CarbohydratesCarbohydrates
Carbohydrates (Fuels)Carbohydrates (Fuels)
Carbohydrates are the largest source of dietaryCarbohydrates are the largest so...
DigestionDigestion
Starch digestion begins in the mouth by theStarch digestion begins in the mouth by the
salivarysalivary...
Attached to the luminal membrane byAttached to the luminal membrane by
its N-terminal and it is heavilyits N-terminal and ...
Sucrase-Isomaltase ComplexSucrase-Isomaltase Complex
Similar to glucosamylase.Similar to glucosamylase.
Attached to membra...
Trehalase & LactaseTrehalase & Lactase
TrehalaseTrehalase
 One catalytic site, hydrolyzes the glycosidicOne catalytic sit...
Dietary FiberDietary Fiber
Composed principally of polysaccharidesComposed principally of polysaccharides
which can not be...
Glucose AbsorptionGlucose Absorption
Two types of glucose transportTwo types of glucose transport
proteins are present in ...
Glucose TransportersGlucose Transporters
Cell membranes are not inherently permeableCell membranes are not inherently perm...
The Waiting RoomThe Waiting Room
Deria Voider is a 20 year old exchange studentDeria Voider is a 20 year old exchange stud...
The Waiting RoomThe Waiting Room
Lactose intolerance can either be theLactose intolerance can either be the
result of a pr...
GlycogenGlycogen
MetabolismMetabolism
Structure Of Glycogen
GlycogenolysisGlycogenolysis
Occurs mainly in liver and muscles.Occurs mainly in liver and muscles.
Both pathways in the l...
GlycogenesisGlycogenesis
Occurs mainly in liver and muscle.Occurs mainly in liver and muscle.
Both pathways in the liver a...
Regulation of GlycogenRegulation of Glycogen
Metabolism in LiverMetabolism in Liver
When blood glucose level increasesWhen...
Postprandilly, insulin levels decreasePostprandilly, insulin levels decrease
and glucagon levels increase.and glucagon lev...
Regulation of Glycogenolysis &Regulation of Glycogenolysis &
Glycogenesis in Skeletal MuscleGlycogenesis in Skeletal Muscl...
Epinephrine & CaEpinephrine & Ca2+2+
in thein the
Regulation of Liver GlycogenRegulation of Liver Glycogen
Epinephrine rel...
Function of Glycogen inFunction of Glycogen in
Skeletal Muscle & LiverSkeletal Muscle & Liver
It functions as a reservoir ...
In liver, glycogen serves a veryIn liver, glycogen serves a very
different purpose. Liver glycogen is thedifferent purpose...
GlycolysisGlycolysis
Uses only CHOUses only CHO
Occurs in sarcoplasmOccurs in sarcoplasm
First step is glucose transport into tissuesFirst step...
Functions of GlycolysisFunctions of Glycolysis
ATP ProductionATP Production
Synthesis of UDP-glucose, sialicSynthesis of U...
GlycolysisGlycolysis
Lactate ProductionLactate Production
Major tissue sites of lactate production in aMajor tissue sites of lactate production...
Electron Transport Chain (ETC)Electron Transport Chain (ETC)
Oxidative PhosphorylationOxidative Phosphorylation
OxidationO...
1,31,3DPGDPG
2,3 DPG2,3 DPG
2,32,3DPG phosphataseDPG phosphatase
22--PGPG
2,3 DPG Synthesis & Degradation2,3 DPG Synthesis...
Regulation of GlycolysisRegulation of Glycolysis
Hexokinase inhibited by G-6-P with low km forHexokinase inhibited by G-6-...
Dental CariesDental Caries
Ivan Applebod is a 56-year-old morbidlyIvan Applebod is a 56-year-old morbidly
obese accountant...
CommentComment
The dental caries in Ivan Applebod’s mouth wereThe dental caries in Ivan Applebod’s mouth were
caused princ...
Pyruvate goes in one of three directions:Pyruvate goes in one of three directions:
lactate formationlactate formation
Ente...
TCA CycleTCA Cycle
Primary function is to reduce NADPrimary function is to reduce NAD++
and FADand FAD
Acetyl CoA (CAcetyl CoA (C22) combines...
electron
transport
chain
Overview of AerobicOverview of Aerobic
MetabolismMetabolism
Kreb’s
cycle
(proteins)
NADH
FADH2
O2...
Sites include liver and kidney whileSites include liver and kidney while
substrates include, amino acids, lactate,substrat...
Irrversible enzymes ofIrrversible enzymes of
glycolysis are replaced byglycolysis are replaced by
gluconeogenesis enzymes....
Galactose metabolism occurs in liver.Galactose metabolism occurs in liver.
Galactose UDP-galactoseGalactose UDP-galactose
...
Occurs in liver and adipose tissueOccurs in liver and adipose tissue
Fructose Fructose 6 phosphateFructose Fructose 6 phos...
Glucose HomeostasisGlucose Homeostasis
The plasma glucose concentration reflectsThe plasma glucose concentration reflects
...
Metabolic Effects of InsulinMetabolic Effects of Insulin
Insulin acts on three main targets, liver,Insulin acts on three m...
Metabolic Effects of GlucagonMetabolic Effects of Glucagon
Glucagon’s main effect is the mobilization of theGlucagon’s mai...
Stimulation of Insulin SecretionStimulation of Insulin Secretion
by Glucose (1-2by Glucose (1-2))
The glucose level in the...
Stimulation of Insulin SecretionStimulation of Insulin Secretion
by Glucose (2-2by Glucose (2-2))
Insulin secretion is als...
HypoglycemiaHypoglycemia
Hypoglycemia is defined as a blood glucoseHypoglycemia is defined as a blood glucose
concentratio...
Severe Hypoglycemia is aSevere Hypoglycemia is a
Medical EmergencyMedical Emergency
A 12 year old diabetic boy was playing...
Alcohol Excess & Hypoglycemia-1Alcohol Excess & Hypoglycemia-1
A middle aged man, emaciated, chronic alcoholic collapsed a...
Alcohol Excess and Hypoglycemia 2Alcohol Excess and Hypoglycemia 2
Alcohol is metabolized primarily in the liver. Two step...
Diabetes Mellitus ( DMDiabetes Mellitus ( DM))
DM is a group of metabolic diseases characterizedDM is a group of metabolic...
Genetics of DiabetesGenetics of Diabetes
Type OneType One
 It is not genetically predeterminedIt is not genetically prede...
Genetics of DiabetesGenetics of Diabetes
Type TwoType Two
 It is polygenic disorder ( no evidence ofIt is polygenic disor...
Metabolism in Uncontrolled DiabetesMetabolism in Uncontrolled Diabetes
In absence of insulinIn absence of insulin

Hepati...
Metabolism in Uncontrolled DiabetesMetabolism in Uncontrolled Diabetes
In parallel:In parallel:

Rapid lipolysis occursRa...
Type I DiabetesType I Diabetes
Type I diabetes develop in young people, with the peakType I diabetes develop in young peop...
Type 2 DiabetesType 2 Diabetes
Type 2 diabetes usually develops in patientsType 2 diabetes usually develops in patients
wh...
Long Term Complications ofLong Term Complications of
DiabetesDiabetes
Diabeteic ketoacidosis, a sudden (acute )Diabeteic k...
Treatment of DiabetesTreatment of Diabetes
Type 1:Type 1: Daily subcutaneous insulin injections throughoutDaily subcutaneo...
Typical Presentation of DiabeticTypical Presentation of Diabetic
KetoacidosisKetoacidosis
A 15 year old girl is admitted t...
Emergency Treatment ofEmergency Treatment of
Diabetic KetoacidosisDiabetic Ketoacidosis
Addresses four issues:Addresses fo...
Diabetic Ketoacidosis & PotassiumDiabetic Ketoacidosis & Potassium
Insulin increases potassium uptake by cells. Lack ofIns...
The Importance of GoodThe Importance of Good
Glycemic ControlGlycemic Control
Maintaining near normal blood glucose levels...
Glycated Hemoglobin (HbA1CGlycated Hemoglobin (HbA1C((
The measurement of blood glucose remains the mostThe measurement of...
HbA1C Identifies Patients who doHbA1C Identifies Patients who do
not Comply with Treatment (1-2not Comply with Treatment (...
HbA1C Identifies Patients who doHbA1C Identifies Patients who do
not Comply with Treatment (2-2not Comply with Treatment (...
GalactosemiaGalactosemia
An apparently normal baby began to vomit and developAn apparently normal baby began to vomit and ...
GalactosemiaGalactosemia
Comment:Comment: The accumulation of galactose in theThe accumulation of galactose in the
blood i...
Fructose IntoleranceFructose Intolerance
An autosomal recessive condition, due toAn autosomal recessive condition, due to
...
Von Gierk’s DiseaseVon Gierk’s Disease
A baby girl is irritable, sweaty and lethargic andA baby girl is irritable, sweaty ...
Glucose 6 PhosphateGlucose 6 Phosphate
Dehydrogenase Deficiency 1Dehydrogenase Deficiency 1
Just prior to planned departur...
Glucose 6 PhosphateGlucose 6 Phosphate
Dehydrogenase Deficiency 2Dehydrogenase Deficiency 2
Comments:Comments: A number of...
Thank You
Cho metabolism dentistry 2013
Cho metabolism dentistry 2013
Cho metabolism dentistry 2013
Cho metabolism dentistry 2013
Cho metabolism dentistry 2013
Cho metabolism dentistry 2013
Cho metabolism dentistry 2013
Cho metabolism dentistry 2013
Cho metabolism dentistry 2013
Cho metabolism dentistry 2013
Cho metabolism dentistry 2013
Cho metabolism dentistry 2013
Cho metabolism dentistry 2013
Cho metabolism dentistry 2013
Cho metabolism dentistry 2013
Cho metabolism dentistry 2013
Cho metabolism dentistry 2013
Cho metabolism dentistry 2013
Cho metabolism dentistry 2013
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Cho metabolism dentistry 2013

  1. 1. CarbohydratesCarbohydrates
  2. 2. Carbohydrates (Fuels)Carbohydrates (Fuels) Carbohydrates are the largest source of dietaryCarbohydrates are the largest source of dietary calories.calories. The major carbohydrates are starch, lactose andThe major carbohydrates are starch, lactose and sucrosesucrose The main carbohydrates in body metabolism isThe main carbohydrates in body metabolism is glucoseglucose Transported to muscle (and other tissues) via bloodTransported to muscle (and other tissues) via blood Stored in liver and muscle asStored in liver and muscle as glycogenglycogen ATP produced more quickly from CHO than fromATP produced more quickly from CHO than from fats or proteinsfats or proteins CHO stores can be depletedCHO stores can be depleted
  3. 3. DigestionDigestion Starch digestion begins in the mouth by theStarch digestion begins in the mouth by the salivarysalivary αα-amylase which converts starch to-amylase which converts starch to smaller polysaccharides calledsmaller polysaccharides called αα-dextrins-dextrins PancreaticPancreatic αα-amylase continues the digestion of-amylase continues the digestion of αα-dextrins into maltose, maltotriose and-dextrins into maltose, maltotriose and oligosaccharides called limited dextrinsoligosaccharides called limited dextrins Digestion of maltose, maltotriose, sucrose andDigestion of maltose, maltotriose, sucrose and lactose is continued by disaccharidases attachedlactose is continued by disaccharidases attached to the membrane of surface of the brush borderto the membrane of surface of the brush border (microvilli) of intestinal epithelial cells(microvilli) of intestinal epithelial cells The monosaccharides produced are transportedThe monosaccharides produced are transported into the intestinal cellsinto the intestinal cells
  4. 4. Attached to the luminal membrane byAttached to the luminal membrane by its N-terminal and it is heavilyits N-terminal and it is heavily glycosylated with oligosaccharides.glycosylated with oligosaccharides. Begins at non-reducing ends of limitedBegins at non-reducing ends of limited dextrin and sequentially hydrolyzesdextrin and sequentially hydrolyzes αα-- (1-4) glycosidic bonds to produce(1-4) glycosidic bonds to produce glucose.glucose. Will digest limited dextrin down toWill digest limited dextrin down to isomaltose.isomaltose. GlucosamylaseGlucosamylase
  5. 5. Sucrase-Isomaltase ComplexSucrase-Isomaltase Complex Similar to glucosamylase.Similar to glucosamylase. Attached to membrane with two polypeptides.Attached to membrane with two polypeptides. Protrudes into the intestinal lumen.Protrudes into the intestinal lumen. An intestinal protease clips in into two separateAn intestinal protease clips in into two separate subunits that remain attached to each other.subunits that remain attached to each other. Each subunit site has a catalytic site that differsEach subunit site has a catalytic site that differs in substrate specificity.in substrate specificity. The sucrase-maltase site accounts for 100% ofThe sucrase-maltase site accounts for 100% of intestinal ability to hydrolyze sucrose in additionintestinal ability to hydrolyze sucrose in addition to maltase activity.to maltase activity. The isomaltase-maltase site accounts forThe isomaltase-maltase site accounts for almost all activity to hydrolyzealmost all activity to hydrolyze αα 1-6 bonds in1-6 bonds in addition to maltase activity.addition to maltase activity.
  6. 6. Trehalase & LactaseTrehalase & Lactase TrehalaseTrehalase  One catalytic site, hydrolyzes the glycosidicOne catalytic site, hydrolyzes the glycosidic bond in trehalose (disaccharide of twobond in trehalose (disaccharide of two glucosyl units attached by their anomericglucosyl units attached by their anomeric carbons).carbons). LactaseLactase  Glucosyl cermidase Complex:Glucosyl cermidase Complex: GlycoproteinGlycoprotein found in the brush border that has twofound in the brush border that has two caralytic sites extending in the intestinal lumin.caralytic sites extending in the intestinal lumin. It hydrolyzes lactose and the B-bondsIt hydrolyzes lactose and the B-bonds between glucose or galactose and ceramide inbetween glucose or galactose and ceramide in glycolipids.glycolipids.
  7. 7. Dietary FiberDietary Fiber Composed principally of polysaccharidesComposed principally of polysaccharides which can not be digested by humanwhich can not be digested by human enzymes of the intestinal tract.enzymes of the intestinal tract. Derivatives of lignan (cellulose, hemicellulose,Derivatives of lignan (cellulose, hemicellulose, lignin, pectins, mucilages and gums)lignin, pectins, mucilages and gums) Bacterial flora of the colon metabolize theBacterial flora of the colon metabolize the fibers to gases(Hfibers to gases(H22,CO,CO22,CH,CH44) and short chain) and short chain fatty acids.fatty acids. Fatty acids are absorbed by colonic cells.Fatty acids are absorbed by colonic cells. Fibers soften the stool, thereby reducingFibers soften the stool, thereby reducing pressure on the colonic wall and enhancingpressure on the colonic wall and enhancing expulsion of fecesexpulsion of feces
  8. 8. Glucose AbsorptionGlucose Absorption Two types of glucose transportTwo types of glucose transport proteins are present in the intestinalproteins are present in the intestinal cells.cells. NaNa++ dependent: an activedependent: an active transport which depends ontransport which depends on cotransport of sodium andcotransport of sodium and glucose.glucose. Facilitated: passive transportFacilitated: passive transport known as Glut 1 -4.known as Glut 1 -4.
  9. 9. Glucose TransportersGlucose Transporters Cell membranes are not inherently permeableCell membranes are not inherently permeable to glucose. There are many glucose transporters.to glucose. There are many glucose transporters.  GLUT-1: Enables basal non- insulin stimulatedGLUT-1: Enables basal non- insulin stimulated glucose uptake (erythrocytes)glucose uptake (erythrocytes)  GLUT-2: Transports glucose into beta cells, aGLUT-2: Transports glucose into beta cells, a pre- requisite for glucose sensing.pre- requisite for glucose sensing.  GLUT-3: Enables non-insulin mediated glucoseGLUT-3: Enables non-insulin mediated glucose uptake into brain.uptake into brain.  GLUT-4: Enables much of the peripheral actionGLUT-4: Enables much of the peripheral action of insulin (muscles, adipose)of insulin (muscles, adipose)
  10. 10. The Waiting RoomThe Waiting Room Deria Voider is a 20 year old exchange studentDeria Voider is a 20 year old exchange student from Nigeria who has noted gastrointestinalfrom Nigeria who has noted gastrointestinal bloating, abdominal cramps, and intermittentbloating, abdominal cramps, and intermittent diarrhea ever since arriving in the United Statesdiarrhea ever since arriving in the United States 6 months earlier. A careful history shows that6 months earlier. A careful history shows that these symptoms occur most commonly aboutthese symptoms occur most commonly about 45 minutes to 1 hour after eating breakfast, but45 minutes to 1 hour after eating breakfast, but may occur after other meals as well. Dairymay occur after other meals as well. Dairy products, not a part of Deria’s diet in Nigeria,products, not a part of Deria’s diet in Nigeria, were identified as the probable offending agentwere identified as the probable offending agent because her gastrointestinal symptomsbecause her gastrointestinal symptoms disappeared when milk and milk products weredisappeared when milk and milk products were eliminated from her diet.eliminated from her diet.
  11. 11. The Waiting RoomThe Waiting Room Lactose intolerance can either be theLactose intolerance can either be the result of a primary deficiency of lactaseresult of a primary deficiency of lactase production in the small bowel or it can beproduction in the small bowel or it can be secondary to an injury to the intestinalsecondary to an injury to the intestinal mucosa where lactase is normallymucosa where lactase is normally produced.produced. The lactose that is not absorbed isThe lactose that is not absorbed is converted by colonic bacteria to lacticconverted by colonic bacteria to lactic acid, methane gas and H2 gas.acid, methane gas and H2 gas. The osmotic effect of lactose and lacticThe osmotic effect of lactose and lactic acid in the bowel lumen is responsible foracid in the bowel lumen is responsible for the diarrhea seen oftenthe diarrhea seen often
  12. 12. GlycogenGlycogen MetabolismMetabolism
  13. 13. Structure Of Glycogen
  14. 14. GlycogenolysisGlycogenolysis Occurs mainly in liver and muscles.Occurs mainly in liver and muscles. Both pathways in the liver and muscle areBoth pathways in the liver and muscle are the same.the same. End product in liver is glucose, while inEnd product in liver is glucose, while in muscle the end product is glucose 6muscle the end product is glucose 6 phosphate.phosphate.
  15. 15. GlycogenesisGlycogenesis Occurs mainly in liver and muscle.Occurs mainly in liver and muscle. Both pathways in the liver and muscleBoth pathways in the liver and muscle are the same.are the same. End product is glycogen.End product is glycogen. Main enzyme is glycogen synthetase.Main enzyme is glycogen synthetase.
  16. 16. Regulation of GlycogenRegulation of Glycogen Metabolism in LiverMetabolism in Liver When blood glucose level increasesWhen blood glucose level increases immediately after a meal, insulin levelimmediately after a meal, insulin level increases, whole glycogen levelincreases, whole glycogen level decreases.decreases. Increase in insulin/glucagon ration inhibitsIncrease in insulin/glucagon ration inhibits glycogenolysis and stimulatesglycogenolysis and stimulates glycogenesis.glycogenesis. The immediate removal of blood glucoseThe immediate removal of blood glucose helps bring circulating blood glucosehelps bring circulating blood glucose levels back to normal 80-100 mg/dl range.levels back to normal 80-100 mg/dl range.
  17. 17. Postprandilly, insulin levels decreasePostprandilly, insulin levels decrease and glucagon levels increase.and glucagon levels increase. The fall of the insulin/glucagon ratiosThe fall of the insulin/glucagon ratios results in inhibition of glycogenesis andresults in inhibition of glycogenesis and increased glycogenolysis.increased glycogenolysis. Substantial proportion of liver glycogenSubstantial proportion of liver glycogen is degraded within the few first hoursis degraded within the few first hours after eating.after eating.
  18. 18. Regulation of Glycogenolysis &Regulation of Glycogenolysis & Glycogenesis in Skeletal MuscleGlycogenesis in Skeletal Muscle Skeletal muscle glycogen is degraded only whenSkeletal muscle glycogen is degraded only when the demand for ATP generation is high.the demand for ATP generation is high. Regulation of glycogen metabolism differs fromRegulation of glycogen metabolism differs from that in liver.that in liver.  Glucagon has no effect (muscle glycogen doesGlucagon has no effect (muscle glycogen does not vary with fasting/feeding state).not vary with fasting/feeding state).  AMP is an alosteric activator of muscleAMP is an alosteric activator of muscle glycogen phosphorylase but not liver isozyme.glycogen phosphorylase but not liver isozyme.  Glucose is not a physiological inhibitor ofGlucose is not a physiological inhibitor of glycogen phosphorylase.glycogen phosphorylase.  Epinephrine effects are similar to that in liver.Epinephrine effects are similar to that in liver.
  19. 19. Epinephrine & CaEpinephrine & Ca2+2+ in thein the Regulation of Liver GlycogenRegulation of Liver Glycogen Epinephrine released from adrenal medulla inEpinephrine released from adrenal medulla in response to neural signals reflecting an increasedresponse to neural signals reflecting an increased demand for glucose.demand for glucose. Epinephrine stimulated glycogenolysis in liverEpinephrine stimulated glycogenolysis in liver through two different receptors.through two different receptors.  B-Receptors: Transmit a signal through G-B-Receptors: Transmit a signal through G- protein to adeylate cyclase, which increasesprotein to adeylate cyclase, which increases CAMP.CAMP.  ΑΑ-Receptors: Increases CA-Receptors: Increases CA2+2+ levels in the liver,levels in the liver, which is mediated by the phosphatidylinositolwhich is mediated by the phosphatidylinositol bisphosphate - CAbisphosphate - CA2+2+ signal transductionsignal transduction system.system.
  20. 20. Function of Glycogen inFunction of Glycogen in Skeletal Muscle & LiverSkeletal Muscle & Liver It functions as a reservoir of glucosylIt functions as a reservoir of glucosyl units for ATP generation.units for ATP generation. Glycogen is usually degraded toGlycogen is usually degraded to glucose-1-phosphate which isglucose-1-phosphate which is converted into glucose-6-phosphate.converted into glucose-6-phosphate. In skeletal muscles and other cellIn skeletal muscles and other cell types, glucose-6-phosphate is used bytypes, glucose-6-phosphate is used by the cell to produce ATP (Absence ofthe cell to produce ATP (Absence of glucose-6-phosphatase).glucose-6-phosphatase).
  21. 21. In liver, glycogen serves a veryIn liver, glycogen serves a very different purpose. Liver glycogen is thedifferent purpose. Liver glycogen is the first and immediate source of glucosefirst and immediate source of glucose for the maintenance of blood glucosefor the maintenance of blood glucose level. In liver, glucose-6-phosphate islevel. In liver, glucose-6-phosphate is converted to free glucose by G-6-converted to free glucose by G-6- phosphatase, present only liver andphosphatase, present only liver and kidneys.kidneys.
  22. 22. GlycolysisGlycolysis
  23. 23. Uses only CHOUses only CHO Occurs in sarcoplasmOccurs in sarcoplasm First step is glucose transport into tissuesFirst step is glucose transport into tissues After entry, 2 ATP are used (with glucose)After entry, 2 ATP are used (with glucose) Glucose (CGlucose (C66) is split into two C) is split into two C33 moleculesmolecules Final product isFinal product is pyruvatepyruvate 4 ATP are synthesized4 ATP are synthesized Pyruvate forms eitherPyruvate forms either lactatelactate or entersor enters mitochondriamitochondria GlycolysisGlycolysis
  24. 24. Functions of GlycolysisFunctions of Glycolysis ATP ProductionATP Production Synthesis of UDP-glucose, sialicSynthesis of UDP-glucose, sialic acid and mannosaacid and mannosa Synthesis of serine & alanineSynthesis of serine & alanine Synthesis of TG from DHAP andSynthesis of TG from DHAP and fatty acidsfatty acids In RBC, synthesis 2,3 DPGIn RBC, synthesis 2,3 DPG
  25. 25. GlycolysisGlycolysis
  26. 26. Lactate ProductionLactate Production Major tissue sites of lactate production in aMajor tissue sites of lactate production in a resting man (g/day)resting man (g/day) RBCRBC 2929 SkinSkin 2020 BrainBrain 1717 Skeletal musclesSkeletal muscles 1616 Renal medullaRenal medulla 1515 Intestinal mucosaIntestinal mucosa 88 Other tissuesOther tissues 1010 Total ProductionTotal Production 115115
  27. 27. Electron Transport Chain (ETC)Electron Transport Chain (ETC) Oxidative PhosphorylationOxidative Phosphorylation OxidationOxidation NADH and FADHNADH and FADH22 transfer electrons to ETCtransfer electrons to ETC Final acceptor of electrons is OFinal acceptor of electrons is O22 PhosphorylationPhosphorylation Energy generated by oxidation used toEnergy generated by oxidation used to resynthesize ATPresynthesize ATP  3 ATP from each NADH3 ATP from each NADH  2 ATP from each FADH2 ATP from each FADH22
  28. 28. 1,31,3DPGDPG 2,3 DPG2,3 DPG 2,32,3DPG phosphataseDPG phosphatase 22--PGPG 2,3 DPG Synthesis & Degradation2,3 DPG Synthesis & Degradation ADP ATP 2,3 DPG mutase2,3 DPG mutase 3 Phosphoglycerate3 Phosphoglycerate
  29. 29. Regulation of GlycolysisRegulation of Glycolysis Hexokinase inhibited by G-6-P with low km forHexokinase inhibited by G-6-P with low km for glucoseglucose PFk-1 is the rate limiting enzyme activated byPFk-1 is the rate limiting enzyme activated by AMP and Fructose-2-6 bisphosphate (alosteric)AMP and Fructose-2-6 bisphosphate (alosteric) PFK-1 inhibited by ATP & citrate.PFK-1 inhibited by ATP & citrate. Pyruvate kinase present in brain and skeletalPyruvate kinase present in brain and skeletal muscles has no alosteric site and hence doesmuscles has no alosteric site and hence does not contribute toward regulation of glycolysis innot contribute toward regulation of glycolysis in these tissues.these tissues. Liver pyruvate kinase is inhibited byLiver pyruvate kinase is inhibited by phosphorylation (CAMP) & alosterically inhibitedphosphorylation (CAMP) & alosterically inhibited by ATP.by ATP.
  30. 30. Dental CariesDental Caries Ivan Applebod is a 56-year-old morbidlyIvan Applebod is a 56-year-old morbidly obese accountant. He decided to see hisobese accountant. He decided to see his dentist because he felt excruciating pain indentist because he felt excruciating pain in his teeth when he ate ice-cream. He reallyhis teeth when he ate ice-cream. He really likes sweets and keeps hard candy in hislikes sweets and keeps hard candy in his pocket. The dentist noted from Mr.pocket. The dentist noted from Mr. Applebod’s history that he had numerousApplebod’s history that he had numerous cavities as a child in his baby teeth. At thiscavities as a child in his baby teeth. At this visit, the dentist found cavities in two of Mr.visit, the dentist found cavities in two of Mr. Applebod’s teeth.Applebod’s teeth.
  31. 31. CommentComment The dental caries in Ivan Applebod’s mouth wereThe dental caries in Ivan Applebod’s mouth were caused principally by the low ph generated fromcaused principally by the low ph generated from lactic acid production by oral bacteria. Below a phlactic acid production by oral bacteria. Below a ph of 5.5, decalcification of tooth enamel and dentineof 5.5, decalcification of tooth enamel and dentine occurs.occurs. Lactobacilli and s. mutants are majorLactobacilli and s. mutants are major contributors to this process because almost all ofcontributors to this process because almost all of their energy is derived from the conversion oftheir energy is derived from the conversion of glucose or fructose to lactic acid, and they are ableglucose or fructose to lactic acid, and they are able to form well at low ph generated by this process.to form well at low ph generated by this process. The dentist explained that bacteria in his dentalThe dentist explained that bacteria in his dental plaque could convert all the sugar in his candy intoplaque could convert all the sugar in his candy into acid in less than 20 minutes. The acid is bufferedacid in less than 20 minutes. The acid is buffered by bicarbonate and other buffers in saliva, butby bicarbonate and other buffers in saliva, but saliva production decreases in the evening. Thus,saliva production decreases in the evening. Thus, the acid could dissolve the hyroxyapptite in histhe acid could dissolve the hyroxyapptite in his tooth enamel during the night.tooth enamel during the night.
  32. 32. Pyruvate goes in one of three directions:Pyruvate goes in one of three directions: lactate formationlactate formation Enters mitochondria (i.e. Kreb’sEnters mitochondria (i.e. Kreb’s cycle)cycle) Formation of Kreb’s cycleFormation of Kreb’s cycle intermediatesintermediates Metabolic Fate of PyruvateMetabolic Fate of Pyruvate
  33. 33. TCA CycleTCA Cycle
  34. 34. Primary function is to reduce NADPrimary function is to reduce NAD++ and FADand FAD Acetyl CoA (CAcetyl CoA (C22) combines with a C) combines with a C44 molecule forming a Cmolecule forming a C66 moleculemolecule CC66 molecule is partially degraded back to amolecule is partially degraded back to a CC44 moleculemolecule Each loss of C gives off a COEach loss of C gives off a CO22 Kreb’s Cycle (Citric Acid Cycle)Kreb’s Cycle (Citric Acid Cycle)
  35. 35. electron transport chain Overview of AerobicOverview of Aerobic MetabolismMetabolism Kreb’s cycle (proteins) NADH FADH2 O2 H2O ADP + Pi ATP acetyl CoA 1. Preparation for entry into Kreb’s cycle 2. Removal of “energized” electrons 3. 1º ATP synthesis; Oxidation- phosphorylation mitochondria Beta Oxidation (fats) Glycolysis (carbohydrates)
  36. 36. Sites include liver and kidney whileSites include liver and kidney while substrates include, amino acids, lactate,substrates include, amino acids, lactate, pyruvate, glycerol.pyruvate, glycerol. Cori and alanine cycles for transport ofCori and alanine cycles for transport of intermediates between site of production ofintermediates between site of production of these metabolites and site of synthesis.these metabolites and site of synthesis. Many enzymes of glycolysis are common toMany enzymes of glycolysis are common to gluconeogenesis.gluconeogenesis. Gluconeogenesis (1)Gluconeogenesis (1)
  37. 37. Irrversible enzymes ofIrrversible enzymes of glycolysis are replaced byglycolysis are replaced by gluconeogenesis enzymes.gluconeogenesis enzymes. 1.1. Pyruvate kinase –Pyruvate kinase – pyruvate carboxylase &pyruvate carboxylase & PEPCKPEPCK 2.2. PFK ---- F 2,6PFK ---- F 2,6 diphosphatasediphosphatase 3.3. Glucokinase --- Glu 6Glucokinase --- Glu 6 phosphatasephosphatase Gluconeogenesis (2)Gluconeogenesis (2)
  38. 38. Galactose metabolism occurs in liver.Galactose metabolism occurs in liver. Galactose UDP-galactoseGalactose UDP-galactose GKGK Uridyl transferaseUridyl transferase UDP- glucoseUDP- glucose Galactose MetabolismGalactose Metabolism
  39. 39. Occurs in liver and adipose tissueOccurs in liver and adipose tissue Fructose Fructose 6 phosphateFructose Fructose 6 phosphate fructokinasefructokinase Glucose 6 phosphateGlucose 6 phosphate Fructose MetabolismFructose Metabolism
  40. 40. Glucose HomeostasisGlucose Homeostasis The plasma glucose concentration reflectsThe plasma glucose concentration reflects the balance between intake, tissuethe balance between intake, tissue utilization and endogeneous production .utilization and endogeneous production . Insulin promotes up take of glucose thusInsulin promotes up take of glucose thus decreasing plasma glucose whiledecreasing plasma glucose while glucagon stimulates both the release ofglucagon stimulates both the release of glucose from glycogen stores and itsglucose from glycogen stores and its denovo synthesis, thus causing andenovo synthesis, thus causing an increase in plasma glucose.increase in plasma glucose. Glucose stimulates the secretion of insulinGlucose stimulates the secretion of insulin and suppresses the secretion of glucagon.and suppresses the secretion of glucagon.
  41. 41. Metabolic Effects of InsulinMetabolic Effects of Insulin Insulin acts on three main targets, liver,Insulin acts on three main targets, liver, adipose and muscles.adipose and muscles. In liver insulin stimulates glycolysis,In liver insulin stimulates glycolysis, glycogenesis and lipogenesis andglycogenesis and lipogenesis and suppresses lipolysis.suppresses lipolysis. In peripheral tissues, insulin inducesIn peripheral tissues, insulin induces lipoprotein lipase activity and thuslipoprotein lipase activity and thus stimulates triglyceride synthesis.stimulates triglyceride synthesis. In muscles, insulin increases glucose andIn muscles, insulin increases glucose and amino acid transport and glycogenamino acid transport and glycogen synthesis.synthesis.
  42. 42. Metabolic Effects of GlucagonMetabolic Effects of Glucagon Glucagon’s main effect is the mobilization of theGlucagon’s main effect is the mobilization of the fuel reserves for the maintenance of the bloodfuel reserves for the maintenance of the blood glucose level between meals.glucose level between meals. Glucagon inhibits glucose- utilizing pathways andGlucagon inhibits glucose- utilizing pathways and the storage of metabolic fuels.the storage of metabolic fuels. It acts on liver to stimulate glycogenolysis andIt acts on liver to stimulate glycogenolysis and inhibit glycogenesis, glycolysis and lipogenesis.inhibit glycogenesis, glycolysis and lipogenesis. Gluconeogenesis and ketogenesis are thenGluconeogenesis and ketogenesis are then activated.activated. Epinephrine has effects similar to glucagon in theEpinephrine has effects similar to glucagon in the liver but works through a different receptor. Itliver but works through a different receptor. It promotes an increase in blood glucose in responsepromotes an increase in blood glucose in response to stress.to stress.
  43. 43. Stimulation of Insulin SecretionStimulation of Insulin Secretion by Glucose (1-2by Glucose (1-2)) The glucose level in the vicinity of the B- cell isThe glucose level in the vicinity of the B- cell is sensed by the transporter GLUT- 2. Glucose issensed by the transporter GLUT- 2. Glucose is carried into the cell, where it is phophorylatedcarried into the cell, where it is phophorylated into G-6- P by glucokinase which also is a part ofinto G-6- P by glucokinase which also is a part of the glucose sensing mechanism. Increased G-6-the glucose sensing mechanism. Increased G-6- P increases glucose utilization and ATPP increases glucose utilization and ATP production in the B- cell. This changes the flux ofproduction in the B- cell. This changes the flux of ions across the cell membrane, depolarizes theions across the cell membrane, depolarizes the cell and increases the concentration of Cacell and increases the concentration of Ca2+2+ .. Hence insulin is exocytosed.Hence insulin is exocytosed. Insulin secretion is biphasic. The first phaseInsulin secretion is biphasic. The first phase occurs over 10- 15 minutes of stimulation whichoccurs over 10- 15 minutes of stimulation which release the preformed insulin. The secondrelease the preformed insulin. The second phase, which lasts up to 2 hours, is the releasephase, which lasts up to 2 hours, is the release of newly synthesized insulin.of newly synthesized insulin.
  44. 44. Stimulation of Insulin SecretionStimulation of Insulin Secretion by Glucose (2-2by Glucose (2-2)) Insulin secretion is also stimulated byInsulin secretion is also stimulated by gastrointestinal hormones (insulinotropicgastrointestinal hormones (insulinotropic peptide, cholecystokinin) and aminopeptide, cholecystokinin) and amino acids, such as leucine, arginine, andacids, such as leucine, arginine, and lysine. Thus, the insulin response tolysine. Thus, the insulin response to orally administered glucose is greaterorally administered glucose is greater than to an intravenous infusion.than to an intravenous infusion.
  45. 45. HypoglycemiaHypoglycemia Hypoglycemia is defined as a blood glucoseHypoglycemia is defined as a blood glucose concentration below 2.5 mmol/ L ( 45 mg/dl).concentration below 2.5 mmol/ L ( 45 mg/dl). Epinephrine and glucagon are released, resulting in aEpinephrine and glucagon are released, resulting in a stress response, the manifestation of which maystress response, the manifestation of which may include sweating, trembling, increased heart rate andinclude sweating, trembling, increased heart rate and feeling of hunger. If blood glucose continues to fall,feeling of hunger. If blood glucose continues to fall, brain function is compromised (neuroglycopenia).brain function is compromised (neuroglycopenia). Hypoglycemia in healthy individuals is usually mildHypoglycemia in healthy individuals is usually mild and may occur during exercise, after a period ofand may occur during exercise, after a period of fasting or due to alcohol ingestion.fasting or due to alcohol ingestion. Hypoglycemia may be caused by a rare insulinHypoglycemia may be caused by a rare insulin secreting tumor of the beta- cells ( insulinoma) orsecreting tumor of the beta- cells ( insulinoma) or overdose of exogenous insulin.overdose of exogenous insulin.
  46. 46. Severe Hypoglycemia is aSevere Hypoglycemia is a Medical EmergencyMedical Emergency A 12 year old diabetic boy was playing with his friends.A 12 year old diabetic boy was playing with his friends. He received his normal insulin injection in the morningHe received his normal insulin injection in the morning but continued playing through the lunch time without abut continued playing through the lunch time without a meal. He became confused and fainted. He wasmeal. He became confused and fainted. He was instantly given an injection of glucagon from theinstantly given an injection of glucagon from the emergency kit his father carried and recovered withinemergency kit his father carried and recovered within minutes.minutes. Comment:Comment: An immediate improvement after glucagonAn immediate improvement after glucagon injection confirms this boy’s symptoms were caused byinjection confirms this boy’s symptoms were caused by hypoglycemia ,caused by the exogenous insulin andhypoglycemia ,caused by the exogenous insulin and insufficient food intake. Spectacular recovery frominsufficient food intake. Spectacular recovery from hypoglycemia was due to the action of glucagon. Inhypoglycemia was due to the action of glucagon. In hospital, hypoglycemic patients who can not eat or drinkhospital, hypoglycemic patients who can not eat or drink are treated with an intravenous infusion of glucose. Anare treated with an intravenous infusion of glucose. An intramuscular glucagon injection is an emergencyintramuscular glucagon injection is an emergency measure that can be applied at home.measure that can be applied at home.
  47. 47. Alcohol Excess & Hypoglycemia-1Alcohol Excess & Hypoglycemia-1 A middle aged man, emaciated, chronic alcoholic collapsed andA middle aged man, emaciated, chronic alcoholic collapsed and was transported to ER. Physical examination revealed awas transported to ER. Physical examination revealed a somewhat clammy skin, unusual for winter morning, rapidsomewhat clammy skin, unusual for winter morning, rapid breathing and a rapid heart rate. Laboratory tests indicate abreathing and a rapid heart rate. Laboratory tests indicate a blood sugar of 2.5 mmol/l (50g/dl), and a blood alcohol level ofblood sugar of 2.5 mmol/l (50g/dl), and a blood alcohol level of 0.2 %. Subsequent tests indicated a normal level of CPK, high0.2 %. Subsequent tests indicated a normal level of CPK, high serum level of AST, a slight acidic pH (7.29), low pCOserum level of AST, a slight acidic pH (7.29), low pCO22 and highand high blood lactate. The man responded to infusion of a glucoseblood lactate. The man responded to infusion of a glucose solution & regained consciousness.solution & regained consciousness. Comment:Comment: This patient probably had not eaten breakfastThis patient probably had not eaten breakfast before starting his morning drinking. His glycogen stores werebefore starting his morning drinking. His glycogen stores were negligible, so he was dependent on gluconeogenesis fornegligible, so he was dependent on gluconeogenesis for maintenance of blood glucose concentration, butmaintenance of blood glucose concentration, but gluconeogenesis may be compromised both by liver damagegluconeogenesis may be compromised both by liver damage and by limited muscle mass available to mobilize amino acidsand by limited muscle mass available to mobilize amino acids for gluconeogenesis.for gluconeogenesis.
  48. 48. Alcohol Excess and Hypoglycemia 2Alcohol Excess and Hypoglycemia 2 Alcohol is metabolized primarily in the liver. Two stepsAlcohol is metabolized primarily in the liver. Two steps metabolism of alcohol is relatively unregulated, leadingmetabolism of alcohol is relatively unregulated, leading to a rapid increase in hepatic NADH. This shifts theto a rapid increase in hepatic NADH. This shifts the equilibrium of LDH catalyzed reaction towards lactateequilibrium of LDH catalyzed reaction towards lactate formation (lacticacidemia). Also shifts cytosolicformation (lacticacidemia). Also shifts cytosolic oxaloacetate towards malate formation, reducingoxaloacetate towards malate formation, reducing gluconeogenesis from TCA. In addition DHAP isgluconeogenesis from TCA. In addition DHAP is shifted toward glycerol- 3- phosphate formation andshifted toward glycerol- 3- phosphate formation and thus reducing gluconeogenesis from glycerol.thus reducing gluconeogenesis from glycerol. The low blood glucose leads to a stress response 9The low blood glucose leads to a stress response 9 rapid heart beat, clammy skin), an effort to enhancerapid heart beat, clammy skin), an effort to enhance stimulation of gluconeogenesis combined action ofstimulation of gluconeogenesis combined action of glucagon and epinephrine. Rapid breathing isglucagon and epinephrine. Rapid breathing is physiological response to metabolic acidosis.physiological response to metabolic acidosis.
  49. 49. Diabetes Mellitus ( DMDiabetes Mellitus ( DM)) DM is a group of metabolic diseases characterizedDM is a group of metabolic diseases characterized by hyperglycemia leading to long term complication.by hyperglycemia leading to long term complication. It is common, which affects 1-2 % of populations.It is common, which affects 1-2 % of populations. There are two main forms diabetes, 10 % have typeThere are two main forms diabetes, 10 % have type I and 90% have type 2.I and 90% have type 2. Type 1 patients are unable to produce insulin andType 1 patients are unable to produce insulin and must receive exogenous insulin to survive.must receive exogenous insulin to survive. Type 2 patients have at least partially preservedType 2 patients have at least partially preserved insulin secretion, but often insulin resistant.insulin secretion, but often insulin resistant. Some patients may have no clinical symptoms at all,Some patients may have no clinical symptoms at all, with diagnosis made exclusively on the basis ofwith diagnosis made exclusively on the basis of laboratory results.laboratory results.
  50. 50. Genetics of DiabetesGenetics of Diabetes Type OneType One  It is not genetically predeterminedIt is not genetically predetermined  Increase susceptibility to the diseases isIncrease susceptibility to the diseases is inheritedinherited  Sibling has a 10 % chance of developingSibling has a 10 % chance of developing diabetes by the age of 40diabetes by the age of 40  Susceptibility is associated with HLA genesSusceptibility is associated with HLA genes ( HLA DR3 and or DR4, DQ W)( HLA DR3 and or DR4, DQ W)
  51. 51. Genetics of DiabetesGenetics of Diabetes Type TwoType Two  It is polygenic disorder ( no evidence ofIt is polygenic disorder ( no evidence of immune involvement)immune involvement)  Sibling have 50 % increased risk ofSibling have 50 % increased risk of developing diabetesdeveloping diabetes  Genes for majority of cases have yet to beGenes for majority of cases have yet to be identifiedidentified  Many genetic causes which include:Many genetic causes which include:  Mutations of insulin receptorsMutations of insulin receptors  Deletion of mitochondrial DNADeletion of mitochondrial DNA  Mutations effect the structure of insulinMutations effect the structure of insulin
  52. 52. Metabolism in Uncontrolled DiabetesMetabolism in Uncontrolled Diabetes In absence of insulinIn absence of insulin  Hepatic glucose production accelerateHepatic glucose production accelerate  Peripheral glucose uptake is reducedPeripheral glucose uptake is reduced Hyperglycemia leads to:Hyperglycemia leads to:  Osmotic diuresisOsmotic diuresis  Loss of fluid and electrolytesLoss of fluid and electrolytes  DehydrationDehydration  Plasma osmolality rises and renal perfusionPlasma osmolality rises and renal perfusion fallsfalls
  53. 53. Metabolism in Uncontrolled DiabetesMetabolism in Uncontrolled Diabetes In parallel:In parallel:  Rapid lipolysis occursRapid lipolysis occurs  Elevated circulatory FFAElevated circulatory FFA  Rising ketogenesisRising ketogenesis  Rising plasma ketone bodies which produceRising plasma ketone bodies which produce  Metabolic acidosisMetabolic acidosis  Vomiting leads to further loss of fluid andVomiting leads to further loss of fluid and electrolyteselectrolytes  Progressive dehydration impairs renalProgressive dehydration impairs renal excretion of hydrogen ions and ketonesexcretion of hydrogen ions and ketones
  54. 54. Type I DiabetesType I Diabetes Type I diabetes develop in young people, with the peakType I diabetes develop in young people, with the peak incidence at approximately 12 years of age.incidence at approximately 12 years of age. It is caused by autoimmune destruction of pancreatic B-It is caused by autoimmune destruction of pancreatic B- cells. The precipitating cause is still unclear (viralcells. The precipitating cause is still unclear (viral infection initiate the chain of autoimmune reaction,infection initiate the chain of autoimmune reaction, alternatively, cytokine response to viral infection, oralternatively, cytokine response to viral infection, or another insult, could attract monocytes andanother insult, could attract monocytes and macrophages that infiltrate and destroy the pancreaticmacrophages that infiltrate and destroy the pancreatic islets).islets). A proportion of patients have antibodies against B- cellA proportion of patients have antibodies against B- cell proteins.proteins. Auto-antibodies to insulin are also seen in someAuto-antibodies to insulin are also seen in some individuals.individuals.
  55. 55. Type 2 DiabetesType 2 Diabetes Type 2 diabetes usually develops in patientsType 2 diabetes usually develops in patients who are over 40 years old and are typicallywho are over 40 years old and are typically obese.obese. The pathogenesis in type 2 diabetes involves theThe pathogenesis in type 2 diabetes involves the impairment of insulin secretion and insulinimpairment of insulin secretion and insulin resistance.resistance. The response of the diabetic B-cell to theThe response of the diabetic B-cell to the glucose stimulus is suboptimal and there is noglucose stimulus is suboptimal and there is no first phase of insulin secretion.first phase of insulin secretion.
  56. 56. Long Term Complications ofLong Term Complications of DiabetesDiabetes Diabeteic ketoacidosis, a sudden (acute )Diabeteic ketoacidosis, a sudden (acute ) metabolic disturbance, is only one part of themetabolic disturbance, is only one part of the diabetic syndrome.diabetic syndrome. The other is the slow development of changes inThe other is the slow development of changes in small (microangiopathy) and largesmall (microangiopathy) and large (macroangiopathy) arteries.(macroangiopathy) arteries. Diabetic complications lead to diabetic kidneyDiabetic complications lead to diabetic kidney failure ( nephropathy), blindness ( retinopathy)failure ( nephropathy), blindness ( retinopathy) and to the impairment of nerve functionand to the impairment of nerve function ( neuropathy).( neuropathy). Peripheral vascular disease is a major cause ofPeripheral vascular disease is a major cause of foot ulcers and lower limb amputations.foot ulcers and lower limb amputations.
  57. 57. Treatment of DiabetesTreatment of Diabetes Type 1:Type 1: Daily subcutaneous insulin injections throughoutDaily subcutaneous insulin injections throughout life. Patients in whom blood glucose is difficult to controllife. Patients in whom blood glucose is difficult to control are treated with several injections per day, or sometimes,are treated with several injections per day, or sometimes, with a constant insulin infusion, delivered by awith a constant insulin infusion, delivered by a programmable, portable pump. Diet and exercise areprogrammable, portable pump. Diet and exercise are also important in the management of diabetes.also important in the management of diabetes. Type 2:Type 2: Diabetic patients do not usually require insulinDiabetic patients do not usually require insulin treatment because insulin synthesis is at least partlytreatment because insulin synthesis is at least partly preserved. Instead, the treatment relies on diet and oralpreserved. Instead, the treatment relies on diet and oral hypoglycemic agents. Drugs such as sulfonylureahypoglycemic agents. Drugs such as sulfonylurea derivatives stimulate insulin secretion. Another class ofderivatives stimulate insulin secretion. Another class of compounds ( metformin) reduce hyperglycemia bycompounds ( metformin) reduce hyperglycemia by increasing peripheral glucose uptake.increasing peripheral glucose uptake.
  58. 58. Typical Presentation of DiabeticTypical Presentation of Diabetic KetoacidosisKetoacidosis A 15 year old girl is admitted to the Accident andA 15 year old girl is admitted to the Accident and Emergency department. She is confused and her breathEmergency department. She is confused and her breath smells of acetone. She has dry skin and tongue, which aresmells of acetone. She has dry skin and tongue, which are signs of dehydration. She also takes quick, deep breathssigns of dehydration. She also takes quick, deep breaths (hyperventilation). Her RBG is 18.0 mmol/l ( 324 mg/dl) and(hyperventilation). Her RBG is 18.0 mmol/l ( 324 mg/dl) and ketones are present in the urine. Her serum potassiumketones are present in the urine. Her serum potassium concentration is 3.5 mmol/l ( normal 3.5- 5.0 mmol/l) and herconcentration is 3.5 mmol/l ( normal 3.5- 5.0 mmol/l) and her arterial blood pH is 7.2 (normal 7.37 – 7.44).arterial blood pH is 7.2 (normal 7.37 – 7.44). Comment:Comment: This is a typical presentation of diabeticThis is a typical presentation of diabetic ketoacidosis. Hyperventilation is a compensatory responseketoacidosis. Hyperventilation is a compensatory response to acidosis. This patient needs to be treated as a medicalto acidosis. This patient needs to be treated as a medical emergency. She will receive an intravenous infusionemergency. She will receive an intravenous infusion containing physiologic saline with potassium supplement tocontaining physiologic saline with potassium supplement to replace lost fluid and an insulin infusion.replace lost fluid and an insulin infusion.
  59. 59. Emergency Treatment ofEmergency Treatment of Diabetic KetoacidosisDiabetic Ketoacidosis Addresses four issues:Addresses four issues: Insulin infusion to reverse the metabolic effectsInsulin infusion to reverse the metabolic effects of the excess of anti- insulin hormones.of the excess of anti- insulin hormones. Infusion of fluids to treat dehydration.Infusion of fluids to treat dehydration. Intravenous fluids normally contain potassiumIntravenous fluids normally contain potassium supplements to prevent a decrease in plasmasupplements to prevent a decrease in plasma potassium ( hypokalemia).potassium ( hypokalemia). When acidosis is severe, infusion of an alkalineWhen acidosis is severe, infusion of an alkaline solution ( sodium bicarbonate) may be required.solution ( sodium bicarbonate) may be required.
  60. 60. Diabetic Ketoacidosis & PotassiumDiabetic Ketoacidosis & Potassium Insulin increases potassium uptake by cells. Lack ofInsulin increases potassium uptake by cells. Lack of insulin leads to release of potassium, particularly frominsulin leads to release of potassium, particularly from skeletal muscle. Since uncontrolled diabetes isskeletal muscle. Since uncontrolled diabetes is accompanied by an osmotic diuresis, the releasedaccompanied by an osmotic diuresis, the released potassium is excreted through the kidney. Most diabeticpotassium is excreted through the kidney. Most diabetic patients admitted to hospital with ketoacidosis arepatients admitted to hospital with ketoacidosis are potassium depleted. Exogenous insulin given to suchpotassium depleted. Exogenous insulin given to such patients stimulates the entry of potassium into cells. Thispatients stimulates the entry of potassium into cells. This further depletes the plasma potassium pool and can leadfurther depletes the plasma potassium pool and can lead to very low plasma potassium level ( hypolkalemia).to very low plasma potassium level ( hypolkalemia). Hypokalemia is dangerous, owing to its effects onHypokalemia is dangerous, owing to its effects on cardiac muscle. Thus, except for patients with very highcardiac muscle. Thus, except for patients with very high potassium level, potassium supplementation needs to bepotassium level, potassium supplementation needs to be considered in treatment of diabetic ketoacidosis.considered in treatment of diabetic ketoacidosis.
  61. 61. The Importance of GoodThe Importance of Good Glycemic ControlGlycemic Control Maintaining near normal blood glucose levels preventsMaintaining near normal blood glucose levels prevents the development of late complications of diabetes. Athe development of late complications of diabetes. A recently completed landmark clinical study, the Diabetesrecently completed landmark clinical study, the Diabetes Control Complications trial , has shown that theControl Complications trial , has shown that the development of late complications of diabetes in type Idevelopment of late complications of diabetes in type I diabetes is related to long term glycemia. This study hasdiabetes is related to long term glycemia. This study has also shown that in patients who have complications,also shown that in patients who have complications, good control of glycemic delays further development ofgood control of glycemic delays further development of retinopathy, nephropathy and neuropathy. Similar resultsretinopathy, nephropathy and neuropathy. Similar results were obtained for type 2 diabetic patients during the UKwere obtained for type 2 diabetic patients during the UK Prospective Diabetes Study completed in 1998. Thus theProspective Diabetes Study completed in 1998. Thus the aim of treatment of diabetes should be the achievementaim of treatment of diabetes should be the achievement of blood levels as close to normal as possible, withoutof blood levels as close to normal as possible, without precipitating hypoglycemia.precipitating hypoglycemia.
  62. 62. Glycated Hemoglobin (HbA1CGlycated Hemoglobin (HbA1C(( The measurement of blood glucose remains the mostThe measurement of blood glucose remains the most important laboratory test in diabetes.important laboratory test in diabetes. As erythrocytes age, there is gradual conversion of aAs erythrocytes age, there is gradual conversion of a fraction of native hemoglobin ( HbA) to its glycated form,fraction of native hemoglobin ( HbA) to its glycated form, HbAHbA1C1C, so that an older red cell, a greater fraction of HbA, so that an older red cell, a greater fraction of HbA exist as HbAexist as HbA1C1C.. HbAHbA1C1C concentration in blood reflects the time – averagedconcentration in blood reflects the time – averaged level of glycemia over the 3-6 weeks preceding thelevel of glycemia over the 3-6 weeks preceding the measurement.measurement. The normal concentration of HbAThe normal concentration of HbA1C1C is 4-6% of HbA.is 4-6% of HbA. Levels below 7% indicate acceptable control of diabetes.Levels below 7% indicate acceptable control of diabetes. Higher levels suggest poor control.Higher levels suggest poor control.
  63. 63. HbA1C Identifies Patients who doHbA1C Identifies Patients who do not Comply with Treatment (1-2not Comply with Treatment (1-2(( A 15 year old insulin dependent boy visited aA 15 year old insulin dependent boy visited a Diabetic Clinic for a check up. He tells theDiabetic Clinic for a check up. He tells the doctor that he complies with all the dietarydoctor that he complies with all the dietary advice and never misses insulin. Indeed, hisadvice and never misses insulin. Indeed, his random blood glucose is 6 mmol/l ( 108random blood glucose is 6 mmol/l ( 108 mg/dl), but his HbAmg/dl), but his HbA1C1C concentration is 11 %concentration is 11 % ( normal 4- 6 %). He has no glucosuria or( normal 4- 6 %). He has no glucosuria or ketones in his urine.ketones in his urine.
  64. 64. HbA1C Identifies Patients who doHbA1C Identifies Patients who do not Comply with Treatment (2-2not Comply with Treatment (2-2(( Comment:Comment: Blood and urine glucose resultsBlood and urine glucose results indicate good control of this boy’s diabetes atindicate good control of this boy’s diabetes at the time of measurements, whereas the HbAthe time of measurements, whereas the HbA1C1C level suggests poor control over the last 3-6level suggests poor control over the last 3-6 weeks. The probability is that he only compliesweeks. The probability is that he only complies with treatment days before he was due to comewith treatment days before he was due to come to the clinic. This is not uncommon into the clinic. This is not uncommon in adolescent, who find it hard to accept theadolescent, who find it hard to accept the necessity to adjust to their lifestyle to thenecessity to adjust to their lifestyle to the requirement of diabetes.requirement of diabetes.
  65. 65. GalactosemiaGalactosemia An apparently normal baby began to vomit and developAn apparently normal baby began to vomit and develop diarrhea after breastfeeding. These problems, together withdiarrhea after breastfeeding. These problems, together with dehydration continued for several days, when the babydehydration continued for several days, when the baby began to refuse food and developed jaundice, indicative ofbegan to refuse food and developed jaundice, indicative of liver damage, followed by hepatomegaly and then lensliver damage, followed by hepatomegaly and then lens opacification (cataracts). Measurements of glucose in theopacification (cataracts). Measurements of glucose in the blood and urine by specific enzymatic technique indicatedblood and urine by specific enzymatic technique indicated that levels of glucose were low, consistent with the failurethat levels of glucose were low, consistent with the failure to absorb foods. However glucose measured by a test thatto absorb foods. However glucose measured by a test that determined total reducing sugar was eventually identifieddetermined total reducing sugar was eventually identified as galactose, indicating an abnormality in galactoseas galactose, indicating an abnormality in galactose mechanism known as galactosemia. This finding wasmechanism known as galactosemia. This finding was consistent with the observation that, when milk wasconsistent with the observation that, when milk was removed from the diet and replaced with an infant formularemoved from the diet and replaced with an infant formula containing sucrose rather than lactose, the vomiting andcontaining sucrose rather than lactose, the vomiting and diarrhea stopped, and hepatic function was graduallydiarrhea stopped, and hepatic function was gradually restored.restored.
  66. 66. GalactosemiaGalactosemia Comment:Comment: The accumulation of galactose in theThe accumulation of galactose in the blood is most often a result of deficiency of Gal-1- Pblood is most often a result of deficiency of Gal-1- P uridyl transferase in liver tissues. Accumulation ofuridyl transferase in liver tissues. Accumulation of the latter interferes with phosphate and glucosethe latter interferes with phosphate and glucose metabolism, leading to widespread tissue damage,metabolism, leading to widespread tissue damage, organ failure, and mental retardation. In addition,organ failure, and mental retardation. In addition, accumulation of galactose in tissues results inaccumulation of galactose in tissues results in galactose conversion via polyol pathway togalactose conversion via polyol pathway to galactitol, and the accumulation of galactitol in thegalactitol, and the accumulation of galactitol in the lens results in osmotic stress and formation oflens results in osmotic stress and formation of cataracts. A milder form of galctosemia is caused bycataracts. A milder form of galctosemia is caused by galactokinase deficiency.galactokinase deficiency.
  67. 67. Fructose IntoleranceFructose Intolerance An autosomal recessive condition, due toAn autosomal recessive condition, due to deficiency of fructose – 1- phosphate aldolase.deficiency of fructose – 1- phosphate aldolase. The defect causes:The defect causes:  Intracellular accumulation of fructose -1-Intracellular accumulation of fructose -1- phosphate.phosphate.  Inhibition of fructokinaseInhibition of fructokinase  Increased blood level of fructoseIncreased blood level of fructose  Inhibition of glycogen phosphorylase due toInhibition of glycogen phosphorylase due to depletion of Pidepletion of Pi  Profound hypoglycemiaProfound hypoglycemia
  68. 68. Von Gierk’s DiseaseVon Gierk’s Disease A baby girl is irritable, sweaty and lethargic andA baby girl is irritable, sweaty and lethargic and demands food frequently. Physical examination indicatesdemands food frequently. Physical examination indicates an extended abdomen, resulting from enlarged liver.an extended abdomen, resulting from enlarged liver. Blood glucose, after a meal, was 3.5 mmol/l (70 mg/ dl).Blood glucose, after a meal, was 3.5 mmol/l (70 mg/ dl). After 4 h, the child was exhibiting irritability andAfter 4 h, the child was exhibiting irritability and sweating, her heart rate was increased and bloodsweating, her heart rate was increased and blood glucose had declined to 2 mmol/l ( 40 mg/dl). Theseglucose had declined to 2 mmol/l ( 40 mg/dl). These symptoms were corrected by feeding. A liver biopsysymptoms were corrected by feeding. A liver biopsy showed massive deposition of glycogen in the livershowed massive deposition of glycogen in the liver cytosol.cytosol. Comments:Comments: She has deficiency in glycogenShe has deficiency in glycogen mobilization. Because of the severity of hypglycemia, themobilization. Because of the severity of hypglycemia, the most likely mutation is in hepatic glucose- 6-most likely mutation is in hepatic glucose- 6- phosphatase, which is required for glucose production byphosphatase, which is required for glucose production by both gluconeogenesis and glycogenolysis.both gluconeogenesis and glycogenolysis.
  69. 69. Glucose 6 PhosphateGlucose 6 Phosphate Dehydrogenase Deficiency 1Dehydrogenase Deficiency 1 Just prior to planned departure to the tropics, aJust prior to planned departure to the tropics, a patient visits his physician, complaining ofpatient visits his physician, complaining of weakness and noting that his urine had recentlyweakness and noting that his urine had recently become unexplainably dark. Physicalbecome unexplainably dark. Physical examination revealed slightly jaundiced ( yellow,examination revealed slightly jaundiced ( yellow, icteric) sclera. Laboratory tests indicated a lowicteric) sclera. Laboratory tests indicated a low hematocrit, a high reticulocyte count, andhematocrit, a high reticulocyte count, and significantly increased blood level of bilirubin.significantly increased blood level of bilirubin. The patient has been quite healthy during aThe patient has been quite healthy during a previous visit a month ago when he receivedprevious visit a month ago when he received immunizations and prescriptions for drugsimmunizations and prescriptions for drugs related to his travel plan.related to his travel plan.
  70. 70. Glucose 6 PhosphateGlucose 6 Phosphate Dehydrogenase Deficiency 2Dehydrogenase Deficiency 2 Comments:Comments: A number of drugs, particularly primaquineA number of drugs, particularly primaquine and related antimalarials, undergo reactions in the cell,and related antimalarials, undergo reactions in the cell, producing large quantities of superoxide and Hproducing large quantities of superoxide and H22OO22.. Superoxide dismutase converts superoxide into HSuperoxide dismutase converts superoxide into H22OO22,, which is inactivated by glutathione peroxidase usingwhich is inactivated by glutathione peroxidase using NADPH. Some persons have genetic defect in G6PD,NADPH. Some persons have genetic defect in G6PD, typically yielding an unstable enzyme that has a shortertypically yielding an unstable enzyme that has a shorter life in the RBC. Therefore insufficient production oflife in the RBC. Therefore insufficient production of NADPH under stress, the cell ability to recycle GSSG toNADPH under stress, the cell ability to recycle GSSG to GSH is impaired and drug induced oxidative stress leadsGSH is impaired and drug induced oxidative stress leads to lysis of RBC’s and hemolytic anemia. If the hemolysisto lysis of RBC’s and hemolytic anemia. If the hemolysis is severe enough Hb spills over into the urine, resultingis severe enough Hb spills over into the urine, resulting in hematuria and dark colored urine. Older cells, whichin hematuria and dark colored urine. Older cells, which can’t synthesize and replace their enzyme are thereforecan’t synthesize and replace their enzyme are therefore particularly affected. Genetically the deficiency is X-particularly affected. Genetically the deficiency is X- linked. Favism is associated with G6PD deficiency.linked. Favism is associated with G6PD deficiency.
  71. 71. Thank You

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