Carbohydrates are the largest source of calories and are broken down into glucose, which is the main carbohydrate used in metabolism. Glucose is absorbed into the bloodstream and transported to tissues like muscle where it is either used for energy or stored as glycogen. Carbohydrate digestion begins in the mouth and small intestine where enzymes break starches and sugars into glucose and other monosaccharides that can be absorbed. Glucose is then regulated through various pathways including glycolysis, the citric acid cycle, and oxidative phosphorylation to produce energy in the form of ATP.

1.  Carbohydrates are the largest source of dietary
calories.
 The major cabohydrates are starch, lactose and
sucrose
 The main carbihydrates in body metabolism is
glucose
 transported to muscle (and other tissues) via blood
 stored in liver and muscle as glycogen
 ATP produced more quickly from CHO than from fats
or proteins
 CHO stores can be depleted
Carbohydrates (Fuels)

2. Digestion
 Starch digestion begins in mouth by the
salivary α-amylase which converts starch to
smaller polysaccharides called α-dextrins
 Pancreatic α-amylase continue the digestion of
α-dextrins into maltose, maltotriose &
oligosaccharides called limited dextrins
 Digestion of maltose, maltotriose, sucrose &
lactose continues by disaccharidases attached
to the membrane of surface of the brush
border (microvilli)of intestinal epithelial cells
 The monosaccharides produced are
transported by into the intestinal cells

3. Disaccharidases
 Glucoamylase : Glycoprotein
attached to the luminal
membrane with two catalytic
activities. An exoglucosidase
specific for α-1-4 glycosidic
bonds, acts at the non-reducing
ends of limited dextrins releasing
glucose up to isomaltose.

4. Disaccharidases
 Sucrase-Isomaltase Complex: Similar to
glusamylase attached to membrane with two
polypeptides protrudes into the intestinal lumina,
an intestinal protease clips it into two separate
subunits that remain attached to each other.
Each subunit site has a catalytic site that differs
in substrate specificity. The sucrose maltase site
accounts for 100% of intestinal ability to
hydrolyze sucrose in addition to maltase activity.
The isomaltase-maltase site accounts for almost
all activity to hydrolyze α 1-6 bonds in addition to
maltase activity.

5. Disaccharidases
 Trehalase: one catalytic site and
hydrolyzes the glycosidic bond in
trehalose (disaccharide of two glycosyl
units attached by their anomeric
carbons)
 Lactase-Glucosyl Ceramidase Complex:
glycoprotein found in the brush border
that has two calaytic sites extending in
the intestinal lumin. It hydrolyzes lactose
and the B-bonds betweeen glucose or
galactose and ceramide in glycolipids.

6. Dietary Fiber
 Composed principally of polysaccharides which
can not be digested by human enzymes of
intestinal tract
 Derivatives of lignan ( cellulose, hemicellulose,
lignin, pectin s, mucilages & gums)
 Bacterial flora of the colon metabolize the
fibers to gases(H2,CO2,CH4) & short chain fatty
acids
 Fatty acids are absorbed by colonic cells
 Fibers is seen to soften the stool, thereby
reducing pressure on colonic wall & enhancing
expulsion of feces

7. Absorption of carbohydrates
 Sugars are transported
across the intestinal
epithelial cells into the
blood
 Not all complex sugars
are digested in the
same rate within the
intestine
 Glycemic index of the
food is an indication of
how rapidly blood
glucose level rises after
consumption
Whole weat 100
pasta 67
cornflakes 121
potatoes 120
Ice cream 69
fruits 52

8. Glucose Absorption
 Two types of glucose transport
proteins are present in the intestinal
cells
– Na+ dependent: an active transport
which depends on cotransport of sodium
and glucose
– Facilitated : passive transport known as
Glut 1 -4

9.  Cell membranes are not inherently permeable to
glucose. There are many glucose transporters.
 GLUT- 1 enables basal non- insulin stimulated
glucose uptake (erythrocytes)
 GLUT- 2 transport glucose into beta cells, a pre-
requisite for glucose sensing.
 GLUT- 3 enables non- insulin mediated glucose
uptake into brain.
 GLUT- 4 enables much of the peripheral action of
insulin (muscles, adipose)
Glucose transporters

11. Glycogen Metabolism

13. Glycogenolysis
 Occurs mainly in liver & muscles
 Both pathways in the liver & muscle
are the same
 End product in liver is glucose, while in
muscle is glucose 6 phosphate

16. Glycogenesis

21. electron
transport
chain
Aerobic Metabolism
Oxidation Phosphorylation
Kreb’s
cycle
Glycolysis
(carbohydrates)
(proteins)
Beta Oxidation
(fats)
NADH
FADH2
O2 H2O
ADP + Pi ATP
acetyl
CoA
mitochondria
oxidation
phosphorylation

23.  uses only CHO
 occurs in sarcoplasm
 first step is glucose transport into tissues
 after entry, 2 ATP are used (with glucose)
 glucose (C6) is split into two C3 molecules
 final product is pyruvate
 4 ATP are synthesized
 pyruvate forms either lactate or enters
mitochondria
Glycolysis

24. glucose
ATP
ATP
PFK
4 ATP
pyruvate
lactate acetyl CoA
mitochondria
glycogenolysis
sarcolemma
blood
glycolysis
Overview of Glycolysis

25. Glycolysis

27. Electron Transport Chain (ETC)
Oxidative Phosphorylation
Oxidation
 NADH and FADH2 transfer electrons to ETC
 final acceptor of electrons is O2
Phosphorylation
 energy generated by oxidation used to
resynthesize ATP
– 3 ATP from each NADH
– 2 ATP from each FADH2

28. 1,3 DPG
2,3 DPG mutase
2,3 DPG
2,3 DPG phosphatase
2-PG
2,3 DPG synthesis & degradation
ADP
ATP

29. Regulation of Glycolysis

30. Hexokinase
 Tissue specific isoenzyme, low Km
value, inhibited by G-6-P, in
muscles, brain, RBC and adipose
tissue.
 Liver isoenzyme (glucokinase) has
high Km value, not inhibited by G-
6-P

33. Phosphofructokinase(PFK-1)
 Allosteric enzyme, catalyze rate
limiting step
 Has six binding sites
– 2 for substrates (ATP & F-6-P)
– 4 allosteric regulatory sites
 ATP & Citrates are inhibitors
 AMP & F2,6bp are stimulatory

34. PFK-2
 Not glycolytic enzyme, synthesizes F-2,6 bp,
has two domains, a kinase & phosphatase
 In skeletal muscles, F-6-P activates the kinase
domain and this increases F2-6-bp
concentration
 In liver, PFK-2 regulated by phosphorylation,
which when near amino terminal decreases the
activity of kinase & increases activity of
phosphatase (CAMP)
 Cardiac isoenzyme, phosphorylation near the
carboxylic terminal in response to adrenergic
activator or AMP increases the kinase activity

37. Pyruvate Kinase
 Tissue specific isoenzyme
 Brain & muscle contains no allosteric
site and thus do not contribute toward
regulation of glycolysis.
 In liver, it is regulated by
phosphorylation & dephosphorylation
by CAMP-dependent kinases. It is also
inhibited by allosteric regulators (F-1-
6bp & ATP).

38. Lactate Dehydrogenase
 Tetramer composed of A-subunits (M-
skeletal) and also B subunits (H-heart).
 Different tissues produce different
amounts of the two subunits (M4, M3H
……….H4)
 M4 facilitates conversion of pyruvate into
lactate in skeletal muscles
 M4 facilitates conversion of lactate into
pyruvate in the heart.

39.  lactate formation
 enters mitochondria (i.e. Kreb’s cycle)
 formation of Kreb’s cycle intermediates
Pyruvate goes in one of three directions
Metabolic Fate of Pyruvate

42.  primary function is to reduce NAD+ and FAD
 acetyl CoA (C2) combines with a C4
molecule forming a C6 molecule
 C6 molecule is partially degraded back to a
C4 molecule
 each loss of C gives off a CO2
Kreb’s Cycle
(Citric Acid Cycle)

47. Regulation of TCA Cycle

48. Citrate Synthetase
Has no alosteric regulators
Oxaloacetate concentration
activates the enzyme
Citrate concentration
inhibits the enzyme

49. Isocitrate Dehydrogenase
 Rate limiting step
 Allosteric, activated by ADP & inhibited
by NADH
 Binding of ADP to one subunit causes
the activation of other subunits
(positive cooperativity)
 Binding of ADP shift Km to a lower
value
 Small change in ADP brings about
large change in the rate.

50. α-ketoglutrate Dehydrogenase
 No allosteric regulators
 Product inhibition by NADH and
succinyl CoA
 It may also be inhibited by GTP
 In contracting heart muscle, the
release of Ca2+ may provide activation
of both enzymes when ATP is rapidly
hydrolyzed.

51. NADH
 Plays a central role in Regulation
 Rate of oxidation of NADH depends
on oxidative phosphorylation
 It inhibits all dehydrogenases in TCA
& pyruvate dehydrogenase and thus
regulates entry point of acetyl CoA

54. electron
transport
chain
Overview of Aerobic
Metabolism
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)

56. Gluconeogenesis

57.  Sites include liver & kidney while
substrates include, amino acids,
lactate, pyruvate, glycerol.
 Cori & alanine cycles for transport of
intermediates between site of
production of these metabolites and
site of synthesis.
 Many enzymes of glycolysis are
common to gluconeogenesis.
Gluconeogenesis(1)

59.  Irrversible enzymes of glycolysis are
replaced by gluconeogenesis
enzymes.
1. Pyruvate kinase – pyruvate
carboxylase & PEPCK
2. PFK ---- F 2,6 diphosphatase
3. Glucokinase --- Glu 6 phosphatase
Gluconeogenesis(2)

60. Gluconeogenesis - Bypass Enzymes
Glucose
oxaloacetate
Glucose-6-Phosphate
Fructose-6-Phosphate
Fructose 1,6 Bisphosphate
DHAP + Glyceraldehyde-3-P
Glyceraldehyde-3-P
Pyruvate
PEP
2-Phosphoglycerate
3-Phosphoglycerate
1,3-BPG

61. Gluconeogenesis - Bypass Enzymes
pyruvate + CO2 + ATP + H2O  oxaloacetate + ADP,Pi + 2H+
oxaloacetate + GTP  PEP + GDP + CO2
10. Pyruvate carboxylase & PEP carboxykinase
(+) acetylCoA & (-) ADP
3.Fructose 1,6-bisphosphatase
(-) fructose 2,6-bisphosphate (low fasting – high Fed)
(-) AMP
fructose 1,6 bisphosphate + H2O  fructose 6-phosphate + Pi
1. Glucose 6-phosphatase
glucose 6-phosphate + H2O  glucose + Pi

62. GLUCONEOGENESIS-Liver
2Pyruvate + 4ATP + 2NADH
2GTP
Glucose + 4ADP + 2NAD+
2GDP
to blood

63.  Galactose metabolism occurs in liver.
 Galactose UDP-galactose
GK
Uridyl transferase
UDP- glucose
Galactose metabolism

64.  Occurs in liver & adipose tissue
 Fructose Fructose 6 phos
fructokinase
Glucose 6 phos
Fructose metabolism

65.  The plasma glucose concentration reflects the
balance between intake, tissue utilization &
endogeneous production .
 Insulin promotes up take of glucose thus decreasing
plasma glucose while glucagon stimulates both the
release of glucose from glycogen stores & its denovo
synthesis, thus causing an increase in plasma
glucose.
 Glucose stimulates the secretion of insulin &
suppresses the secretion of glucagon.
Glucose Homeostasis

66.  Insulin acts on three main targets, liver, adipose &
muscles.
 In liver insulin stimulates, glycolysis, glycogenesis &
lipogenesis & suppresses lipolysis.
 In peripheral tissues, insulin induces lipoprotein
lipase activity & thus stimulates triglyceride synthesis.
 In muscles, insulin increases glucose & amino acid
transport & glycogen synthesis.
Metabolic effects of insulin

67.  Glucagon main effect is the mobilization of the fuel
reserves for the maintenance of the blood glucose
level between meals.
 Glucagon inhibits glucose- utilizing pathways and the
storage of metabolic fuels.
 It acts on liver, to stimulate glycogenolysis and inhibit
glycogenesis, glycolysis and lipogenesis.
 Gluconeogenesis and ketogenesis are then activated
 Epinephrine has effects similar to glucagon in the
liver but works through a different receptor. It
promotes an increase in blood glucose in response to
stress
Metabolic effects of Glucagon

68.  The glucose level in the vicinity of the B- cell is
sensed by the transporter GLUT- 2. Glucose is carried
into the cell, where it is phophorylated into G-6- P by
glucokinase which also is a part of the glucose
sensing mechanism. Increased G-6- P increases
glucose utilization and ATP production in the B- cell.
This changes the flux of ions across the cell
membrane, depolarizes the cell and increases the
concentration of Ca2+. Hence insulin is exocytosed.
 Insulin secretion is biphasic. The first phase occurs
over 10- 15 minutes of stimulation which release the
preformed insulin. The second phase, which lasts up
to 2 hours, is the release of newly synthesized
insulin.
Stimulation of insulin secretion by glucose

69.  Insulin secretion is also stimulated by gastrointestinal
hormones (insulinotropic peptide, cholecystokinin)
and amino acids, such as leucine, arginine, and
lysine. Thus, the insulin response to orally
administered glucose is greater than to an
intravenous infusion.
Stimulation of insulin secretion by glucose

70.  Hypoglycemia is defined as a blood glucose
concentration below 2.5 mmol/ L ( 45 mg/dl).
 Epinephrine and glucagon are released, resulting in a
stress response, the manifestation of which may
include sweating, trembling, increased heart rate and
feeling of hunger. If blood glucose continues to fall,
brain function is compromised (neuroglycopenia).
 Hypoglycemia in healthy individuals is usually mild
and may occur during exercise, after a period of
fasting or due to alcohol ingestion.
 Hypoglycemia may be caused by a rare insulin
secreting tumor of the beta- cells ( insulinoma) or
overdose of exogenous insulin.
Hypoglycemia

71.  Alcohol is metabolized primarily in the liver. Two steps
metabolism of alcohol is relatively unregulated, leading
to a rapid increase in hepatic NADH. This shifts the
equilibrium of LDH catalyzed reaction towards lactate
formation ( lacticacidemia). Also shifts cytosolic
oxaloacetate towards malate formation, reducing
gluconeogenesis from TCA. In addition DHAP is shifted
toward glycerol- 3- phosphate formation and thus
reducing gluconeogenesis from glycerol.
 The low blood glucose leads to a stress response (
rapid heart beat, clammy skin), an effort to enhance
stimulation of gluconeogenesis combined action of
glucagon and epinephrine. Rapid breathing is
physiological response to metabolic acidosis.
Alcohol Excess and Hypoglycemia 2

72.  Maintaining near normal blood glucose levels
prevents the development of late complications of
diabetes. A recently completed landmark clinical
study, the Diabetes Control Complications trial , has
shown that the development of late complications of
diabetes in type I diabetes is related to long term
glycemia. This study has also shown that in patients
who have complications, good control of glycemic
delays further development of retinopathy,
nephropathy and neuropathy. Similar results were
obtained for type 2 diabetic patients during the UK
Prospective Diabetes Study completed in 1998. Thus
the aim of treatment of diabetes should be the
achievement of blood levels as close to normal as
possible, without precipitating hypoglycemia.
The importance of good glycemic control

73.  The entry of glucose into brain, peripheral nerve
tissue, kidney, intestine, lens and RBC does not
depend on insulin action.
 During hyperglycemia, the intracellular level of
glucose in these cells is high, which promotes the
non- enzymatic attachment of glucose to protein
molecules.
 Glycation involves glucose and alpha- amino terminal
amino acid and ε- amino groups of lysine residues.
 Hemoglobin, albumin and collagen become glycated
which effects their function.
 For instance, glycation of apolipoprotein B slows
down the rate of receptor dependent metabolism of
LDL.
Protein modification by glucose

74.  The measurement of blood glucose remains the most
important laboratory test in diabetes.
 As erythrocytes age, there is gradual conversion of a
fraction of native hemoglobin ( HbA) to its glycated
form, HbA1C, so that an older red cell, a greater
fraction of HbA exist as HbA1C.
 HbA1C concentration in blood reflects the time –
averaged level of glycemia over the 3-6 weeks
preceding the measurement.
 The normal concentration of HbA1C is 4-6% of HbA.
Levels below 7% indicate acceptable control of
diabetes. Higher levels suggest poor control.
Glycated Hemoglobin (HbA1C)

75. 0
50
100
150
200
250
6 7 8 9 10 11 12 13
MBG

76.  Glucose can be reduced to sorbitol by the action of aldose
reductase. Sorbitol is further oxidized by sorbitol
dehydrogenase to fructose. Since aldose reductase has a
high Km for glucose, the pathway is not very active at
normal glucose level.
 In hyperglycemia, however, glucose levels in insulin
independent tissues, such as the RBC, nerve and lens,
increase and consequently there is an increase in the activity
of the polyol pathway with depletion of NADPH.
 Like glucose, sorbitol exerts an osmotic effect. This is
thought to play a role in the development of diabetic
cataracts.
 In addition, the high level of sorbitol decreases cellular
uptake of another alcohol, myoinositol, which in turn causes
a decrease in the activity of membrane Na+/ K+ ATPase. This
in turn effects nerve function and, along with hypoxia and
reduced nerve blood, contributes to the development of
diabetic neuropathy. Drugs inhibiting aldose reductase
improve nerve function in diabetes.
The Polyol Pathway

79.  Comments: A number of drugs, particularly primaquine
and related antimalarials, undergo reactions in the cell,
producing large quantities of superoxide and H2O2.
Superoxide dismutase converts superoxide into H2O2,
which is inactivated by glutathione peroxidase using
NADPH. Some persons have genetic defect in G6PD,
typically yielding an unstable enzyme that has a
shorter life in the RBC. Therefore insufficient
production of NADPH under stress, the cell ability to
recycle GSSG to GSH is impaired and drug induced
oxidative stress leads to lysis of RBC’s and hemolytic
anemia. If the hemolysis is severe enough Hb spills
over into the urine, resulting in hematuria and dark
colored urine. Older cells, which can’t synthesize and
replace their enzyme are therefore particularly
affected. Genetically the deficiency is X- linked. Favism
is associated with G6PD deficiency.
Glucose 6 phosphate dehydrogenase deficiency 2

80. 0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
ATP ADP AMP
Rest
Exercise
Changes in ATP, ADP, and AMP concentrations in skeletal muscle