2. Overview of metabolism
⢠The term metabolism can be defined as the entire biochemical
reactions that are taking place in the body.
⢠The compounds that take part in the reactions are called
metabolites.
⢠Metabolism consists of 2 categories :
(i) Anabolism : the chemical reaction pathways leading to the
synthesis of a compound is termed as anabolism. It requires
energy.
(ii) Catabolism: the chemical reaction pathway leading to the
degradation of compound is called catabolism. It releases
energy.
4. â˘Breakdown of glucose into pyruvate or lactate with the
production of energy is known as glycolysis.
â˘There are 2 types :
â˘Aerobic glycolysis (in the presence of oxygen)
â˘Anaerobic glycolysis (in the absence of oxygen)
5. ďImportance of glycolysis :
â˘It is the only pathway that is taking place in all the
cells of the body
â˘It can produce even in the absence of oxygen
â˘It is a major source of energy for RBC.
8. ⢠ENERGETICS:
⢠Net ATP produced = total no. of ATPâS produced â total no. of ATPâS
utilized
⢠Aerobic glycolysis : 2+2+5=9 ATPâS
⢠Total 9 ATPâS
⢠2 ATPâS are used during the initial reaction so net ATP produced is
(9-2= 7 ATPâS)
⢠Anaerobic glycolysis:
⢠Total no. of ATPâS produced = 4
⢠Total no. of ATPâS utilised during the reaction = 2
⢠(4-2=2 ATPâS)
9.
10. Regulation :
â˘The energy requirement of the cell regulates the rate of
glycolysis.
â˘When the cell requires energy the glycolysis operates in a
faster rate and when the cell has sufficient energy glycolysis
runs slowly.
â˘Hexokinase , phosphofructokinase, pyruvate kinase are the
regulatory enzymes of glycolysis.
11. Inhibitors of glycolysis
⢠Arsenate inhibit the enzyme glyceraldehyde-3-phosphate
dehydrogenase
⢠Fluoride inhibits the enzyme enolase. It is commonly used to
prevent glycolysis during the blood glucose estimation in the
laboratory.
13. â˘This takes place in the RBCâS .
â˘2,3 BPG is a regulator of oxygen transport in
erythrocytes.
â˘In the presence of 2,3 BPG, oxy Hb will unload O2
more easily in tissues.
14. Citric acid cycle
â˘Synonyms : Tricarboxylic acid cycle (TCA) ,Krebs cycle, final
common metabolic pathway.
ďIt is the final common metabolic pathway for the oxidation
of Acetyl CoA
15. Starting material : Acetyl CoA
end products : CO2 , H2O and energy
ďSITE:
â˘Tissue site : all the tissues of the body except
RBCâS
â˘Intracellular site : mitochondrial matrix
18. Energetics :
⢠In the entire reactions 3 molecules of NADH + H is
formed so it wil produce ď 3x2.5= 7.5 ATPâS
⢠1 FADH2 wil produce ď 1.5 ATPâS
⢠1 ATP
⢠So total 10 ATPâS are formed from 1 molecule of
Acetyl CoA.
19. Inhibitors of TCA cycle
⢠Fluoroacetate is an inhibitor of aconitase
⢠Arsenite is an inhibitor of alpha ketogluterate
dehydrogenase.
⢠Malonate is an inhibitor of succinate dehydrogenase.
20. Functions of TCA cycle
â˘It has amphibolic role
â˘(a) catabolic role : it is the final common metabolic
pathway for the production of energy from acetyl CoA
obtained from carbohydrates, lipids and proteins.
21. â˘(b) anabolic role :
â˘It can produce biologically important compounds.
â˘Heme synthesis
â˘Synthesis of aspartate and glutamate
â˘Fatty acid synthesis
â˘Glucose synthesis
â˘Regulation :
â˘Citrate synthase
â˘Isocitrate dehydrogenase
â˘Îą- ketogluterate are the regulatory enzymes.
22. â˘The energy (ATP) requirement of the cell regulates the rate
of TCA cycle
â˘When the cell requires energy, TCA cycle runs in a faster
rate and when the cell has sufficient energy, TCA cycle runs
slowly.
â˘So ATP is the inhibitor and ADP is activator of TCA cycle.
23. Anaplerotic reactions
â˘In its anabolic role several intermediates of TCA
cycle are used up for biosynthesis of many
compounds.
â˘These intermediates should be replenished
â˘The reactions which replenish these
intermediates are called anaplerotic reactions or
anaplerosis.
27. Glycogen metabolism
â˘Glycogen is the major storage form of glucose mainly in the
liver and muscle
â˘It is a homopolysaccharide made up of many glucose
residues joined together by Îą (1,4) glycosidic bonds
â˘and at the branching points by Îą (1,6) glycosidic bonds.
28. Functions of glycogen :
â˘The major function of liver glycogen is to provide glucose
during fasting.
â˘When blood glucose level lowers liver glycogen is broken
down and helps to maintain blood glucose level.
29. â˘GLYCOGENESIS (GLYCOGEN SYNTHESIS):
â˘Formation of glycogen from glucose is called glycogenesis
â˘SITE :
â˘Cytosol of liver and skeletal muscle
â˘Starting compound : glucose
â˘End product : glycogen
30. 1. Activation of Glucose
â˘UDP glucose is formed from glucose-1-phosphate and UTP
(uridine triphosphate) by the enzyme UDPglucose
pyrophosphorylase
Glucose-1-phosphate +UTP ââââââââ UDP-glucose
UDP-glucosepyrophosphorylase
31. 2) initiation of glycogen synthesis
a special protein glycogenin (glycogen primer) acts as
an initiator Glycogenin takes up glucose residue from
UDP glucose
It then extends the glucose chain by accepting seven
more glucose residues from UDP glucose
32. 3. Branching Enzyme
⢠The glycogen synthase can add glucose units only in
alpha-1,4 linkage. A branching enzyme is needed to
create the alpha-1,6 linkages
⢠When the chain is lengthened to 11 - 12 glucose
residues, the branching enzyme will transfer 6 to 8
glucose residues from this chain and forms this alpha-
1,6 linkage
36. â˘It is broken down by the combined action of 3
enzymes:
â˘(i) glycogen phosphorylase : it acts on glycogen and
breaks the terminal Îą (1,4) glycosidic bonds of
glycogen and releases the terminal glucose molecule
â˘(ii) transferase : it transfers 3 glucose residues from
one chain to another chain and thus exposing the
(1,6) glycosidic bonds.
38. Gluconeogenesis
â˘Synthesis of new glucose molecules from non carbohydrate
sources is termed as gluconeogenesis or neoglucogenesis.
â˘SITES :
â˘(a) tissue site : liver (90%) and renal cortex(10%)
â˘(b) intracellular site : partly in cytosol and partly in
mitochondria.
â˘Starting compounds
â˘(a) lactate.
39. â˘(b) glycerol : from fats
â˘(c) glucogenic amino acids like glutamate, aspartate and
alanine
â˘(d) propionyl CoA : from β- oxidation
â˘Reaction pathway : it involves
â˘Reactions of TCA cycle.
â˘Reversible reactions of glycolysis.
44. ďSignificance of gluconeogenesis :
â˘Gluconeogenesis meets the needs of the body for glucose
and maintains blood glucose homeostasis when
carbohydrate is not available in sufficient amounts from the
diet.
â˘Some tissues such as brain, erythrocytes require continuous
supply of glucose as a source of energy.
45. â˘the absence of dietary intake of carbohydrates.
â˘As the glycogen store starts depleating
gluconeogenesis takes place which ensures a
continuous supply of glucose to brain and other
tissues.
47. Glycosuria
â˘It refers to excretion of sugars (mainly glucose) in
urine.
â˘Glucose is reabsorbed almost completely in renal
tubules and hence urine contains almost no glucose.
â˘When blood glucose level exceeds 180mg/dl, glucose
will be excreted in urine.
â˘This level is called the renal threshold for glucose.
48. Types
⢠Hyperglycemic glycosuria: when blood glucose level
exceeds the renal threshold glucose is excreted in urine.
⢠Renal glycosuria : glucose is excreted in urine even though
the blood glucose level is within normal limits.
â˘Alimentary glycosuria : it is following a rich carbohydrate
meal
⢠Glycosuria of pregnancy.
49. Hormonal regulation of glucose
⢠Normal fasting plasma glucose level is 70-110mg/dl
â˘Levels above this range are called hyperglycemia.
⢠Below are called hypoglycaemia.
⢠Blood glucose level is under the influence of various
hormones.
⢠These hormones are of 2 types:
(i) Hypoglycemic hormone : insulin
(ii) Hyperglycemic hormones : glucagon,
adrenalin,glucocorticoids, GH, thyroid hormone.
50. Insulin
â˘When plasma glucose level is increased insulin is secreted
by beta cells of islets of Langerhans.
â˘Insulin is hypoglycemic hormone which decreases plasma
glucose level by
â˘Increased uptake of glucose by muscle and adipose tissue.
â˘Stimulates glycolysis
â˘Stimulates glycogenesis
â˘Stimulates HMP shunt pathway.
52. ďGlucagon : when plasma glucose level is
decreased glucagon is secreted by alpha-cells of
islets of Langerhans which increase plasma glucose
level by
â˘It stimulates hepatic glycogenolysis.
â˘It stimulates gluconeogenesis.
â˘It decreases glycogenesis.
â˘It inhibits glycolysis, TCA cycle, HMP shunt
pathway etc.
CLAUDIA JOHNNY
54. ďCortisol :secreted by adrenal cortex
â˘It increases blood glucose level by
â˘It stimulates gluconeogenesis.
â˘It stimulates glycogenolysis
â˘It decreases glycolysis.
â˘It inhibits insulin secretion.
CLAUDIA JOHNNY
55. ďGrowth hormone : it is secreted by anterior pituitary
â˘It increases the blood glucose level by :
â˘It decreases the uptake of glucose by muscle tissues.
â˘It decreases glycolysis.
ďThyroid hormone : it is secreted by thyroid glands
â˘Thyroid hormones increases the blood glucose level by
â˘It increases the absorption of glucose from intestine
â˘It stimulates glycogenolysis.
56. Renal control mechanism
â˘When blood glucose rises to relatively high levels the
kidney regulates the absorption.
â˘Glucose is continuously filtered by the glomeruli but is
normally reabsorbed completely in renal tubules.
â˘The capacity of the tubular system to reabsorb glucose is
limited.
â˘If the blood glucose level is raised above 180mg/dl
complete reabsorption of glucose does not occur and extra
amount appear in the urine causing glycosuria.
57. â˘180mg/dl is the limiting level of glucose in the
blood above which tubular reabsorption does
not occur which is known as renal threshold
value for glucose.
59. â˘GLYCOGENOSIS (GLYCOGEN STORAGE DISEASE)
TYPE NAME ENZYME DEFECT
I Von-Gierkes disease Glucose-6-phosphatase in
liver
II Pompes disease Lysosomal acid maltase
III Coris disease Debranching enzyme
IV Andersons disease Branching enzyme
V McArdles disease Muscle glycogen
phosphorylase
VI Hers disease Liver glycogen
phosphorylase
60. ⢠Glycogen Storage Disease
⢠Type- 1
⢠It is also called Von Gierke's Disease.
⢠Most common type of glycogen storage disease is type I.
⢠Glucose-6-phosphatase is deficient.
⢠Glucose-6-phosphate is accumulated, so it is channeled to
HMP shunt pathway, producing more ribose and more
nucleotides
⢠Purines are then catabolized to uric acid, leading to
hyperuricemia
⢠Glycogen gets deposited in liver. Massive liver enlargement
may lead to cirrhosis
61. â˘Children usually die in early childhood.
â˘Treatment is to give small quantity of food at
frequent intervals.
⢠ketosis is also seen
62. Diabetes mellitus
â˘It is a metabolic disease caused either due to insulin
deficiency or failure in insulin action.
â˘CLASSIFICATION :
It is classified into 2 types
(a) Type I diabetes mellitus (insulin dependent diabetes
mellitus IDDM )
(b) Type II diabetes mellitus (Non-insulin dependent
diabetes mellitus,NIDDM)
63. Type I diabetes mellitus (insulin dependent
diabetes mellitus IDDM )
⢠It is due to decreased insulin production.
⢠Circulating insulin level is very low.
⢠These patients are dependent on insulin injections.
Onset is usually below 30 years of age, most
commonly during adolescence.
⢠They are more prone to develop ketosis.
64. â˘It may be due to
â˘Autoimmune disorder; Circulating antibodies against
insulin is seen
65. â˘Type II diabetes mellitus (Non-insulin dependent
diabetes mellitus,NIDDM) :
â˘95% of the patients belong to this type.
â˘The disease is due to the decreased biological response to
insulin, otherwise called insulin resistance
â˘Type 2 disease is commonly seen in individuals above 40
years.
â˘These patients are less prone to develop ketosis
â˘About 60% patients are obese
66. Metabolic changes in Diabetes
⢠in Carbohydrate Metabolism
⢠Net effect is an inhibition of glycolysis and stimulation of
gluconeogenesis leading to hyperglycemia.
⢠in Lipid Metabolism
⢠Fatty acid breakdown leads to high FFA levels
⢠The excess of acetyl CoA therefore, is diverted to ketone bodies,
leading to ketogenesis
67. ⢠in Protein Metabolism
⢠Increased breakdown of proteins and amino acids
68. Clinical Presentations in Diabetes Mellitus
⢠When the blood glucose level exceeds the renal threshold glucose is
excreted in urine (glucosuria)
⢠Polyuria
⢠more water is taken (polydypsia)
⢠patient will take more food (polyphagia).
69. Acute Metabolic Complications
⢠Diabetic Keto Acidosis
⢠ketonemia, excretion in urine (ketonuria) and smell of acetone in
breath. All these three together constitute the condition known as
ketosis
70. Chronic Complications of Diabetes Mellitus
⢠cataract of lens
⢠Pregnancy: Diabetic mothers tend to have big babie, Chances of
abortion, premature birth
⢠Neuropathy
⢠Atherosclerosis
71. Diagnosis of DM
ďBlood glucose estimation :
⢠Normal fasting plasma glucose level is 70-110mg/dl.
⢠Post prandial plasma glucose : < 140mg/dl (after 2hrs of food
intake)
⢠Random plasma glucose : 70-150mg/dl
ďUrine testing:
⢠Urine is tested for the presence of glucose by benedict's test
⢠Urinary glucose is poor marker of diabetes mellitus because the
renal threshold for glucose is 180mg/dl blood glucose level
should exceed this value.
72. ďGlucose tolerance test (GTT) /OGTT (oral GTT)
ď: it is the test to measure the capacity of the body to utilize
an additional load of glucose entering into the body.
â˘It is performed in diagnosis of doubtful cases of diabetes
mellitus.
â˘PROCEDURE :
â˘In the morning a sample of blood and urine is collected in
the fasting condition (8-12hrs) this is denoted as the â0â hour
sample.
â˘Glucose load dose : the dose is 75gm anhydrous glucose in
250-300ml of water.
73. Glycated haemoglobin (HbA1)
â˘Glucose is attached to Hb
â˘the rate of addition is directly proportional to the blood
glucose level.
â˘Normal level : 4 to 7%
â˘Diabetics : 8 to 15%
74. â˘Significance :
â˘Glycated Hb measurement is an index of long term control
of blood glucose once attached cannot be removed from hb
â˘Once formed remains inside the RBC throughout the life
span of RBCs (120days)
â˘Therefore it reflects the blood glucose level over a period of
2-3 months.
75. Management of diabetes mellitus
â˘Diet , exercise , drugs and insulin are the options for
management of diabetes mellitus.
â˘Insulin injections : it is used in type I diabetes, also used in
type II where oral drugs are not sufficient.
â˘Diet and exercise : it can control about 50% of type II
diabetes.
â˘A diabetic patient is advised to take a diet low in
carbohydrates and fat and rich in protein and fibers.