METABOLIC CHANGES IN DIABETES MELLITUS & DIABETIC PREGNANT WOMAN DEPARTMENT OF BIOCHEMISTRY Siti Annisa Devi Trus

1. METABOLIC CHANGES IN DIABETES MELLITUS & DIABETIC PREGNANT WOMAN DEPARTMENT OF BIOCHEMISTRY Siti Annisa Devi Trusda

2. Humans are able to use a variable fuel input to meet a variable metabolic demand Variable fuel input storage fuels O 2 Variable ADP + Pi metab demand ATP CO + H O + urea 2 2

4. Disposition of glucose, amino acids, and fatby various tissues in the well-fed state

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

6. Glucose Insulin receptor Insulin + 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 transporters

7. b). Decrease of glycolysis pathways activity, that caused by low activity of three kinds of glycolytic enzymes : - glucokinase /Hexokinase - Phosphofructokinase - Pyruvate kinase

8. 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 +

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

10. Glycogen Phosphorylase Glucose-1 P Insulin Glucose-6 P Glucose-6 P-ase Glucose - -

11. Glucagon Insulin Adenylate Phospho di- cyclase esterase ATP cAMP 5 AMP Glycogenolysis Note : Glycogenolysis is glycogen breakdown to form glucose + + +

12. d). Decrease of glycogenesis pathways activity, that caused by low activity of glycogen synthase enzymes

13. 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 +

14. 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 ).

15. + + + Glycogen Glucose Hexokinase Glucose-6 glucokinasephosphatase Glucose-6 P Fructose-6 P PhosphoFructose-1,6 fructokinasebiphosphatase 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

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

17. Glucose Lipids Protein FFA Amino acids Pyruvate Insulin + Acetyl Co A Citrate synthase Oxalo acetate citrate T.C.C Malate Iso citrate Fumarate  Keto glutarate Succianate

18. 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.

19. 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

20. 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 ).

21. 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 reductase HMG CoA lyase

23. + FFA (Blood) Liver VLDL Intestine Chylomicron (TG) VLDL (TG) Extra hepatic tissues Insulin Lipoprotein lipase FFA Glycerol Decrease of lipoprotein lipase enzymes activity cause hypertriglyceridemia

24. 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.

25. II. METABOLIC CHANGES IN TYPE-2 DM ( NIDDM )

26. 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.

27. 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 ).

28. + + + Glucagon Insulin epinephrin etc Adenylate cyclase Phosphodiesterase ATP cAMP 5 AMP Lipolysis

29. III. DIABETES MELLITUS AND PREGNANCY 1. Metabolic Changes in Normal Pregnant Woman

30. 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.

31. 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.

32. * 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

33. * 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

34. 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)

35. * 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.

36. 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

37. * 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

39. A Vicious Cycle???

40. REFERENCE • Devlin, T.M. : Textbook of Biochemistry with Clinical Correlati- • tions. 6th edition., 2006, page 875 - 881, 920. A Wiley • Medical Publication. • Harper, H.A. : Illustrated Biochemistry. 27th edition, 2006, page • 112 - 230. A Lange Medical Book • Lehninger, A.L. : Principles of Biochemistry. 2nd edition, 1993, • page 400 - 642. Worth Publisher.

41. Alhamdulillah THANK YOU

42. 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?