uptake of glucose but not by increasing cellular transporters (GLUT 2) but by promoting conversion of glucose to glycogen(mass action) glucoseÆglycogen Insulin lowers blood glucose (cont’d) • Increasing glycogen synthesis in liver and muscle • Glucose utilization – Insulin promotes glycogenesis and also promotes glucose utilization glucose break down Ågluc.Æ glycogen synth. Insulin on Protein metabolism • Increases Amino Acid uptake by muscle cells • Increases protein synthesis and decreases protein breakdown Insulin on fat metabolism Insulin increases: 1. Glucose uptake by fat cells 2. Triglyceride uptake by fat cells (increase endothelium capillary bound lipoprotein lipases – clears fat from the blood) 3. Lipogenesis (triglyceride synthesis) Effects of Insulin on Fat metabolism Insulin decreases: Triglyceride breakdown in adipose tissue by decreasing the activity of hormone sensitive lipase Insulin and C-peptide • Beta Cells make and secrete Pre-pro-insulin cleaved Pro-insulin cleaved Insulin C-peptide* * Measures endogenous insulin secretion when exogenously administered insulin interferes with measurement Insulin Increases activity of Na+/K+ pump • Glucose is taken up and broken down to make ATP • Excess ATP is present and therefore activity of Na+/K+ ATPase is enhanced In Diabetes Mellitus as K+ moves out of cells H+ Moves in • When Insulin is deficient there is a net efflux K+ from the cell. • Usually [Plasma K+] does not rise because excess K+ is lost in the urine (this occurs bc the glucose in the tubules that cannot be reabsorbed due to exceeding its Tm acts as a diuretic and pulls water and K+ down with it) this osmotic diuresis depletes the body stores of K+) In Diabetes Mellitus as K+ moves out of cells H+ Moves in (cont’d) • With low Insulin you also have a deficiency in Na+/K+ activity which allows more Na+ to enter cells Na+ Na+ H+ K+ • As Na+ increases the Na/H countertransporter runs less efficiently causing [intracellular H+] to increase Things that stimulate and inhibit the Insulin secreting Beta Cell Stimulation of insulin secretion Glucose Amino Acids Intestinal Hormones Glucagon Parasympathetic innervation (Ach) Inhibition of insulin secretion Somatostatin (Delta-Cell) Sympathetic innervation (Epi and NorEpi) GIP Intestinal Hormone • Promotes Insulin secretion • Oral dose of glucose evokes more insulin secretion than does the same dose of glucose administered intravenously Mechanism • You eat foodÆ broken down to glucose • Glucose in intestine causes release of GIP • Glucose and GIP BOTH act on B-cells to increase insulin secretion Glucose’s effect on Insulin secretion 5 easy steps 1. Glucose goes into B-Cell and is broken down into ATP 2. High [ATP] closes ATP regulated K+ channels on cell membrane 3. Decreased K+ conductance causes cell membrane to partially depolarize (its true, try it with the Nernst Eqn.) 4. Slight depolarization causes V-gated Ca++ channels to open (on cell membrane and intracellular stores) Glucose’s effect on Insulin secretion step by step 5.Increase in Ca++ causes microtubules to contract which moves insulin vesicles to the cell surface for dumping Supporting this theory: 1. Hyperpolarization diminishes secretion of insulin 2. Certain hypoglycemic agents promote insulin secretion by decreasing K+ conductance Exercise • Exercise means high sympathetic stimulation which means low insulin secretion (see previous slide) • You would expect that with exercise not as much glucose would enter the cell due to low insulin levels…but this is not the case! • With exercise you have a high rate of glucose utilization thus there is a favorable [gradient] that promotes glucose uptake in spite of low insulin levels Glucagon The hormone of fasting • • • • • Increases liver glycogenesis Increases liver gluconeogenesis Decreases lipogenesis Increases ureagenesis Increases insulin-secretion – paracrine action (prevents severe ketoacidosis) How does Glucagon increase ureagenesis? • Glucagon increases the production of glucose from pyruvate • Therefore glucagon indirectly stimulates the transamination of alanine to pyruvate • The amine group is eliminated as urea (Pay attention to the “left” liver cell) Glucagon Control of Glucagon Secretion Alpha Cell Stimuli which promote glucagon secretion Hypoglycemia Amino Acids (arginine and lysine) Parasympathetic Sympathetic CCK Stimuli which inhibit glucagon secretion Hyperglycemia Insulin Somatostatin Hypoglycemia • Hypoglycemia has a direct action on the alpha cell • Hypoglycemia also stimulates the CNS to increase discharge of Symp. And Parasymp. Neurons • Alpha cell has adrenergic and cholinergic receptors that when occupied increase glucagon secretion Increased Glucagon secretion with ingestion of a protein rich meal Due to: 1. Direct action of amino acids on the alpha cell 2. Stimulatory action of CCK on alpha cell **Peptides in duodenum stimulate CCK secretion Metabolism III.Hormonal regulation of nutrient metabolism 1) Insulin (β-cells of the endocrine pancreas) Functions • Kglucose uptake in muscle and adipose tissue • Kglucose uptake in liver (indirectly) • Kglycogenesis in muscle and liver • Lglycogenolysis • Lgluconeogenesis • Kuptake of fatty acids and triglycerides by adipocytes • Klipogenesis (from glucose) and Llipolysis • Lketone bodies • K uptake of amino acids by muscle and liver • Kprotein synthesis and L protein degradation Insulin promotes insertion of GLUT 4 in adipocytes and muscle cells Insulin promotes glucose uptake by stimulating hexokinase activity Metabolism Factors influencing insulin secretion • • • • • Kblood glucoseJKinsulin secretion, Lglucagon Kamino acids in bloodJKinsulin secretion Kfatty acidsJKinsulin secretion, Lglucagon Kparasympathetic activityJKinsulin secretion Ksympathetic activityJLinsulin secretion Kglucagon secretion • KGIP(gastric-inhibiting peptide)JKinsulin secretion • Kglucagon-like peptide 1 (GLP-1)JKinsulin secretion Regulation of insulin secretion Blood glucose concentration Gastrointestinal hormones Blood amino acid concentration Major control Food intake Parasympathetic stimulation Islet b cells Insulin secretion Blood glucose Blood fatty acids Blood amino acids Protein synthesis Fuel storage Sympathetic stimulation (and epinephrine) Insulin predominates in the fed-state Metabolism 2) Glucagon (α cells of endocrine pancreas) Functions: • • • • • • Kblood glucose Lglycogenesis and Kglycogenolysis Kgluconeogenesis in liver cells Llipogenesis and Klipolysis Kketone production little effect on muscle protein Metabolism Factors influencing glucagon secretion • Low blood glucoseJKglucagon secretion, Linsulin • High blood glucoseJLglucagon secretion • Laa in bloodJKglucagon secretion • Sympathetic stimulation Glucagon predominates in the fasted state (Silverthorn, 21-18) Hormone and nutrient levels before and after a meal in humans High-carbohydrate meal High-protein meal Metabolism 3) Epinephrine (adrenal medulla) Functions: • Reinforces sympathetic nervous system during stress and exercise • Mobilization of stored carbohydrates and fat to provide energy for muscular work • Increases blood glucose by K hepatic gluconeogenesis and K glycogenolysis in liver and muscle • Linsulin secretion, Kglucagon and K ACTH secretion • Klipolysis Hypothalamus and posterior pituitary Hypothalamus and anterior pituitary Anterior pituitary hormones Metabolism 4) Glucocorticoids (adrenal cortex) Functions of cortisol: • • • • • • • Main stimulus for secretion is stress Increases blood glucose concentration at the expense of protein and fat stores Khepatic gluconeogenesis and Kglycogenolysis Lglucose uptake in many tissues (except brain) Kprotein degradation to form free amino acids Klipolysis in adipose tissue Immunosuppressive effects Metabolism Factors influencing cortisol secretion • CRH (corticotropin-releasing hormone) is stimulated to release in response to stress (physical, chemical, physiological, psychological) and • CRH secretion under circadian control (Ksecretion in morning, Lnight) • CRH stimulates secretion of ACTH (adrenocorticotropic hormone) from the anterior pituitary • ACTH stimulates cortisol secretion from the adrenal cortex Regulation of cortisol secretion (Silverthorn, Fig. 21-21) Metabolism 5) Growth hormone (somatotropin) Synthesized and secreted by the anterior pituitary Secretion under circadian control Stimulates insulin-like growth factors (IGFs) from liver and other tissues Secreted in adults and has metabolic effects unrelated to growth Metabolism Functions of GH • • • • Stimulates IGF secretion Kprotein synthesis and growth Kuptake of amino acids by liver and muscle Klipolysis in adipose tissueJKfatty acids in blood • Lglucose uptake by muscleJKblood glucose Metabolism Factors influencing GH secretion • • • • Kamino acids in bloodJKGH secretion Lfatty acids in bloodJKGH secretion Lblood glucoseJKGH secretion Deep sleep, exercise, stress and hypoglycemia influence GH secretion • Growth hormone-releasing hormone (GHRH) stimulates GH secretion • Somatostatin inhibits GH secretion Growth hormone pathway Metabolism 6) Thyroid hormone (follicular cells of thyroid) Two iodine-containing hormones Tetraiodothyronine (T4 or thyroxine) and triiodothyronine (T3) T4 + T3 = thyroid hormones TH synthesis takes place on thyroglobulin molecules in colloid T4 is converted to T3 at liver, kidneys, heart Metabolism Functions of TH • • • • • • TH is primary determinant of MR KBMR (calorigenic effect) Thermogenic Kheart rate KGH secretion Essential for development and normal functioning of the nervous system • Concentration-dependent effects on protein, carbohydrates and fat metabolism • Modulates the effects of other hormones by exerting a “permissive action” Metabolism Factors influencing TH secretion • Thyrotropin-releasing hormone (TRH) is tonically secreted • Neuronal stimuli (e.g. stress or exposure to cold) stimulates release of TRH from the hypothalamus • TRH stimulates release of thyroid-stimulating hormone (TSH) from the anterior pituitary • TSH in turn stimulates the release of thyroid hormones (T4 and T3) • THs exerts a negative feedback on their own production Regulation of TH secretion Neuronal stimuli (stress, skin temp) -Secreted T4 : T3 (20:1) - T3 is 5X more potent than T4 (Fig. 21-28, Silverthorn) T4 converted to T3 at the kidneys, liver and heart
