GLYCOGENGLYCOGEN

METABOLISM
 Introduction
• highly branched homo polymer
• carbohydrate-based energy store in the body.
• crucial to both homeostasis of blood glucose and to muscle work
• located in the cytosol.
• alpha 1-4 glycosidic linkage, with alpha1-6 glycosidic linkages
• forming branches after approximately every 8 to 10 glucose residues
.
Con….
Con….
Con….
• nearly all cells of the body contain trace amounts of glycogen, the
major glycogen stores are found in liver and skeletal muscle.
• The liver contains the greatest concentration of glycogen of any
organ, accounting for as much as 10% of tissue wet weight.
• On a mass basis, however, the largest portion of the body’s total
glycogen stores is in muscle
• the liver contains about 400 g of glycogen, whereas muscle contains
approximately 1200 g of glycogen
• stores serve two distinctly different purposes
Con….
• glucose derived from liver glycogen used to maintain the
concentration of glucose in the blood.
• By contrast, glucose arising from glycogen
• breakdown in skeletal and heart muscle remains in the muscle cells
and is used to provide energy for muscle work
 Glycogen metabolism
• Glycogenolysis
• Glycogenolysis (glycogen breakdown)
• Degradation of Glycogen
• the process by which glucose units are removed, one at a time, from
the numerous non reducing ends of glycogen.
• provides a readily available source of glucose when it is needed.
Con…..
• Glycogen synthesis functions to replenish the glycogen stores in liver
and muscle when dietary carbohydrates are available
• phosphorolytic and utilizes orthophosphate (Pi).
• to maintain the concentration of glucose in the blood.
• used to provide energy for muscle work
Shortening of chains
• The first step in glycogenolysis is catalyzed by glycogen
phosphorylase, commonly called phosphorylase.
• This enzyme cleaves the alpha 1-4 glycosidic bonds of glycogen
Con….
Con…
• Glycogen phosphorylase catalyzes the cleavageof a- 1,4 glycosidic
bonds but not of a- 1,6 glycosidic bonds.
• Furthermore, glycogen phosphorylase is incapable of removing
glucose residues that lie within four residues of a branch point.

• Removal of Branches

• Debranching Enzyme

• The debranching enzyme that solves this problem has two distinct
catalytic activities
Con…
• Glucantransferase and Glucosidase

• First, the oligo-alpha- 1,4- a- 1,4-glucanotransferase catalytic site

transfers three glycosyl residues from the alpha - 1, 6 branch to an
adjacent alpha-1,4 chain, leaving behind a single glucose unit in alpha
- 1 , 6 glucosidic linkage.
Con….
 The a- 1,6-glucosidase catalytic site of the debranching enzyme then
hydrolyzes the a- 1,6 glycosidic bond of the remaining glucose unit,
 releasing free glucose and producing a long, unbranched alpha-1,4
glycosidic chain
 is a suitable substrate for continued glycogenolysis by glycogen
phosphorylase
Con….
 Fate of Glucose 1-Phosphate
transfer of the phosphate group from carbon-1 to carbon-6.
• Phosphoglucomutase catalyzes

the resulting glucose 6-phosphate molecule then enters the glycolytic

pathway and is catabolized to provide energy
Con….
• the fate of glucose 6-phosphate is different
• The glucose 6-phosphate generated by glycogenolysis in liver is not
catabolized within the hepatocyte
• instead, released from the cell as free glucose
• catalyzed by glucose 6-phosphatase
Con…
Con….
• Glucose 6-phosphatase is expressed in liver and the renal cortex, but
not in muscle,
• and plays an important role in providing blood glucose from
gluconeogenesis as well as glycogenolysis
con…
 Glycogen Synthesis
• Synthesis of glycogen from Glucose.
• carried out by the enzyme Glycogen Synthase

liver and muscle are poised to synthesize glycogen, phosphoglucomutase

then shifts the phosphate group from C6 to C1
Con….
activation of glucose
• carried out by the enzyme UDP glucose
pyrophosphorylase.
• the synthesis of UDP-l-glucose from glucose 1-phosphate
Con…
• enzyme exchanges the phosphate on C-1 of glucose-1-phosphate for
UDP (Uridinediphosphate).
• energy of the phospho glycosyl bond of UDPglucose is utilized
• by glycogen Synthase to catalize the incorporation of glucose in to
Glycogen
Con…
• Glycogen synthase then transfers the activated glucose moiety of
UDP-l-glucose to the 4-hydroxyl group of a glucose residue at one of
the numerous non reducing ends of the branched glycogen molecule
• thereby forming a new a- 1,4 linkage and extending the carbohydrate
chain by one glucose unit
Con…
 UDP is subsequently released from the enzyme
Con…
• Formation of Branches in the Growing Glycogen Molecule
• the branching enzyme is amylo-(alpha- 1,4- alpha- 1,6)
transglycosylase.
• The enzyme transfers six- to seven-residue oligosaccharide from the
Non reducing end of a newly elongated alpha-1,4 glucose polymer to
form a new alpha-1,6 glycosidic linkage
• at the C-6 hydroxyl position
Con….
• Glycogenin serves as a primer for glycogen synthesis.
• Glycogenin is self-glucosylating and catalyzes both the covalent
attachment of the initial glucose moiety to the protein and the
subsequent addition of glucose units to form an alpha-1,4 glucose
oligomer which can serve as substrate for glycogen synthase.
•
Con….
 The glycogenin molecule remains in the core of the resulting
glycogen polymer, where it is attached to the reducing end of the
initial glucose unit
 REGULATION OF GLYCOGEN METABOLISM
• synthesis occurs in the fed state, whereas glycogenolysis occurs both
in the fasted state and in response to strenuous exercise.
• both processes are not active at the same time.
• metabolism is regulated by both allosteric and
hormonal mechanisms.
 Glycogen Storage Diseases
• a group of genetic diseases
• result from a defect in an enzyme required for either glycogen
synthesis or degradation
• result in either formation of glycogen that has an abnormal structure
or the accumulation of excessive amounts of normal glycogen in
specific tissues,
Con…..
• A particular enzyme may be defective in a single tissue such as the
liver or the defect may be more generalized
• affecting muscle, kidney, intestine and myocardium.
• The severity of the diseases may range from fatal in infancy to mild
disorders that are not life threatening some of the more prevalent
glycogen storage diseases are the following
Con….
• abnormalities of glycogen metabolism
• a number of inborn errors of metabolism which result in excessive
accumulation of intracellular glycogen; these are called glycogen
storage diseases.
Con….
• Deficiencies in the activity of the liver isozymes of glycogen
phosphorylase or phosphorylase kinase result in liver enlargement
(hepatomegaly) and fasting hypoglycemia.
• A deficiency of glucose 6-phosphatase (von Gierke disease) where
neither glycogenolysis nor gluconeogenesis is available to support
blood glucose homeostasis because glucose 6-phosphate cannot be
dephosphorylated and released from the hepatocytes
Con…
• a genetic deficiency of the muscle isozyme of glycogen
phosphorylase (McArdle disease) is accompanied by muscle-specific
accumulation of glycogen and a limited ability to exercise
strenuously.
• In the absence of glycogenolysis to support exercise, affected persons
rapidly develop a depleted energy charge within the muscle that
causes severe muscle pain and weakness
Pompe Disease
• During cellular recycling and tissue remodeling, most cells of healthy
persons accumulate some glycogen within lysosomes.
• Catabolism of glycogen within lysosomes utilizes an
alternative pathway in which lysosomal acid maltase
hydrolyzes both alpha- 1,4- and alpha- 1,6-glycosidic
bonds.
• deficiency of acid maltase results in accumulation of
glycogen in lysosomes
 Diabetes mellitus
• Diabetes mellitus is not one disease
• rather is a heterogeneous group of multi factorial, polygenic
syndromes characterized by an elevation of fasting blood glucose
caused by a relative or absolute deficiency in insulin.
• leading cause of adult blindness and amputation, and a major cause of
renal failure, nerve damage, heart attacks and strokes
Con….
• Two groups type 1 (formerly called insulin-dependent diabetes
mellitus)
• and type 2 (formerly called non insulin-dependent diabetes)
 TYPE 1 DIABETES
• type 1 diabetes constitute approximately 10%
• characterized by an absolute deficiency of insulin caused by an
autoimmune attack on the β cells of the pancreas
• islets of Langerhans become infiltrated with activated T
lymphocytes,leading to a condition called insulitis.
• Over a period of years, this autoimmune attack on the β cells leads to
gradual depletion of the β-cell population
Con….
• symptoms appear abruptly when 80–90% of the β cells have been
destroyed.
• At this point, the pancreas fails to respond adequately to ingestion of
glucose, and insulin therapy is required to restore metabolic control
and prevent life-threatening ketoacidosis.
• β Cell destruction requires both a stimulus from the environment
(such as a viral infection) and a genetic determinant that allows the β
cells to be recognized as “non self
Con…
• (identical) twins, if one sibling develops type 1 diabetes mellitus, the
other twin has only a 30–50% chance of developing the disease.
• This contrasts with type 2 disease in which the genetic influence is
stronger, and in virtually all monozygotic twin ships, the disease
eventually develops in both individuals.
• Patients with type 1 diabetes have virtually no functional β cells, and
can neither respond to variations in circulating fuels nor maintain a
basal secretion of insulin
• Diagnosis of type 1 diabetes
• childhood or puberty, and symptoms develop suddenly.
• Patients with type 1 diabetes can usually be recognized by the abrupt
appearance of polyuria (frequent urination), polydipsia (excessive
thirst), and polyphagia (excessive hunger), often triggered by stress or
an illness.
• symptoms are usually accompanied by fatigue, weight loss, and
weakness
Con…..
• diagnosis is confirmed by a fasting blood glucose (FBG) greater than
or equal to 126 mg/dl, commonly accompanied by keto acidosis.
• 100–125 mg/dl is categorized as an impaired FBG.
• Fasting is defined as no caloric intake for at least 8 hours.
• When the diagnosis of type 1 diabetes is uncertain by clinical
presentation, testing for circulating islet-cell antibodies is
recommended
 Metabolic changes in type 1 diabetes
• metabolic abnormalities result from a deficiency of insulin which
profoundly affects metabolism in three tissues: liver, muscle, and
adipose tissue
• Hyperglycemia and ketoacidosis:
• Elevated levels of blood glucose and ketones are the
hallmarks of untreated type 1 diabetes mellitus.
Con…
• Hyperglycemia is caused by increased hepatic production of glucose,
combined with diminished peripheral utilization (muscle and adipose
have the insulin-sensitive GLUT-4)
• Ketosis results from increased mobilization of fatty acids from
adipose tissue, combined with accelerated hepatic fatty acid β-
oxidation and synthesis of 3-hydroxybutyrate and acetoacetate
Con….
• Diabetic ketoacidosis (DKA, a type of metabolic acidosis) occurs in
25–40% of those newly diagnosed with type 1 diabetes, and may
recur if the patient becomes ill (most commonly with an infection) or
does not comply with therapy.
• DKA is treated by replacing fluid and electrolytes, and administering
short-acting insulin to gradually correct hyperglycemia without
precipitating hypoglycemia
Con…
Hypertriacylglycerolemia
• excess fatty acids are converted to triacylglycerol, which is packaged
and secreted in very-low-density lipoproteins (VLDL)
Treatment of type 1 diabetes
• rely on exogenous insulin injected subcutaneously to control the
hyperglycemia and ketoacidosis.
• Two therapeutic regimens are currently in use standard and intensive
insulin treatment
• typically consists of one or two daily injections of recombinant
human insulin.
Con…..
• Mean blood glucose levels obtained are typically in the 225–275
mg/dl range, with a hemoglobin A1C (HbA1C) level of 8–9% of the
total hemoglobin .
• The rate of formation of HbA1C is proportional to the average blood
glucose concentration over the previous 3 months
Con…
• HbA1C provides a measure of how well treatment has normalized
blood glucose in the diabetic over that time.
• In contrast to standard therapy, intensive treatment seeks to more
closely normalize blood glucose through more frequent monitoring,
and subsequent injections of insulin—typically three or more times a
day.
•
Con….
• Mean blood glucose levels of 150 mg/dl can be achieved, with
HbA1C approximately 7% of the total hemoglobin
• Normal mean blood glucose is approximately 100 mg/dl and HbA1C
is 6%
• Thus, normalization of glucose values (euglycemia) is not achieved
even in intensively treated patients.
Con….
• patients on intensive therapy show a 50% or more reduction in the
long-term micro vascular complications of diabetes retinopathy,
nephropathy, and neuropathy—compared with patients receiving
standard care.
• This confirms that the complications of diabetes are related to an
elevation of plasma glucose.
• One of the therapeutic goals in cases of diabetes is to decrease blood
glucose levels in an effort to minimize the development of long-term
complications of the disease
Con….
• However, appropriate dosage of insulin is difficult to achieve.
• Hypoglycemia caused by excess insulin is the most common
complication of insulin therapy, occurring in over 90% of patients.
• The frequency of hypoglycemic episodes, coma, and seizures is
particularly high with intensive treatment regimens
 TYPE 2 DIABETES
• the most common form of the disease, afflicting approximately 90%
of the diabetic population
• type 2 diabetes develops gradually without obvious symptoms.
• The disease is often detected by routine screening tests.
• many individuals with
• type 2 diabetes have symptoms of polyuria and polydipsia of several
weeks duration.
• Polyphagia may be present, but is less common.
• Patients with type 2 diabetes have a combination of insulin resistance
and dysfunctional β cells
Con….
• but do not require insulin to sustain life, although insulin eventually
will be required to control hyperglycemia and keep HbA1c below 7%
in 90% of patients.
• The metabolic alterations observed in type 2 diabetes are milder than
those described for type 1.
• Type 2 diabetes mellitus is characterized by hyperglycemia, insulin
resistance, and relative impairment in insulin secretion
Con….
• Diagnosis is based most commonly on the presence of hyperglycemia
—that is, a fasting blood glucose concentration of equal to or greater
than 126 mg/dl.
• Pathogenesis does not involve viruses or autoimmune antibodies.
• An acute complication of type 2 in the elderly is a hyperglycemic
hyperosmolar state characterized by severe hyperglycemia and
dehydration, and altered mental status
Con…
• Insulin resistance
• the decreased ability of target tissues, such as liver, adipose, and
muscle, to respond properly to normal (or elevated) circulating
concentrations of insulin.
• For example, insulin resistance is characterized by uncontrolled
hepatic glucose production , and decreased glucose uptake by muscle
and adipose tissue
Con…
• Obesity is the most common cause of insulin resistance; however,
most people with obesity and insulin resistance do not become
diabetic.
• In the absence of a defect in β-cell function, non diabetic, obese
individuals can compensate for insulin resistance with elevated levels
of insulin
Con…
• Insulin resistance alone will not lead to type 2 diabetes.
• Rather, type 2 diabetes develops in insulin-resistant individuals who
also show impaired β-cell function.
• Insulin resistance and subsequent risk for the development of type 2
diabetes is commonly observed in the elderly, and in individuals who
are obese, physically inactive, or in the 3–5% of pregnant women who
develop gestational diabetes.
• These patients are unable to sufficiently compensate for insulin
resistance with increased insulin release.
Metabolic changes in type 2 diabetes
• The metabolic abnormalities of type 2 diabetes mellitus are the result
of insulin resistance expressed primarily in liver, muscle, and adipose
tissue.
• Hyperglycemia is caused by increased hepatic
production of glucose, combined with diminished
peripheral use.
• Ketosis is usually minimal or absent in type 2 patients
because the presence of insulin—even in the presence
of insulin resistance diminishes hepatic ketogenesis.
• Dyslipidemia:resulting in hypertriacylglycerolemia.
• Low HDL levels are also associated with type 2 diabetes
Con…..
• Treatment of type 2 diabetes
• The goal in treating type 2 diabetes is to maintain blood glucose
concentrations within normal limits, and to prevent the development
of long-term complications.
• Weight reduction, exercise, and medical nutrition therapy (dietary
modifications) often correct the hyperglycemia of newly diagnosed
type 2 diabetes.
• Hypoglycemic agents or insulin therapy may be required to achieve
satisfactory plasma glucose levels.
 CHRONIC EFFECTS AND PREVENTION OF DIABETES
• The long-standing elevation of blood glucose is associated with the
chronic complications of diabetes—premature atherosclerosis
(including cardiovascular disease and stroke), retino pathy,
nephropathy, and neuropathy.
• Intensive treatment with insulin delays the onset and slows the
progression of these long-term complications.
Con….
• For example, the incidence of retinopathy decreases as control of
blood glucose improves and HbA1C levels decrease.
• The benefits of tight control of blood glucose outweigh the increased
risk of severe hypoglycemia in most patients
Con….
• elevated blood glucose leads to increased intracellular glucose and its
metabolites.
• For example, increased intracellular sorbitol contributes to the
formation of cataracts in diabetics.
• Furthermore, hyperglycemia promotes the non-enzymic condensation
of glucose with cellular proteins in a reaction analogous to the
formation of HbA1C .
Con….
• These glycated proteins mediate some of the early microvascular
changes of diabetes.
• There is currently no preventative treatment for type 1 diabetes.
• The risk for type 2 diabetes can be significantly decreased by a
combined regimen of medical nutrition therapy, weight loss, exercise
and aggressive control