Carbohydrate Metabolism
Digestion & Absorption of Carbohydrates
1- In the Mouth
Salivary amylase digests starch partially into mixtures of dextrins and
maltose.
2- In the Stomach
Salivary amylase acts for short time till the gastric HCL inhibits the enzyme
(due to drop of pH). Small amount of acid hydrolysis occurs in stomach.
3- In the Small Intestine
a- Pancreatic amylase
It completes the digestion of starch to maltose and isomaltose.
b- Intestinal disaccharidases
They complete the action of other enzymes with production of
monosaccharides e.g. sucrase, maltase, lactase acting on sucrose,
maltose,lactose.
 So, the end products of carbohydrate digestion are mainly
glucose, galactose and fructose.
 Monosaccharides are then absorbed actively by small intestine.
 The portal vein carries simple sugars to the liver where they are
metabolized.
 Liver does not consume all sugars passing through it, but a large
proportion of these sugars is deliverded to systemic blood in
order to be utilized by other tissues.
Fructose
Summary Diagram for Fate of Absorbed
Sugars
Glucose
Glycerol 3-phosphate
Galactose
FA
Oxidation
Glycogen
Carbon skeleton of
Amino acids
Other
carbohydrates
Cholesterol & other steroids
TAG
Glycerophosphatides
OXIDATION OF GLUCOSE
A- The Major Pathways for Oxidation which are mainly concerned
with energy production.
I- Glycolysis: It produces pyruvate under aerobic condition and lactate
under anaerobic condition.
II- Citric acid cycle (Krebs’ cycle): Under aerobic condition,
pyruvate is converted to active acetate for oxidation through citric acid
cycle.
B- The Minor Pathways for Oxidation which are mainly for
synthesis of other glucose derivatives and not for energy production.
I- Hexose monophosphate pathway (HMP): For production of
pentoses and NADPH.
II- Uronic acid pathway: For production of uronic acids.
A- The Major Pathways for Oxidation
I-GLYCOLYSIS
 Sequence of enzymatic reactions in which one molecule of
glucose is converted into two molecules of three carbon
compound, either pyruvate in the presence of oxygen or
lactate in the absence of oxygen.
 Glycolytic pathway proceeds in the cytosol of all cells (all of
the enzymes of glycolysis are found in the cytosol).
 Glycolysis is also termed anaerobic oxidation of glucose as
it can proceed in the absence of oxygen.
Steps of Glycolysis can be divided into two phases:
Phase I
In this preparatory stage, glucose is phosphorylated and cleaved to yield
two molecules of glyceraldehyde 3-phosphate. This process
consumes 2 ATP.
Phase II
The two molecules of glyceraldehyde 3-phosphate are converted to
pyruvate under aerobic state with generation of 4 ATP at
substrate level and 6 ATP at the respiratory chain level.
Under anaerobic state only 4 ATP are formed at the substrate
level with conversion of pyruvate to lactate.
Regulation of Glycolysis:
Glycolysis is regulated at three nonequilibrium
(irreversible) reactions, i.e. 3 key enzymes:
 Glucokinase (or hexokinase),
 Phosphofructokinase-1 (PFK-1)
 Pyruvate kinase (PK).
II- CITRIC ACID CYCLE
(Tricarboxylic Acid Cycle or Krebs' Cycle)
 It is formed of a series of reactions that are responsible for the
complete oxidation of the acetyl moiety of acetyl-CoA.
 It is the final common pathway for the oxidation of
carbohydrates, lipids and proteins because glucose, fatty acids
and most amino acids are metabolized to acetyl-CoA or intermediates
of the cycle.
 During the oxidation of acetyl-CoA, coenzymes (NAD and FAD) are
reduced and subsequently reoxidized in the respiratory chain
with the formation of ATP.
Site:
 The enzymes of the TCA cycle are found in the mitochondrial
matrix except succinate dehydrogenase which is tightly
bound to the inner mitochondrial membrane (forms complex II
of the respiratory chain).
 The enzymes of the TCA cycle are in close proximity to the
enzymes of the respiratory chain.
B- The Minor Pathways for Oxidation
I- Hexose Monophosphate Pathway (HMP):
The pentose phosphate pathway (PPP) is an alternative route for glucose
oxidation. It has two major functions, formation of:
1) Ribose-5-p required for nucleotide and nucleic acid
synthesis
2) NADPH
The enzymes of the pentose phosphate pathway are cytosolic. HMP is
active in certain tissues e.g. liver, thyroid, adrenal cortex, adipose
tissue, gonads, retina, lactating mammary gland and RBCs.
NADPH is required for the following reactions:
 Reduction of metabolically impotant compounds as glutathione and
folic acid.
 Synthesis of fatty acids
 Cholesterol synthesis
 Hydroxylation reactions.
 Glutathione is of particular importance to combat oxidation stress
in tissues and to keep hemoglobin active by conserving iron in
ferrous state
II-Uronic Acid Pathway
Uronic acid pathway is also an alternative oxidative pathway
for glucose that does not lead to the formation of ATP. Uronic
acid pathway is a cytosolic pathway that occurs in the liver. In humans,
it catalyzes the conversion of glucose to glucuronic acid, and pentoses.
Importance of Uronic acid pathway
The main function is the formation of UDP-glucuronate which is
utilized in the following pathways:
 Glycosaminoglycans (GAGs) synthesis.
 Conjugation reactions with many compounds to increase their water
solubility such as: all steroid hormones and their metabolites,
bilirubin and certain detoxification reactions of xenbiotics such as
phenols.
GLYCOGEN METABOLISM
 Glycogen is a highly branched polymer of glucose. It is the main
storage form of carbohydrates in animals. It is present mainly in
the liver and in muscles.
 Liver glycogen (forms 8 – 10% of its wet weight) maintains
blood glucose between meals. After 12–18 hours of fasting,
liver glycogen is almost totally depleted.
 Muscle glycogen (forms 2% of its wet weight) :Muscle
glycogen supplies the contracting muscles with a
readily available source of glucose.
Glycogen metabolism includes the following:
I- GLYCOGENESIS
Glycogenesis is synthesis of glycogen from glucose-6-p.this requires
presence of the enzyme glycogen synthase.
II- GLYCOGENOLYSIS
Glycogenolysis is breking-down of glycogen to glucose (in the liver) or to
g-6-p (in the muscle)
Both glycogenesis and glycogenolysis are under strict hormonal control
mediated by a second messenger cyclic AMP
GLUCONEOGENESIS
 It is the synthesis of glucose and /or glycogen from noncarbohydrate precursors e.g. glycerol, glucogenic amino
acids and lactate.
 Its main function is to supply blood glucose in case of
carbohydrate deficiency (fasting, starvation and low
carbohydrate diet).
 It starts 4 to 6 hours after the last meal and continues
throughout fasting state.
REGULATION OF BLOOD GLUCOSE
 The normal fasting plasma glucose level (after 8-12 hours fasting)
is between 70 to less than 100 mg/dL, increases after meal and
returns back to <140 mg/dL at two hours after feeding (2 hour
postprandial or 2h PP).
 The maintenance of blood glucose is an important function of different
tissues. Glucose is the principal source for energy production in the
brain.
 Sudden decrease in blood glucose if not treated may produce coma or
even death.
After-meal rise in blood glucose stimulates insulin secretion from
pancreatic β-cells of islets of langerhans.
Insulin action:
It is secreted by the B-cells of pancreatic islets in response to
hyperglycemia. It produces its effects through the following
mechanisms:
 It increases the uptake of glucose by extrahepatic tissues (heart,
skeletal muscles and adipose tissues).
 It increases utilization of glucose (oxidation ,glycogenesis and
lipogenesis) in different tissues.
 It decreases output of glucose by liver (decreases glycogenolysis
and gluconeogenesis).
 During fasting blood glucose decreases so insulin secretion is
inhibited whereas the anti-insulin hormones increase
leading to activation of mechanisms of glucose production:
glycogenesis and gluconeogenesis.
Diabetes Mellitus
Definition
The term diabetes mellitus describes a metabolic disorder that is
characterized by persistent rise in blood glucose (hyperglycemia)
result from defects in insulin secretion, insulin action, or both.
Classification of DM
1) Type I Diabetes Mellitus
Type I diabetes is primarily a disease of the young. It was previously known
as insulin dependent diabetes mellitus (IDDM) means that it
necessitates insulin to control hyperglycaemia
2) Type II Diabetes Mellitus
It is previously known as noninsulin dependent diabetes mellitus
(NIDDM) means that drugs stimulate endogenous insulin secretion and
promoting glucose utilization are required.
Metabolic Changes in DM
All the metabolic changes are due to decrease in the insulin / antiinsulin ratio, which produces changes reversal to insulin action or as a
consequent of hyperglycemia.
1) Changes in carbohydrate metabolism include:
This leads to hyperglycemia, glucosuria, polyuria, loss of
electrolytes, dehydration, and polydepsia.
2) Changes in lipid metabolism include:
Decreased lipogenesis and increased lipolysis. This leads to weight loss
and increases plasma free fatty acids.
3) Changes in protein metabolism include:
it leads to increased sensitivity to infection and delayed healing
of wounds.
 Complications of DM:
 These complications can occur over a long period of time.
 They can be divided in macrovascular and microvascular
complications.
 Diabetes accelerates atherosclerosis that can lead to coronary artery
disease, stroke and peripheral vascular disease (macrovascular
disease)
 Damage to the retina (retinopathy), kidney (nephropathy) and
nerves (neuropathy) (microvascular disease).
Types of Diabetic Coma
I- Diabetic Ketoacidosis:
 Diabetic ketoacidosis is considered a medical emergency that results
from uncontrolled hyperglycemia and deficiency of insulin.
 The condition can be precipitated by stress and infection. Diabetic
ketoacidosis is much more common in type I diabetes, but can also
occur in patients with type II diabetes.
II- Hypoglycemic Coma
 Hypoglycemia results from taking too much diabetes medication or
insulin.
 It is manifested as headache, feeling dizzy, poor concentration, tremors
of hands, and sweating are common symptoms of hypoglycemia. Coma
occurs if blood sugar level gets too low.
Diagnosis of DM:
 Many patients with diabetes remain asymptomatic for long
periods, so that the first presentation of the disease is
frequently a chronic complication.
 Symptoms include polyuria, polydipsia, polyphagia,
prolonged time of wound healing, and weight loss.
 Polyphagia results from the decreased glucose uptake by the
satiety centre in the brain.
Tests for Diagnosis and Assessment of DM Control
I- Fasting and 2-hour (post-glucose or postprandial) plasma
glucose levels in an oral glucose tolerance test (OGTT).
Non-diabetic healthy subjects will have:
Fasting plasma glucose < 100 mg/dL,
Two-hours value in an OGTT (2-h PG) < 140 mg/dL.
Patients with diabetes mellitus will have:
Fasting plasma glucose > 126 mg/dL,
2-hour value in an OGTT (2-h PG) at or above 200 mg/dL.
II- Oral Glucose Tolerance Test (OGTT)
Normal OGTT: There is an increase in plasma glucose levels after 30
and 60 minutes from the glucose load due to the absorption of glucose
followed by a drop due to increased uptake and utilization of glucose
under the effect of the stimulated insulin secretion. No glucosuria
occurs during the test.
III- Measurement of Glycated- Hb (HbA1C):
It is a good for diagnosis and monitor of blood glucose to assess
diabetic control and to follow up of diabetic patients.
Normal HBA1C is 4 – 6.5%; levels above 6.5% are
diagnostic of diabetes mellitus and levels > 8 %
indicate poor diabetic control.
Treatment of Diabetes Mellitus
 Diet control
It is to achieve weight reduction in overweight patients with type II DM. If
improvement in hyperglycemia is not achieved by diet, trial with an oral
drug should be started.
 Oral Anti-diabetic Drugs:
These drugs are used for type II DM but not for type I DM oral
hypoglycemic drugs are:
Drugs that increase insulin secretion , improve insulin
sensitivity or decrease the intestinal absorption of
carbohydrates and fats
 Insulin:
Human insulin is now available in the market and often it is preferred.
It is injected subcutaneously, or as an insulin pen. Recently, inhaled
insulin is under trials.