Download Glucose Metabolism

Carbohydrates
Part 1
Introduction
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Organisms rely on the oxidation of complex
organic compounds to obtain energy
Three general types of such compounds are:
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Carbohydrates (CHO)
Amino acids
And lipids
CHO are the primary source of energy for
brain, erythrocytes and retinal cells
Stored primarily as liver & muscle glycogen
M. Zaharna Clin. Chem. 2009
Carbohydrates: CHO
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Compounds containing C, H, O
General formula (CH2O)n
All CHO contain C=O and –OH functional groups
There are some derivatives of this formula,
carbohydrate derivatives can be formed addition of
other chemical groups (phosphates, amines…)
Classification of CHO is based on four different
properties:
1.
2.
3.
4.
The size of the base carbon chain
The location of the CO functional group
The number of sugar units
The stereochemistry of the compound
M. Zaharna Clin. Chem. 2009
1- The size of the base carbon chain
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Can be classified based on the number of
carbons in the molecule
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Trioses ( 3 Carbons)
Tetroses
Pentoses
And hexoses
The smallest CHO is
glyceraldehyde (3 Carbon)
M. Zaharna Clin. Chem. 2009
2. The location of the CO functional group
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CHO are Hydrates of aldehyde or ketone
derivatives based on the location of the CO
functional group
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Aldose form – aldehyde as functional group
Ketose form – ketone as functional group
M. Zaharna Clin. Chem. 2009
3- The number of sugar units
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Classification based on the number of
sugar units in the chain
1.
2.
3.
4.
Monosaccharide
Disaccharide
(2 sugars linked together)
Oligosaccharide (2 – 10 linked sugars)
Polysaccharide (Long sugar chains)
M. Zaharna Clin. Chem. 2009
Monosaccharides
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Simplest sugars; cannot be broken down into any
simpler sugar
3 carbons = triose, 4 carbons = tetraose, 5 carbons =
pentose, & 6 carbons = hexose
Important pentose (5 carbon) sugars include ribose and
2-deoxyribose
M. Zaharna Clin. Chem. 2009
Disaccharides
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Formed from two monosaccharide with the
production of water.
Most common form is sucrose (table sugar), which
is glucose and fructose
Other forms include:
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Lactose (glucose and galatose)
and maltose (glucose and glucose)
M. Zaharna Clin. Chem. 2009
Common Disaccharides
Glucose + Glucose
Glucose + Galactose
Glucose + Fructose
Sucrose ( table sugar )
M. Zaharna Clin. Chem. 2009
Polysaccharides
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Plants (cellulose); not digested by humans.
Starch: principle CHO (polysaccharide)
storage product of plants
Glycogen: principle CHO storage product in
animal.
Formed by the combination of
monosaccharide.
M. Zaharna Clin. Chem. 2009
4- Stereochemistry
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Mirror image forms
D = right side OH, L = left side OH
D & L designations are based on the
configuration about the single asymmetric C
M. Zaharna Clin. Chem. 2009
Glucose Metabolism
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Glucose is a primary source of energy.
Various tissues and muscles throughout the
body depend on glucose from the
surrounding extracellular fluid for energy.
Nervous tissue cannot concentrate or store
CHO, critical to maintain steady supply
If glucose levels fall below certain levels the
nervous tissue lose its primary energy source
and is incapable of maintaining normal
function.
M. Zaharna Clin. Chem. 2009
Fate of glucose
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CHO is digested (starch and glycogen).
Amylase digest the nonabsorbable forms of
CHO to dextrin and disaccharide which are
hydrolyzed to monosaccharide.
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Maltase is an enzyme released by intestinal
mucosa that hydrolze maltose to two glucose units
Sucrase hydrolyze sucrose to glucose & fructose
Lactase: hydrolyze lactose to glucose & galatose.
M. Zaharna Clin. Chem. 2009
Fate of glucose
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Disaccharides are converted into
monosaccharide – absorbed by the gut
transported to the liver by the hepatic portal
venous blood supply.
Glucose is the only CHO to be directly used
for energy or stored as glycogen.
Others (galactose & fructose) have to be
converted to glucose before they can be used
M. Zaharna Clin. Chem. 2009
Lactose intolerance
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Lactose intolerance: due to a deficiency of
lactase enzyme on or in the intestinal lumens,
which is needed to metabolize lactose.
Results in an accumulation of lactose in the
intestine as waste lactic acid- causing the
stomach upset and discomfort.
M. Zaharna Clin. Chem. 2009
Fate of glucose
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After glucose enters the cell it can go into one
of three metabolic pathways based on
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availability of substrate and
nutritional status of cell.
Ultimate goal is to convert glucose to CO2
and H2O.
During this process the cell obtains the highenergy molecule (ATP) from (ADP).
M. Zaharna Clin. Chem. 2009
Glucose metabolism
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1st step in all pathways Glucose is converted
to glucose -6 phosphate using ATP- catalyzed
by hexokinase.
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Glucose-6- phosphate enters the pathways:
2.
Embden-Meyerhof pathway
Hexose Monophosphate shunt
3.
Glucogenesis (storage of glucose as glycogen)
1.
M. Zaharna Clin. Chem. 2009
Glucose metabolism
Embden-Meyerhof pathway
1.
Glucose is broken down into two, three-carbon
molecules of pyruvic acid that can enter the
tricarboxylic acid cycle (TCA cycle) on conversion to
acetyl-coenzyme A (acetyl-CoA).
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2.
Hexose Monophosphate shunt
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The principal functions of the pathway are the
production of:
o Deoxyribose and ribose sugars for nucleic-acid
synthesis;
o The generation of reducing power in the form of
NADPH for fatty-acid and/or steroid synthesis;
M. Zaharna Clin. Chem. 2009
Pathways in glucose metabolism
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Major energy pathways involved either directly or
indirectly with glucose metabolism
1.
Glycolysis
 Breakdown of glucose for energy production
2.
Glycogenesis
 Excess glucose is converted and stored as glycogen
 High concentrations of glycogen in liver and skeletal muscle
 Glycogen is a quickly accessible storage form of glucose
3.
Glycogenolysis
 Breakdown of glycogen into glucose
 Glycogenolysis occurs when plasma glucose is decreased
 Occurs quickly if additional glucose is needed
M. Zaharna Clin. Chem. 2009
Pathways in glucose metabolism
Gluconeogenesis
4.
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Conversion of non-carbohydrate carbon substrates to glucose
Gluconeogenesis takes place mainly in the liver
Lipogenesis
5.
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Conversion of carbohydrates into fatty acids
Fat is another energy storage form, but not as quickly
accessible as glycogen
Lipolysis
6.
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Decomposition of fat
M. Zaharna Clin. Chem. 2009
Regulation of Carbohydrate
Metabolism
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The liver, pancreas, and other endocrine glands are all
involved in controlling the blood glucose concentrations
within a narrow range
During a brief fast, glucose is supplied to the ECF from
the liver through glycogenolysis.
When the fasting period is longer than 1 day, glucose is
synthesized from other sources through
gluconeogenesis.
Control of blood glucose is under two major hormones:
insulin and glucagon, both produced by the pancreas
M. Zaharna Clin. Chem. 2009
Regulation of Carbohydrate
Metabolism
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Other hormones also exert some control over
blood glucose concentrations
As needed hormones regulate release of
glucose.
Hormones work together to meet 3
requirements:
1. Steady supply of glucose.
2. Store excess glucose
3. Use stored glucose as needed
M. Zaharna Clin. Chem. 2009
Insulin
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Primary hormone responsible for the
entry of glucose into the cell.
Synthesized in the beta cells of islets
of langerhans in the pancreas.
Insulin release cause increase
movement of glucose into the cells and
increase glucose metabolism
Is the only hormone that decreases
glucose levels and is referred as a
hypoglycemic agent.
M. Zaharna Clin. Chem. 2009
Glucagon
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Peptide hormone that is synthesized by the
alpha cells of the islets cells of the pancreas
Released during stress and fasting states.
Released in response to decreased body
glucose.
Main function is to:
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increase hepatic glycogenolysis,
and increase gluconeogenesis.
Hyperglycemic agent
M. Zaharna Clin. Chem. 2009
M. Zaharna Clin. Chem. 2009
Action of Hormones
M. Zaharna Clin. Chem. 2009
Epinephrine (adrenaline)
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Hormone produced by the adrenal gland
Increases plasma glucose by:
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inhibiting insulin secretion,
increasing glycogenolysis
and promotes lipolysis.
Release during times of stress
M. Zaharna Clin. Chem. 2009
Glucocorticoids
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Primarily Cortisol is released when
stimulated by adrenocorticotropic hormone
(ACTH).
Cortisol increases plasma glucose by:
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Increasing gluconeogenesis,
Inhibition of glucose uptake in muscle
and adipose tissue
and lipolysis.
Insulin antagonist
M. Zaharna Clin. Chem. 2009
Thyroxine
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The thyroid gland releases
thyroxine.
Increases glucose levels by:
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increasing glycogenolysis,
gluconeogenesis
And intestinal absorption of
glucose.
M. Zaharna Clin. Chem. 2009
Somatostatin
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Produced by the delta cells of the lslets of
langerhans of the pancreas.
The inhibition of insulin, glycagon
Therefore only minor overall effect
M. Zaharna Clin. Chem. 2009
M. Zaharna Clin. Chem. 2009
Hyperglycemia
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Increase in plasma glucose levels
In healthy persons during a hyperglycemia
state, insulin is secreted by the beta cells of
the pancreatic islets of langerhans.
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Insulin enhances membrane permeability to cells
in the liver, muscle, and adipose tissue.
Hyperglycemia is caused by an imbalance of
hormones.
M. Zaharna Clin. Chem. 2009
Diabetes Mellitus
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Metabolic diseases characterized by
hyperglycemia resulting from defect in insulin
secretion, insulin action or both.
Two major types: (in 1979)
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Type I, (insulin dependent) and Type 2, (non
insulin dependent)
1995: further categories by WHO:
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Type 1 diabetes, type 2 diabetes, other specific
types and gestational diabetes mellitus.
M. Zaharna Clin. Chem. 2009
Type 1 diabetes
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Due to cellular-mediated autoimmune destruction of
the β cells of the pancreas, causing an absolute
deficiency of insulin secretion
Or idiopathic type 1 diabetes that has no known
etiology
Commonly occurs in children (juvenile diabetes)
Constitutes only 10% to 20% of all cases of diabetes
Genetics play a minimal role, can be due to exposure
to environmental substances or viruses.
Treatment: insulin
M. Zaharna Clin. Chem. 2009
Characteristics of T1DM
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Abrupt onset,
Insulin dependence,
and ketosis tendency.
One or more of the following markers are found
in 85% to 90% of individuals with fasting
hyperglycemia:
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Islet cell autoantibodies,
Insulin autoantibodies,
Glutamic acid decarboxylase autoantibodies
M. Zaharna Clin. Chem. 2009
M. Zaharna Clin. Chem. 2009
Type 2 diabetes mellitus
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Due to insulin resistance and relative insulin
deficiency .
Type 2 constitutes the majority of the diabetes
cases
Most patients in this type are obese or have an
increased percentage of body fat distribution in
the abdominal region
often goes undiagnosed for many years and is
associated with a strong genetic predisposition
M. Zaharna Clin. Chem. 2009
Characteristics of T2DM
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Adult onset of the disease
Ketoacidosis seldom occurring.
These patients are more likely to go into a
hyperosmolar coma
and are at an increased risk of developing
macrovascular and microvascular
complications.
M. Zaharna Clin. Chem. 2009
Other specific types
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Secondary conditions,
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genetic defect in beta cell function
or insulin action,
pancreatic disease,
disease of endocrine origin,
drug or chemical induced.
Characteristics of the disease depends on
the primary disorder.
M. Zaharna Clin. Chem. 2009
Gestational diabetes mellitus
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Glucose intolerance that is induced by
pregnancy
Caused by metabolic and hormonal changes
related to the pregnancy.
Glucose tolerance usually returns to normal
after delivery.
An increased risk for development of
diabetes in later years
M. Zaharna Clin. Chem. 2009