11.metabolic pregnant woman(baru)
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METABOLIC CHANGES
IN DIABETES MELLITUS
&
DIABETIC PREGNANT WOMAN
DEPARTMENT OF BIOCHEMISTRY
Siti Annisa Devi Trusda
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CO2 + H2O + urea
storage fuels
ADP + Pi
ATP
O2
Variablemetabdemand
Variable fuel input
Humans are able to use a variable fuel input to meet a
variable metabolic demand
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Disposition of glucose, amino acids, and fat
by 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
levela). Decrease of glucose transports into the cells that caused
by low activity of glucose transporter
Glucose transportersInsulin
Glucose
Insulin
receptor
+
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b). Decrease of glycolysis pathways activity, that caused by
low activity of three kinds of glycolytic enzymes :
- glucokinase /Hexokinase
- Phosphofructokinase
- Pyruvate kinase
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Glucose
Glucokinase /hexokinase
Glucose-6 P
Fructose-6 P
Phospho fructokinase
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
+
+
+
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c). Increase of glycogenolysis pathways activity in the
liver, that caused by high activity of phosphorylase
enzymes in the liver
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Glycogen
Phosphorylase
Glucose-1 P Insulin
Glucose-6 P
Glucose-6 P-ase
Glucose
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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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d). Decrease of glycogenesis pathways activity, that
caused by low activity of glycogen synthase enzymes
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Glucose
Glucose-6 P
Glucose-1 P
UTP
Insulin
Uridine diphosphate
glucose ( UDPG )
Glycogen
Primer Glycogen
synthase
Glycogen
Note : Glycogenesis is synthesis of glycogen from glucose
+
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e). Increase of gluconeogenesis pathways activity, that
caused by high activity of four kinds of gluconeo-
neogenetic 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
GlucoseHexokinase Glucose-6glucokinase phosphatase
Glucose-6 P
Fructose-6 PPhospho Fructose-1,6fructokinase biphosphatase
Fructose-1,6 bi P
Insulin Insulin
PEPPEP car- Pyruvateboxykinase kinase
Oxalo acetate Pyruvate
PyruvatePyruvatecarboxylase
Oxalo aqcetate
Malate Malate TCC
Mitochondrial matrix
Insulin
+
+
+
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f). Decrease of TCC activity, may be caused by decrease
of citrate synthase enzyme activity, or lack of
oxaloacetate
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Iso citrate
citrate
Acetyl Co A
Keto glutarateSuccianate
Fumarate
Malate
Oxalo acetate
Citrate
synthase
Pyruvate
Glucose
FFA Amino acids
Lipids
Protein
Insulin
T.C.C
+
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Decrease of citrate synthase enzymes activity or lack of
oxaloacetate 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 CoA
reductaseHMG CoA lyase
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FFA (Blood)
Liver
VLDL
VLDL (TG)
Lipoprotein lipase
FFA
Intestine
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 TAG 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.
* Ketoacidosis rarely 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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Pathophysiology
Normal pregnancy is
characterized by:
Mild fasting hypoglycemia
Postprandial hyperglycemia Hyperinsulinemia
Due to peripheral insulin
resistance which ensures an
adequate supply of glucose
for the baby.
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Pathophysiology Human Placental Lactogen (HPL)
Produced by syncytiotrophoblasts of placenta.
Acts to promote lipolysisincreased FFAand to decrease maternal glucose uptake andgluconeogenesis. Anti-insulin
Estrogen and Progesterone
Interfere with insulin-glucose relationship.
InsulinasePlacental product that may play a minor role.
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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 falls to fasting state rapidly
caused by increase of glucose and amino acid consumption by
the fetus
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* Blood glucose, amino acids & insulin level falls 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
control blood glucose in diabetic pregnant woman
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2. Gestational Diabetes Mellitus
* A normal woman before pregnant, can develop Diabetes
mellitus when she is pregnant, its called gestational DM
* Usually she has a diabetic gene that inherited from her parents
* Exessive feeding in pregnancy cause excessive increase
of body weight and increase of tumor necrosis factor (TNF ),
and a new protein called resistin
* TNF , resistin, estrogen and progesteron, induce insulinresistance to develop Diabetes mellitus in pregnant woman
(gestational DM)
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* Gestational DM are generally reversible after pregnancy,
approximately 3050% of woman 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.
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3. Diabetes Mellitus that Super Imposed with Pregnancy
* Diabetic pregnant woman, cause very difficult to controlblood glucose concentration
* High level of estrogen and progesteron will increase insulin
resistance and cause more severe DM in diabetic pregnant
woman
* Maternal hyperglycemia, cause hyperglycemia in the fetus
that transferred via fetal cord
* Fetal hyperglycemia, stimulate fetal hyperinsulinemia that
stimulate synthesis of triglyceride in adipose tissues of the
fetus and the fetus become bigger* Insulin like growth factors ( IGF ) also increase in the fetus so
the fetus not only bigger, but also longer. If the fetus weight
more than 4,00 kg, it is called giant baby
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* When the giant baby is born, fetal cord is cutted, fetal
blood glucose level decrease rapidly, cause babys
hypoglycemia, because there is no glucose supply from
maternal blood, but hyperinsulinemia still occur in the baby
* Glucose infuse or lactation must be given as soon as
possible to increase babys blood glucose
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A Vicious Cycle???
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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. 2ndedition, 1993,
page 400 - 642. Worth Publisher.
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lhamdulillah
TH NK YOU
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QUIZ
Enzim-enzim apa saja dalam jalur glikolisisyang dipengaruhi oleh insulin?(3)
Enzim-enzim apa saja dalam jalurglukoneogenesis yang dipengaruhi oleh
insulin?(4) Apa perbedaan hormon sensitive-lipase dengan
lipoprotein lipase?
Apa yang menyebabkan resistensi insulin padaibu hamil?
Apa yang menyebabkan terjadinya GiantBaby?