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Metabolic Pregnant Edit
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METABOLIC CHANGES IN DIABETES MELLITUS & DIABETIC PREGNANT WOMEN
BY
ESON DARSONO
DEPARTMENT OF BIOCHEMISTRYFACULTY OF MEDICINE
UNIVERSITAS PADJADJARAN
Metabolic Pregnant Edit
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CO 2 + H 2O + urea
storage fuels
ADP + Pi
ATP
O 2
Variablemetabdemand
Variable fuel input
Humans are able to use a variable fuel input to meet a variable metabolic demand
Metabolic Pregnant Edit
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Disposition of glucose, amino acids, and fatby various tissues in the well-fed state
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I. METABOLIC CHANGES IN TYPE-1 DM ( IDDM )
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1. Carbohydrates metabolic changes, that cause hyperglycemia
Defect of cells of pancreas, cause absolutely lack of insulin
level
a). Decrease of glucose transports into the cells that caused
by low activity of glucose transporter
Glucose transportersInsulin
Glucose
Insulinreceptor
+
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Glucose
Glucokinase / hexokinase
Glucose-6 P
Fructose-6 P
Phospho fructo kinase
Fructose-1,6 bi P
2 Triose-P
2-Phosphoenol pyruvate ( PEP )
Pyruvate kinase
2-Pyruvate
Note : Glycolysis is oxidation of glucose to form pyruvate or lactate
Insulin
+
+
+
b). Decrease of
glycolysis
pathways ac-
tivity caused by
decrease of
three kinds of
glycolytic
enzymes :
- Hexokinase /
glucokinase
- Phosphofruc-
tokinase
- Pyruvate ki-
nase
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Glycogen
Phosphorylase
Glucose-1 P Insulin
Glucose-6 P
Glucose-6 P-ase
Glucose
-
-
c). Increase of glycogenolysis pathways activity in the
liver, that caused by high activity of phosphorylase
enzymes in the liver
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Glucagon Insulin
Adenylate Phospho di-
cyclase esterase
ATP cAMP 5 AMP
Glycogenolysis
Note : Glycogenolysis is glycogen breakdown to form glucose
+
++
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Glucose
Glucose-6 P
Glucose-1 P
UTP
Uridine diphosphate
glucose ( UDPG )
r
Glycogen
Note : Glycogenesis is synthesis of glycogen from
glucose
+
Insulin
Glycogensynthase
Glycogenprimer
d). Decrease of glyco-
genesis pathways
activity, that caused
by low activity of
glycogen synthase
enzymes
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e). Increase of gluconeogenesis pathways activity, that
caused by high activity of four kinds of gluconeo-
genetic enzymes :
- Glucose-6 phosphatase
- Fructose-1,6 biphosphatase
- PEP carboxykinase
- Pyruvate carboxylase
Note : Gluconeogenesis is glucose synthesis from non carbo-
hydrate substrates ( lactic acids, glucogenic amino
acids, glycerols and propionic acids ).
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Glycogen
Glucose Hexokinase Glucose-6 glucokinase phosphatase Glucose-6 P
Fructose-6 P Phospho Fructose-1,6 fructokinase biphosphatase Fructose-1,6 bi P
Insulin Insulin
PEP PEP car- Pyruvate boxykinase kinase
Oxalo acetate Pyruvate
Pyruvate Pyruvate carboxylase Oxalo aqcetate
Malate Malate TCC
Mitochondrial matrix
Insulin
+
+
+
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Iso citrate
citrate
Acetiyl Co A
Keto glutarateSuccianate
Fumarate
Malate
Oxalo acetate
Citrate synthase
Pyruvate
Glucose
FFA Amino acids
LipidsProtein
Insulin
T.C.C
+
f). Decrease of
TCC activity,
may be caused
by decrease
of citrate syn-
thase enzyme
activity, or lact
of oxalo acetate.
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Decrease of citrate synthase enzymes activity or lact of
oxalo acetate cause acetyl CoA can not be oxidized in TCC
( decrease of TCC activity ) in Diabetes Mellitus.
Note : TCC ( Tricarboxylic acid cycle ) is oxidation of acetyl
CoA to form CO2, H2O and energy ATP.
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2. Lipids metabolic changes, that cause keto acidosis, hyper-
triglyceridemias and hypercholesterolemias
* Energy production failure from carbohydrates ( glucoses )
metabolism cause increase of lipolysis from adipose tissues
Insulin
Hormon sensitive lipase
* Triglycerides Free fatty acids
Glycerols
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Increase of hormon sensitive lipase enzymes activity in
IDDM, cause increase of lipolysis from adipose tissues and
high blood level of free fatty acids and would be taken by
the tissues to be oxidized ( oxidation ).
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FFA
oxidation
Acetyl CoA
TCC
Hydroxy Methyl Glutaryl CoA
( HMG CoA )
Cholesterol Keton bodies
(Hypercholesterolemia) (Keto acidosis)
Extra-hepatic tissues
Acetyl CoA
TCC
HMG CoAreductase HMG CoA lyase
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FFA (Blood)
Liver
VLDL
VLDL (TG)
Lipoprotein lipase
FFA
Intestin
Extra hepatic tissues
Insulin
Chylomicron (TG)
Glycerol
+
Decrease of lipoprotein lipase enzymes activity cause hypertriglyceridemia
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3. Amino acids metabolic change
Amino acids ( glucogenic a.a. ) from diet ( intestine ) and
from proteolysis of protein in the muscle, enter gluconeo-
genesis pathways in the liver to maintain blood glucose
concentration.
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II. METABOLIC CHANGES IN TYPE-2 DM ( NIDDM )
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CARBOHYDRATE METABOLIC CHANGES
Insulin level may be normal or slight increase, but there is
insulin resistance.
The insulin receptors can not fully respond to insulin, so
glucose transporters become inactive. Glucoses can not enter
into the cells of the tissues especially muscle tissues and
cause hyperglycemia.
Insulin resistance is induced by tumor necrosis factor ( TNF
) and a new protein called resistin that produced by adipose
tissues.
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Lipid Metabolic Changes
* Lipoprotein lipase enzymes that stimulated by insulin, also in
active, so triglyceride content of VLDL and chylomicrons can
not split into free fatty acid ( FFA ) and glycerols and cause
hypertriglyceridemia.
* Increase of VLDL production in the liver is induced by
hyperglycemia and hyperinsulinemia.
* Keto acidosis can not develop, because the cells of adipose
tissues still sensitive to the insulin effect on lipolysis (insulin
inhibits lipolysis pathways in adipose tissues ).
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Glucagon Insulin
epinephrin etc
Adenylate cyclase Phosphodiesterase
ATP cAMP 5 AMP
Lipolysis
++
+
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III. DIABETES MELLITUS AND PREGNANCY
1. Metabolic Changes in Normal Pregnant Woman
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* Two reasons that cause metabolic changes in pregnant woman
a). Changes of hormonal level in pregnancy especially estrogen
and progesteron that stimulate insulin resistance
b). Fetal needs for energy and synthesis especially from
glucose, and amino acids that cause maternal hypoglycemia,
also lactate, free fatty acids and keton bodies
* Maternal LDL-cholesterol is precursor for placental steroids
synthesis ( estrogen and progesteron )
* Placenta also produce placental lactogen hormon ( peptide )
that stimulates lipolysis in adipose tissues
* After feeding, pregnant woman fals to fasting state rapidly
caused by increase of glucose and amino acid consumption by
the fetus
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* Blood glucose, amino acids and insulin level fals rapidly, and on
the other hand glucagon and placental lactogen increase
that cause increase of lipolysis and ketogenesis pathways
* Changes of steroid hormons and fuels cause very difficult to
controle blood glucose in diabetic pregnant woman
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2. Gestational Diabetes Mellitus
* Normal women before pregnant, can develop Diabetes
mellitus when they are pregnant, its called gestational DM
* Usually they have diabetic gene that inhereted from their parents
* Exessive feeding when they are pregnant cause exessive
increase of body weight and increase of tumor necrosis factor
(TNF ), and a new protein called resistin
* TNF , resistin, estrogen and progesteron, induce insulin
resistance to develop Diabetes mellitus in pregnant women
(gestational DM)
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* Gestational DM are generally reversible after pregnancy,
aproximately 30 – 50% of women with a history of GDM go
on to develop type-2 DM later in life, particularly if they
are obese.
Although the cellular mechanisms responsible for the
insulin resistance in GDM are not fully understood, the resis-
tance to insulin-mediated glucose transport appear to be grea-
ter in skeletal muscle from GDM subjects than in women who
are pregnant but do not have GDM. Recent data indicate that
defects in insulin action, rather than a decrease in insulin re-
ceptor binding afinity, may contribute to the pathogenesis of
GDM. More specially, skeletal muscle cells of GDM subjects
appear to overexpress plasma cell membran glycoprotein-1
(PC-1), which has been reported to inhibit the tyrosine kinase
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activity of the insulin receptor by directly interacting with -
subunits and blocking the insulin-induced conformational change.
Additionally, excessive phosphorylation of serine / threonine
residues located within muscle insulin receptors appears to
down-regulate tyrosine kinase activity in GDM. Thus an over-
expression of PC-1 and a decrease in receptor kinase activity,
coupled with a decreased expression and phosphorylation
(tyrosine residues) of the insulin receptor substrate-1 (IRS-1), may
underlie the insulin resistance in GDM.
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3. Diabetes Mellitus that Super Imposed with Pregnancy
* Diabetic pregnant women, cause verry difficult to control
blood glucose concentration
* High level of estrogen and progesteron will increase insulin
resistance and cause more severe DM in diabetic pregnant
women
* Maternal hyper glycemia, cause hyperglycemia in the fetus
that transfered via fetal cord
* Fetal hyperglycemia, stimulate fetal hyperinsulinemia that
stimulate synthesis of triglyceride in adipose tissues of the
fetus and the fetus become biger
* Insulin like growth factors ( IGF ) also increase in the fetus so
the fetus not only biger, but also longer. If the fetus weight
more than 4,00 kg, its called giant baby
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* When the giant baby is born, fetal cord is cut, fetal blood
glucose level decrease rapidly, cause baby’s hypoglycemia,
because there is no glucose supply from maternal blood,
but hyper insulinemia still occur in the baby
* Glucose infus or lactation must be given as soon as possible
to increase baby’s blood glucose concentration.
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REFERENCE
1. Devlin, T.M. : Textbook of Biochemistry with Clinical Correlati-
tions. 6th edition., 2006, page 875 - 881, 920. A Wiley
Medical Publication.
2. Harper, H.A. : Illustrated Biochemistry. 27th edition, 2006, page
112 - 230. A Lange Medical Book
3. Lehninger, A.L. : Principles of Biochemistry. 2nd edition, 1993,
page 400 - 642. Worth Publisher.
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