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Digestion of Dietary Carbohydrates

Dietary carbohydrates from which humans gain


energy enter the body in complex forms, such as
disaccharides and the polymers starch (amylose
and amylopectin) and glycogen. The polymer
cellulose is also consumed but not digested. The
first step in the metabolism of digestible
carbohydrate is the conversion of the higher
polymers to simpler, soluble forms that can be
transported across the intestinal wall and
delivered to the tissues. The breakdown of
polymeric sugars begins in the mouth. Saliva has
a slightly acidic pH of 6.8 and contains lingual
amylase that begins the digestion of
carbohydrates. The action of lingual amylase is
limited to the area of the mouth and the
esophagus; it is virtually inactivated by the much
stronger acid pH of the stomach. Once the food
has arrived in the stomach, acid hydrolysis
contributes to its degradation; specific gastric
proteases and lipases aid this process for
proteins and fats, respectively. The mixture of
gastric secretions, saliva, and food, known

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collectively as chyme, moves to the small
intestine.
The main polymeric-carbohydrate digesting
enzyme of the small intestine is α-amylase. This
enzyme is secreted by the pancreas and has the
same activity as salivary amylase, producing
disaccharides and trisaccharides. The latter are
converted to monosaccharides by intestinal
saccharidases, including maltases that hydrolyze
di- and trisaccharides, and the more specific
disaccharidases, sucrase, lactase, and trehalase.
The net result is the almost complete conversion
of digestible carbohydrate to its constituent
monosaccharides. The resultant glucose and
other simple carbohydrates are transported
across the intestinal wall to the hepatic portal
vein and then to liver parenchymal cells and
other tissues. There they are converted to fatty
acids, amino acids, and glycogen, or else
oxidized by the various catabolic pathways of
cells.
Oxidation of glucose is known as glycolysis.
Glucose is oxidized to either lactate or pyruvate.
Under aerobic conditions, the dominant product
in most tissues is pyruvate and the pathway is

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known as aerobic glycolysis. When oxygen is
depleted, as for instance during prolonged
vigorous exercise, the dominant glycolytic
product in many tissues is lactate and the
process is known as anaerobic glycolysis.

GLYCOLYSIS PATHWAY

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The Energy Derived from Glucose Oxidation
Aerobic glycolysis of glucose to pyruvate,
requires two equivalents of ATP to activate the
process, with the subsequent production of four
equivalents of ATP and two equivalents of
NADH. Thus, conversion of one mole of
glucose to two moles of pyruvate is
accompanied by the net production of two moles
each of ATP and NADH.
Glucose + 2 ADP + 2 NAD+ + 2 Pi -----> 2
Pyruvate + 2 ATP + 2 NADH + 2 H+
The NADH generated during glycolysis is used
to fuel mitochondrial ATP synthesis via
oxidative phosphorylation, producing either two
or three equivalents of ATP. (depending upon
whether the glycerol phosphate shuttle or the
malate-aspartate shuttle is used to transport the
electrons from cytoplasmic NADH into the

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mitochondria. The net yield from the oxidation
of 1 mole of glucose to 2 moles of pyruvate is,
therefore, either 6 or 8 moles of ATP. Complete
oxidation of the 2 moles of pyruvate, through the
TCA cycle, yeilds an additional 30 moles of
ATP; the total yield, therefore being either 36 or
38 moles of ATP from the complete oxidation of
1 mole of glucose to CO2 and H2O.)

Anaerobic Glycolysis
Under aerobic conditions, pyruvate in most cells
is further metabolized via the TCA cycle. Under
anaerobic conditions and in erythrocytes under
aerobic conditions, pyruvate is converted to
lactate by the enzyme lactate dehydrogenase
(LDH), and the lactate is transported out of the
cell into the circulation. The conversion of
pyruvate to lactate, under anaerobic conditions,
provides the cell with a mechanism for the
oxidation of NADH (produced during the
G3PDH reaction) to NAD+; which occurs
during the LDH catalyzed reaction. This
reduction is required since NAD+ is a necessary
substrate for G3PDH, without which glycolysis
will cease. Normally, during aerobic glycolysis

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the electrons of cytoplasmic NADH are
transferred to mitochondrial carriers of the
oxidative phosphorylation pathway generating a
continuous pool of cytoplasmic NAD+.
Aerobic glycolysis generates substantially more
ATP per mole of glucose oxidized than does
anaerobic glycolysis. The utility of anaerobic
glycolysis, to a muscle cell when it needs large
amounts of energy, stems from the fact that the
rate of ATP production from glycolysis is
approximately 100X faster than from oxidative
phosphorylation. During exertion muscle cells
do not need to energize anabolic reaction
pathways. The requirement is to generate the
maximum amount of ATP, for muscle
contraction, in the shortest time frame. This is
why muscle cells derive almost all of the ATP
consumed during exertion from anaerobic
glycolysis.
The lactate produced during anaerobic
glycolysis diffuses from the tissues and is
transproted to highly aerobic tissues such as
cardiac muscle and liver. The lactate is then
oxidized to pyruvate in these cells by LDH and
the pyruvate is further oxidized in the TCA

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cycle. If the energy level in these cells is high
the carbons of pyruvate will be diverted back to
glucose via the gluconeogenesis pathway.

Regulation of Glycolysis
. The rate limiting step in glycolysis is the
reaction catalyzed by PFK-1. The major sites for
regulation of glycolysis and gluconeogenesis are
the phosphofructokinase-1 (PFK-1) and
fructose-1,6-bisphosphatase (F-1,6-BPase)

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catalyzed reactions. PFK-2 is the kinase activity
and F-2,6-BPase is the phosphatase activity of
the bi-functional regulatory enzyme,
phosphofructokinase-2/fructose-2,6-
bisphosphatase.

Ethanol Metabolism
Animal cells (primarily hepatocytes) contain the
cytosolic enzyme alcohol dehydrogenase (ADH)
which oxidizes ethanol to acetaldehyde.
Acetaldehyde then enters the mitochondria
where it is oxidized to acetate by acetaldehyde
dehydrogenase (AcDH).

Acetaldehyde forms adducts with proteins,


nucleic acids and other compounds, the results
of which are the toxic side effects (the hangover)
that are associated with alcohol consumption.
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The ADH and AcDH catalyzed reactions also
leads to the reduction of NAD+ to NADH. The
metabolic effects of ethanol intoxication stem
from the actions of ADH and AcDH and the
resultant cellular imbalance in the
NADH/NAD+.

Regulation of Blood Glucose Levels


If for no other reason, it is because of the
demands of the brain for oxidizable glucose that
the human body exquisitely regulates the level
of glucose circulating in the blood. This level is
maintained in the range of 5mM.

SOURCE OF GLUCOSE
• Nearly all carbohydrates ingested in the diet
are converted to glucose following transport
to the liver.
• Catabolism of dietary or cellular proteins

generates carbon atoms that can be utilized


for glucose synthesis via gluconeogenesis.

• Other tissues besides the liver that


incompletely oxidize glucose
(predominantly skeletal muscle and

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erythrocytes) provide lactate that can be
converted to glucose via gluconeogenesis.

GLUCOSE HOMEOSTASIS
Maintenance of blood glucose homeostasis is of
paramount importance to the survival of the
human organism. The predominant tissue
responding to signals that indicate reduced or
elevated blood glucose levels is the liver.
Indeed, one of the most important functions of
the liver is to produce glucose for the
circulation. Both elevated and reduced levels of
blood glucose trigger hormonal responses to
initiate pathways designed to restore glucose
homeostasis.
Low blood glucose triggers release of glucagon
from pancreatic α-cells. Glucagon binds to its'
receptors on the surface of liver cells leading to
an increased rate of glycogenolysis by activating
glycogen phosphorylase. This is the same
response hepatocytes have to epinephrine
release. The resultant increased levels of G6P in

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hepatocytes is hydrolyzed to free glucose, by
glucose-6-phosphatase, which then diffuses to
the blood.
High blood glucose triggers release of insulin
from pancreatic β-cells. In opposition to the
cellular responses to glucagon (and epinephrine
on hepatocytes), insulin stimulates extrahepatic
uptake of glucose from the blood and inhibits
glycogenolysis in extrahepatic cells and
conversely stimulates glycogen synthesis. As the
glucose enters hepatocytes it binds to and
inhibits glycogen phosphorylase activity. Why is
it that the glucose that enters hepatocytes is not
immediately phosphorylated and oxidized?
Liver cells contain an isoform of hexokinase
called glucokinase. Glucokinase has a much
lower affinity for glucose than does hexokinase.
Therefore, it is not fully active at the
physiological ranges of blood glucose.
Additionally, glucokinase is not inhibited by its
product G6P, whereas, hexokinase is inhibited
by G6P.

One major response of non-hepatic tissues to


insulin is the recruitment, to the cell surface, of
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glucose transporter complexes. Glucose
transporters comprise a family of five members,
GLUT-1 to GLUT-5. GLUT-1 is ubiquitously
distributed in various tissues. GLUT-2 is found
primarily in intestine, kidney and liver. GLUT-3
is also found in the intestine and GLUT-5 in the
brain and testis. GLUT-5 is also the major
glucose transporter present in the membrane of
the endoplasmic reticulum (ER) and serves the
function of transporting glucose to the cytosol
following its' dephosphorylation by the ER
enzyme glucose 6-phosphatase. Insulin-sensitive
tissues such as skeletal muscle and adipose
tissue contain GLUT-4. When the concentration
of blood glucose increases in response to food
intake, pancreatic GLUT-2 molecules mediate
an increase in glucose uptake which leads to
increased insulin secretion. Recent evidence has
shown that the cell surface receptor for the
human T cell leukemia virus (HTLV) is the
ubiquitous GLUT-1.
Hepatocytes, unlike most other cells, are freely
permeable to glucose and are, therefore,
essentially unaffected by the action of insulin at
the level of increased glucose uptake. When

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blood glucose levels are low the liver does not
compete with other tissues for glucose since the
extrahepatic uptake of glucose is stimulated in
response to insulin. Conversely, when blood
glucose levels are high extrahepatic needs are
satisfied and the liver takes up glucose for
conversion into glycogen for future needs.
Under conditions of high blood glucose, liver
glucose levels will be high and the activity of
glucokinase will be elevated. The G6P produced
by glucokinase is rapidly converted to G1P by
phosphoglucomutase, where it can then be
incorporated into glycogen

Additional signals, ACTH (adrenocorticotrophic


hormone - a peptide hormone that is produced
by the anterior pituitary gland. It stimulates the
adrenal cortex to secrete glucocorticoid
hormones, which help cells synthesize glucose)
and growth hormone, released from the pituitary
act to increase blood glucose by inhibiting
uptake by extrahepatic tissues.

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Glucocorticoids also act to increase blood
glucose levels by inhibiting glucose uptake.
Cortisol, the major glucocorticoid released from
the adrenal cortex, is secreted in response to the
increase in circulating ACTH.
The adrenal medullary hormone, epinephrine,
stimulates production of glucose by activating
glycogenolysis in response to stressful stimuli.

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The glucose from liver (ie. from
gluconeogenesis or glycogenolysis) enters
extrahepatic cells where it is re-phosphorylated
by hexokinase. Since muscle and brain cells lack
glucose-6-phosphatase, the glucose-6-phosphate
product of hexokinase is retained and oxidized
by these tissues.

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