Carb 1 Flashcards
Well fed state
1-4 hrs after food
Increased protein synthesis
Fasting types
Early fasting 4 -16 glycogenolysis
Fasting 16-48 hrs gluconeogenesis (OAA decreases)
Prolonged fasting or starvation 2-5 days hydrolysis of TAG in adipose tissue to produce acetyl CoA(OAA has decreased) to ketone body synthesis
Prolonged starvation after 5 days muscle proteolysis/wasting
Role of beta oxidation in fasting
In gluconeogenesis , ATP is required
and
acetyl Co A is an activator of first step of it I.e pyruvate carboxylase
Ketone body important use
Prevent structural protein lysis
Prevents cachexia
Earliest effect of insulin
Increased GLUT4 in
1 skeletal muscle(very much)
2. Heart
3. Adipose
Insulin increases hexokinase or glucokinase?
Glucokinase
RBC glucose transport
GLUT 1
During starvation brain depends on
Glucose 80% GLUT
3( highest affinity)
Ketone body 20%
FA cannot cross blood brain barrier( bound to albumin)
No anabolic process so no storage of nutrition
Glucagon starts increasing at ___glucose level
Insulin starts at
50mg/dl
80mg/dl
cAMP dependent protein kinase A has in inactive state
2 regulatory and 2 catalytic subunit
Changes in beta cell in fed state following increased ATP production
ATP sensitive K+ channels close Depolarisation Leads to opening Ca+2 channels Ca+2 influx Insulin vesicle exocytosed
Tyrosine and insulin
Insulin leads to Receptor Tyrosine Kinase phosphorylates tyrosine residues in the beta subunit of receptor
Leads to phosphorylation of IRS
Glycogen phosphorylase is active in __ state
Phosphorylated
Liver metabolic fuels
Fed glucose> FFA
Early fasting/fasting
FFA> glucose
Prolonged fasting, starvation
Amino Acids/FFA
NO ketone bodies
Heart metabolic fuels
fed/ early fasting/fasting
FFA>glucose
Prolonged fasting
Ketone bodies
Brain metabolic fuels
Fed /Early fasting/fasting
Glucose
Prolonged fasting
80% glucose
20% ketone bodies
Skeletal muscle metabolic fuel
Fed
Glucose> FFA
Early fasting/ fasting
FFA> glucose
Prolonged fasting
FFA,
(Slow twitch) ketone bodies
Adipocytes metabolic fuels
Fed
Glucose>FFA
Early fasting
FFA> Glucose
Starvation
FFA,ketone bodies
Fate of acetyl Co A in DM increased due to beta oxidation of increased FA (HS Lipase)
No OAA so no TCA cycle
No insulin so no FA synthesis
Increased ketone body synthesis
Lactulose
Galactose + fructose
Synthetic
Osmotic laxative
Glycogen occurs in liver and muscle as
Beta particle having 60000 glucose molecules
Dextran
Homopolysaccharide of glucose
Plasma volume expander
Product of glucose oxidase method
Gluconic acid an aldonic acid
Mucic acid test
Galactose test
it is a sachcharic acid of galactose
Dulcitol/ galactitol
Cataract in Galactosemia
Mannitol
Intracranial pressure reducer
Mannose alcohol
Fructose alcohol(s)
2 since an aldose
Sorbitol and mannose
Which carb function test is a liver function test
Galactose
Normally <3 gm appear in urine after 40gm galactose ingestion
The only GAG which is not formed by the Golgi apparatus
Hyaluronic acid at plasma membrane
Glycosaminoglycans or mucopolysaccharides are
Complex carbohydrates made of uronic acid and amino sugars
May be attached to proteoglycans ( which have bottle brush appearance)
Keratin sulphate 1 in
Cornea
Glycosaminoglycans are polysaccharides made of repeating
Disaccharide units of amino sugar and acidic sugar (glucuronic acid and iduronic acid)
Mucous secretions are slippery and resilient (compressibility) because
Glycosaminoglycans repel each other and absorb water due to negative charge
Chondroitin sulphate
Most abundant and most heterogenous GAG
Cartilage bones and CNS
Keratin sulphate
Two types I and II
It has galactose instead of uronic acid as the second unit
I cornea(transparent) II cartilage , loose connective tissue
Heparan sulphate
Glucosamine + glucuronic acid Seen in plasma membrane receptors Lipoprotein lipase is anchored by it Basement membrane of renal glomeruli, it is present so charge selectiveness( albumin not allowed) Present in synaptic and other vesicles
Heparin
Glucosamine+iduronic acid
Only intracellular GAG (Mast cells lungs)
Deramatan sulphate
Widely distributed GAG
Abundant in skin
It binds to LDL so atherogenic GAG
Hyaluronic acid
N acetyl glucosamine+ glucuronic acid (no sulphate)
Not covalently attached to proteins
Helps in cell migration( tumour metastasis, morphogenesis, wound repair)
Found in bacteria
Proteoglycan
Protein(5%)+ GAG( 95%)
GAG is attached by a stalk Gal- Gal- Xylulose to the protein frame
Thus a bottle brush appearance
Glycoprotein
Carb (5%) + protein (95%)
Synthesis of GA
degradation in
ER & Golgi apparatus
Lysosome
General clinical features of MPS
Coarse facial appearance
Frontal bossing
Depressed nasal bridge
Gingival hypertrophy Large tongue (noisy breathing, ear infection( hearing loss) , URTI( copious nasal discharge))
Mucopolysaccharides in urine
General skeletal features of MPS
Skeletal dysplasia
Dysostosis multiplex
Bullet shaped middle phalanx
Claw hand
Special manifestations of MPS I ,Hurler syndrome
Corneal clouding Visceromegaly
( protuberant abdomen and hernias)
Short stature
Mental retardation
Reilly body inclusions
Visceral manifestations of MPS
Valvular heart diseases
Mitral and aortic regurgitations
Scheie’s disease
MPS I S Normal intelligence Accumulation of dermatan sulphate ( rest as Hurler disease) Alpha L idurorinidase (partial deficiency ) Gene IDA
Hurlers disease biochemical effect
MPS I H
alpha L iduronidase
Heparan sulphate and dermatan sulphate in urine
Gene IDA
Hunter’s disease
L iduronate
MPS II
Gene IDS
X linked
Males only affected
Clear vision
( like Sanfillippo syndrome)
Heparan sulphate & dermatan sulphate
Difference between Hurler and hunter disease
Hunter is more common and has slower progression, hunters have clear vision and are males
Most common MPS
Sanfillippo (MPS III) followed by Hunter
MPS with no mental retardation
Scheie I S
Morquio MPS IV
(no visceromagaly and no leukocyte inclusion)
Maroteaux Lamy MPS VI
I cell(inclusion cell) disease
Protein targeting disorder to the lysosome Resembles MPS( more severe)
Enzyme defect( N Acetyl Glucose Phospho transferase) Mannose 6 P not formed
Enzyme replacement therapy ( ERT) for MPS in
MPS I (H & S) Aldurazyme MPS II (H) Elaprase MPS VI (ML) Naglazyme
GLUT 2 is found in
- Beta cells
- Sinusoidal cells of liver
- Basolateral side of intestine
4 PCT
It can transport fructose also
Fructose transporter
GLUT 5
(GLUT 2)
But it transports other sugars
GLUT 6
Pseudogene in spleen and leukocyte
GLUT 7
Liver ER
Glycemic index of glucose and galactose( and hence lactose also)
100%
because all of it absorbed due to SGLT I
But not fructose and sucrose
GLUT in blastocyst
GLUT 8
Deficiency of glycolysis enzymes cause
Hemolysis
Eg pyruvate kinase ( 2nd most common enzyme deficiency )
PFK 1
Muscle fatigue and a glycogen storage disorder
Inhibitor of glyceraldehyde 3 P dehydrogenase
Iodoacetate
Inhibitor of 1,3 BP Glycerate kinase
Arsenate
Gluconeogenesis occurs in
Liver , kidney
Their enzymes are seen in intestine
Cytoplasm and mitochondria
Gluconeogenic substrate
- Glucogenic aa ( alanine - Cahill cycle)
- Lactate (Cori cycle)
- Glycerol
- Propionyl CoA
In fasting state blood level of which aa increases
Alanine due to Cahill cycle
Cori cycle involves which organs
Muscle (exercise)
RBC(always)
Lactate
Which step of gluconeogenesis takes place in mitochondrion
Pyruvate carboxylase requiring ATP
The OAA then enter cytoplasm via malate aspartate shuttle
PEPCK requires
GTP
OAA
CO2 and PEP are released
decarboxylation and phosphorylation
Propionyl CoA enters gluconeogenesis via
Propionyl CoA carboxylase ( biotin) converts it into D methyl Malonyl CoA
Isomerised by racemase to L form
Then converted by methyl malonyl CoA mutase (B12) to Succinyl CoA
It enters TCA ,converged to OAA which enters gluconeogenesis
Enzyme of gluconeogenesis requiring B12
Methyl malonyl CoA mutase converting l methyl malonyl CoA to succinyl CoA
Explain glycogenin structure
A polypeptide
Has many tyrosine residues which are glycosylated
Enzymes for production of UDP glucose
Hexokinase
Phosphoglucomutase (G-1-P formed)
UDP Glucose pyrophosphorylase
RDE of glycogenesis
Glycogen synthase
Branching enzyme
Alpha 1,4 1,6 glucan transferase
It transfers a hexasaccharide
Why density of glycogen is more in liver
Roster of beta particles
Storage organelles for glycogenolysis
Cytoplasm of muscle and liver
1-2% lysosome (pompe disease
Smooth endoplasmic reticulum involved
Vitamin required for glycogen phosphorylase the RDS
Vitamin B6
Hence B6 is found mostly in muscle
It stops 4 glucose molecules from 1,6 linkage till which it removes mainly as G 6 P
Name of debranching enzymes
Alpha 1,4 1,4 glucose transferase
Alpha 1,6 glucosidase ( removes as GLUCOSE)
This accounts for the small proportion of glucose among the glucose-6-P
Enzyme common for glycogenesis and glycogenolysis
Phosphogluco mutase
Enzyme absent in muscle but present in liver (in ___ organelle) and common to glycogenolysis and gluconeogenesis
Glucose 6 phosphatase
This enzyme is present in the smooth ER ( G-6-P is transported into SER by T1 protein and the glucose is transported to cytoplasm by GLUT7 )
Hence there is a delay in forming glucose
3 ATP from anaerobic glycolysis in muscle
Glucagon acts in the
Liver
Not muscle
(Reference - glycogen metabolism )
Mineral which is activated of glycogenolysis
Ca+2
Regulation of muscle glycogenolysis (allosteric)
Activators are
Ca+2 (Calcium calmodulin dependent protein kinases) and AMP
Inhibitors are
ATP, G-6-P
Glucose is not an inhibitor for muscle glycogenolysis
Regulators of liver glycogenolysis
Inhibitors are
ATP, Glucose, G-6-P
Muscle in extreme anoxia
5’AMP acts as a allosteric activator without involvement of phosphorylation
Liver glycogen storage disorder general features
Hypoglycaemia
Hepatomegaly(mostly)
Usually no exercise intolerance
Muscle GSD features
No hypoglycaemia
Exercise intolerance
Von gierke disease
Biochemical defect
Type 1 A GSD
Most common
Glucose 6 Phosphatase
Increased G-6-P
Increased glycogen
Von gierke disease clinical features
3-4 months Doll like facies with thin extremities Massive hepatomegaly but no splenomegaly RENOMEGALY Milky white plasma (triglyceridemia)
Biochemical hallmarks of Von gierke disease
Fasting Hypoglycaemia Lactic acidosis Hyperlidemia Ketosis Hyperuricemia
Ketosis and hyperlipidemia in Von gierke disease
As glycogenolysis is ineffective , gluconeogenesis takes place.
Thus OAA is depleted.
Beta oxidation of FA is increased.
Acetyl CoA cannot enter TCA as there is no OAA , thus ketosis and hyperlipidemias
Type 1 B GSD
G6P transporter in liver ER is defective
Neutropenia and recurrent bacterial infection
Forbes/ Chris disease / Limit dextrinosis
Type 3 GSD
Debranching enzyme
Abnormal glycogen
(limit dextrin with few outer branches)
IV corn starch syrup
Clinical features of Forbes disease and Anderson’s disease
Hypoglycaemia Hepatosplenomegaly No renomegaly Progressive liver cirrhosis Myopathy
After puberty sometimes may be reversible or death in cori disease
But in Amylopectinosis , portal hypertension to death by about 5 years due to liver failure
IV glucagon gives response in well fed state but no response after overnight fasting
Limit dextrinosis
No problem in absorption of glucose
But after overnight fast debranching enzyme is deficient so no response
Anderson’s disease / amylopectinosis
Type 4 GSD
Branching enzyme
Abnormal glycogen insoluble in water and amylopectin-like
Muscle glycogen disorder with hypertrophic cardiomyopathy
Pompe’s disease
Danon disease
Defect in LAMP 2 protein Lysosomal Associated Membrane Protein 2
Muscle GSD without hypertrophic cardiomyopathy
McArdle disease (type 5) Tarui disease (type 7)
Pompe’s disease
Type 2 GSD
Lysosomal storage disorder
Acid maltase/ acid alpha 1,4 glucosidase
Clinical features of Pompe’s disease
Hypotonia Early onset Floppy infant Failure to thrive Macroglossia Cardiomegaly and progressive cardiac failure to death (2 years)
Treatment for Pompe’s disease
ERT of
myozyme / aglucosidase alpha / recombinant acid alpha glucosidase
Diagnosis of Pompe’s disease
Increased levels of serum :
Creatinine kinase
Lactate dehydrogenase
Acid phosphatase
Enzymes elevated in type 3 and 4 GSD
Liver enzymes like aminotransferases especially ALT (AST)
McArdle’s disease
Type 5 GSD
Muscle (glycogen) phosphorylase
Most common GSD in adolescents and adults
Characteristics of McArdles disease
Normoglycemia
Exercise intolerance
Second wind phenomenon
(If they rest after the onset of first pain, they can resume the exercise with more ease.)
Rhabdomyolysis
(myoglobinuria - burgundy coloured urine)
Tarui’ disease
Type 7 GSD
muscle and erythrocyte PFK
Exercise intolerance
No second wind phenomenon
Hemolysis
Her’s disease
Type 6 GSD
Hepatic phosphorylase
Fanconi Bickel syndrome
Affecting GLUT 2
recently added GSD
Type 0 GSD
Glycogen synthase defect
Tandem enzyme / bifunctional enzyme of glycolysis and gluconeogenesis
A single polypeptide having the activity of PFK-2 and F-2,6-BPase
PFK 2 produces F 2,6 BP from F-2-P
F-2,6-BPase
This takes part in reciprocal regulation
PFK 2 role
The product of PFK-2 (F-2,6-BP) is an activator for PFK-1
i.e, PFK-2 activates glycolysis
F-2,6-BPase inhibits PFK-1 so activates gluconeogenesis
