Biochemistry lecture 28 intermediary metabolism, diseases with case study examples
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Biochemistry lecture 28 intermediary metabolism, diseases with case study examples
- 1. Integration of Metabolism Intermediary Metabolism Diseases of Metablic Regulation Dr Rakesh Sharma, DHA,FICN,ABR
- 2. Tools of Metabolism Intact Organism Organ Perfusion Organ Slices Intact cells and Tissue culture Tissue homogenates Enzymes and Regulation DNA and Genes
- 3. Intermediary Metabolic Pathways • Sequence of carbohydrate, protein, lipid, nucleic acid metabolic reactions • Substrate-Product Relationship • Mechanism of reaction(stimulation or inhibition) • Crossover points • Regulatory Control mechanisms(effector molecules, hormone regulation,DNA directed enzyme synthesis) • Metabolic blocks • Metabolic defects • Genetic knockout or gene manipulation
- 4. Meaning of Metabolism • Energy balance and flow across organs in body • Metabolite balance (Metabolic Flux) and Regulation(at Enzyme,Hormone,DNA levels) • Cross-over reactions among different cycles • Specific roles of substrate, enzyme, co- enzyme, co-factor, hormone, receptor, stimulator, inhibitor in biochemical reactions • Metabolic Characteristics of isolated cells or tissues
- 5. What is Metabolism? • Catabolism, Anabolism, Amphibolic nature • Food oxidation and Metabolite biosynthesis • Metabolite storage and Detoxification • Food breakdown (Primary Metabolism) • Oxidation to CO2+H2O by NADH,FADH2 (Secondary or Intermediary Metabolism) • Electron Transport Chain (Tertiary Metabolism) • Carbs/Lipids/Proteins/V,MEnergy+Products
- 6. Metabolic Balance in the Human Body Anabolism = Catabolism Cytosol: Glycolysis, Pentose Phosphate Pathway Fatty Acid Synthesis Mitochondria matrix: Citric Acid Cycle, Oxidative Phosphorylation, B-Oxidation of fatty acids Ketone Bodies Gluconeogenesis Urea Cycle End.Reticulum & Golgi Apparatus Protein Synthesis & Sorting Microsome: Drug metabolism Nucleus: DNA,RNA synthesis Peroxisomes: Xenobiotic metabolism Free radical metabolism NUTRIENTS SUPPLY IN BODY Lipids Polysaccharides Proteins Nucleic Acids Lipolysis Glycogenolysis Proteolysis Digestion Fatty Acid/Glycerol Glucose Amino Acids Nucleotides Fatty Acid Oxidation Glycolysis Degradation Degradation Acetyl CoA Pyruvate Acetyl CoA NH3 Pyrimidines/Purines Ketone Bodies TCA cycle Urea Cycle Uric Acid NADH/FADH2 CO2 Urea CO2 B-NH2-Butyrate Oxidative Phosphorylation ATP Aminoacid Gluconeogenesis Fatty Acid Synthesis Synthesis Amino Acids + Glucose + Fatty Acids Protein synthesis Nucleotides Glycogen Triglycerides lipid, steroids, ecosanoids biogenic amines Nucleic Acid catacholamines Synthesis heme RNA,DNA Catabolism Anabolism
- 7. Integrated Metabolism Keeps All Body Organs Functioning Well (Healthy State) Muscle glycogen,ATP,proteins BLOOD Liver lipids, amino acids Brain catacholamines,glucose Glycogen Adipose lipids Galactose,GLUCOSE Glycerol Glycolysis Nucleotide Metabolism Fatty acid synthesis Acetyl CoA Nucleic Acids (DNA, RNA) Fatty Acids Beta Oxidation Acetoacetate Protein Synthesis Cholesterol Ketone Bile Salts, Hormones Bodies Amino Acids Urea Cycle glycine Heme metabolism • Oxidative Phosphorylation Lecture 31 TCA | Foods Carbs/Proteins/Lipids/V,MEnergy+MetabolitesCells-Organs(Health)
- 9. Imbalanced Metabolic Regulatory Enzymes Enzyme name Metabolic pathway Type(s) of regulation Activators & inducers Inhibitors & repressors 1. Pyruvate dehydrogenase aerobic glycolysis covalent modification Ca++ ATP, NADH & acetyl-CoA 2. Pyruvate carboxylase gluconeogenesis & lipogenesis allosteric acetyl-CoA - 3. Pyruvate kinase glycolysis allosteric & covalent mod fructose -1,6-bisphosphate alanine, ATP & cAMP 4. PEPCK (PEP carboxykinase) gluconeogenesis gene expression corticosteroids, cyclic AMP insulin 5. ATP:citrate lyase lipogenesis gene expression insulin corticosteroids 6. Acetyl-CoA carboxylase lipogenesis gene expression, covalent mod. & allosteric insulin, ??? citrate corticosteroids, cyclic AMP? palmitoyl CoA 7. Phospho fructokinase glycolysis gene expression & allosteric insulin AMP, F-2,6-bisP corticosteroids ATP, citrate 8. Fructose-1,6-bisphosphatase gluconeogenesis gene expression & allosteric corticosteroids? ATP, citrate insulin? AMP, F-2,6-bisP 9. Triglyceride lipase Lipolysis covalent modification cyclic AMP - 10. a-glycero phosphate acyl transferase lipogenesis covalent modification - cyclic AMP 11. "malic" enzyme lipogenesis gene expression insulin corticosteroids 12. fatty acid synthetase lipogenesis gene expression insulin corticosteroids 13. Isocitrate dehydrogenase Krebs cycle allosteric ADP, calcium ATP, NADH. NADPH 14. Oxoglutarate dehydrogenase Krebs cycle allosteric calcium - 15. Glutamate dehydrogenase nitrogen excretion allosteric ADP, GDP ATP, GTP 16. Carbamyl phosphate synthetase nitrogen excretion gene expression allosteric N-acetyl glutamate - 17. Glycogen phosphorylase glycogen breakdown covalent mod. allosteric cyclic AMP, calcium, 5'AMP - 18. Glycogen synthetase glycogen synthesis covalent mod. allosteric glucose-6-phosphate cyclic AMP calcium 19. Glucokinase (liver, pancreatic b-cells) blood glucose control gene expression insulin cortisol, cyclic AMP 20. Glucose-6-phosphatase blood glucose control gene expression cortisol, cyclic AMP insulin 21. HMG-CoA reductase cholesterol synthesis gene expression insulin, thyroxin glucagon, cortisol, cholesterol
- 10. • How Different Organs Play Role in Organ Functions (Physiology) by Biochemical Regulation (Metabolism and Hormone Control)? • How Different Tissue in Organs have specific Role in Intermediary Metabolism by Keeping Metabolic Balance?
- 11. Digestive System Anatomy & Physiology
- 12. Hepatobiliary System Anatomy and Physiology Biochemistry
- 13. Circulatory System Anatomy and Physiology Biochemistry
- 15. Excretory System Anatomy & Physiology Biochemistry
- 19. Endocrine SystemAnatomy Physiology Biochemistry
- 20. Identify Organ/Tissue associated with Metabolism
- 21. Identify Organ/Tissue Biochemistry • GAG • Proteoglycans • Collagen • Elastin • Calcium • 1,25-DHCC • Cartilage • TG Storage • Adiponectin • Leptin • Sodium Gradient • Carbonic Anhydrase • Glutaminase/GluDH • BNP/ADH • Renin/Angiotensinogen • 1,25 DHCC
- 22. Identify the Organ/Tissue Biochemistry •CaM-Caldesmon •Glycogen metabolism •Cori cycle •Glucose-Alanine cycle •Creatine/CK •β-FA Oxidation •Ketone bodies •Glutamate metabolism •TCA cycle/ATP •GLUT-4 •Myoglobin •Eicosanoids •ActinoMyosin •Amino Acid/Protein Synthesis •Urea synthesis •FA,VLDL,LDL,HDL synthesis •FA Elongation •Cholesterol Synthesis •Ketogenesis •Glycogen synthesis •Heme synthesis •Detoxification(Phase I,II,III) •Alcohol A-DH metabolism •Glycogenolysis •Gluconeogenesis
- 23. Identify Organ/Tissue Biochemistry •Selectin •ICAM/VCAM •Nitric Oxide/cGMP •Eicosanoid synthesis •Renin-Angiotensin-Aldosterone • Erythropoietin Receptor • RBC Oligosaccharide Ag • Hemoglobin-Oxygen • ROS,Glutathione,SOD • PPP/HMP •Leucopoiesis-CFU, CSF •PhOX, MPO •Respiratory Burst •G-Protein/NADPH Oxidase •Platelet activation-TrGlobulin • Fibrinogen/Thrombin • Lipoproteins • Bilirubin • FFA
- 24. Identify Organ/Tissue Biochemistry • ACTH,ADH,LH,FSH,GH,TSH,PL,Oxytocin • Glucagon,Insulin • PTH • Chorionic Gonadotropin,HCG • Glucocorticoids,Mineralocorticoids,Sex hormones • Catecholamines, NOS • Leptins, Adiponectins • Progesterone, Estradiol, Testosterone • Gastrin, Cholecystokinin, Pancreozymin • T3,T4, Iodine
- 25. Identify Tissue/Organ Signal Molecules • Epinephrin/Norepinephrin • Serotonin • GABA • Acetyl Choline • 5-Hydroxy Tryptamine • Catacholamines(COMT/MAO) • G-Proteins • Receptors of neurotransmitters, Tyrosine Kinase/Phosphatase, Insulin • CREB,CRE,DAG,IP3,PI3K • JAK/STAT • MAP Kinase
- 26. Integrated System Approach Anatomy-Physiology-Biochemistry Structure - Function - Metabolism • Muscles – Muscle Contraction-Carbohydrate, Amino Acids, Protein metabolism • Bones - Ossification-Calcium, phosphorus metabolism • Digestive System – Digestion- Carbohydrate, Protein, Bile, Lipid metabolism • Nerves, CNS – Conduction- Amines, Neurotransmitter metabolism • Blood, Vascular System –Circulation-Heme, Lipid, Lipoprotein metabolism • Urinary system –Excretion - Urea Cycle, Ammonia metabolism • Reproductive System-Baby making- HCG, inborn metabolic genetic errors • Endocrine System – Regulation - Hormone metabolism Healthy Body and Introduction to Disease in 1st Prof. & Treatment in 2nd Prof. onwards :Prof. Rakesh Sharma’s Rule: Live Human Body - (Biochemistry + Physiology) = Cadaver (Anatomy)…… …… ....Eq. 1st Prof
- 27. Metabolism as Health Check Tool NUTRIENTS Carbohydrate Protein Lipid Nucleic Acid Vitamin/Mineral Enzyme, Hormones Signal molecules •ENERGY-RICH MOLECULES •CIRCULATING METABOLITES END PRODUCTS Perfect Balance Means Good Health Anabolism = Catabolism Medical Biochemistry Clinical Biochemistry FAMILY HEALTH PRACTICE Or CONFIRMING GOOD HEALTH (EVERY BODY PART DOING WELL) HEALTHY STATE Atoms Molecules Assemblies Organelles Cell Tissue Organs EVERY BODY PART DOING WELL: CNS/BRAIN NEUROLOGY LIVER/GB GASTROENTEROLOGY KIDNEY UROLOGY LUNGS PULMONOLOGY BONES ORTHOPEDIC HEART/VESSELS CARDIOLOGY MUSCLES OSTEOPATHY OVARY OBS/GYN EYE OPTHALMOLOGY EAR,NOSE,THROAT ENT SKIN DERMATOLOGY A + BP DNA- RNA
- 28. FoodsEnergy + Metabolites Maintain Health Under Hormone Control How Metabolism Begins and Integrates In Different Organs? How Fed and Fasting States Maintain Metabolic Balance? How Metabolic Balance Repairs Metabolites & Metabolism?
- 30. Fed state Fasting State Figure shows flow of metabolites across organs shared by several metabolisms
- 31. Tissue Metabolisms and Organ Functions • Metabolic Profile of Organs -Brain -Skeletal Muscle -Liver, Gastrointestinal System -Cardiovascular System/Heart -Adipose Tissue -Kidney
- 32. Brain • Brain needs 120 gm/day glucose fuel or 60% carbohydrate intake is metabolized in brain • Utilizes 20% cardiac output(750 mL/min) Anoxia causes lactate production (Pasteur Effect at <30 mg/dL glucose) • Brain can utilize acetoacetate and ketone bodies (in starvation)
- 33. Skeletal Muscle • After meal, Muscle glucose breakdown(insulin influence) or glycogen synthesis is rapid • During aerobic exercise, muscle uses glycogen to make lactate and glucose(gluconeogenesis) using fatty acid as fuel. • In starvation, Branched chain amino acids and ketone bodies are utilized by skeletal muscle Fatty acids undergo β oxidation
- 34. Lungs • Respiration OxygenCO2 (Hemoglobin and Heme metabolism) • Lungs oxidise glucose, fatty acid, amino acids, lactate and glycerol by: Glycolysis,HMP shunt, PyDH, TCA cycle • Convert glucose to polysaccharides,lipids,proteins(Nucleoproteins ,proteins) • Glucose to fatty acids, phospholipids
- 35. Adipose Tissue • Energy stores in TAG, VLDL, Chylomicron • Lipases break down the lipoproteins • Glycerol 3P DHAP + NADH • Lactin, Adiponectin • During starvation, free fatty acids from adipose tissue get change into glucose for brain.
- 36. Cardiac Muscle • Heart Utilizes 6 kg ATP every day(from β- oxidation + Glucose) • Creatine makes Creatine Phosphate that releases energy to cardiac muscle fiber • ATP from mitochondria is needed for Creatine kinase
- 37. Liver • In fed state, GlucoseGlycogen; FATAG, LP; Amino acids and Ammonia Urea • After long starvation, glucose is formed from: Glycogenolysis Alanine formed from protein breakdown Ketogenesis to supply ketones to brain Gluconeogenesis
- 38. Kidney • Urea cycle excretes out urea • Ammonia is removed from the kidneys by urea cycle
- 39. Blood • Blood maintains the balance of metabolites by oxygen, metabolites transport across the organs in the body
- 40. Tissue Metabolism Disorders • Collagen Storage Diseases, Glycogen Storage Disease, Mucopolysaccharides, Diabetes • Fatty Liver, Cirrhosis, Ketosis, Obesity, Dyslipidemia, Gall stones, • Lipoprotein disorders, Atherosclerosis • Aminoaciduria, Nephrosis, Nephritis, Albinism • Porphyria, Thalassemia, Hemoglobinopathies, Hemolysis, Leukemia, Coagulation • Post-op Acid-Base imbalance, Electrolyte imbalance, Trace element toxicity • Nutritional Vitamin-Mineral Defects • Genetic DNA-RNA mutations and Genomics • Pitutary, Adrenal, Thyroid Hormone defects • Tumors, Cancer • Musculopathy(Actin-Myosin loss), Lens protein loss • Prion disease
- 41. • Lactose Intolerence: Aldolase deficiency • Fructose Intolerence • Fructosuria: Fructokinase deficiency • Galactosemia: Gal-1-PUT deficiency • Essential pentosuria: Xylitol Dehydrogenase deficiency • Pyruvate Carboxylase deficiency • Glucose-6-P DH deficiency; Hexokinase deficiency; Pyruvate Kinase deficiency; Pyruvate Dehydrogenase deficiency
- 43. Heritable Diseases of Connective Tissues
- 45. Diseases of Lipid Metabolism • Carnitine deficiency • Carnitine Transport Defects (CPT I,CPTII, Translocase deficiency) cause musculopathy and hypoglycemia, improved by short chain FA in diet. • FAcyl CoA DH deficiency • Jamaican Vomiting Syndrome • Methyl malonic Aciduria • Organic Aciduria(Methyl Malonic, Propionic, FA CoA DH deficiency) • Refsum Disease • Zellweger Syndrome • X-linked Adrenoleukodystrophy • Diabetic Ketoacidosis (Hyperglycemic Hyperosmolar state • Diabetic foot • PUFA required in diet • Prostaglandins as COX-1 inhibitors • Prostaglandins in abortion • Prostaglandins as H2 blockers in Gastric ulcers • Obesity (adiponectin, leptin, resistin enhance TAG) improved by Orlistat • Fatty Liver( defective VLDL synthesis, poor Apo-B/Apo-C/Apo-E synthesis due to puromycin, ethionine, CCl4 drugs) • Alcoholic Cirrhosis (Alcohol DH + Aldehyde DH for alcohol acetate + NADH) cause liver failure, improved by Lipotropic factors (Choline,Met,Ser+Essential FA+vit E- Se) • Atherosclerosis, Hypertension (HDL and bad cholesterol) • Hypercholesterolemia(hypothyroidism, DM,Jaundice,Nephrotic syndrome) improved by statins • Respiratory Distress Syndrome (Dipalmitoyl Lecithin surfactant deficiency) in infants, improved by Steroids. • Leukodydtrophy(sulfatase deficiency) • SPHINGOLIPIDOSES (ganglioma,TaySach, Febry,Gaucher,Niemann Pick,Metachromatic Leucodystrophy)
- 46. Lipoprotein Transport Diseases Tuberoeryptive Xanthoma:Knee,Buttock, Elbow Palmar Xanthoma:Palm, Wrist Chylomicron+VLDL remain Alzheimer Disease due to ApoE4 MTP gene mutationNo Chylomicron,VLDL,LDL HYPOLIPOPROTEINEMIA: -Absent Chy,ApoB-100 -Absent αLP:Tangier, Fish Eye disorder HYPERLIPOPROTEINEMIA: -Absent LPL Lipase or Apo CII(Type I) -Hypercholesterolemia(No LDL-R) (Type IIa) -No Apo E (Type III) -HyperTAG or High VLDL (Type IV) -High HDL or Hyper αLP and LP-a -Low lipase, LCAT -High LpA
- 47. Hemochromatosis
- 48. Diagnosis of Acute and Cutaneous Porphyrias Symptoms First-Line Test: Abnormality Possibl e Porphy ria: Second-Line Testing if First-Line Testing Is Positive: To include: urine (U), plasma (P), and fecal (F) porphyrins; for acute porphyrias add red blood cell (RBC) HMB-synthase; for blistering skin lesions add P & RBC porphyrins Confirmatory Test: Enzyme Assay and/or Mutation Analysis Neurovisceral Spot U: ALA & normal PBG ADP U porphyrins: , mostly COPRO III P & F porphyrins: normal or slightly RBC HMB-synthase: normal Rule out other causes of elevated ALA; ↘↘ RBC ALA-dehydratase activity (<10%); ALA-dehydratase mutation analysis Spot U: PBG AIP U porphyrins: , mostly URO & COPROP & F porphyrins: normal or slightly RBC HMB-synthase: usually ↘ HMB-synthase mutation analysis " HCP U porphyrins: , mostly COPRO III P porphyrins: normal or slightly ( if skin lesions present) F porphyrins: , mostly COPRO III Measure RBC HMB-synthase: normal activity COPRO-oxidase mutation analysis " VP U porphyrins: , mostly COPRO III P porphyrins: (characteristic fluorescence peak at neutral pH) F porphyrins: , mostly COPRO & PROTO Measure RBC HMB-synthase: normal activity PROTO-oxidase mutation analysis Blistering Skin Lesions P: porphyrins PCT & HEP U porphyrins: , mostly URO & heptacarboxylate porphyrin P porphyrins: F porphyrins: , including increased isocoproporphyrin a RBC URO-decarboxylase activity: half-normal in familial PCT (20% of all PCT cases); substantially deficient in HEP URO-decarboxylase mutation
- 49. Cutania Turda and Photosensitivity
- 50. Purine and Pyrimidine Metablism Inborn Errors of Pyrimidine Metabolism Enzyme Activit y Inheritanc e Clinical Features Uridine-5'- monophosphate synthetase Deficienc y Autosomal recessive Orotic acid crystalluria; obstructive uropathy, hypochromic megaloblastic anemia Pyrimidine 5'- nucleotidase Deficienc y Autosomal recessive Hemolytic anemia Pyrimidine 5'- nucleotidase Superactiv ity Uncertain Developmental delay, seizures, ataxia, language deficit Classification of Hyperuricemia by Pathophysiology Thymidine phosphorylase Deficienc y Autosomal recessive Mitochondrial neurogastrointestinal encephalopathy Dihydropyrimidine dehydrogenase Deficienc y Autosomal recessive Seizures, motor and mental retardation Urate Overproduction Dihydropyrimidinase Deficienc y Uncertain Seizures, mental retardation Primary idiopathic HPRT deficiency PRPP synthetase overactivity Hemolytic processes, Lymphoproliferative diseases Ureidopropionase Deficienc y Uncertain Hypotonia, dystonia, developmental delay Decreased Uric Acid Excretion Inborn Errors of Purine Metabolism Enzyme Activity Inheritance Clinical Features Laboratory Features Hypoxanthine phosphoribo— syltransferase Complete deficiency Partial deficiency X-linked X-linked Self-mutilation, choreoathetosis, gout, and uric acid lithiasis Gout, and uric acid lithiasis Hyperuricemia, hyperuricosuria Hyperuricemia, hyperuricosuria Phosphoribosylpyrophosp hate synthetase OveractivityX-linked Gout, uric acid lithiasis, and deafnessHyperuricemia, hyperuricosuria Adenine phosphoribosyl— transferase Deficiency Autosomal recessive 2,8-Dihydroxyadenine lithiasis — Xanthine oxidase Deficiency Autosomal recessive Xanthinuria and xanthine lithiasis Hypouricemia, hypouricosuria Adenylosuccinate lyase Deficiency Autosomal recessive Autism and psychomotor retardation — Myoadenylate deaminase Deficiency Autosomal recessive Myopathy with exercise intolerance or asymptomatic — Adenosine deaminase Deficiency Autosomal recessive Severe combined immunodeficiency disease and chondroosseous dysplasia — Purine nucleoside phosphorylase Deficiency Autosomal recessive T cell–mediated immunodeficiency — Classification of Hyperuricemia Urate Overproduction Primary idiopathic HPRT deficiency PRPP synthetase overactivity Hemolytic processes Lymphoproliferative diseases Myeloproliferative diseases Polycythemia vera Psoriasis Paget's disease Glycogenosis III, V, and VII Rhabdomyolysis Exercise Alcohol Obesity Purine-rich diet Decreased Uric Acid Excretion Primary idiopathic Renal insufficiency Polycystic kidney disease Diabetes insipidus Hypertension Acidosis Lactic acidosis Diabetic ketoacidosis Starvation ketosis Berylliosis Sarcoidosis Lead intoxication Hyperparathyroidism Hypothyroidism Toxemia of pregnancy Bartter's syndrome Down syndrome Drug ingestion Salicylates (>2 g/d) Diuretics Alcohol Levodopa Ethambutol Pyrazinamide Nicotinic acid Cyclosporine Combined Mechanism Glucose-6-phosphatase deficiency Fructose-1-phosphate aldolase deficiency Alcohol Shock
- 51. Uric Acid Pathway in Kidney
- 53. Inborn Errors of Amino Acid Metabolism • Hyperphenylalaninemia • Homocystinuria • Alkaptonuria • Urea Cycle Defects Inherited Disorders of Amino Acid Metabolism Amino acid(s) Condition Enzyme Defect Clinical Findings Inheritance Phenylalanine Phenylketonuria Phenylalanine hydroxylase Mental retardation, microcephaly, hypopigmented skin and hairs, eczema, "mousy" odor AR DHPR deficiency hyperphenylalaninemia Dihydropteridine reductase Mental retardation, hypotonia, spasticity, myoclonus AR PTS deficiency hyperphenylalaninemia 6-Pyruvoyl-tetrahydropterin synthase Dystonia, neurologic deterioration, seizures, mental retardation AR
- 54. Inherited Diseases of Membrane Transport Genetic Disorders of Membrane Transport (Selected Examples) Class of Substance and Disorder Individual Substrates Tissues Manifesting Transport Defect Molecular Defect Major Clinical Manifestations Inherita nce Amino Acids Cystinuria Cystine, lysine, arginine, ornithine Proximal renal tubule, jejunal mucosa Shared dibasic-cystine transporter SLC3A1, SLC7A9 Cystine nephrolithiasis AR Dibasic aminoaciduria Lysine, arginine, ornithine Proximal renal tubule, jejunal mucosa Dibasic transporter SLC7A7 Type I: Benign Type II: Protein intolerance, hyperammonemia, mental retardation AR Hartnup disease Neutral amino acids Proximal renal tubule, jejunal mucosa Neutral amino acid transporter SLC6A19 Constant neutral aminoaciduria, intermittent symptoms of pellagra AR Methionine malabsorption Methionine Jejunal mucosa Methionine transporter White hair, mental retardation, convulsions, hyperpneic attacks, edema Probabl e AR Histidinuria Histidine Proximal renal tubule, jejunal mucosa Histidine transporter Mental retardation AR Iminoglycinuria Glycine, proline, hydroxyproline Proximal renal tubule, jejunal mucosa Shared glycine–imino acid transporter None AR Dicarboxylic aminoaciduria Glutamic acid, aspartic acid Proximal renal tubule, jejunal mucosa Shared dicarboxylic amino acid transporter None Probabl e AR Cystinosis Cystine Lysosomal membranes Lysosomal cystine transporter CTNS Renal failure, hypothyroidism, blindness AR Hexoses Glucose-galactose malabsorption d-Glucose d-GalactoseProximal renal tubule, jejunal mucosa Sodium-dependent glucose/galactose transporter SGLT1 Watery diarrhea on feeding glucose, lactose, sucrose, or galactose AR Glucose-transport defectd-Glucose Ubiquitous blood brain barrier Facilitative glucose transporter GLUT1 Seizures, mental retardation AD Fanconi-Bickel syndrome d-Glucose Liver, kidney, pancreas, intestine Facilitative glucose transporter GLUT2 Growth retardation, rickets, hepatorenal glycogenosis, hypo- and hyperglycemia AR Urate Hypouricemia Uric acid Proximal renal tubule Urate transporter SLC22A12 Hypouricemia, uric acid urolithiasis AR Anions Congenital Chloride, sulfate Ileal and colonic Cl-/HCO3- exchanger (DRA) Hydramnios, watery diarrhea, elevated fecal AR
- 55. Amino acid(s) Condition Enzyme Defect Inheritan ce Phenylalanine Phenylketonuria Phenylalanine hydroxylase AR DHPR deficiency hyperphenylalaninemia Dihydropteridine reductase AR PTS deficiency hyperphenylalaninemia 6-Pyruvoyl-tetrahydropterin synthase AR GCH1 deficiency hyperphenylalaninemia GTP cyclohydrolase I AR Carbinolamine dehydratase deficiency Pterin-4-carbinolamine dehydratase AR Tyrosine Tyrosinemia type I (hepatorenal) Fumarylacetoacetate hydrolase AR Tyrosinemia type II (oculocutaneous) Tyrosine transaminase AR Tyrosinemia type III 4-Hydroxyphenylpyruvate dioxygenase AR Hawkinsinuria 4-Hydroxyphenylpyruvate dioxygenase AD Alkaptonuria Homogentisic acid oxidase AR Albinism (oculocutaneous) Tyrosinase AR Albinism (ocular) Different enzymes or transporters AR, XL DOPA-responsive dystonia Tyrosine hydroxylase AR GABA 4-Hydroxybutyric aciduria Succinic semialdehyde dehydrogenase AR Tryptophan Kynurenic aciduria Kynurenine-3-monooxygenase AR Hydroxykynureninuria (xanthurenic aciduria) Kynureninase AR Histidine Histidinemia Histidine-ammonia lyase AR Urocanic aciduria Urocanase AR Formiminoglutamic aciduria Formiminotransferase AR Clinical Findings Mental retardation, microcephaly, hypopigmented skin and hairs, eczema, "mousy" odor Mental retardation, hypotonia, spasticity, myoclonus Dystonia, neurologic deterioration, seizures, mental retardation Mental retardation, seizures, dystonia, temperature instability Transient hyperphenylalaninemia (benign) Liver failure, cirrhosis, rickets, failure to thrive, peripheral neuropathy, "boiled cabbage" odor Palmoplantar keratosis, painful corneal erosions with photophobia, mental retardation (?) Hypertyrosinemia with normal liver function, occasional mental delay Transient failure to thrive, metabolic acidosis in infancy Ochronosis, arthritis, cardiac valve involvement, coronary artery calcification Hypopigmentation of hair, skin, and optic fundus; visual loss; photophobia Hypopigmentation of optic fundus, visual loss Rigidity, truncal hypotonia, tremor, mental retardation Seizures, mental retardation, ataxia Niacin deficiency, pellagra, colitis Niacin deficiency, mental retardation, spasticity Benign Benign Occasional mental retardation
- 56. Glycine Glycineencephalopathy Glycine cleavage (4 enzymes) AR Sarcosinemia Sarcosine dehydrogenase AR Hyperoxaluria type I Alanine:glyoxylate aminotransferase AR Hyperoxaluria type II d-Glyceric acid dehydrogenase/glyoxylate reductase AR Serine Phosphoglycerate dehydrogenase deficiency Phosphoglycerate dehydrogenase AR Proline Hyperprolinemia type I Proline oxidase AR Hyperprolinemia type II 1-Pyrroline-5-carboxylate dehydrogenase AR Hyperhydroxyprolinemia Hydroxyproline oxidase AR Prolidase deficiency Prolidase AR Methionine Hypermethioninemia Methionine adenosyltransferase AR S-Adenosylhomocysteine hydrolase deficiency S-Adenosylhomocysteine hydrolase AR Glycine N-methyltransferase deficiency Glycine N-methyltransferase AR Homocystine Homocystinuria Cystathionine -synthase AR Homocystinuria 5,10-Methylenetetrahydrofolate reductase AR Homocystinuria Methionine synthase (cblE, -G) AR Homocystinuria and methylmalonic acidemia Vitamin B12 lysosomal efflux and metabolism (cbl C, -D, -F) AR Cystathionine Cystathioninuria -Cystathionase AR Cystine Cystinosis Cystinosin CTNS (lysosomal efflux) AR S-Sulfo-l- cysteine Sulfocysteinuria Sulfate oxidase or molybdenum cofactor deficiency AR Lysine Hyperlysinemia, saccharopinuria -Aminoadipic semialdehyde synthaseAR Pyridoxine-dependent seizures L-1-Piperideine-6-carboxilate dehydrogenase AR Infantile seizures, lethargy, apnea, profound mental retardation Benign Calcium oxalate nephrolithiasis, renal failure Calcium oxalate nephrolithiasis, renal failure Seizures, microcephaly, mental retardation Benign Febrile seizures, mental retardation Benign Mild mental retardation, chronic dermatitis Usually benign Hypotonia, mental retardation, absent tendon reflexes, delayed myelination Elevated liver transaminases Lens dislocation, thrombotic vascular disease, mental retardation, osteoporosis Mental retardation, gait and psychiatric abnormalities, recurrent strokes Mental retardation, hypotonia, seizures, megaloblastic anemia Mental retardation, lethargy, failure to thrive, hypotonia, seizures, megaloblastic anemia Benign Renal Fanconi syndrome, rickets, photophobia,hypotonia, renal failure Seizures, mental retardation, dislocated lenses Benign Seizures
- 57. Lysine, tryptophan -Ketoadipic acidemia -Ketoadipic acid dehydrogenase ? Glutaric acidemia type I Glutaryl-CoA dehydrogenase AR Glutaric acidemia type II Electron transfer flavoprotein (ETF) or ETF:ubiquinone oxidoreductase AR Ornithine Gyrate atrophy of the choroid and retina Ornithine--aminotransferase AR Urea cycle Carbamoylphosphate synthase- 1 deficiency Carbamoylphosphate synthase-1 AR N-Acetylglutamate synthase deficiency N-Acetylglutamate synthase AR Ornithine transcarbamylase deficiency Ornithine transcarbamylase XL Citrullinemia type I Argininosuccinate synthase AR Argininosuccinic acidemia Argininosuccinate lyase AR Arginase deficiency Arginase AR Hyperornithinemia, hyperammonemia, homocitrullinuria Mitochondrial ornithine carrier ORNT1 AR Citrullinemia type 2 Mitochondrial aspartate/glutamate carrier CTLN2 AR Benign Severe dystonia and athetosis, mild mental retardation Hypoglycemia, metabolic acidosis, "sweaty feet" odor, hypotonia, cardiomyopathy, exercise-induced myopathy Myopia, night blindness, loss of peripheral vision, cataracts, chorioretinal degeneration Lethargy progressing to coma, protein aversion, mental retardation, hyperammonemia Lethargy progressing to coma, protein aversion, mental retardation, hyperammonemia Lethargy progressing to coma, protein aversion, mental retardation, hyperammonemia Lethargy progressing to coma, protein aversion, mental retardation, hyperammonemia Lethargy progressing to coma, protein aversion, mental retardation, hyperammonemia, trichorrhexis nodosa Spastic tetraparesis, mental retardation, mild hyperammonemia Vomiting, lethargy, failure to thrive, mental retardation, episodic confusion, hyperammonemia, protein intolerance Neonatal intrahepatic cholestasis, adult presentation with sudden behavioral changes and stupor, coma, hyperammonemia
- 58. Proline, ornithine, arginine 1-pyrroline-5-carboxylate synthase deficiency 1-pyrroline-5-carboxylate synthase AR Glutamine Glutamine synthase deficiency Glutamine synthase AR Valine Isobutyryl-CoA dehydrogenase deficiency Isobutyryl-CoA dehydrogenase AR Valine, leucine, isoleucine Maple syrup urine disease (defective E1, E1, E2, E3) Branched chain ketoacid dehydrogenase AR Leucine Isovaleric acidemia Isovaleryl-CoA dehydrogenase AR 3-Methylcrotonyl glycinuria 3-Methylcrotonyl-CoA carboxylase AR 3-Methylglutaconic aciduria type I 3-Methylglutaconyl-CoA hydratase deficiency AR 3-Hydroxy-3-methylglutaric aciduria 3-Hydroxy-3-methylglutaryl- CoA lyase AR Isoleucine 2-Methylbutyryl-glycinuria 2-Methylbutyryl-CoA dehydrogenase AR 2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency 2-Methyl-3-hydroxybutyryl-CoA dehydrogenase XL 3-Oxothiolase deficiency 3-Oxothiolase AR Valine, isoleucine, methionine, threonine Propionic acidemia (pccA,-B,-C) Propionyl-CoA carboxylase AR Multiple carboxylase/biotinidase deficiency Holocarboxylase synthase or biotinidase AR Methylmalonic acidemia (mutase, racemase, CblA, -B, -D) Methylmalonyl-CoA mutase/racemase or cobalamin reductase/adenosyltransferase AR Hypotonia, seizures, hyperammonemia, neurodegeneration Brain malformations, pachygyria, seizures, hypotonia, dysmorphic features Failure to thrive, anemia, and dilated cardiomyopathy(?) Lethargy, vomiting, encephalopathy, seizures, mental retardation, "maple syrup" odor, protein intolerance Acidosis, ketosis, vomiting, coma, hyperammonemia, "sweaty feet" odor, protein intolerance Stress-induced metabolic acidosis, hypotonia, hypoglycemia, "cat's urine" odor Stress-induced acidosis, leukoencephalopathy Stress-induced hypoketotic hypoglycemia and acidosis, encephalopathy, hyperammonemia Fasting-induced metabolic acidosis/hypoglycemia Developmental regression, seizures, and rigidity sometimes triggered by illnesses Fasting-induced acidosis and ketosis, vomiting, lethargy Metabolic ketoacidosis, hyperammonemia, hypotonia, lethargy, coma, protein intolerance, mental retardation, hyperglycinemia Metabolic ketoacidosis, diffuse rash, alopecia, seizures, mental retardation Metabolic ketoacidosis, hyperammonemia, hypertonia, lethargy, coma, protein intolerance, mental retardation, hyperglycinemia
- 59. Inborn Errors of Amino Acid Metabolism • Cystinuria • Cystinosis • Dibasic Aminoaciduria • Dicarboxylic aminoaciduria • Histidinuria • Hartnup Disease • Glucose-galactose malabsorption • Glucose-transport defect • Fanconi-Bickel syndrome • Hypouricemia • Congenital chloridorrhea • Dent disease(X-linked recessive hypophosphatemic rickets and nephrocalcinosis) • Nephrogenic diabetes insipidus type 2 • Hyperinsulinemic hypoglycemia • Benign familial neonatal epilepsy • Thiamine-responsive megaloblastic anemia • Creatine deficiency
- 60. Class of Substance and Disorder Individual Substrates Tissues Manifesting Transport Defect Molecular Defect Major Clinical Manifestations Inheritance Amino Acids Cystinuria Cystine, lysine, arginine, ornithine Proximal renal tubule, jejunal mucosa Shared dibasic- cystine transporter SLC3A1, SLC7A9 Cystine nephrolithiasis AR Dibasic aminoaciduria Lysine, arginine, ornithine Proximal renal tubule, jejunal mucosa Dibasic transporter SLC7A7 Type I: Benign Type II: Protein intolerance, hyperammonemia, mental retardation AR Hartnup disease Neutral amino acids Proximal renal tubule, jejunal mucosa Neutral amino acid transporter SLC6A19 Constant neutral aminoaciduria, intermittent symptoms of pellagra AR Methionine malabsorption Methionine Jejunal mucosa Methionine transporter White hair, mental retardation, convulsions, hyperpneic attacks, edema AR Histidinuria Histidine Proximal renal tubule, jejunal mucosa Histidine transporter Mental retardation AR Iminoglycinuria Glycine, proline, hydroxyproline Proximal renal tubule, jejunal mucosa Shared glycine– imino acid transporter None AR Dicarboxylic aminoaciduria Glutamic acid, aspartic acid Proximal renal tubule, jejunal mucosa Shared dicarboxylic amino acid transporter None AR Cystinosis Cystine Lysosomal membranes Lysosomal cystine transporter CTNS Renal failure, hypothyroidism, blindness AR
- 61. Hexoses Glucose-galactose malabsorption d-Glucose d- Galactose Proximal renal tubule, jejunal mucosa Sodium-dependent glucose/galactose transporter SGLT1 Watery diarrhea on feeding glucose, lactose, sucrose, or galactose AR Glucose-transport defect d-Glucose Ubiquitous blood brain barrier Facilitative glucose transporter GLUT1 Seizures, mental retardation AD Fanconi-Bickel syndrome d-Glucose Liver, kidney, pancreas, intestine Facilitative glucose transporter GLUT2 Growth retardation, rickets, hepatorenal glycogenosis, hypo- and hyperglycemia AR Urate Hypouricemia Uric acid Proximal renal tubule Urate transporter SLC22A12 Hypouricemia, uric acid urolithiasis AR Anions Congenital chloridorrhea Chloride, sulfate Ileal and colonic mucosa Cl-/HCO3- exchanger (DRA) Hydramnios, watery diarrhea, elevated fecal chloride, metabolic alkalosis with volume depletion, hyperaldosteronism AR Dent disease, X-linked recessive hypophosphate rickets , nephrocalcinosis Chloride, phosphate Proximal renal tubule Voltage-gated Cl- channel CLCN5 Proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, rickets XL Cations Hyperinsulinemic hypoglycemia Potassium Pancreatic cell Sulfonylurea receptor SUR1, K+ channel KCNJ11 Neonatal hypoglycemia, hyperinsulinemia AR Benign familial neonatal epilepsy Potassium Brain Voltage-gated K+ channels KCNQ2, KCNQ3 Neonatal seizures, normal development AD Water Nephrogenic diabetes insipidus type 2 Water Renal collecting tubule Aquaporin 2 ( water channel) Polyuria, dehydration, hyposthenuria AR Vitamins Thiamine-responsive megaloblastic anemia Thiamine Ubiquitous Thiamine transporter SLC19A2 Megaloblastic anemia, deafness, diabetes mellitus AR Other Carnitine deficiency Carnitine Kidney, muscle, heart Carnitine transporter OCTN2 Hypoketotic hypoglycemia, cardiomyopathy, hypotonia AR Creatine deficiency Creatine Brain Creatine transporter SLC6A8 Mental retardation, seizures, hypotonia XL
- 62. Scope and Purpose of Integrated Metabolism • Disorders of fluid and electrolyte balance: H+ ion, Gas concentration, Polyuria, Polydyspsia • Disease of GI function: Malabsorption,Vitamin/Mineral Malnutrition,Acute abdominal pain • Diseases of Blood: Porphyria, Hemoglobinopathies,Anemia, Blood coagulation,Plasma proteins • Diseases of Renal Tract: Acute,Chronic Uremia,Urolithiasis, Abnormal Urine Chemistry • Diseases of Skeletal System: Calcium, Phosphorus metabolism, Connective tissues and Joint pain • Disorders of Endocrine System: Anterior Pitutary, Thyroid, Pancreas, Adrenal Cortex, GI and Gonads • Pharmacology: Patients with poison, toxicants and Heavy metals; Drug therapy monitoring; Trauma, Shock and Surgery • Diseases of Neuromuscular System: Investigations of Coma, Stupor, Neuropathy, Myopathies,CSF chemistry • Diseases of CVS: Degenerative vascular disease, Chest pain, Cardiac failure, Hypertension • Diseases of Neuropsychiatry: Acquired and genetic mental deficiency • Diseases of Pregnancy and Neonatal Period: Monitoring pregnancy; Inborn Errors of metabolism; Neural Tube Defects/Lung maturity • Cancer and Tumor markers
- 63. Questions • Describe DKA with mechanism, clinical manifestations and management (CCSU 2017) • Describe Diabetes type 1 and type 2 mechanisms with complications • Describe Metabolic Syndrome involving different organs • Write short Notes: Diabetes mellitus Fatty Liver, Trauma & Critical illness, Metabolic Syndrome, Atherosclerosis, Starvation Obesity, Pregnancy and Lactation Life style Diseases
- 64. How Metabolisms in Different Organs Co-ordinate For Specific Tissue/Organ Functions To Keep Good Health or Develop Diseases? Carb,Protein,Lipid, V/MMetabolism Hormone Control Signs and Symptoms Clinical Manifestations Lab Tests Investigations ClinicalconditionMedicalCondition DifferentialDiagnosis Organ Function Tests Dis 1 Dis 2 Dis 3 Dis 4 Dis 5 T Op 1 Prevent T Op 1 Prevent T Op 1 Prevent T Op 1 Prevent T Op 1 Prevent T Op 2 Drugs T Op 2 Drugs T Op 2 Drugs T Op 2 Drugs T Op 2 Drugs T Op 3 Medical T Op 3 Medical T Op 3 Medical T Op 3 Medical T Op 3 Medical T Op 4 Surgery T Op 4 Surgery T Op 4 Surgery T Op 4 Surgery T Op 4 Surgery T Op 5 Discove ry T Op 5 Discove ry T Op 5 Discover y T Op 5 Discove ry T Op 5 Discove ry Physical Sign Sym+Lab Tests+Mechanism+Pathochemistry+ Incidence+ Diff.Diagnosis+ Treatment
- 65. Liver All cells Liver,Muscle GABADOPAGlutamine(Brain) Ca/P Bones,Muscle,Membranes Adipose ATP Fat (ETC+OxiPhos) Muscle, Liver, Kidney + GlycineHemeBilirubin (Hb in RBC) CO2 and O2+ H2OHCO3 - +H+ + ATP (Lungs and mitochondria)
- 66. Multi-Organ Metabolic Diseases • Diabetes • Obesity • Metabolic Syndrome • Fatty Liver • Trauma and Critical Illness • Infancy and Increased Metabolic Demand • Life Style Health and Diseases • Pregnancy and Lactation
- 67. Integrated Metabolism Keeps All Body Organs Functioning Well (Healthy State) Muscle glycogen,ATP,proteins BLOOD Liver lipids, amino acids Brain catacholamines,glucose Glycogen Adipose lipids Galactose, GLUCOSE Glycerol Glycolysis Nucleotide Metabolism • • Fatty acid synthesis Acetyl CoA Nucleic Acids (DNA, RNA) • Fatty Acids Beta Oxidation Acetoacetate Protein Synthesis • Cholesterol Ketone • Bile Salts, Hormones Bodies Amino Acids • • Urea Cycle • glycine • Heme metabolism • • Oxidative Phosphorylation Lecture 31 TCA Disturbed Metabolic Balance causes Metabolic and Life Style Diseases
- 68. Metabolism as Medical Practice Tool (Gene, Hormone, Enzyme Replacement, Metabolite Supplements, Drugs) NUTRIENTS Carbohydrate Protein Lipid Nucleic Acid Vitamin/Mineral Enzyme, Hormones Signal molecules •ENERGY-RICH MOLECULES •CIRCULATING METABOLITES END PRODUCTS Anabolism = Catabolism Imbalance Means Disease Energy Loss, metabolic deposits,enzymes/hormones/ signal molecules Medical Biochemistry Clinical Biochemistry MEDICAL PRACTICE or THERADIAGNOSTICS -THERAPY CORRECTS THE IMBALANCE (DISEASE HEALTHY STATE) Atoms Molecules Assemblies Organelles Cell Tissue Organs Environment, Age, Infection, Toxin DISEASES: CNS/BRAIN NEUROLOGY LIVER/GB GASTROENTEROLOGY KIDNEY UROLOGY LUNGS PULMONOLOGY BONES ORTHOPEDIC HEART/VESSELS CARDIOLOGY MUSCLES OSTEOPATHY OVARY OBS/GYN EYE OPTHALMOLOGY EAR,NOSE,THROAT ENT SKIN DERMATOLOGY Gene Added (Treatment)
- 69. How to approach for Treatment? Physical Examination: Sign and Symptoms Clinical Lab tests: Glucose, HbA1c Assessment of Disease burden and monitoring: Obesity with Diabetes Diabetes typing- Serum Glucose values (GTT), Microalbumin Treatment: Orlistat or Insulin Injections
- 70. Metabolism in Thera-nosis: Decision Making of Disease Burden and Therapy Physical Diagnosis(signs and symptoms) Laboratory Investigations Molecular Diagnosis Therapeutic Monitoring Home Referral to nodal Medical Center Open for Discovery Example: CORONA virus •Disease/Drug induced change in: •3D Structure of molecules, Chemistry, •Regulatory Kinetics of Enzymes, Hormone actions, Receptors •Metabolic control, •Molecule size, shape, localization, bioimaging BIOCHEMICAL DISEASE BURDEN CONFIRMED AND THERAPY RESPONSE IS GOOD Integrated Lab tests
- 71. 1. Metabolic Diseases • Obesity • Diabetes Mellitus
- 72. Obesity Physical Symptoms: Pear shape or Apple shaped Belly Fat ladden hanging bags Mechanism: Abnormal LEPTIN Insulin Resistance Hyperlipidemia High FFA, High LDL,VLDL Metabolic Syndrome or Syndrome X Diagnosis: BMI > 40 morbid obesity, Hypothyroidism, Depression Clinical Lab Test: TG >600 mg%, CHOL >250 mg%, VLDL >160 mg%, FBS: >100 mg% Intervention: Weight, Diet restriction, Bariatic Surgery
- 73. 16 y boy complained obese family history,sedentary, overeating habit, over wt, truncal obesity, lethargy, sleepness,yellow spot xanthoma. Orlistat & bariatic surgery responded. Obesity means excess adipose tissue mass load. Physical Sign & Symptoms: BMI >30: Girth 102 cm: FFT, Waist/hip >1 Grade:SevereObese(BMI >40);Morbid Obese(BMI 40-50); SuperObese(BMI>50) Lab Tests:TG 500,TC 350,LDL 250,HDL <25,FBG >250 mg/dL Etiology: Energy input = Energy Output regulation by endocrine+Vagus -Energy input: Wt gain(overeating) appetite falls, energy expenditure more(no physical activity Obesity by leptin trigger in hypothalamusintegrated Metabolism).Vagus Gut distention by Cholecystokinin Insulin,Cortisol,Y-neuropeptide,AgRP, MSH,MCH, Serotonin,Catecholamine,Endocannabinoids, Opiod signals from HypothalamusGlucose,Lipid,Protein Metabolic controlAppetite -Energy Expenditure: BMR+Food metabolism+Body heating (Adipostat hunger) +Thermogenesis(BAT,UCP1)(70%) + Exercise(20%). Role of ob-db gene-leptin+Receptor -Adipocytes(stroma+macrophages+lipids) release leptin,cytokine,complements,PAI1, Angiotensin,Adiponectin,Resistin,RBP4 Ob gene,db gene,fat gene, environment,diet and culture influence leptin(Hypothalamus)carb, bone, reproductive metabolismswt regulation(F<C) LEPTIN/POMC/PC-1/MSH/tub/fat genes mutationTG synthesis (Obesity). Associated Causes: Hypothyroidism,Cushing Syn,Insulinoma,Polycyst ovary,Genetic diseases (Pradderwilli,Laurence-Moon,Cohen,Carpenter,Frohlich Syn),Pregnancy,GH deficiency, Hypogonadism,Pseudohypoparathyroidism,Eating disorders,Smoking withdrawl. Comorbidities:CVS,CNS,GI,Respiratory,Malignancy,Psychotic,Orthopedic,Metabolic, Reproductive,Obs/Gyn,Surgical,Pelvic,Skin,Venous Clinical Evaluation: BMI,Diet,Exercise,Behavior,Personal habits,,Drug history,Lipid profile,Hormone profile Treatment: Wt loss,Hypocaloric diets,Behavior modification, eating no fat-complex carb-high fibre diet habits, Aerobic exercise; Drugs-phentermine,diethylpropion,mazindol,10 mg Sibutramine,120 mg x3 Orlistat. Bariatic Surgery(Roux-en-Y-Gastric Bypass) (complication- peritonitis)
- 75. 2. Diabetes Mellitus Symptoms: • Tiredness, Headache, Depression Diagnosis: • Controllable, Controlled and Not controlled Types:Insulin dependent DM type1(nextslide-case1) Insulin Independent DM type 2(next slide-case 2) Clinical Lab Test: FBS: >100-150 mg% (mild diabetes); >150-300 mg%(moderate diabetes); >300-500 mg% (severe diabetes) Post-prandial BS: >300-500 mg% ” ) HbA1c > 7 (severe diabetes) Treatment: Insulin therapy Lipid, Carbohydrate, Protein Metabolisms involved in liver, Muscle, Pancreas, Brain, Eye, Kidney organs
- 76. 10 y girl complained wt loss,thirst,urination,ab pain had diabetes family history. Physical Examination: thin, distress,dry mouth, Age <30(Autoimmune β-cell DM type 1; >30 DM type 2) Symptoms:Polyuria,Polydipsia,Wt loss,Paresthesia,Ketoacidosis, Muscle wasting, Hypotension Lab Test: GTT, FBS 411mg/dL,HbA1c 9,BUN 24,Na 93,Cl 93,K 5.4,HCO3 23, pCO2 23, Ketones +ve, WBC 11600(Glycosuria, Ketonuria, Microalbuminuria) Mechanism: Insulin Deficiency/less secretion/receptor defectHyperglycemia Autoimmunity destroys βcells (cf.Insulin resistanceDM type 2) ProinsulinInsulin+C-peptide --GLUT2-Glucokinase makes ATPK+ /Ca channels……...release insulin in blood. Insulin-receptor-Tyrosine Kinase(Phosphorylation)Mitosis, PI3 Glucose (liver) uptake in muscle & fat, Glycogen, Protein, Lipid synthesis and Gene regulation FastingGluconeogenesis+Glycogenolysis(low uptake),Lipolysis Postprandial state(insulin)Carbs,Fat,Protein Synthesis,(high uptake) Age,history,symptoms,Metabolism (hyperglycemia,Gases,Ketones)DM type 1
- 77. Diabetes Mellitus Type 1 Variants Differential Diagnosis: Gene+Glucose balance+ Environment+Insulin • Type 1:βcell destroyedImmunity and Idiopathic or Type 2:Insulin secretion(resistance) -Genetic DM(MODY1-6):Mutations in HNF4,Glucokinase, HNF1α,IPF1,HNF1β,NeuroD1,Mito DNA,K channel,c- peptide -Insulin action defect(type A resistance, Leprechaunism, Robson-Mendenhall syndrome,Lipodystrophy) -Endocrines(Acromegaly,Cushing disease,Glucagonoma, Pheochromocytoma,,Hyperthyroidism, Aldosteronoma -Exocrines: Pancreas, Neoplasm, Cystic Fibrosis, Hemochromatosis, Fibrocalculous -Genetic Diabetes: Down Syndrome,Klinefelter Syndrome, Turner Syndrome,Wolfram Syndrome,Friedreich Ataxia, Huntington Chorea,DMD, Gastrointstinal DM
- 78. DM type 1 Immune mediated DM type1Genes: HLA-DR3,-DR4,- DQ loci on insulin genesT cells linkage(haplotypes) DM1 if KetosisDM2(LADA) with virus infections Islet cell cytoplasmic antibodies: ICCA(IDDM), islet cells loss Islet cell surface antibodies: ISCA high titres decline later Islet cell antigen targets: Glutamic acid decarboxylase (Anti GAD Abs)IDDM in future Anti-Insulin Abs Idiopathic DM type 1(Insulinopenia,DKA):PAX-4(Arg133Trp) mutation No islet cell (β-cells developed) Pathochemistry: α-cell, δ, 𝑃𝑃cells stay. β − cells die (by autoimmunity)Inflammation,NO,Apoptosis,CD8+T cell cytotoxicity)No Insulin secretion(IDDM)+Hypoglycemia(high glucagon) DKA (Somatostatin arrests glucagon)
- 79. Integrated Metabolism in DM type 1 Insulin deficiency: High FFA(Adipose tissue lipolysis) 1.Low Muscle glucose utilization 2.Liver Glucokinase, Adipose GLUT4 genes Glucose Metabolism:Gluconeogenesis(Glucagon),Glucose uptake(A,M) + low Glucokinaseless dephosphorylation in liverHigh glucose in blood+Low glucose absorption(Kidney) Hyperglycemia,Glycosuria+Polyuria+Polydipsia+Polyphagia Lipid Metabolism: Less food energy(glycogen) storage(L,M)+TG synthesis(A)High FFA,TG(A,L,S) 1.MalonylCoA in mitochondiaKetone Bodies(smell in breath) L,B,H,M Hyperglycemia 2.Low Lipase cannot break TG down to FFA(Hypertriglyceridemia) Protein Metabolism: Low protein synthesis(High AA in blood) Gluconeogenesis(Hyperglycemia)
- 80. Self Tests in DM Type 1 • Serum Fructosamine (+ve) • Solid strip glucometer test( >250 mg%) • Lipid profile(high LDL, TG and Low HDL) • KFT, LFT, TFT, • Stress test (Poor tolerance) • C-Peptide (present) • Islet cell antibodies(Present) No Anti-Glutamic Acid Decarboxylase 65(Type 2) Latent Autoimmune Diabetes in Adults(LADA) (Type 1)
- 81. DM type 1: Differential Diagnosis • Secondary hypoglycemia: Tissues L,M,A, Overactive Endocrines of GH, Glucocorticoids, Catecholamines,Glucagon, Somatostin Carb intolerance(Hormone tumors); Drug; Liver cirrhosis;Muscle dysrophy; Adipose lipodystrophy,Obesity; Insulin-R acanthosis nigracans, Leprechaunism) • Non-DM Glycosuria: Renal Glycosuria Autosomal transmitted gene disorder of proximal renal tubule, pregnancy(high GFR)
- 82. MANAGEMENT OF DM Type 1: Treat hyperglycemia, Treat vascular complications, Good life style; Diet control; Inject Basal, Exogenous Insulin(Treat Gluconeo- gensis, Lipolysis, Ketogenesis, Glycogenolysis) Control glucose:Amylin peptide, Stem cell therapy Insulin once (for FBG 225-275,HbA1c 8-9) + Real- time glucose recording/insulin infusion pump+Education+Nutrition(FBG 180,HbA1c 7%)+check retinopathy,Neuropathy,Nephropathy Insulin dose by syringe,Pen,Pump,Inhaled: Insulin NPH(Lispro,Aspart,Glulisine,Glargine,Detemir) Complications: Lipodystrophy, Insulin resistance, Hypoglycemia
- 83. 53 y female complained weakness, thirst,4 times urination,,wt loss,pain in feet,,finger tingling,blurr vision,family history of kidney and diabetes . Physical Exam: Obese,100+ Kg,BMI 30,Pulse 76,BP 145/78, All ages, over fed, sedentary, Lab Test: RBS 46 mg/dL,Urine glucose 4+(No Ketones+Proteins),HbA1c 16.4%,TC 240,HDL 20,TG 415 Gene factor:Insulin resistance+ βcell loss Cyteine protease,Calpain-10 gene defect on chromosome 2 DM type 2 Variants: Maturity Onset Diabetes of Young: MODY2(mild,vasculature injury, diet works), MODY3(angiopathy, drug resistant) Insulin Mutations:Autosomal Dominant transmission Insulin receptor Mutations:Acanthosis Nigricans,Leprechaun phenoype DM associated with mtDNA mutation(MELAS):No Leu and Lys transfer(Hearing loss, Myopathy, Encepahalopathy, Lactic Acidosis, Stroke) Insulin Resistance Syndrome(Syndrome X, Metabolic Syndrome):High TG and BP,Low HDL,Hyperuricemia, Plasminogen Activator Inhibitor 1, Proinflammation state, Ab Obesity,ProthrombinATH Wolfram Syndrome: diabetes insipidus, optic atrophy, Deafness(DIDMOD) WFS gene Permanent Neonatal Diabetes: Mutations in ATP sensitive K channel subunits, Homozygous glucokinase No Insulin secretion in neonates (Sulfonylurea treat it)
- 84. • Pathochemistry of Diabetes Mellitus type 2: Impaired insulin secretion, resistance,high glucose production Overt DM(hyperglycemia, hyperinsulinemia, Resistancehigh PP Glucose β-cell damage (Defective Insulin-R-Tyr Kinase- Dephosphorylation-PI3 Kinase-GLU4)Lipid deposits(ATH), less FFA oxidation, lipid oxides,RO*,Mitogen PK paths, less ATP formed Abnormal fat metabolism: Muscle,liver,Adipose cannot use glucose+Insulin resistancePP Hyperglycemia(high FBG); Muscle glycogen stores Obesity-central,visceral: Adipocyte mass High FFA,Retinol Binding Protein-4,Leptin,TNFα,resistin, adiponectin,adipokine secretion (Insulin resistance in liver,muscle)Apetite,Wt gain FFA,adiponectinHigh liver glucose+Insulin resistanceInflammation IL-6+c-Reactive Protein) Impaired insulin sensitivity: Islet amyloid polypeptide(amylin) gene amyloid fibril deposited in islet cellsDamaged islet,B-cell,Glycemic control Lipid Production: Adipose Insulin resistance,Obesity High FFA,VLDL,LDL,TG(Liver LFT)Dyslipidemia, normal GTT • Risk Factors: DM 2 Siblings,BMI>25,Sedentary, Ex-IFG/IGT,GDM history,HT,HDL <35,TG >250,Acanthosis Nigricans(Polycystic ovary),CVD
- 85. 3.Diabetic Ketoacidosis contd. 22 y male complains vomiting and pain, drowsy, deep breath, fruit smell in breath. Diabetic ketoacidosis is high FBS, ketone bodies, organic acids by insulin deficiency(DM I/II). Possible causes are pneumonia,influenza,gastroentritis, UTI,pregnancy,Stroke, DMII (obesity,family history). Pathophysiology: 1.DKA with excess Glucagon, Catecholamines,Cortisol,GHGlycogenolysis. 2.In liver, low insulin causes reduced GLUT4transporter,gluconeogenesis, glycogenolysis, KB formation, fatty acid /amino acid mobilization from muscle, adipose tissue. 3.PFK and F2,6BisPase aftered by FDiP (Glucose formation) 4.Excess Glucagon reduces PyKinase, PEPCK(Glucose formation) 5.In liver, high glucagon FFAKB by CPT1(mitochondria) 6.KBlow pH, bicarbonate buffer system cause hyperventilation(low CO2)KASSMAUL, Ketodiuresis, high glucose with Na,K,Cl-,Ca,Mg,P electrolyte loss 7.High lactate cause acidosis, high FFAVLDL+TG(LP lipase); DM1 DKA Physical Symptoms: Nausea, Vomiting, Thirst, Dehydration, Tachycardia, Low BP, Fruity smell breath, Pain,Hyperglycemia, Deep breath, Cerebral edema,Tender abdomen, Pancreatitis, Appendicitis, GI perforation, Coffee vomiting, Oesophagus erosion, Lethargy, Stupor, Headache, Coma,Confusion, Pupil reflex..
- 86. • Diagnosis of DKA: Hyperglycemia,Ketonuria,Acidosis(Gases),KFT, Electrolytes, CRP, Amylase, Lipase • Management DKA: Fluid replacement,Bicarbonate infusion, Mannitol+Hypertonic saline used. • Prevention of DKA: Measure blood glucose Measure urine ketones(blood glucose >300 mg/dL) Drink fluid to maintain hydration Increase insulin Manage vomiting,hyperglycemia, low potassium
- 87. 22 y diabetic boy complained 2-day history of vomiting and abdominal pain with drowsy, deep rapid breaths with acetone smell. Diagnose & suggest management. -Physical Signs and Symptoms:Dehydration,Tachycardia, Ketonic fruity odor, Nausea, Vomiting, Thirst, Excessive urine, Abdominal pain, Cerebral edema, Headache, Pupil reflex -Clinical Manifestations:Hyperglycemia,Deep gasping(Kussmaul respiration),Coffee color vomiting, Stupor, Lethargy, Confusion, Coma -Mechanism: Low insulin results high blood sugar(DM-1) and Ketones+Organic acids in urine or DIABETIC ACIDOSIS as a result of Pneumonia, Influenza, Gastroentritis, Pregnancy, Stroke, Cardiac arrest, High cocaine intake. -Integrated Metabolism: Glucagon,Catecholamines, Cortisol,Growth Hormones Low Insulin/Glucagon Glut-4 Transporter Enzymes of Gluconeogenesis(L), Glycogenolysis (M) Hyperglycemia No β-Oxidation Ketogenesis Low pHMetabolic lactic+Ketoacidosis CO2 compensation by HCO3Buffer+ Ventilation(Kussmaul respiration) Ketones Osmotic Diuresis + Na/K/Cl/P/Mg/Ca Electrolyte Loss Dehydration FATG+VLDL DM1+CKD -Lab diagnosis: Blood glucose 250 mg/dL; Ketonuria, KetoAcidosis(low blood pH); Low GFR(Cr/U); Low electrolytes; High Amylase + Lipase; CT for fluid accumulation -Management and Prognosis: 1.Replace fluids+electrolytes; Insulin injection to reduce blood glucose + ketogenesis 2.Monitor heart rate and correct potassium levels(Hypokalemia Heart failure) Insulin given 3.Correct blood acidosis by NaHCO3 solution 4.Correct cerebral edema by iv mannitol+ 3% hypertonic saline 5.Follow up Hypo-glycemia/-Kalemia/-Phosphatemia; Thrombosis,RDS,GI bleeding 6.Monitor insulin resistance in pregnant mothers to save fetal loss -Prevention: Life style with regular insulin, Drink Water, Checks of FBS, ketones in urine
- 88. Diabetes Mellitus Complications 1. Diabetic Ketoacidosis(treatable), Hyperglycemia due to insulin deficiency, Volume depletion, Acid- Base Imbalance(emergency). 2. Hyperosmolar Hyperglycemic state(HHS): Signs: Polyuria,Wt Loss,poor oral intake, confusion, lethargy ,coma Physical Exam: Nausea,Vomiting, Ab pain, Dehydration, Kassmaul respiration,Hyperosmolality, Tachycardia, MI, Stroke,Mental retardation, Sepsis, Pneumonia Pathophysiology: Less fluid intake Gluconeogenesis muscle loss; Hyperglycemia Osmotic diuresisVascular depletion+No ketones Lab tests: Plasma glucose > 1000 mg/dL, pre-renal azotemia,High osmolality >350 mg/dL, highNa, High Lactate, No Ketonemia, small anion gap Treatment: 0.5-0.9 % saline Rehydration therapy to make Na levels 160140. Contd..
- 89. 3.Lactic Acidosis:Hypoxia, High anion gap, lactate(L)Metabolic Acidosis,No ketones Treatment: iv sodium bicarbonate,Dialysis 4.Vascular Complications: Hyperglycemia years decide: Microvascular(Retinopathy,Neuropathy, Nephropathy) within 20 yr DM 1 Macrovascular(CAD,Peripheral artery disease,Cerebrovascular diseases Non vascular (gastroparesis,infections,skin changes,hearing loss) long time DM 2
- 90. Vascular Complications of Diabetes Mellitus: Microvascular Complications: Ocular Complications 1.Diabetic Retinopathy:DM history & glycemic control -Proliferative (after long years)neovascularization near optic nerve,maculaVitreous hemmorhage,fibrosis,retinal detachment,Edema, hypoxia, HT -Nonproliferative(DM1 within 10 y)Aneurysms,blot hemorrhage,cotton wool spots,venous vessel caliber, abnormal retinal vasculature Treatment: In DM 1&2,Keep glycemic and BP control, Panetinal/Focal Laser photocoagulation Diabetic Cataract: Chronic hyperglycemiaLens protein glycosylation Glucoma:Iris neovascularizationclosed Iris angle glucoma 2.Diabetic Nephropathy:
- 91. Complications:Diabetic Nephropathy Symptoms: Nephrotic range proteinuria • Hypertension • Progressive renal failure(End stage Renal Failure) • Overt nephrotic syndrome (diabetic nephropathy is the common) • Diabetes mellitus of long duration (at least 10 years) • Poor glycemic control • Inadequately controlled hypertension • Microvascular disease(diabetic retinopathy and neuropathy). Risk Factors: Cigarette smoking, ethnicity, family history, Low Socioecomics Clinical Exam: funduscopy for diabetic retinopathy & limb examination • Volume state examination for evidence of the • Nephrotic syndrome • Blood pressure measurement • Vascular tree examination for atherosclerotic vascular disease, renal • Bruits. Investigations • Proteinuria on urine dipstick. • Urine protein:creatinine ratio >350 mg/mmol. • impaired renal function, • elevated HbA1c, elevated triglycerides. • diagnostic clinical grounds and renal biopsy , haematuria, short duration of diabetes, rapid decline in renal function, rapid onset of nephrosis, abnormal immunological investigations.
- 92. Diabetic Neuropathy Physical symptoms: Lazy,Apathy,Morning, Nausea,Wt loss,Diarrhea, hangover,Blurred vision, Diabetic foot,Gastroparesis Mechanism: Lab Tests: • High FBS(>600 mg%) • Poor insulin control • High Blood Urea,Cr • Low ADH • Low GABA levels • Low HT, serotonin Risks: Retinopathy, Nephropathy, Hypertension, CHD Therapy: Insulin pump, Vit A therapeutic dose, TricyclicAntidepressants,SSRI,AEDs
- 93. Diabetic Complications: NeuropathyBoth DM 1 and 2 show: Polyneuropathy(distal sensory loss, Hyperesthesia, Paresthesis,Dysesthesia)Numbness,tingling,sharp leg pain,burning feetLater Glycemic control, less pain, Poor sense in pelvis,legs,Poor ankle reflex,position sense Mononeuropathy, Loss of myelin/non-myelin fibers Cranial,Peripheral nerve dysfunction Pain, Motor weakness, Cholinergic,Noradrenergic, Peptidergic dysfunction of Multiorgan CVS,GIT,GUS, Endocrines Hypoglycemia,Poor Glycemic control, Eractile dysfunction, Anhidrosis feet(dry skin,cracks, ulcers) Diabetic Gangrene:No Motor/Sensory sensation, No pain/ inflammation,Ulceration(peripheral/small vascular disease) Infections Hammer toe, Claw toe,MTP Metatarsal heads,Charcot jointsBad Anhidrosis+less blood flow(foot skin fissures, PAD, infected cracks, UlcersAmputation Hypertriglyceridemia + Poor Glycemic Control Eruptive Xanthoma, Ankle NecrobioLipidicaDiabetes(NLD) Treatment: Education, Amputation,No S/A/T/ propranolol, Endarterectomy, Treat Pyogenic skin fungal candida infection at breast/Axilla, Vulvo-vaginitis, Glucoma, Pruritis
- 94. • Macrovascular Complications Large vessel diseases: Blood flow obstruction(Narrowing) causes coronary(MI), cerebral(Stroke), peripheral carotid artery(ATH), femoral (Ischemia, Angina, Impotance) artery diseases Management of DM2: 1.Weight reduction, 2.Hypoglycemic agents: a.Insulin stimulants-Chlorpremide,Tolazemide, Tolbutamide, Glimepiride,Glipzide,Glybutride,Repaglinide,Nateglinide; b.Biguinides-Metamorphin speeds up circulating glucose utilization (FBS,Lipid profile); c.Glycoside inhibitors(50-100 mg acarbose, 50 mg miglitol); d.Thiazolidiones (Rosiglitazone,Pioglitazone bind to PPAR γ-R); e.Insulin therapy (lean,renal/liver patients, in hospitals)
- 95. 4. Alcoholic Liver Disease Mechanism: Diagnosis: Fibrosis in liver cells Inflammation markers: ICAM,VCAM,IL,Cytokines(TNF,NFkB,IL) Complement activation, CMI, RES activity Treatment: Propylthiouracil (to counteract the enhanced metabolism and hypoxia of cells), chlorpromazine and S-adenosyl methionine (to stabilise cell membranes), corticosteroids, anabolic steroids and anti- cytokine treatment (to reduce the immune effects) Cirrhosis: Inflammation with accumulation of fatty droplets in hepatocytes in a macrovesicular pattern Ballooned hepatocytes containing Mallory bodies. Alcoholic hepatitis: fibrosis, inflammation and parenchymal cell damage
- 96. FATTY LIVER (Non-Alcoholic Fatty Liver Disease) • NO LIPOPROTEIN SYNTHESIS or Metabolic Block • No lipotropic factors(Vit E,Se,Choline, Betaine, Met, Linoleic acid,Pyridoxin,Pentothenate) • Starvation,High fat feeding,Uncontrolled DM, Twin LambDisease, Cattle ketosis • Orotic Acid Symptoms: NADH/NADTG, LactateGout (Alcoholic FD:Alcohol DH,Aldehyde DHLipogenesis)
- 97. Gout, Lesch Nyhan Syndrome • Gout is bone tophi, renal stones,inflammed joints • Acute joint/renal pain due to urate/uric acid crystals • Hyperurecemia, Spasticity, mental retardation, Self mutilation • HGPRTase deficiency due to RECESSIVE HGPRTase GENE on X-chromosome in males (females carrier) high Xanthine accumulation during brain development causes kidney failure • Treatment: Allopurinol relieves hyperuricemia (inhibits Xanthine Oxidase)
- 98. 5.Hypertension and Gradual Risk of CVD/CHD LDL-C (IV), LDL-Receptor TG HDL3-C • Asymptomatic, • High Diastolic BP • Normal Systolic BP Symptomatic, High Systolic BP High Diastolic BP Endothelial Dysfunction Atherosclerosis CVD/CHD Dyslipidemia Optimal risk Mild Risk Moderate Risk High Risk is MRI visible Pre-Hypertension Hypertension Diet Modification High LDL+ TG Carotid arteries Coronary Arteries Heart wall motion and wall defects Trans-Saturated fatty acidsAcyl-CoAAcetyl CoACholesterol deposits Triglycerides Solid calcium deposits Apo E,B100 Mechanism Thrombus deposits JNC criteria WHO criteria Left Ventricular Hypertrophy HMG.CoA-R
- 99. DyslipidemiaAtherosclerosisCoronary Artery Disease Stroke Risk factor Cause Age,Sex,Smoking Elderly Female smokers show high lipids,vasoconstriction Sedentary life style Poor physical activity Obesity Blood lipids & Abdominal fats Diet High Carb,Saturated fats Hyperlipidemia High cholesterol,TG Diabetes mellitus,HT DyslipidemiaCAD LP(a) Atherosclerosis Hypothyroidism Hypercholesterolemia Hyperhomocyteinuria Risk of CAD • Stop smoking, • Regular physical exercise, • Weight management, • MUFA+PUFA rich diet, • Low Cholesterol diet • No egg,butter, meat,drugs • Maintain BP
- 100. 6. Metabolic Syndrome(Insulin Resistance Syndrome) 64 y man complained dizziness, numb legs, BP 200/120 mm Hg, BMI 32, sedentary life style with Obesity, Hyperglycemia, Dyslipidemia, Glucose intolerance. Metabolic Syndrome or X-syndrome or insulin Resistance Syndrome: Metabolic factors (age, genetic) increase the risk of atherosclerosis,CVD, heart failure(arrhythmia, ,thrombosis) Metabolic Syndrome (HT, Dyslipidemia, Insulin Resistance, Inflammation, Fibrinolysis, Central Obesity, Procoagulation). Definition: National Cholesterol Education/Adult Treatment Panel III Criteria: Waist circumference M/F 102/90 cm, TG 150 mg/dL, BP 130/85 mmHg, HDL-C <40/50,FBS 110 mg/dL Physiochemistry: Metabolic + Risks (Obesity, Dyslipidemia, HT, Insulin resistance, Proinflammation, Thrombosis)
- 101. Metabolic Syndrome • No Insulin Use in body due to: Obesity+Dyslipidemia(High TG+low HDL)+High Plasma Glucose+Hypertension Metabolic Syndrome: TG >150 mg/dL BP: >130/85 mm Hg Fasting Glucose: >100 mg/dL High plasma fatty acid and Acetyl-CoA Ketone bodies Hyperglycemia: Low glycolysis, more gluconeogenesis Insulin resistance (more circulating insulin) Hyperuricemia, Microalbuminuria, High CRP Prevention: exercise, low fat-low salt, low-weight
- 102. Acetyl CoA, ATP, NADH Glucose Amino Acids Fatty Acids Nucleic Acids Diet Overflowing Glucose Deposited amino acid products Deposited Lipids Loss in Nucleotide phosphates Metabolic Imbalance: Disturbed Integration of Transaminases, Gluconeogenesis, Ketolysis, Lipolysis By Poor Hormone Regulation, Messenger Molecules, poor Enzyme Reactions Control and low Synthesis of proteins Leads to Metabolic Syndrome Low Glucose, Lipids, Low vitamins Insulin resistance Dyslipidemia Obesity, Hypothyroidism, Diabetes, Cardiovascular diseases (Hypertension, Atherosclerosis, Stroke, Heart Attack)
- 103. Metabolic ImbalanceMetabolic Syndrome Anabolism = Catabolism NUTRIENTS SUPPLY IN BODY Lipids Polysaccharides Proteins Nucleic Acids Lipolysis Glycogenolysis Proteolysis Digestion Fatty Acid/Glycerol Glucose Amino Acids Nucleotides Fatty Acid Oxidation Glycolysis Degradation Degradation Acetyl CoA Pyruvate Acetyl CoA NH3 Pyrimidines/Purines Ketone Bodies TCA cycle Urea Cycle Uric Acid NADH/FADH2 CO2 Urea CO2 B-NH2-Butyrate Oxidative Phosphorylation ATP Aminoacid Gluconeogenesis Fatty Acid Synthesis Synthesis Amino Acids + Glucose + Fatty Acids Protein Synthesis Nucleotides Glycogen Triglycerides Lipid, Steroids, Ecosanoids Biogenic Amines Nucleic Acid Catacholamines Synthesis Heme RNA,DNA Cytosol: Glycolysis, Pentose Phosphate Pathway Fatty Acid Synthesis Mitochondria matrix: Citric Acid Cycle, Oxidative Phosphorylation, B-Oxidation of fatty acids Ketone Bodies Gluconeogenesis Urea Cycle Microsome: Drug metabolism Peroxisomes: Xenobiotic metabolism Free radical metabolism
- 104. a.Abdominal Obesity 1.Abdominal fat(lipolysisFFA under skin) HT,LDL- C,low HDL-C,Hyperglycemia,CVD 2.Viseral fat(FFA in liver)waist circumference b.Dyslipidemia 1.Insulin resistance or High TG(TG+FFA)Apo-B 2.Low Cholesterol Ester Transfer ProteinLDL-C,low HDL-C,TG >180 mg/dL(damage GAG in endothelium,Oxidation Stress,Macrophage Receptor)VLDL1/2Atherogenesis c.Hypertension 1.Insulin vasodilator+Na resorption+PI3Kinase Endothelium NO,Endothelin-1 Low blood flow(HT) d.Low Insulin <200 U Ketosis 1.Insulin Receptor mutations,GLUT4 2.Diet,Physical activity,Glycemic control,FFA,Aging
- 105. METABOLIC SYNDROME Hypertension >130/85 mmHg Triglycerides High FBS >150 mg/dL Metabolic >110 mg/dL Syndrome HDL-C Abdominal Obesity <40 mg/dL(man) waist >40” (man) <50 mg/dL(female) waist>35”(female)
- 106. Clinical Manifestations • Waist circumference, High BP, Signs(lipoarthropathy,Acanthosis nigricans) • CVD • DMII • Nonalcoholic fatty Liver Disease • Hyperuricemia • Microalbuminuria • Polycystic Ovary Syndrome • Obstructive Sleep Apnoea
- 107. Diagnosis:Metabolic Syndrome • Monitor body weight • BMI • Waist circumference measurement • Hip-waist ratio • Subcutaneous fat measured at bicep,tricep,subscapular,suprailliac sites • BP measurement • FBS and lipid profile, ApoB,CRP,Fibrinogen,Uric Acid,Microalbumin,LFT • Testosterone, LH,FSH,Anovulation for PCOS
- 108. Treatment:Reduce DMII+CVD • Insulin Resistance by life style (diet,exercise, weight reduction,aerobic exercise) low CVD • Biguanides, thiazolidinediones for insulin sensitivity in liverGlucose uptake in muscle,adipose tissue,PCOS,NonAlcoholic FLD • Treat the lipids Keep Low HDL,LDL,TGWeight loss,Exercise, Drug therapy • Treat Hypertension Statins,fibrates,niacin, Aspirin, Antihypertensive ACE inhibitor,Angioensin receptor blockers,Calcium channel blockers,thiazide,βblocker • Treat FBS, glycemic control (TG+HDL) by life style (wt mgt,diet,physical activity) • Life Style Modification Wt mgt,physical activity, nutrition therapy,immunity boost(MY-IDEAprogram).
- 109. 7.Hypercholesterolemia and Gall Stones Physical Symptoms: Pain in upper right quadrant Mechanism: High ratio >3 of HMG CoA Reductase/Cholesterol 7α Hydroxylase causes more cholesterol synthesis In bile(bile salt+cholesterol+phospholipids), High cholesterol synthesis inhibits bile salt formation and precipitation makes GALLSTONES CDCAFarnesoid X Receptor7αHydroxylase high •Clinical Lab Test: Plasma CHOL: >250 mg%, TG >160 mg%, PL < 50 mg% Diagnosis: Cholelithiasis Intervention: •Diet low in cholesterol, Fibrate drugs, synthetic Bile salts CDCA Surgery: •Laproscopic cholecystectomy (Gall Bladder removal)
- 110. 44 y female complained midepigastric discomfort, nausea/vomiting with severe pain soon after oily meals and later relapsed. Lab tests showed high S.cholesterol, US showed gall stones in normal gall bladder wall. Physical Signs and Symptoms:Abd. upper quard. pain, Sudden wt loss or High carb diets, Obesity or no physical activity, Crohn diseaseintestine Clinical Manifestations: Colic pain in gall bladder & lower abd, Pancreatitis Cholangitis(fever, chills, jaundice), Peritonitis, DM, Cirrhosis, Hepatitis Mechanism: Cholelithiasis(Gall Stones) High ratio Pathophysiology: 1.HMGCoA-R(CyP7A1) poor control over bile acid synthesis 2.Saturated Bile(Cholesterol+PL+Bile salts)C Crystals 3.Low Acyl CoA:Cholesterol AcylTransferase(ACAT)C 4.Deoxycholate BS inhibits HMG-CoA-Reductase . Diagnosis:Elevated cholesterol, bilirubin, ALT/AST in serum, Cholesterol Gall stones by US/CT/ERCP Treatment: Low fat diet, BS,Gall bladder Laparoscopic cholecystectomy Prognosis: Low carb-high MUFA/PUFA-high fiber diet, physical activity, caffinated coffee HMGCoA Reductase -------------------------------------------- Cholesterol 7α Hydroxylase
- 111. 8.Atherosclerosis • Atherosclerosis: Cholesterol deposits in arteries cause lumen narrowing, Plaques • Smooth Muscle Cells in artery make foam cells and deposit lipids, cholesterol • Endothelial layer dysfunction in carotid and coronary arteries • Very less blood reaching in heart and brain cause death
- 112. 51 y male complained chest pain since a year spreading from chest to left side with nausea and sweats. On examination,ECG showed high ST-QRS changes. Lab tests showed high cholesterol,LDL-C. Discharged with Lovastatin + Telmasartan & low fat diet. Physical Signs/Symptoms:Chest pain with sweats,High BP Mechanism: AcetylCoAHMGCoA Mevalonate; MevalonateIsoprene; 6 IsoprenesGPFPSqualene; CyclizationLanosterolCholesterol LDL-C/HDL-Cholesterol Lovastatin arrests cAMP-HMGCoA Reductase Dephosphorylation Thyroid Hormones+Insulin enhance Sterol Regulatory Element BP Diet Risk: Butter,Beef, Palm Oil, Starch/Sucrose/Fructose Physical Examination: Pale, diaphoretic, HT, Hypotension(ventricle dysfunction,Ischemia,RVI), Acute valve dysfunction, Mitral regurgitation, Neck vein distension, Heart S4 sound, Dysarrhythmia, Fever, Peripheral pulses, ST segment > 1 mm and new Q waves (MI), depressed ST-T wave, inverted T wave(immediate MI) Lab Tests: CPK, CK-MB, Troponin, Myoglobin, LDH, CBC, C-reactive protein, Lipid profile, Creatinine, K+, Mg++ levels, ESR, plasma homocyteine levels Imaging tests: Chest radiography, Echo, 99mTc scan, Thallium scan, CT scan, MRI, Coronary artery calcium Pathophysiology: Cholesterol+EstersVLDL+LDL deposits cause atherosclerois with DM, Nephrosis, Hypothyroidism Ischemic HDCHD Narrowed arteries, Atherosclerosis plaques, coronary thrombosis, platelet aggregation, coagulation, endothelial injury, myocardial necrosis, STEMI; Occluded/Thrombus in AD branch(ALV, IVseptum MI), LCA branch(AL or PL MI), Right coronary branch(PInf LV or RV MI) with AV block or sinus node block. Causes of Atherosclerosis: Thrombus formation due to age, male, menopause, pre CAD/CHD; Smoking, Alcohol, HT, DM, Obesity, Dyslipidemia, High homocysteine, baldness, slow life, stress; Vasculitis, Coronary emboli, trauma, spasm, high oxygen needs, exersion Clinical Manifestations: Chest pain, Left arm pain, Dyspnea, Nausea, Vomiting, Infarction, Anxiety, Syncope, Diaphoresis, Fatigue, Dementia Treatment: General care by oxygen supply, pulse oximetry, iv aspirin, Nitroglycerin spray, Telemetry and ECG Perfusion restoration (myocardium salvage) by PCI or CABG Medical therapy: Antithrombotics(aspirin, heparin), Vasodilators- Nitrates, Beta-adrenergic blockers, Thrombolytic agents (Alteplase, Tenecteplase, Anistreplase, Streptokinase, Reteplase), Platelet aggregation inhibitors (Clopidogrel, Eptifibatide, Tirofiban, Abciximab), Analgesics(Morphine), ACE inhibitors(Captopril), Angiotensin receptor blocker(Telmasertan), Calcium channel blockers (Diltiazem, Varapamil) Surgery: Percutaneous coronary intervention, CABG
- 113. 9. Starvation 25y women complained weakness,lethargy, pain,pale, long fast.Lab Test: High Ala, acetoacetate, Hydroxybutyrate, BUN,Normal glucose,1800 Kcal diet. Mechanism: In Muscle AlaGlucose in Liver(Cori cycle); Acetoacetate+βHB; BUN; Amino acidsUrea Starvation: No food results High glucagon, Low Glu,AA,TG Glycogen,Protein,TG (circumvent in liver,adipose, muscle,brain tissues) Energy supply (glucose to RBC and brain, adipose FFA ketone bodies reach to brain). Total 161000Kcal body store for 3 months. Energy Supply: 1.Gluconeogenesis: Brain need 40 mg/dL;TGGlucose;AAGlucose; Ketone bodiesGlucose; 2.Fatty Acid Oxidation: Glucagon stimulates TG(adipose)ATP(liver); β-OxidationAcetyl CoA-- PDH (muscle); Pyruvate AlanineKeto acids, lactate go to liver, AA go to muscle In liver, heart,muscle, TG,FFA Lipolysis to Glycerol by lipaseGlucose 3.Ketosis: AcetylCoAAcetoacetate, β-OH butyrate(Ketogenesis); Low OAA,KBATP(Brain,Heart); Protein breakdownFunction loss HLK
- 114. Fatty Acid Oxidation & Ketones Triglycerides Fatty Acids β-Oxidation Fatty Acids Actoacetate Acetyl CoA TCA cycle ATP Acetyl-CoA CO2+H2O CoA Acetoacetate β-HydroxyButyrate β-HydroxyButyrate STARVATION Liver Peripheral Tissue
- 115. 10.Fatty Liver • Symptoms: hepatic failure, low metabolic activity, nausea, vomiting, yellow eyes, lethargy, Ab.pain,jaundice, mental depression,bleeding,polyuria,polydipsia,infection,encepaho pathy. • Fatty Liver: TG in liverFibrosisCirrhosis 1.TG synthesis or TG-Lp or FFA(adipose) FFA in blood Fatty Liver(VLDL) or starvation or fat diet or uncontrolled DM 2.Blocked plasma LpTAG accumulationLesion(Apo LP synthesis block; Lp synthesis block; PLs blockedFatty liver • Factors: Obesity,DM,Hyperglyceridemia, Drugs (steroids, amiderone,diltiazem,tamoxifen,antivirals), poisons, Endocrinopathies,Obs Sleep Apnoea,Starvation • Treatment: MgSO4 to prevent seizures, blood replacement, hyptertension management. 20 y female 36 wk gastation had nausea, vomiting, yellow eyes, BP 190/110 mmHg, proteinuria,high LFT,long CT,bilirubin,fibrinogen, low glucose. In Fatty liver condition, operated cessarian. After developed hypoglycemia,renal failure, coagulopathy, coma.
- 116. 11.Trauma and Critical Illness • Endocrine, Metabolic, Immunological changes Stress due to: Hypothalamus-Pituitary-Adrenal axis Cortisol, Epinephrine, Glucagon, GH Adipose FFA,TGEnergy Protein degradation(L) • Metabolic Response: High Catecholamines,Cortisol High TG,FFA breakdown rate+ve N2Protein Synthesis Muscle loss • Post-Trauma Response: Lipid breakdown: ACTH,Cortisol,Catecholamine,GH,Glucagon,Insulin stimulate FFA+TGGluconeogenesis,LipolysisGlucose+Energy Protein breakdown: Glucocorticoids wt loss Carb breakdown: Hormones,Cytokines LactateGlu. Insulin: Glucagon,Catecholamines,Cortisol,GH Glu.
- 117. Pregnancy and Lactation • Hormonal Changes(Estrogen, Progesterone, Ca++,β-hCG, Prolactin, PTH, Cortisol,Aldosterone) • Cardiovascular Changes(AldosteroneHR, CO, Stroke Volume) • Hematological Changes(Coagulation VIII,Fibrinogen) • Metabolic Alterations(Protein, Carb metabolism) • Nutrition(300 kcal energy + 75 gm protein + 0.8 mg Folate)/day • Renal Function(50% GFR,low urea+Creatinine,Glucosuria) • Pregnancy Conditions(DM,HT,Albuminuria,Convulsions)
- 118. 12. Lactation • In 3rd,Galactopoiesis due to placenta lactogen + PRL • GlucoseLactose+TAG;AAProteins • Proteolysis,Gluconeogenesis,Lipolysis Lactogen • PRL Alveoli,ducts, milk formation • OxytocinMilk Formation • Estrogen Milk ducts • High PRL Galactorrhea Milk Production
- 119. Infancy and Increased Metabolic Demand • Gluconeogenesis in brain(low glycogen & fats) • TPN is choice
- 120. 13.Life Style Health and Diseases(MY-IDEA) • Diet, Habits, Environmental pollution • Practice of healthy eating,Exercise,Yoga,Meditation • Atherosclerosis,Hypertension, CAD,CHD,Stroke, Obesity, DMII,Smoking/Alcohol abuse • Cancer,Chronic liver disease, Cirrhosis,COPD, Alzheimer Disease, Kidney Disease National Health Policy • Reduced CVS,Cancer(Cervix,Breast,Oral), Diabetes, Chronic Respiratory Disease, Hypertension • Modifiable (Diet, Habit, Metabolic) and Non- modifiable Factors(Family, Genetics)