1

METABOLIC CHANGES

IN DIABETES MELLITUS

&

DIABETIC PREGNANT WOMAN

DEPARTMENT OF BIOCHEMISTRYSiti Annisa Devi Trusda

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

4

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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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 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

+

+

+

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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 esteraseATP 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 )

GlycogenPrimer 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

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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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 glutarateSuccianateFumarate

Malate

Oxalo acetate

Citrate synthase

Pyruvate

Glucose

FFA Amino acids

LipidsProtein

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 CoAreductase HMG 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

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.

Pathophysiology• Human Placental Lactogen (HPL)

– Produced by syncytiotrophoblasts of placenta.– Acts to promote lipolysis increased FFA

and to decrease maternal glucose uptake and gluconeogenesis. “Anti-insulin”

• Estrogen and Progesterone– Interfere with insulin-glucose relationship.

• Insulinase– Placental 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 insulin

resistance to develop Diabetes mellitus in pregnant woman

(gestational DM)

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* Gestational DM are generally reversible after pregnancy,

approximately 30 – 50% 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 control blood 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 baby’s

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 baby’s blood glucose

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. 2nd edition, 1993,

page 400 - 642. Worth Publisher.

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Alhamdulillah

THANK YOU

QUIZ• Enzim-enzim apa saja dalam jalur glikolisis

yang dipengaruhi oleh insulin?(3)• Enzim-enzim apa saja dalam jalur

glukoneogenesis yang dipengaruhi oleh insulin?(4)

• Apa perbedaan hormon sensitive-lipase dengan lipoprotein lipase?

• Apa yang menyebabkan resistensi insulin pada ibu hamil?

• Apa yang menyebabkan terjadinya Giant Baby?