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LIPID METABOLISM. Metabolism (Catabolism and Anabolism), Regulation and Importance of fatty acids (FÂ) and lipids and clinical applications FÂ -Saturated.

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Presentation on theme: "LIPID METABOLISM. Metabolism (Catabolism and Anabolism), Regulation and Importance of fatty acids (FÂ) and lipids and clinical applications FÂ -Saturated."— Presentation transcript:

1 LIPID METABOLISM

2 Metabolism (Catabolism and Anabolism), Regulation and Importance of fatty acids (FÂ) and lipids and clinical applications FÂ -Saturated FÂ -Unsaturated FÂ -Monounsaturated FÂ -Polyunsaturated FÂ -Eicosanoids

3 Lipids Storage lipids ; Fat, oils Membrane lipids Phospholipids Glycolipids Cholesterol Precursor & derived lipids Sterols Polyprenoid compounds

4 FA TG FA MGGLYCEROL FA DG CHOLESTEROL – FA = CH. ESTER R – COOHcarboxylic acid R – C - acyl=FA - O FA P PA FA P-X PL FA P-X LYSO-PL PA=phosphatidic acid PL=phospholipid =phosphatidyl - x ( x = choline ; lecithin ) LYSO - PL=lysophosphatidyl - x MG=monoacylglycerol CTP=cytidine triphosphate CDP=cytidine diphosphate FA

5 small intestine dietary lipids and proteins gall bladder pancreas secretin (in blood) gut endocrine cells (enlarged) cholecystokinin (in blood) stomach gastric motility bicarbonate pancreatic enz. bile secretes duodenum Hormones action gastrin intestinal motility

6 LCTG MG FA G CH.E CH FA PL LPL FA MG FA G CH FA LPL FA TG CH.E PL apoprotein chylomicron MCTG FFAG Int. lipase portal vein target tissue lymphatic TG, CHE, PL, PROT. FCH + alb DIGESTION AND ABSORPTION OF LIPIDS pan.lipase

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8 CHYLOMICRON

9 dietary lipids gall bladder pancreas pancreatic juice bile defective cells liver small intestine Intestinal mucosal cells Excess lipid in feces (steatorrhea) Ca ++ + FA Ca SOAP Possible causes of steatorrhea : Feces : bacteria ¼ - ½ total large intestine bile pigment stercobilin ( สี feces ) steatorrhea

10 Orlistat (xenecal, tetrahydrolipstatin) - Inhibit gastric and pancreatic lipases - Obesity, non-alcoholic steatohepatitis (NASH) treatment

11 ENZYMES DIGEST LIPIDS : LIPASE FA TG FA+ 2FA MG + 3FA GLYCEROL ; 12 PANCREATIC (CO-LIPASE) : LC-FA 2.1gastric : SC&LC-FA (30% in adults and 50% in infants) 2.2lipoprotein (extrahepatic tiss.) TG in chylomicron, VLDL activated by heparin, apo –C-II 2.3hormone sensitive lipase in adipocyte : stim.:Gg, Epi, T 4, etc. inh.:Pgs, Is 2.4Int. Lipase : MCTG 2.5 lingual lipase 1 2

12 FATTY ACIDS : 1.CHAIN :RCOOH short chain (SC) medium chain (MC) long chain (LC) very long chain (VLC) ( 20) 2.ODD CHAIN :WAX ( C 25 – C 35 ), EVEN CHAIN VS. 3.SAT. VS. UNSAT. : SAT. :palmitic acid ( C 16 : 0 ) stearic acid ( C 18 : 0 ) CH 3 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 COOH    UNSAT. :oleic acid ( C 18 : 1 ▲ 9 ) palmitoleic acid ( C 16 : 1 ▲ 9 ) LINOLEICLINOLENICARACHIDONIC 18 : 2 ▲ 9,12 18 : 3 ▲ 9,12,15 20 : 4 ▲ 5,8,11,14

13 FATTY ACID OXIDATION : supply energy : 40 % normal ; 90 + % - fast 3 ways :  - (major) ;  - &  - (minor) STEPS : activation : 2ATP (cyto -) GTP (FAs in mito -, severe starvation) transfer ( cyto mito ) - carnitine  - oxidation ( mito ) 1.DHase : FAD + 2.hydratase : + H 2 O 3.DHase : NAD + 4.thiolase : 2C end products : Ac. CoA ; propionyl CoA Krebs succinyl CoA palmitic ac. (C 16 ) + 23 O 2 16 CO H 2 O + E C 16 H 32 O 2

14 FATTY ACID ACTIVATION AND TRANSPORT RCOOH + CoA + ATP RCSCoA + AMP +PPi O Acyl CoA synthetase (thiokinase) SC-FA and MCFA can cross the inner membrane of mitochondria without the aid of carnitine or CAT system translocase Acyl CoA ligase Activation: cytosol Translocation: matrix

15 cytosol outerinner mito-memb. matrix PPi + AMP ATP RCOOH RCSCoA CoASH carnitine RCO-C RCSCoA CoASH RCOOH GDP + Pi GTP O III Acyl CoA-synthetase or thiokinase CAT I : carnitine acyl transferase I is inhibited by malonyl CoA and is stimulated by long chain fatty acyl CoA CAT II : carnitine acyl transferase II ACTIVATION TRANSLOCATION

16 Synthesized from lysine and methionine in liver and kidney but not in skeletal and heart muscles (MCFAs are plentiful in human milk) Deficiency cause cardiomyopathy and muscle weakness - liver disease - strictly vegetarian diets

17 BETA – OXIDATION (not found in nerve and red cells) FAR – CH 2 – CH 2 – CH 2 – C - OH O R – CH 2 – CH 2 – CH 2 – CO ~S CoA R – CH 2 – CH = CH – CO ~S CoA R – CH 2 – CH - CH – CO ~S CoA OHOHH R – CH 2 – C - CH 2 – CO ~S CoA O R – CH 2 CO ~S CoA + CH 3 CO ~S CoA GTP, CoA GDP, PiAMP, PPi CoA, ATP FADH 2 FAD - hydratase H2OH2O NADH + H + CoA SH THIOKINASE Acyl CoA - DHase ▲ 2- TRANS - ENOYL CoA L – 3 – OH – acyl CoA -DHase 3 – KETO – acyl CoA THIOLASE (  -)

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20 END PRODUCTS OF β - OXIDATION OF FA EVEN – CARBON FA : CH 3 – CH 2 – CH 2 – CH 2 – CH 2 - CH 2 – CH 2 – C ~S CoA O  1 23 n ครั้ง ; CH 3 CO.SCoA=n + 1 ODD – CARBON FA : CH 3 – CH 2 – CH 2 – CH 2 – CH 2 - CH 2 – C ~S CoA O PROPIONYL CoA + n ACETYL CoA SUCCINYL CoA “KREBS” “TCA” OAA GLUC. CO 2 + H 2 O + E

21 FATE OF PROPIONYL CoA : CH 2 CH 3 C ~ S CoA O HCCH 3 O C ~ S CoA COOH CARBOXYLASE ( B 7 ) ( BIOTIN ) CO 2 ATPADP, Pi PROPIONYL CoA D – Mt – MALONYL CoA CHH3CH3C O C ~ S CoA COOH L – Mt – MALONYL CoA MUTASE ( B 12 ) CH 2 CO ~ S CoA COOH SUCCINYL CoA B 12 DEF : PROPIONIC ; Mt – MALONIC ACID ACIDEMIA & ACIDURIA ( PERNICIOUS ANEMIA ) RACEMASE

22 Acyl CoA dehydrogenase 1. short-chain acyl CoA dehydrogenase - oxidised 4 and 6 carbon 2. medium-chain acyl CoA dehydrogenase - oxidised carbon 3. long-chain acyl CoA dehydrogenase - oxidised carbon Medium-chain acyl CoA dehydrogenase deficiency - deficiency of ketone bodies but high in dicarboxylic acid (use ω-oxidation instead) - fasting hypoglycemia sudden infant death syndrome - avoid excessive fasting

23 hyhoglycin from unripened akee fruit inhibits acyl CoA DH hypoglycemia Vomiting, convulsion, coma, death (Jamaican vomiting sickness)

24 BETA - OXIDATION C 16 S CoA  O BETA - OXIDATION PALMITIC ACIDAc. CoA ( n+1 ); n = BETA - OXIDATION OLEIC ACID:C 18 : 1 ▲ 9 CIS- O S CoA CIS S CoA + 3 Ac. CoA 312 ▲ 3 - CIS - O O S CoA 2 12 ▲ 2 - TRANS - 6Ac. CoA ISOMERASE SAT. UNSAT. double bond at an odd-numbered carbon

25 UNSAT. double bond at an even-numbered carbon CoA 5

26 POLYUNSAT. Acyl CoA DH

27 cis

28  -oxidation of very long chain fatty acid - Peroxisome - Membrane transport is unknown - Peroxisomal oxidation differs from β-oxidation in the initial dehydrogenase reaction - FADH 2 of acyl dehydrogenase in peroxisome transfers electron to O 2 to yield H 2 O 2 - Catalase is needed to convert H 2 O 2 into H 2 O and O 2 - Subsequent steps are identical with β-oxidation

29 H 2 O + 1/2O 2 catalase Acyl-CoA DH hydratase DH β-ketothiolase

30 Zellweger syndrome (cerebrohepatorenal syndrome) - in the family of leukodystrophies - result from the defect in the import of enzymes into peroxisome and cause defects in peroxisomal β-oxidation leading to accumulation of very long chain fatty acid in plasma and tissue body - characterized by liver, kidney, brain and muscle abnormalities - Death by age six to twelve

31 Symptoms -Enlarged liver - Lack of muscle tone, an inability to move, suck and/or swallow - Glaucoma ( ต้อหิน ) - Mental retardation, seizure - albuminuria

32 พลังงานจากการสลายกรดไขมัน กรดไขมันแต่ละชนิด ให้พลังงานไม่เท่ากัน ขึ้นอยู่กับ จำนวนคาร์บอน และ unsaturation ตัวอย่าง 1. การสลายกรด palmitic ; ( กรดไขมันอิ่มตัวมีคาร์บอน 16 ตัว ) ได้ 106 ATP C 16 : 0 palmitoyl CoA CH 3 – CH 2 – CH 2 – CH 2 – CH 2 - CH 2 – CH 2 – C ~S CoA 8 acetyl CoA 16 CO 2 Activation  - oxidation x 7 TCA cycle x 8 AMP (FADH 2 + NADH) x 7 = 4 ATP x 7 (3NADH + FADH 2 + GTP) x 8 = 10 ATP x ATP 28 ATP 80 ATP Net = 106 ATP

33 2. การสลายกรด stearic ; ( กรดไขมันอิ่มตัวมีคาร์บอน 18 ตัว ) ได้ 120 ATP C 18 : 0 Activation  - oxidation x 8 TCA cycle x 9 18 CO 2 AMP - 2 ATP 4 ATP x 8 32 ATP 10 ATP x 9 90 ATP Net = 120 ATP 3. กรดไขมันไม่อิ่มตัว จะเป็นไปตามปกติ จนกว่าจะถึงพันธะคู่ ของกรดไขมัน ซึ่งเป็นแบบ cis จะต้องมี เอนไซม์อื่นช่วยเปลี่ยนให้เป็นแบบ trans เพื่อให้ เอนไซม์ตัวที่ 2 ของ  - oxidation ทำงานได้ เนื่องจากมีพันธะคู่แล้ว จึงไม่ได้ FADH 2 (1.5 ATP) ทำให้ได้ พลังงานน้อยลง 1.5 ATP ต่อ 1 พันธะคู่

34 ^  - OXIDATION OF FATTY ACIDS : - MICROSOME, PEROXISOME, MITO. (HEART, LIVER, OTHERS) - BRANCHED CHAIN FA,  -OH – FA ( CEREBROSIDE in brain) CH 3 CH 2 CH 2 COOHCH 3 CH 2 COOH + CO 2 COOH ( PHYTANIC ACID ) PHYTOL ( CHLOROPHYLL IN GREEN VEGETABLE ) O COOH OH COOH O OH + CO 2 O  Hydroxylase, Vc (dioxygenase), 4H-biopterin O2O2 H2OH2O H2H2 REFSUM’S DISEASE (phytanic acid storage disease) -hydroxylase deficiency -slowly progressive peripheral neuropathy with weakness and muscle wasting, combined with blindness -avoid green vegetables dehydrogenase Pristanic acid Isobutyryl CoA 3 Acetyl CoA3 Propionyl CoA  -OH – FA Lyase + oxidation

35 + O 2 CO 2

36  - OXIDATION OF FATTY ACID : - LIVER MICROSOME - MEDIUM, LONG CHAIN FA. - OXYGENASE SYSTEM : ANIMAL : CYT. P 450, NADPH 2 BACT : RUBRIDOXIN : HC, DETERGENT COOHH3CH3C   H2CH2C OH HC O HOC O COOH O2O2  -

37 FA OXIDATION :  -  -  - 1.SITEmito microsome 2.ORGANgeneral general, brain L, others 3.P’ waymajor minor 4.FAeven, oddBr, OH -MC, LC sat, unsat 5.ENZYMEmulti oxygenase ( hydroxylase ) 6.PRODUCTS :Ac. CoAFA ( - 1C )  - Propionyl CoA + CO 2 DI - COOH 7.NEXT O :TCA  -  - ^ ( KREBS )

38 LIPOLYSIS summary

39 -liver -mitochondrial matrix -significant amount of HMG-CoA synthase* -HMG CoA synthase is a rate-limiting enzyme -stimulated by fasting, dietary fat, insulin deficiency KETOGENESIS *

40 KETOLYSIS EXTRAHEPATIC TISSUES -brain, heart, kidney, skeletal tissue -mitochondrial matrix -significant amount of  - ketoacyl-CoA transferase (thiophorase)* - stimulated by fasting, dietary fat, insulin deficiency *

41 KETOGENESIS AND KETOLYSIS

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43 Myocardial ischaemia reduced O 2 anaerobic glycolysis lactate increase cell acidosis  -oxidation acetyl CoA increase ketone bodies increase cell acidosis

44 trimetazidine inhibits  -ketothiolase in  -oxidation inhibits fatty acid oxidation increases carbohydrate oxidation reduces lactate production higher cell pH reduces angina pectoris (chest pain)

45 FA SYNTHESIS : cytosol, ACP palmitic acid Acetyl CoA + 7 malonyl CoA + 14 NADPH 2 Palmitic Acid (C 16 ) + 8 CoA + 14 NADP CO H 2 O - liver, lactating mammary gland, adipose tissue Note: ACP = acyl carrier protein

46 A. Production of cytosolic acetyl CoA fat

47 B. Carboxylation of acetyl CoA to form malonyl CoA

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49 CONTROL OF FATTY ACID SYNTHESIS NADH, Citrate activates acetyl CoA carboxylase Long chain fatty acyl CoA inhibits acetyl CoA carboxylase

50 C. Major sources of NADPH required for fatty acid synthesis 1.Pentose phosphate pathway (major) 2.NAD(P) + - dependent malate dehydrogenase (malic enzyme) (minor)

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52 D. Fatty acid synthesis Palmitoyl thioesterase (TE) Liberation of palmitate product

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54 TE

55 FATTY ACID SYNTHESIS transferase transacetylase synthase

56 FATTY ACID SYNTHESIS TE

57 1.MITO : SAT. FA ; Ac. CoA 2.MICROSOME : SAT., UNSAT. FA ; Mal. CoA R CH 2 COSCoA + 2 NADPH 2 + ACETYL CoA( MITO ) R (CH 2 ) 3 COSCoA + 2 NADP + + CoA FA ELONGATION : elongase 3. PEROXISOME : VERY LONG CHAIN FA : Ac. CoA Peroxisome are required for normal brain development and function and formation of myelin, the whitest substance that coats the nerve fiber and are also required for normal eye, liver, kidney and bone functions. Defects called Zellweger syndrome.

58 β-trans-Enoyl-CoA reductase

59 FA. DESATURATION : SAT. FA UNSAT. FA - MICROSOME ; ER of liver, adipose tissue - MONOXYGENASE SYSTEM : NADPH 2, O 2 CH 3 – (CH 2 ) 7 – CH 2 – CH 2 – (CH 2 ) 7 –COOH + NADPH 2, O 2 CH 3 – (CH 2 ) 7 – CH = CH – (CH 2 ) 7 –COOH + NADP + + 2H 2 O desaturase

60 DESATURATION OF FATTY ACID non-heme iron

61 FATTY ACID SYNTHESIS IN PLANT AND ANIMAL (in mammals) essential fatty acid deficiency - dermatitis - poor wound healing EPA and DHA support neural and visual development Eicosanoids synthesis (ω6-series)

62 Linoleic, C 18:2 9, 12  - Linolenic, C 18:3 9, 12, 15 (C 18:2n-6) (C 18:3n-3)  - Linolenic, C 18:3 6, 9, 12 C 18:4 6, 9, 12, desaturase (C 18:3n-6) (C 18:4n-3) elongase Dinorno - y - linolenic, C 20:3 8, 11, 14 C 20:4 8, 11, 14, 17 (C 20:3n-6) (C 20:4n-3) Arachidonic, C 20:4 5, 8, 11, 14 Eicosapentaenoic, C 20:5 5, 8, 11, 14, desaturase (C 22:4n-6) (C 22:5n-3) elongase C 22:4 7, 10, 13, 16 C 22:5 7, 10, 13, 16, 19 (C 20:4n-6) (C 20:5n-3) (C 22:5n-6) (C 22:6n-3) C 22:5 4, 7 10, 13, 16 C 22:6 4, 7, 10, 13, 16, desaturase -2H C2 -2H EPA DHA FISH OIL Docosahexaenoic

63 Fish oil benefit (ω3-series) - supports brain and retina development - slow or prevent progression of osteoarthritis by inhibition : proteoglycan (aggrecan) degrading enzyme (aggrecanase) : expression of inflammation- inducible cytokines - IL-1 α - TNF-α - cyclooxygenase-2 (COX-2) not COX-1

64 Function of COX - constitutive COX-1 : cytoprotective stomach : renal function : platelet homeostasis : vascular tone of endothelium - inducible COX-2 : เกี่ยวข้องกับการอักเสบ ทำให้ปวด บวม ร้อน Note: COX เป็นเอนไซม์ที่เปลี่ยน arachidonic acid ให้เป็น PGs ชนิดต่างๆ มีตัวยับยั้งคือ aspirin and NSAIDs

65 C 2 +2C 3 ( Ac.CoA) C 2 C 2 - C (MALONYL CoA) ATP + CO 2 CO 2 2 NADPH 2 C 2 - C 2 2 NADPH 2 CO 2 C 2 - C 2 - C CO 2 CH 3 - CH 2 - CH 2 - CH 2 - CH 2 COOH C 6 : 0 C 6 : 1 3 CH 3 CH 2 - CH = CH - CH 2 COOH + C 2 C 8 : 1 5 CH 3 CH 2 - CH = CH - CH 2 CH 2 CH 2 COOH DESATURATION : - H 2, NADPH 2, O 2 STEARIC ; CH 3 : -(CH 2 ) 7 - CH 2 - CH 2 - (CH 2 ) 7 COOH (C18 : 0) OLEIC ; CH 3 : -(CH 2 ) 7 - CH = CH - (CH 2 ) 7 COOH (C18 : 1 9 ) 9 PLANT -2H ANIMAL, คน LINOLEIC ( ω -6) C18 : 2 9, 12 C18:2 6, 9 ( ω -9) ( ω -3) -2H LINOLENIC C 18 : 3 9, 12, 15 C18 : 3 3, 6, SUMMARY OF FA SYNTHESIS + ELONGATION

66 Triacylglycerol (fat) synthesis Glycerol phosphate production 1.Liver and adipose tissue synthesized from dihydroxyacetone phosphate (DHAP) by glycerol phosphate dehydrogenase 2. Liver synthesized from glycerol by glycerol kinase

67 SYNTHESIS OF GLYCEROL 3 - PO 4 LIVER ONLY LIVER AND ADIPOCYTE INSULIN

68 3. Conversion of free fatty acid to its activated form - Attached to CoA by fatty acyl CoA synthetase before participating in TG synthesis

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70 4. Fate of TG - TG is stored in adipose tissue and serves as depot fat - TG in liver is exported through apo B-100 in the form of lipoprotein particles called VLDL and secreted into the blood to the peripheral tissue

71 Tg, triglyceride; CE, cholesterol ester; FC, free cholesterol; Pl, phospholipid Apo C-II C Apo C-III VLDL

72 adipocyte (visceral fat) adipocytokines (adipokines) - plasminogen activator inhibitor-1 (PAI-1) - tumor necrosis factor-α (TNF- α) : induce inflammation : thrombosis and insulin resistance - adiponectin : insulin-sensitizing, anti-atherogenic effect - interleukin-6 (IL-6) - monocyte chemotactic protein-1(MCP-1) : inflammation : กระตุ้น NADPH oxidase reactive oxygen species (ROS) T2DM, CAD, liver cancer

73 Obesity Elevated levels of fatty acids -increase oxidative stress via NADPH oxidase activation - decrease antioxidant enzymes

74 NEFA (nonesterified fatty acid or free fatty acid) ยับยั้ง glycolysis ในกล้ามเนื้อ และ กระตุ้น gluconeogenesis ที่ตับ ทำให้เกิด hyperglycemia Insulin resistance T2DM

75 Fatty liver ก. steatosis โดยเฉพาะในตับ ทำให้เกิด insulin resistance ยังไม่มีอาการของตับ risk factors 1. DM 2. protein mulnutrition 3. hypertension 4. obesity 5. anoxia 6. alcohol 7. cell toxin

76 Alcohol and FA synthesis Ethanol + NAD + Acetaldehyde + NADH Acetyl CoA+ NADH Alcohol DH Aldehyde DH, NAD + ข. non-alcoholic steatohepatitis (NASH) มีอาการตับอักเสบเรื้อรังเกิดจาก TNF- α ที่ ไม่ได้เกิดจากเชื้อ hepatitis B, C, alcohol หรือ รับประทานยา

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78 Treatment - reduce weight by diet control - follow healthy diet - increase physical activity - avoid alcohol - avoid unnecessary medications - metformin and orlistat may be used - take antioxidants

79 Cholesterol synthesis - cholesterol is the least soluble membrane lipid - only important membrane steroid in animals - most of it are in the form of “free” (unesterified) cholesterol in cellular membrane - brain contains large amounts of cholesterol - brain is considered as unhealthy kind of food - also used for synthesized steroid hormones and bile salts

80 Steroid hormones –Progestins (Progesterone) –Glucocorticoids (Cortisol) –Mineralocorticoids ( Aldosterone) –Androgens (Testosterone) –Estrogens (Estradiol)

81 CHOLESTEROL SYNTHESIS - occur in liver and intestine - cytosol, ER

82 CHOLESTEROL SYNTHESIS Regulation of cholesterol synthesis - HMG CoA reductase is allosteric enzyme - feedback-inhibited by free cholesterol - insulin stimulates HMG CoA reductase *

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84 - liver - intestine

85 HMG CoA REDUCTASE INHIBITORS

86 Plant sterols - inhibit cholesterol absorption - found in cereals and vegetables (most), fruit (less)

87 EXOGENOUS DIET CHOLESTEROL สมอง ไข่แดง ตับ เนย หอยนางรม ไขมัน สัตว์ กะทิ CHOLESTEROL ENDOGENOUS SYNTHESIS PERIPHERAL LIVER C 2 TISSUE INTESTINE LDL- RECEPTOR SAT. FA HORMONES: STEROID SEX CELL MEMB. CATABOLISM BILE ACIDS EXCRETION COPROSTEROL FECES HMG CoA REDUCTASE INHIBITORS RESIN CHOLESTEROL METABOLISM

88 CBH MET. IN LIVER

89 LIPID MET. IN LIVER

90 DIABETES MELLITUS 1.IDDM: INSULIN DEPENDENT 2.NIDDM: INSULIN INDEPENDENT

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95 LIPID METABOLISM IN DIABETES MELLITUS KETOLYSIS ( Is dependent,indirect ) CHOLESTEROL


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