生物化学资料：UNIT V：Integration of Metabolism

1、UNIT V：Integration of Metabolism,What is the Integration of Metabolism,Integration of metabolism is the metabolism in the context of the entire organism-coordination of metabolic activities Our bodies are an integrated system of organs. Requirements for nourishment and energy utilization. The blood

2、levels of ions, lipids and sugars These restrictions are valid at rest, while we work and after meals,Interrelations among the Metabolic Pathways,1. Compartmentation 2. Metabolic specializations of organs 3. Enzymes Control of enzyme levels Enzyme protein synthesis and degradation Control of enzyme

3、activity Allosteric Interactions; Covalent modifications 4. Distributive control of metabolism 5. Hormonal regulation of body mass,How do our body realize the integration of metabolism,Allosteric Interactions Covalent modifications,Key enzymes (rate limiting enzyme ) catalyzing committed steps in un

4、idirectional anabolic and catabolic pathways, which act as natural governors of metabolic flow and represent the most efficient regulatory intervention,Examples of key regulatory enzymes,the following are plainly important: glycogen synthase / glycogen phosphorylase; phosphofructokinase / fructose b

5、isphosphatase; pyruvate kinase / PEPCK; pyruvate dehydrogenase; pyruvate carboxylase; glutamate dehydrogenase; Triglyceride lipase(hormone-sensitive lipase，HSL), carnitine acyltransferase I (CAT-I)；acetyl CoA carboxylase; HMG CoA reductase; HMG CoA synthase,Distributive Control of Metabolism,1. ATP/

6、ADP are the universal regulators: 2. ATP is the universal currency of energy and generated by the oxidation of fuel molecules such as glucose, fatty acids and amino acids: 3. NAD+ is the cofactor for most dehydrogenases that oxidize metabolites. 4. NADPH is the major electron donor in reductive bios

7、ynthesis,Neuronal and hormonal signaling,Integration of Metabolism is Very Important to Our Healthy,Integration of metabolism is essential on both short-term and long-term bases. The most crucial short-term element is maintenance of a stable blood glucose level. Integration of metabolism is importan

8、t on a long-term basis too. Glucose is toxic! Diabetes Mellitus Obesity Nutrition Vitamins,Chapter 23 Metabolic Effects of Insulin and Glucagon Chapter 24 The Feed/Fast Cycle Chapter 25 Diabetes Mellitus Chapter 26 Obesity Chapter 27 Nutrition Chapter 28 Vitamins,Contents in UNIT V,Chapter 23 Metabo

9、lic Effects of Insulin and Glucagon,Students Should Gain a Mastery of】 1. regulation of insulin secretion 2. metabolic effects of insulin 3. mechanism of insulin action 4. the stimulation and inhibition of glucagon secretion 5. the mechanism of action of glucagon. 6. metabolic effects of glucagon 【S

10、tudents Should Gain a Familiarity with】 1. symptoms of hypoglycemia 2. glucoregulatory systems such as epinephrine，cortisol and growth hormone 3. synthesis of insulin,OBJECTIVE AND REQUIREMENT,the human body functions are as one community. The four major organs play a dominant role in fuel metabolis

11、m： liver, adipose tissue, muscle and brain. The integration of metabolism is controlled primarily by the action of hormones, including insulin, glucagon and catecholamines (epinephrine and nor epinephrine,I. Overview,II. Insulin,Insulin is a polypeptide hormone produced by the -cells of the islets o

12、f Langerhans of the pancreas. Insulin is one of the most important hormones coordinating the utilization of fuels by tissues. Its metabolic effects are anabolic stimulating the synthesis of glycogen (glycogensis), triacylglycerols (lipogenesis) and protein,Endocrine tissue / islets of Langerhans: wh

13、ich are scattered throughout the exocrine pancreas,Mature pancreas,A human pancreas contains 1 million islets. -Islets (50-500m diameter) contain 24 thousand cells,Islets of Langerhans: 13% of pancreas (by mass,A. Structure of Insulin,Insulin is a highly conserved (similar among species) 51 amino ac

14、id peptide,24aa,110aa,21 + 30aa,Insulin molecules have a tendency to form dimers in solution due to hydrogen-bonding between the C-termini of B chains. Additionally, in the presence of zinc ions, insulin dimers associate into hexamers,B. Synthesis of Insulin,preproinsulin,proinsulin,insulin,C-peptid

15、e,secreted in equimolar amounts A marker of insulin secretion from- cells in the diabetic patients Biological action is not clear,C. Regulation of insulin secretion,1. Stimulation of insulin secretion,a)Glucose: the most important stimulus for insulin secretion. b)Amino Acids: elevated plasma argini

16、ne is a particularly potent stimulus for insulin secretion c)Gastrointestinal hormones(GIP,GLP-1): They stimulate insulin secretion after the ingestion of the food. They cause an anticipatory rise in insulin secretion,Note: The same amount of glucose given orally stimulates more insulin secretion th

17、an if given intravenously,Insulin secretion in beta cells is triggered by rising blood glucose levels,2. Inhibition of insulin secretion,The synthesis and release of insulin are decreased during starvation and stress. These effects are mediated by epinephrine which is secreted by the adrenal medulla

18、 in response to stress, trauma or extreme exercise,Gastric Inhibitory Peptide (GIP,Glucagon-Like Peptides (GLP-1,D. Metabolic effects of insulin,1. Effects on carbohydrate metabolism,Insulin is the only hypoglycemic hormone. Insulin increases glucose oxidation and utilization by tissues The effects

19、of insulin on glucose metabolism are most prominent in three tissues: liver, muscle and adipose tissue. Insulin mediates glucose into these tissues and increases glucose uptake by increasing number of glucose transporters (GLUT) in the cell membrane,A) insulin increases the synthesis of GLUT1 and GL

20、UT4. (B) insulin increases the insertion of GLUT1 and GLUT4 into the plasma membrane In some tissues, glucose uptake is insulin-independent: liver,brain,cornea,erythrocytes In liver, inhibits gluconeogenesis and glycogen breakdown In muscle and liver, increases glycogen synthesis,Insulin switches ON

21、 glycogen synthetase (GS,GS,GS,Active,Inactive,ATP,ADP,Phosphoprotein phosphatase,cAMP- INDEPENDENT kinase,Insulin,Insulin,GSK3,2. Effects on Lipid Metabolism,Insulin decreases the release of fatty acids from adipose tissue by: a) Decrease in triglycerol degradation: Insulin inhibits the activity of

22、 hormone- sensitive lipase in adipose tissue. b) Increase triglycerol synthesis: Insulin increases the transport and metabolism of glucose into adipocytes, providing glycerol 3- phosphate for triglycerol synthesis. Insulin also increases lipoprotein lipase activity of adipose tissue by increasing th

23、e enzyme synthesis, providing fatty acids for esterification,Insulin switches ONacetly-CoA carobxylase,Acetyl-CoA carboxylase,Active,Inactive,ATP,ADP,Phosphoprotein phosphatase,Acetyl-CoA carboxylase,cAMP- INDEPENDENT kinase,Insulin,Insulin,LEC1-31,3. Effects on protein synthesis,Amino acid metaboli

24、sm: Insulin stimulates entry of amino acids in most tissues Insulin increases protein synthesis in most tissues,E. Mechanism of insulin action,Insulin binds to specific, high-affinity receptors in the cell membrane of most tissues, including liver, muscle and adipose. This is the first step in a cas

25、cade of reactions leading to many biological actions,1. Insulin receptors,Insulin receptors exist in most tissues Consist of and subunits assembled into a tetramer, intrinsic receptor with tyrosine kinases (RTKs) , transduce signals to the interior of cells,The subunit is autophos-phorylated on Tyr

26、(tyrosine kinase) It then phosphorylates other proteins (e.g., IRS, which then activates other protein kinases and phosphatases) Dephosphorylation of receptors inactivates them,2. Signal transduction,Activated receptor TyrK phosphorylates Tyr residues on Insulin Receptor Substrate (IRS)-1 and IRS-2,

27、IRS-1/IRS-2 act as adapter proteins - phospho-tyrosine residues interact with src-homology (SH)2 domains in downstream signalling proteins,PI3K (inserts GLUT4*) + ( PKB GSK3,Grb2 ( SOS ras MAPKK MAPK,Inhibitors of insulin signalling are potential targets for the development of drugs for diabetes,3.

28、Membrane effects of Insulin,Glucose transport in many tissues, such as skeletal muscle and adipocytes, increases in the presence of insulin. Insulin stimulates the recruitment of glucose transporters (GLUT-4) from a pool present in intracellular vesicles,The tissues have different responses to insul

29、in,4. Receptor regulation,Elevated levels of insulin increase the degradation of receptors, thus decreasing the number of surface receptors. This is one type of down regulation,Insulin-receptor complexes are internalized; receptors are recycled, while insulin is degraded in lysosomes,5. Time course

30、of insulin actions,After insulin binding to the receptors the responses will be: a) Increase glucose transport (seconds). b) Change in enzyme activity (change in phosphorylation states) minutes to hours c) Increase in the amount of enzymes e, g glucokinase, phosphofructokinase, and pyruvate kinase (

31、hours to days) this means increase protein synthesis,III. Glucagons,The amino acid sequence of glucagon is the same in all mammalian species. Epinephrine, glucagon, cortisol, and growth hormone are anti-insulin (counter regulatory) hormones,A. Stimulation of glucagon secretion,1. Low blood glucose:

32、hypoglycemia is the primary stimulus for glucagon secretion. 2. Amino acids: stimulate the secretion of both glucagon and insulin. 3. Epinephrine and norepinephrine: stimulate glucagon secretion (during stress, severe exercise,B. Inhibition of glucagon secretion,Glucagon secretion is markedly decrea

33、sed by elevated blood sugar and by insulin,C. Metabolic effects of glucagons,1. Effects on carbohydrate metabolism,Glucagon switches OFF glycogen synthetase (GS,GS,GS,Active,Inactive,ATP,ADP,Phosphoprotein phosphatase,cAMP- dependent kinase,Glucagon,Glycogen phosphorylase a,Glucagon,LEC1-25,2. Effec

34、ts on lipid metabolism: Glucagon stimulates hepatic oxidation of fatty acids and formation of ketone bodies. The lipolytic effect of glucagon in adipose tissue is minimal in humans,Glucagon - CATABOLIC - stimulates net breakdown of TAG stores (spares glucose,inactivates acteyl-CoA carboxylase,activa

35、tes hormone-sensitive lipase (HSL,Glucagon switches OFF acetly-CoA carobxylase,Acetyl-CoA carboxylase,Active,Inactive,ATP,ADP,Phosphoprotein phosphatase,cAMP- dependent kinase,Glucagon,Acetyl-CoA carboxylase,LEC1-30,Glucagon together with cortisol, epinephrine, and norepi-nephrine, they opposes the

36、actions of insulin,3. Effects on protein metabolism: Glucagon increases the uptake of amino acids by the liver for gluconeogenesis,D. Mechanism of action of glucagons,Endocrine Regulation of Metabolism,IV. Hypoglycemia,Hypoglycemia is low blood glucose (4.5 mmol/L; 40 mg/dL or less) Abrupt glucose f

37、all causes adrenergic hormone to secretion Brain is critically dependent on glucose The decrease glucose cause brain dysfunction (neuroglycopenia,Normal level of blood glucose is maintained near 4.5-5.5 mmol/L,A. Symptoms of hypoglycemia,The symptoms of hypoglycemia can be divided to two groups, 1.

38、Adrenergic symptoms: Anxiety, palpitation, tremor, and sweat. These symptoms occur when the blood glucose levels fall rapidly. 2. Neuroglypenic Symptoms: The decrease glucose supply to the brain leads to brain dysfunction causing headache, confusion, slurred speech, seizures, coma and death. These s

39、ymptoms result from a gradual decrease in blood glucose,B. Glucoregulatory systems -Responses to hypoglycemia,Humans have two overlapping glucose-regulating systems that are activated by hypoglycemia: 1) Glucagon and epinephrine (the secretion through the autonomic nervous system) 2) Cortisol and gr

40、owth hormone the secretion of ACTH and growth hormone (GH) by the anterior pituitary gland. Short term control glucagon and epinephrine Long term cortisol and growth hormone,C. Types of hypoglycemia,a) insulin-induced b) postprandial c) fasting d) alcohol intoxication Alcohol intoxication results in

41、 large increase in NADH and diversion of gluconeogenesis intermediates (pyruvate and oxaloacetate) which can cause hypoglycemia,1. Insulin induced hypoglycemia,Hypoglycemia occurs frequently in patients with diabetes receiving insulin treatment. Mild hypoglycemia in fully conscious patients is treat

42、ed by oral administration of carbohydrate. More commonly, patients with hypoglycemia are unconscious or have lost the ability to coordinate swallowing. In these cases, glucagon, administered subcutaneously or intramuscularly, is the treatment of choice,2. Postprandial hypoglycemia: This is the secon

43、d most common of the form of hypoglycemia. It is caused by an exaggerated insulin release following a meal, causing a transient hypoglycemia with mild adrenergic symptoms. The blood glucose level returns to normal even if the patient is not fed. The only treatment usually needed is that the patient

44、eat frequent small meals instead of the usual three large meals,3. Fasting hypoglycemia: It is rare and produces neuroglycopenic symptoms. It may be due to: reduction in the rate of glucose production by the liver as in patients with hepatocellular damage or adrenal insufficiency or in fasting perso

45、ns who have consumed large quantities of ethanol which inhibits gluconeogenesis,4. Hypoglycemia and alcohol intoxication,Alcohol metabolized in the liver by two oxidation reactions Ethanol is first converted to acetaldehyde by alcohol dehydrogenase Acetaldehyde is subsequently oxidized to acetate by

46、 aldehyde debydroqenase In each reaction，electrons are transferred to NAD+，resulting in a massive increase in the concentration Of Cytosolic NADH,V. Chapter summary,Chapter 25 Diabetes Mellitus Hyperglycemia,Hyperglycemia,Hyperglycemia,Excessive glucose production,Impaired glucose clearance,Tissue i

47、njury,Normal levels are about 5mM (90mg/dl,Kidney begins excreting urine at about 10mM,5.5mM,What is diabetes mellitus,A chronic condition associated with abnormally high blood sugar Results from either deficiency of or a resistance to insulin,Diabetes Mellitus,The term diabetes came from Greek word

48、s meaning siphon or run through. It means “excessive secretion of sweet urine”. Mellitus “Honey” (1604,Diabetes mellitus Symptoms,HYPERGLYCEMIA: fluid/electrolyte imbalance. Polyuria Sodium, chloride, potassium excreted Polydipsia from dehydration Polyphagia: cells are starving, so person feels hung

49、ry despite eating huge amounts of food. excessive secretion of urine, thirst, weight loss, and tiredness Long Term: Renal Failure, Coma,Very common - nearly 6% of the US population suffers from some form of Diabetes 3rd leading cause of death; leading cause of blindness,Types of Diabetes Mellitus,Co

50、nsists of 3 types: 1) Type 1 diabetes insulin dependent Diabetes Mellitus (IDDM) ; juvenile on set. diabetes patients whose body produces no insulin. 2) Type 2 diabetes non-insulin dependant Diabetes Mellitus (NIDDM) ; adult on set diabetes. diabetes patients that do not always produce enough insuli

51、n. 3) Gestational diabetes,Type 1 Diabetes,Is less common than Type 2. Here the pancrease gradually loses its ability to synthesize insulin. Thought to be an autoimmune disorder，Lab tests can detect antibodies to insulin. Unfortunately, most people are diagnosed after the damage is already done and

52、insulin must be supplied,Type 2 diabetes,Risk factors: genetics (multigenic) obesity (see Metabolic Syndrome) lifestyle (diet, lack of exercise,Gestational diabetes,Certain placental hormones, such as human placental lactogen (HPL), cortisol & estrogen, oppose the action of insulin and can lead to d

53、iabetes during pregnancy 30-50% of women experiencing gestational diabetes go on to develop type 2 diabetes within 10 to 15 years,Metabolic changes in diabetes,Hyperglycemia due to low peripheral utilization of glucose and excessive gluconeogenesis Ketoacidosis due to excessive FA mobilization and production of ketone bodies Hypertriglyceridemia High FA leads to high VLDL and Lipoprotein lipase decreased Amino acids uptake and protein synthesis decreased,Complications,Diabetic retinopathy: a leading cause of blind