metabolic pregnant edit 1 metabolic changes in diabetes mellitus & diabetic pregnant women by...

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


2

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


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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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