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Pathophysiology • JP Advis DVM, Ph.D. Bartlett Hall, Animal Sciences, Cook, 932 - 9240, [email protected] 23 • Course website: rci.rutgers.edu/~advis • Lectures, tests, grades, office hours, textbook, Lectures 1-2: Introduction to Pathophysiology (2) Lectures 3-4: Mechanisms of Self-Defense and Stress (2) Lectures 5-8: Endocrine and Nervous System Dysfunctions (4) Lecture 9: Alterations of Skeletal Muscle Function (1) REVIEW AND TEST #1 Lectures 12-18: Cardiovascular, Respiratory and Renal Dysfunctions (7) REVIEW AND TEST #2 Lectures 21-24: Alterations of Digestive Function and Intermediary Metabolism (4) Lectures 25-26: Alterations of the Reproductive System (2) REVIEW AND TEST #3 • Material to be covered: • About lecture slides: • • • • There are not intended to be the sole source for studying the course material !!!!!!!!!!!!!!!! Slides are good to review the course material after you have study your course textbook Slides are a good indicator of the relative importance of lecture topics (see slide # per topic Group slides by titles when using them to review course material. Match lectures and text. Introduction Structure / Function pancreatic insulin and glucagon, adrenal cortisol, GH axis and GH abuse Metabolic syndrome insulin resistance, compensatory hyperinsulinemia, DM and vascular diseases Diabetes and Obesity risk factor & consequences, hormonesrelated to their complications Link to other diseases metabolic syndrome, coronary heart disease, diabetes mellitus type 2, polycystic ovarian syndrome Page 1 Introduction Structure / Function pancreatic insulin and glucagon, adrenal cortisol, GH axis and GH abuse Metabolic syndrome insulin resistance, compensatory hyperinsulinemia, DM and vascular diseases Diabetes and Obesity risk factor & consequences, hormonesrelated to their complications Link to other diseases metabolic syndrome, coronary heart disease, diabetes mellitus type 2, polycystic ovarian syndrome Page 2 Introduction Structure / Function pancreatic insulin and glucagon, adrenal cortisol, GH axis and GH abuse Metabolic syndrome insulin resistance, compensatory hyperinsulinemia, DM and vascular diseases Diabetes and Obesity risk factor & consequences, hormonesrelated to their complications Link to other diseases metabolic syndrome, coronary heart disease, diabetes mellitus type 2, polycystic ovarian syndrome Page 3 Introduction Structure / Function pancreatic insulin and glucagon, adrenal cortisol, GH axis and GH abuse glycogen phosphorilase insulin resistance, compensatory hyperinsulinemia, DM and vascular diseases glucose G-6-P F - 1,6 -diP F-1,6-diPase triose glucose PFK insulin glucagon epinephrin cortisol pyruvate transaminases acetyl CoA amino acids Link to other diseases metabolic syndrome, coronary heart disease, diabetes mellitus type 2, polycystic ovarian syndrome hexokinase F-6-P Diabetes and Obesity risk factor & consequences, hormonesrelated to their complications glycogen synthetase G-1-P G-6-Pase Metabolic syndrome glycogen proteins Page 4 Krebs cycle fats Glycogen glycogen phosphorilase glycogen synthetase G-1-P G-6-Pase hexokinase G-6–P glucose glucose F-6-P F - 1,6 -diP F-1,6-diPase PFK triose insulin glucagon epinephrine cortisol pyruvate transaminases acetyl CoA amino acids proteins Krebs cycle Introduction Structure / Function pancreatic insulin and glucagon, adrenal cortisol, GH axis and GH abuse Metabolic syndrome insulin resistance, compensatory hyperinsulinemia, DM and vascular diseases Diabetes and Obesity risk factor & consequences, hormonesrelated to their complications Link to other diseases metabolic syndrome, coronary heart disease, diabetes mellitus type 2, polycystic ovarian syndrome Page 5 fats Introduction Structure / Function pancreatic insulin and glucagon, adrenal cortisol, GH axis and GH abuse Metabolic syndrome insulin resistance, compensatory hyperinsulinemia, DM and vascular diseases Diabetes and Obesity risk factor & consequences, hormonesrelated to their complications Link to other diseases metabolic syndrome, coronary heart disease, diabetes mellitus type 2, polycystic ovarian syndrome Page 6 Metabolic syndrome Structure / Function pancreatic insulin and glucagon, adrenal cortisol, GH axis and GH abuse Metabolic syndrome insulin resistance, compensatory hyperinsulinemia, DM and vascular diseases Diabetes and Obesity risk factor & consequences, hormonesrelated to their complications Link to other diseases metabolic syndrome, coronary heart disease, diabetes mellitus type 2, polycystic ovarian syndrome A state of metabolic dysregulation characterized by insulin resistance, hyperinsulinemia and a predisposition to type 2 diabetes, atherosclerosis, vascular disease, hypertension and many other disorders, including Alzheimer’s disease and certain cancers. Affected individuals are obese or show subtle manifestation of increase adiposity (abdominal fat, fat cell size), decrease capacity of exercise and evidence of low grade inflammation and pro-coagulant state. Type 2 diabetes develops when they are no longer able to sustain the high insulin levels required for normal glucose homeostasis. Clinically, it is diagnosed on the basis of abnormalities in plasma glucose and lipids, and increases in blood pressure and waist circumference, which independently might not be sufficient to lead to therapeutic intervention. Its importance is that: 1) antedates the multiple disorders with which it is associated; 2) it might be a target for therapeutic intervention, and 3) it is extremely common (50 millions in the USA alone). Page 7 Metabolic dysfunctions Structure / Function obesity, overnutrition, diet genetics inactivity pancreatic insulin and glucagon, adrenal cortisol, GH axis and GH abuse metabolic dysregulation (peripheral, CNS) Metabolic syndrome insulin resistance, compensatory hyperinsulinemia, DM and vascular diseases Diabetes and Obesity risk factor & consequences, hormonesrelated to their complications diabetes hypertension insulin resistance hyperinsulinemia ectopic lipid certain cancers Alzheimer Link to other diseases proinflammatory and procoagulant states metabolic syndrome, coronary heart disease, diabetes mellitus type 2, polycystic ovarian syndrome atherosclerosis dyspipidemia non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, polycyctic ovarian syndrome Metabolic dysfunctions Structure / Function pancreatic insulin and glucagon, adrenal cortisol, GH axis and GH abuse Metabolic syndrome insulin resistance, compensatory hyperinsulinemia, DM and vascular diseases Diabetes and Obesity risk factor & consequences, hormonesrelated to their complications Link to other diseases metabolic syndrome, coronary heart disease, diabetes mellitus type 2, polycystic ovarian syndrome The presence of insulin resistance in otherwise normal offspring of people with type 2 diabetes, hypertriglyceridemias, and hypertension has led to the notion that is a causal factor for metabolic syndrome or an early pathogenic event. According to this idea, insulin resistance affects a number of organs (muscle, liver, adipose), and hyperinsulinemia due to increase pancreatic secretion and decrease insulin degradation by the liver, is a compensatory phenomenon. This idea is in agreement with observations that treatments increasing insulin sensitivity and lowering plasma insulin, such as life-style modification (diet and exercise) and treatment with metformin ot thiazolidinediones, prevent or delay the onset of diabetes in individuals with glucose intolerance, as well as the efficacy of these therapies in individuals with non-alcoholic fatty liver disease (NAFLD) and polycystic ovarian syndrome (PCOS). Insulin resistance and hyperinsulinemia in humans and animals have been linked to obesity and dysregulation of cellular lipid metabolism. FFA cause insulin resistance in muscle, but newly discovered hormones and intracellular regulators also do it. Page 8 Metabolic dysfunctions Structure / Function pancreatic insulin and glucagon, adrenal cortisol, GH axis and GH abuse Metabolic syndrome insulin resistance, compensatory hyperinsulinemia, DM and vascular diseases Diabetes and Obesity risk factor & consequences, hormonesrelated to their complications Link to other diseases metabolic syndrome, coronary heart disease, diabetes mellitus type 2, polycystic ovarian syndrome Page 9 Metabolic dysfunctions Structure / Function pancreatic insulin and glucagon, adrenal cortisol, GH axis and GH abuse obese adypocyte oxidation in mitochondria (1) FFA Metabolic syndrome insulin resistance, compensatory hyperinsulinemia, DM and vascular diseases FACoA dystrophic adypocyte risk factor & consequences, hormonesrelated to their complications (2) Link to other diseases metabolic syndrome, coronary heart disease, diabetes mellitus type 2, polycystic ovarian syndrome Malonyl-CoA (4) proinflammatory molecules Diabetes and Obesity (3) TG, ceramide DAG, PKC IKKB – NFkß JNK1 ROS ER stress cellular dysfunction Insulin resistance Pathogenesis of the metabolic syndrome-the lipid hypothesis: (1) Increased FFA and inflammatory cytokines (2) secondary to impaired tryglyceride storage an enhanced lipolysis in fat cell, (3) increased FACoA and inappropriately normal or decreased mitochondrial fatty acid oxidation in liver, muscle and other tissues due to increase malonyl CoA and other factors, and (4) increased estearification of FACoA to form triglicerides (TG), DAG and in some tissues ceramide. obese adipocyte oxidation in mitochondria (1) FFA (3) Malonyl-CoA FACoA dystrophic adipocyte (4) proinflammatory molecules (2) TG, ceramide DAG, PKC IKKB – NFkß JNK1 ROS ER stress cellular dysfunction Insulin resistance Pathogenesis of the metabolic syndrome-the lipid hypothesis: (1) Increased FFA and inflammatory cytokines (2) secondary to impaired tryglyceride storage an enhanced lipolysis in fat cell, (3) increased FACoA and inappropriately normal or decreased mitochondrial fatty acid oxidation in liver, muscle and other tissues due to increase malonyl CoA and other factors, and (4) increased estearification of FACoA to form triglicerides (TG), DAG and in some tissues ceramide. By mechanisms only partially understood, these abnormalities can in turn lead to activation of various PKC isoforms, ROS and endoplasmic reticulum stress, and the IJJB-NFkß system. Page 10 Metabolic dysfunctions Structure / Function pancreatic insulin and glucagon, adrenal cortisol, GH axis and GH abuse Metabolic syndrome insulin resistance, compensatory hyperinsulinemia, DM and vascular diseases Diabetes and Obesity risk factor & consequences, hormonesrelated to their complications CRITERIA FOR THE DIAGNOSIS OF METABOLIC SYNDROME (3 of the next 5 traits) 1.- increased waist circumference (>35 - 40 in, females-males). 2.- plasma triglycerides > 150 mg/dl. 3.- plasma HDL cholesterol (> 40 – 50 mg/dl, males – females). Link to other diseases metabolic syndrome, coronary heart disease, diabetes mellitus type 2, polycystic ovarian syndrome 4.- blood pressure > 130 / 85 mmHg. 5.- fasting plasma glucose > 100 mg/dl. Metabolic dysfunctions Structure / Function pancreatic insulin and glucagon, adrenal cortisol, GH axis and GH abuse Metabolic syndrome insulin resistance, compensatory hyperinsulinemia, DM and vascular diseases Diabetes and Obesity risk factor & consequences, hormonesrelated to their complications Link to other diseases metabolic syndrome, coronary heart disease, diabetes mellitus type 2, polycystic ovarian syndrome Pathophysiology of Diabetes Mellitus Page 11 Metabolic dysfunctions Structure / Function pancreatic insulin and glucagon, adrenal cortisol, GH axis and GH abuse Metabolic syndrome insulin resistance, compensatory hyperinsulinemia, DM and vascular diseases Diabetes and Obesity risk factor & consequences, hormonesrelated to their complications Link to other diseases metabolic syndrome, coronary heart disease, diabetes mellitus type 2, polycystic ovarian syndrome Some links among insulin resistance, diabetes, and obesity Page 12 Metabolic dysfunctions Structure / Function pancreatic insulin and glucagon, adrenal cortisol, GH axis and GH abuse Metabolic syndrome insulin resistance, compensatory hyperinsulinemia, DM and vascular diseases Diabetes and Obesity risk factor & consequences, hormonesrelated to their complications Link to other diseases metabolic syndrome, coronary heart disease, diabetes mellitus type 2, polycystic ovarian syndrome Amylin, also known as Islet Amyloid PolyPeptide (IAPP), is cosecreted with insulin in a 100:1 ratio by beta cells. It prevents post-prandial spikes in blood glucose levels. Amylin contributes to glycemic control by slowing the rate of appearance of glucose from a meal by slowing down gastric emptying, inhibiting digestive secretions (gastric acid, pancreatic enzymes, bile ejection) and food intake. Appearance of new glucose is slow down by inhibiting the gluconeogenic hormone glucagon. Amylin actions collectively reduce total insulin demand and are mostly carried out via a glucose-sensitive part of the brain (the area postrema). Amylin effects might be overridden by hypoglycemia. Rodent amylin knock-out experiments show that knock-out animals failed to show the normal anorexia following food consumption, suggesting that amylin might be involved in the anorectic effect. Some links among insulin resistance, diabetes, and obesity Page 13 Metabolic dysfunctions Structure / Function pancreatic insulin and glucagon, adrenal cortisol, GH axis and GH abuse Metabolic syndrome insulin resistance, compensatory hyperinsulinemia, DM and vascular diseases Diabetes and Obesity risk factor & consequences, hormonesrelated to their complications Link to other diseases metabolic syndrome, coronary heart disease, diabetes mellitus type 2, polycystic ovarian syndrome Amylin or IAPP is co-secreted with insulin. Insulin resistance in type II DM produces a greater demand for insulin production which results in the secretion of proinsulin. ProIAPP is secreted simultaneously, but the enzyme that converts these precursors molecules into insulin and IAPP, are not able to keep up with high secretion levels ultimately leading to accumulation of proIAPP. This is the key factor in accumulation of amyloid in beta-cells and the apoptotic process in islet beta-cells. The pro-IAPP acts as a seed, collecting IAPP from neighboring cells and forming an intracellular amyloid. As the amyloid grows, it spreads outside the cell. The extracellular amyloid began to excrete IAPP to other cells, inducing similar amyloid formation in other beta-cells (possible link to Alzheimer). Some links among insulin resistance, diabetes, and obesity Metabolic dysfunctions Structure / Function pancreatic insulin and glucagon, adrenal cortisol, GH axis and GH abuse Metabolic syndrome insulin resistance, compensatory hyperinsulinemia, DM and vascular diseases Diabetes and Obesity risk factor & consequences, hormonesrelated to their complications Link to other diseases metabolic syndrome, coronary heart disease, diabetes mellitus type 2, polycystic ovarian syndrome Diabetic ketoacidosis (DKA) and hyperosmotic hyperglycemic and non-ketotic syndrome (HHNKS) Page 14 Metabolic dysfunctions Structure / Function pancreatic insulin and glucagon, adrenal cortisol, GH axis and GH abuse Metabolic syndrome insulin resistance, compensatory hyperinsulinemia, DM and vascular diseases Diabetes and Obesity risk factor & consequences, hormonesrelated to their complications Link to other diseases metabolic syndrome, coronary heart disease, diabetes mellitus type 2, polycystic ovarian syndrome Diabetes mellitus, insulin resistance and atherosclerosis Page 15 Metabolic dysfunctions Structure / Function pancreatic insulin and glucagon, adrenal cortisol, GH axis and GH abuse Metabolic syndrome insulin resistance, compensatory hyperinsulinemia, DM and vascular diseases Diabetes and Obesity risk factor & consequences, hormonesrelated to their complications Link to other diseases metabolic syndrome, coronary heart disease, diabetes mellitus type 2, polycystic ovarian syndrome Pathophysiology and common complications of obesity Page 16 Metabolic dysfunctions Structure / Function pancreatic insulin and glucagon, adrenal cortisol, GH axis and GH abuse Metabolic syndrome insulin resistance, compensatory hyperinsulinemia, DM and vascular diseases Adiponectin, is a protein hormone that modulates a number of metabolic processes, including glucose regulation and fatty acid catabolism. Adiponectin is exclusively secreted from adipose tissue (and also from the placenta in pregnancy). Its blood levels are inversely correlated with body fat percentage in adults. Transgenic mice with increased adiponectin show impaired adipocyte differentiation and increased energy expenditure associated with protein uncoupling. Diabetes and Obesity risk factor & consequences, hormonesrelated to their complications Adiponectin plays a role in the metabolic derangement that may result in type 2 DM, obesity, atherosclerosis, nonalcoholic fatty acid disease, and an independent risk factor for the metabolic syndrome. Link to other diseases metabolic syndrome, coronary heart disease, diabetes mellitus type 2, polycystic ovarian syndrome Adiponectin in combination with leptin has been shown to completely reverse insulin resistance in mice. Pathophysiology and common complications of obesity Page 17 Metabolic dysfunctions Structure / Function pancreatic insulin and glucagon, adrenal cortisol, GH axis and GH abuse Metabolic syndrome insulin resistance, compensatory hyperinsulinemia, DM and vascular diseases Diabetes and Obesity risk factor & consequences, hormonesrelated to their complications Link to other diseases metabolic syndrome, coronary heart disease, diabetes mellitus type 2, polycystic ovarian syndrome SAME EFFECTS OF ADIPONECTIN Adiponectin metabolic effects: Improved glucose flux by lowering gluconeogenesis and rising glucose uptake Improved lipid catabolism by affecting beta-oxidation and triglyceride clearance Provide protection from endothelial atherosclerotic dysfunction Improved insulin sensitivity Improved weight loss Participate in the control of energy metabolism Up-regulate uncoupling proteins Hypoadiponectinemia is an independent risk factor for the metabolic syndrome and for diabetes mellitus Pathophysiology and common complications of obesity Metabolic dysfunctions Structure / Function pancreatic insulin and glucagon, adrenal cortisol, GH axis and GH abuse Metabolic syndrome insulin resistance, compensatory hyperinsulinemia, DM and vascular diseases Diabetes and Obesity risk factor & consequences, hormonesrelated to their complications Link to other diseases metabolic syndrome, coronary heart disease, diabetes mellitus type 2, polycystic ovarian syndrome BRAIN STRESS AND INFLAMMATION IN THE DEVELOPMENT OF METABOLIC SYNDROME. Overnutrition in the forms of high circulating levels of glucose, free fatty acid (FFA), and amino acids (AA) is the predominant pathogenic inducer of central metabolic inflammation. Excessive nutrients transported into cells can pose severe stresses on cellular metabolic machinery, affecting organelles such as mitochondria and endoplasmic reticulum (ER) which are responsible for nutrient oxidation and protein synthesis, respectively. As a result, intracellular reactive oxygen species (ROS) increase due to heightened mitochondrial activities, leading to intracellular oxidative stress. In parallel, high levels of cellular metabolic activities demand increased protein synthesis and folding by ER, leading to ER stress. Additionally, high levels of intracellular ROS from oxidative stress can escalate ER stress. Prolonged oxidative stress and ER stress can cause intracellular accumulation of dysfunctional mitochondria, ER, and other cytosolic proteins, leading to increased autophagy stress and autophagic defect. Page 18 Metabolic dysfunctions Structure / Function pancreatic insulin and glucagon, adrenal cortisol, GH axis and GH abuse Metabolic syndrome insulin resistance, compensatory hyperinsulinemia, DM and vascular diseases Diabetes and Obesity risk factor & consequences, hormonesrelated to their complications Link to other diseases metabolic syndrome, coronary heart disease, diabetes mellitus type 2, polycystic ovarian syndrome BRAIN STRESS AND INFLAMMATION IN THE DEVELOPMENT OF METABOLIC SYNDROME. All these intracellular stresses are activators of cellular proinflammatory kinases, among which INFk-B kinase (IKK) and cJun N-terminal kinase (JNK) have been implicated. Activation of these pro-inflammatory pathways leads to transcription of inflammatory response genes via nuclear transcription factors NFk-B and AP-1. Endoplasmic Reticulum (ER) stress can also directly induce transcription of inflammatory genes via activating transcription factor X-box binding protein-1 (XBP1). Certain extracellular nutrient species can bind to toll-like receptors to activate intracellular pro-inflammatory signaling. Furthermore, local or systemic inflammatory cytokines can reinforce metabolic inflammation via cytokine receptor signals. Such collective onset of cellular inflammation impairs normal cellular functions, leading to central dysregulation of various physiological processes across energy balance, glucose tolerance, and cardiovascular homeostasis, which underlies the development of metabolic syndrome and related diseases. Metabolic dysfunctions Structure / Function pancreatic insulin and glucagon, adrenal cortisol, GH axis and GH abuse Metabolic syndrome insulin resistance, compensatory hyperinsulinemia, DM and vascular diseases Diabetes and Obesity risk factor & consequences, hormonesrelated to their complications Link to other diseases metabolic syndrome, coronary heart disease, diabetes mellitus type 2, polycystic ovarian syndrome Brain stress and inflammation in the development of the metabolic stress Page 19 Metabolic dysfunctions Structure / Function pancreatic insulin and glucagon, adrenal cortisol, GH axis and GH abuse Metabolic syndrome insulin resistance, compensatory hyperinsulinemia, DM and vascular diseases Diabetes and Obesity risk factor & consequences, hormonesrelated to their complications Link to other diseases metabolic syndrome, coronary heart disease, diabetes mellitus type 2, polycystic ovarian syndrome High fructose consumption combined with low dietary magnesium intake may increase the incidence of the metabolic syndrome by inducing inflammation* Magnesium Research. Volume 19, Number 4, 237-43, 2006, Y Rayssiguier, E Gueux, W Nowacki, E Rock, A Mazur The metabolic syndrome is a cluster of common pathologies: abdominal obesity linked to excess of visceral fat, insulin resistance, dyslipidemia and hypertension. This syndrome is occurring at epidemic rates, with dramatic consequences for human health worldwide, and appears to have emerged largely from changes in our diet and reduced physical activity. An important but not well-appreciated dietary change has been the substantial increase in fructose intake, which appears to be an important causative factor in the metabolic syndrome. There is also experimental and clinical evidence that the amount of magnesium in the western diet is insufficient to meet individual needs and that magnesium deficiency may contribute to insulin resistance. In recent years, several studies have been published that implicate subclinical chronic inflammation as an important pathogenic factor in development of metabolic syndrome. Pro-inflammatory molecules produced by adipose tissue have been implicated in the development of insulin resistance Page 20 High fructose consumption combined with low dietary magnesium intake may increase the incidence of the metabolic syndrome by inducing inflammation* Magnesium Research. Volume 19, Number 4, 237-43, 2006, Y Rayssiguier, E Gueux, W Nowacki, E Rock, A Mazur The metabolic syndrome, high fructose intake and low magnesium (Mg) diet may all be linked to the inflammatory response. In many ways, fructose-fed rats display changes observed in the metabolic syndrome and high-fructose feeding is associated with NADPH oxidase and reninangiotensin activation. The production of reactive oxygen species results in the initiation and development of insulin resistance, hyperlipemia and high blood pressure. In a fructose-fed rat model, a few days of experimental magnesium deficiency produces a clinical inflammatory syndrome characterized by leukocyte and macrophage activation, release of inflammatory cytokines, appearance of the acute phase proteins and excessive production of free radicals. Because magnesium acts as a natural calcium antagonist, the molecular basis for the inflammatory response is probably the result of a modulation of the intracellular calcium concentration. Potential mechanisms include the priming of phagocytic cells, the opening of calcium channels, activation of N-methyl-D-aspartate (NMDA) receptors, the activation of nuclear factor-kappaB (NFkB) and activation of the renin-angiotensin system. Since magnesium deficiency has a proinflammatory effect, the expected consequence would be an increased risk of developing insulin resistance when magnesium deficiency is combined with a high-fructose diet. Accordingly, magnesium deficiency combined with a high-fructose diet induces insulin resistance, hypertension, dyslipidemia, endothelial activation and prothrombic changes in combination with the up-regulation of markers of inflammation and oxidative stress. Page 21