Biochemistry of Diabetes

1. Biochemistry of Diabetes Bruno Sopko Based on presentationsof Alice Skoumalová

2. Content • Regulation of Carbohydrate metabolism • Hormonal Regulation • Markers • Additional effects

3. Regulation of Carbohydrate metabolism - Glycolysis

4. RegulationofCarbohydratemetabolism - Gluconeogenesis

5. Metabolismofglycogen

6. Overview of the major pathways of glucose metabolism

7. Regulationofenzymes:

8. Hormonal Regulation • Glucose homeostasis: • maintenance of blood glucose levels near 80 to 100 mg/dL (4.4-5.6mmol/l) • insulin and glucagon (regulate fuel mobilization and storage) • Hypoglycemia prevention: • release of glucose from the large glycogen stores in the liver (glycogenolysis) • synthesis of glucose from lactate, glycerol, and amino acids in liver (gluconeogenesis) • release of fatty acids from adipose tissue (lipolysis) • Hyperglycemia prevention: • conversion of glucose to glycogen (glycogen synthesis) • conversion of glucose to triacylglycerols in liver and adipose tissue (lipogenesis)

9. Hormonal Regulation • Pathwaysregulated by thereleaseof: • glucagon(in response to a loweringofbloodglucoselevels) • insulin (in response to anelevationofbloodglucoselevels)

10. Synthesis and secretion of insulin and glucagon: • theisletsof Langerhans (β- andα-cells) • preprohormone (modification - in ER, GC, SV)

11. Major sites of insulin action on fuel metabolism: • The storage of nutriens • glucose transport into muscle and adipose tissue • glucose storage as glycogen (liver, muscle) • conversion of glucose to TG (liver) and their storage (adipose tissue) • protein synthesis (liver, muscle) • inhibition of fuel mobilization

12. Insulin receptor signaling: • the tyrosine kinase activity • a dimer (α and ß subunits) Signal transduction: 1.the ß-subunits autophosphorylate each other when insulin binds (activating the receptor) 2. the activated receptor binds and phosphorylates IRS (insulin receptor substrate) 3. multiple binding sites for different proteins

13. Major sites of glucagone action on fuel metabolism: • Mobilization of energy stores • release of glucose from liver glycogen • stimulating gluconeogenesis from lactate, glycerol, and amino acids (liver) • mobilizing fatty acids (adipose tissue)

14. Regulators of insulin and glucagon release:

15. Hormonal Regulation

16. Glucose receptors

17. Stimulation by insulin of glucose transport into muscle and adipose cells: Binding of insulin to its cell membrane receptor causes vesicles containing glucose transport proteins to move from inside the cell to the cell membrane

18. Pathways affected by insulin 1. Carbohydrate metabolism stimulation of glucose utilization: glycogen synthase↑ glycolysis ↑ inhibition of gluconeogenesis the transport of glucose into tissues (muscle, adipose tissue) 2. Lipid metabolism stimulation of the glucose conversion into FA: acetyl CoAcarboxylase ↑ NADPH (PPP ↑) storage of fat: lipoprotein lipase ↑ inhibition of the degradation of fat: hormone sensitive lipase ↓

19. Pathways affected by insulin 1. Carbohydrate metabolism stimulation of glucose utilization: glycogen synthase↑ glycolysis ↑ inhibition of gluconeogenesis the transport of glucose into tissues (muscle, adipose tissue) 2. Lipid metabolism stimulation of the glucose conversion into FA: acetyl CoAcarboxylase ↑ NADPH (PPP ↑) storage of fat: lipoprotein lipase ↑ inhibition of the degradation of fat: hormone sensitive lipase ↓

20. Effects of insulin deficiency 1. Glucose uptake and utilization↓ 2. Proteolysis↑ 3. Gluconeogenesis↑ 3. Degradation of fat↑ Hyperglycemia (≥9mmol/l) Glucosuria Hyperlipidemia Metabolic acidosis Ketonuria

21. Typesof diabetes:

22. The oral glucose tolerance test (oGTT): Used if: • elevated fasting levels of glucose - 5,3-6,7 mmol/l (for diagnosis of diabetes, screening of patients with impaired glucose tolerance) • screening of gestational diabetes Procedure: • administration of 75g glucose in an aqueous solution • after overnight fasting (10h) • „common“ diet and physical activity during previous three days • be seated and do not smoke during the test • determination of the glucose levels in the capillary blood before the glucose load and after 60 and 120 minutes Factors affecting oGTT: previous diet, infection, stress

23. The oral glucose tolerance test (oGTT): The blood glucose level returns to the basal level by 2 hours

24. Diagnostic criteria for diabetes mellitus (according to WHO)

25. Factors influencing glucose measurements:

26. Diabetes Screening(ADA recommendation):

27. The chronic diabetes complications: • A. Microvascular (diabeticretinopathy, nefropathy, neuropathy) • nonenzymaticglycationofproteins in vasculartissue • B. Macrovascular(atherosclerosis) • nonenzymaticglycationofproteins in vasculartissueandlipoproteins • C. Diabeticcataract: • increased osmolarity ofthelens (increasedactivityofthepolyolpathway → ↑sorbitol) • nonenzymaticglycationofproteinsoflens

28. Hyperglycemia - protein glycation: • hemoglobin • vascular tissue proteins → contribute to the diabetic complications (cataracta, atherosclerosis, retinopathy, nephropathy) Glycatedproteins: - impairedstructureandfucntion Theimportanceofthemaintanceoflowglucoselevels in diabeticpatients !

29. Lensmetabolism: Diabetic cataract: ↑glucose concentration in the lens →↑aldose reductase activity → sorbitol accumulation → ↑osmolarity, structural changes of proteins

30. Protein kinase C and DAG

31. Protein kinase C and DAG

32. Literature: Marks´ Basic MedicalBiochemistry, A ClinicalApproach, thirdedition, 2009 (M. Lieberman, A.D. Marks) Color Atlas ofBiochemistry (J. Koolman, K.H. Roehm) Francois R. Jornayvaz1 and Gerald I. Shulman, Diacylglycerol Activation of Protein KinaseCε and Hepatic Insulin Resistance, Cell Metabolism 15, 2012