Biochemistry Second Year

1. CarbohydratesCarbohydrates

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. 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. 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. 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. 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. 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. 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. 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. 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. 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. GlycogenGlycogen
MetabolismMetabolism

13. Structure Of Glycogen

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.

17. 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.

20. 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.

21. 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.

24. 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.

25. 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.

26. 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).

27. 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.

28. GlycolysisGlycolysis

29. 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

30. 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

31. GlycolysisGlycolysis

33. 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

34. 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

35. 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

36. 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.

40. 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.

41. 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.

42. 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

45. TCA CycleTCA Cycle

46. 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)

50. 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)

51. 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)

53. 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)

54. 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

55. 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

56. 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.

57. 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.

58. 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.

59. 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.

60. 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.

61. 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.

62. 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.

63. 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.

64. 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.

65. 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.

67. 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)

68. 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

69. 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

70. 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

71. 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.

72. 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.

73. 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.

74. 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.

75. 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.

76. 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.

77. 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.

78. 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.

79. 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.

80. 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.

81. 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.

82. 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.

83. 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.

84. 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

85. 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.

88. 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.

89. 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.

90. Thank You