METABOLIC CHANGES IN DIABETES MELLITUS

&
DIABETIC PREGNANT WOMAN

DEPARTMENT OF BIOCHEMISTRY Siti Annisa Devi Trusda

Humans are able to use a variable fuel input to meet a variable metabolic demand

Variable fuel input

storage fuels
O2 ADP + Pi ATP CO 2 + H 2 O + urea Variable metab demand

Disposition of glucose, amino acids, and fat by various tissues in the well-fed state

I. METABOLIC CHANGES IN TYPE-1 DM ( IDDM )

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 Insulin

Insulin receptor

Glucose transporters

+
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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

Glucose
Glucokinase / hexokinase

Glucose-6 P

+
Fructose-6 P
Phospho fructo kinase

+
Insulin

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
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c). Increase of glycogenolysis pathways activity in the liver, that caused by high activity of phosphorylase enzymes in the liver

Glycogen

Phosphorylase

Glucose-1 P Glucose-6 P
Glucose-6 P-ase

Insulin

Glucose

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Glucagon

Insulin

+
Adenylate cyclase ATP cAMP

+
Phospho diesterase 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 gluconeoneogenetic enzymes : - Glucose-6 phosphatase - Fructose-1,6 biphosphatase - PEP carboxykinase - Pyruvate carboxylase

Note : Gluconeogenesis is glucose synthesis from non carbohydrate substrates ( lactic acids, glucogenic amino acids, glycerols and propionic acids ).

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Glycogen

Glucose

+
Insulin

Hexokinase glucokinase Glucose-6 P Fructose-6 P Phospho fructokinase Insulin

Glucose-6 phosphatase

Fructose-1,6 biphosphatase Fructose-1,6 bi P Insulin

PEP carboxykinase Oxalo acetate

PEP Pyruvate kinase Pyruvate

Pyruvate Pyruvate carboxylase Oxalo aqcetate Malate Malate TCC 15 Mitochondrial matrix

f). Decrease of TCC activity, may be caused by decrease of citrate synthase enzyme activity, or lack of oxaloacetate

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Glucose

Lipids Protein FFA

Pyruvate Insulin

Amino acids

+
Citrate synthase

Acetyl Co A

Oxalo acetate

citrate

Malate Fumarate

T.C.C

Iso citrate

Succianate

Keto glutarate

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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, hypertriglyceridemias 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 )
HMG CoA reductase HMG CoA lyase

Cholesterol (Hypercholesterolemia)

Keton bodies (Keto acidosis)

Extra-hepatic tissues Acetyl CoA TCC

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FFA (Blood) Liver

VLDL Intestine VLDL (TG)

Chylomicron (TG)

Extra hepatic tissues

Insulin

Lipoprotein lipase FFA

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 gluconeogenesis 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 epinephrin etc

Insulin

+
Phosphodiesterase cAMP 5 AMP

Adenylate cyclase ATP

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.

 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

Pathophysiology

Estrogen and Progesterone

Interfere with insulin-glucose relationship.

Insulinase
Placental product that may play a minor role.

* 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 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???

REFERENCE

1. Devlin, T.M. : Textbook of Biochemistry with Clinical Correlatitions. 6th edition., 2006, page 875 - 881, 920. 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. A Wiley

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Alhamdulillah THANK YOU

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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?