1. Eric Niederhoffer SIU-SOM A 59-year-old man with a history of diabetes and alcohol abuse is brought to the emergency room in a semiconscious and minimally responsive state How are glucose, triacylglycerols, and amino acids normally metabolized and what happens in diabetes?

2. Regulation of Metabolism and Diabetes Clinical focus of glucose metabolism Pathways overview Tissues overview Glucose homeostasis Regulation of carbohydrate metabolism Glycogenesis, glycogenolysis, glycolysis, fructose metabolism gluconeogenesis Regulation of fats metabolism Lipogenesis, lypolysis Impact of diabetes on metabolism Pathway pearls Drug classes Review questions

3. Clinical Focus of Glucose Metabolism Glucose intolerance Type 1 diabetes mellitus Type 2 diabetes mellitus Gestational diabetes Maturity onset diabetes of the young (MODY) Incretin hormone/dipeptidyl peptidase IV defects Insulin resistance (ketoacidosis, nephropathy, neuropathy, retinopathy) Hypoglycemia Glycogen storage diseases

4. Acetyl-CoALactate Production of ATP G6P Glucose Glycolysis Pyruvate Krebs cycle Electron Transport Chain Glycogen Glycogenolysis Fatty acids (TAG) β- Oxidation Ketone bodies Pathways Overview Glycogenesis Gluconeogenesis Lipogenesis Amino acids (Protein) Lipolysis

5. Glycogenesis Glycogenolysis Glycolysis Lipogenesis Lipolysis β-Oxidation Glycogenesis Glycogenolysis Glycolysis Gluconeogenesis Lipogenesis Lipolysis β-Oxidation Ketogenesis Glycogenesis Glycogenolysis Glycolysis β-Oxidation Glycogenesis Glycogenolysis Glycolysis β-Oxidation Tissues Overview Blood Glucose Serum Triglycerides Glycogenesis Glycogenolysis Glycolysis Gluconeogenesis β-Oxidation Liver Adipose Tissue Kidney Heart Skeletal Muscle

6. Glucose Homeostasis

7. Glycogenesis and Glycogenolysis Insulin (ML) IR Ep (ML) βAR cAMP Glucagon (L) GSGS Pn GSK-3 AKTPDK-1 AKT P PKA PPK PPK P GSK-3 P PPa P PPb PPa P PKA PPK P PrPase1 P PrPase1 Glycogenesis Glc Glycogen G6P G1P UDP-Glc Glycogenolysis Glycolysis TCAETC

8. Glycogenesis and Glycogenolysis Insulin (ML) IR GS GS Pn GSK-3 AKTPDK-1 AKT P GSK-3 P PrPase1 P PrPase1 Glycogenesis Glc Glycogen G6P G1P UDP-Glc

9. Glycogenesis and Glycogenolysis Ep (ML) βAR cAMP Glucagon (L) GS GS Pn GSK-3 PKA PPK PPK P PPa P PPb PPa P PKA PPK P Glycogenesis Glc Glycogen G6P G1P UDP-Glc Glycogenolysis Glycolysis TCAETC

10. Glycogenesis and Glycogenolysis Insulin (ML) IR Ep (ML) βAR cAMP Glucagon (L) GSGS Pn GSK-3 AKTPDK-1 AKT P PKA PPK PPK P GSK-3 P PPa P PPb PPa P PKA PPK P PrPase1 P PrPase1 Glycogenesis Glc Glycogen G6P G1P UDP-Glc Glycogenolysis Glycolysis TCAETC

11. PK PFK-1 Glc Acetyl-CoA Pyr F6P F16BP PEP G6P PDH F26BPase PFK-2 Glycolysis: Regulatory Steps HK Insulin Glucagon EpEp Adipose Heart Liver GK Liver Heart

12. PK PFK-1 Glc Acetyl-CoA Pyr F6P F16BP PEP G6P PDH Glycolysis (Liver) Alanine PDHPase PDHK PDH P PKA PK P F26BP F26BPase- PFK-2 F26BPase -PFK-2 P Insulin PrPase2A Glucagon Ep PKA also represses PFK synthesis GK ATP NADH ATP Cit PrPase

13. PK PFK-1 Glc Acetyl-CoA Pyr F6P F16BP PEP G6P PDH Glycolysis (Liver) PDHPase PDHK PDH P F26BP F26BPase- PFK-2 F26BPase -PFK-2 P Insulin PrPase2A GK ATP Cit PrPase

14. PK PFK-1 Glc Acetyl-CoA Pyr F6P F16BP PEP G6P PDH Glycolysis (Liver) Alanine PDHK PDH P PKA PK P F26BP F26BPase- PFK-2 F26BPase -PFK-2 P Glucagon Ep PKA also represses PFK synthesis GK ATP Cit

15. PK PFK-1 Glc Acetyl-CoA Pyr F6P F16BP PEP G6P PDH Glycolysis (Liver) Alanine PDHPase PDHK PDH P PKA PK P F26BP F26BPase- PFK-2 F26BPase -PFK-2 P Insulin PrPase2A Glucagon Ep PKA also represses PFK synthesis GK ATP NADH ATP Cit PrPase

16. PK PFK-1 Glc Acetyl-CoA Pyr F6P F16BP PEP G6P PDH Glycolysis (Skeletal Muscle) PDHPase PDHK PDH P F26BP HK ATP NADH ATP Cit F26BPase- PFK-2 F6P↑ F6P↓

17. PK PFK-1 Glc Acetyl-CoA Pyr F6P F16BP PEP G6P PDH PDHPase PDHK PDH P F26BP HK ATP NADH ATP Cit F26BPase P - PFK-2 F26BPase -PFK-2 PKA Ep Insulin AKT/WISK ??? Glycolysis (Heart)

18. F26BPase-PFK-2 Regulation Comparison F26BPase- PFK-2 F26BPase -PFK-2 P Insulin PrPase2A Glucagon Ep PKA Liver F26BPase- PFK-2 F6P↑ F6P↓ Skeletal Muscle F26BPase P - PFK-2 F26BPase -PFK-2 ??? PKA Ep Insulin AKT/WISK Heart

19. PK PFK-1 Glc Acetyl-CoA Pyr F6P F16BP PEP G6P PDH Fructose Metabolism (Liver) PDHPase PDHK PDH P F26BP F26BPase-PFK-2 F26BPase-PFK-2 P Insulin PrPase2A Glucagon Ep PKA GK ATP NADH ATP Cit GAP DHAP Fructose F1P Glyceraldehyde FK (KHK) Aldolase B Triose kinase

20. Gluconeogenesis (Liver) Glucagon PKA PK P F26BPase - PFK-2 F26BPase - PFK-2 P PKA PK PFK-1 GK G6Pase F16BPase PDHP PDHK PDH P PDH ATP NADH Glc Pyr F6P F16BP PEP G6P Protein MDH PEPCK Mal OAA PC MDH Mal OAA Mit Cyt PrPase2A Insulin Ala KB F26BP Cortisol CREB GR Acetyl-CoA TAG Lipolysis β-Oxidation FA HSL Ep, Glucagon, Cortisol Insulin

21. Gluconeogenesis (Liver) Glucagon PKA PK P F26BPase - PFK-2 F26BPase - PFK-2 P PKA PK PFK-1 GK G6Pase F16BPase PDHK PDH P PDH ATP NADH Glc Pyr F6P F16BP PEP G6P Protein MDH PEPCK Mal OAA PC MDH Mal OAA Mit Cyt Ala KB F26BP Cortisol CREB GR Acetyl-CoA TAG Lipolysis β-Oxidation FA HSL Ep, Glucagon, Cortisol

22. Gluconeogenesis (Liver) F26BPase - PFK-2 F26BPase - PFK-2 P PK PFK-1 GK G6Pase F16BPase PDHP PDH Glc Pyr F6P F16BP PEP G6P PEPCK OAA Mit Cyt PrPase2A Insulin F26BP Acetyl-CoA TAG HSL Insulin

23. Gluconeogenesis (Liver) Glucagon PKA PK P F26BPase - PFK-2 F26BPase - PFK-2 P PKA PK PFK-1 GK G6Pase F16BPase PDHP PDHK PDH P PDH ATP NADH Glc Pyr F6P F16BP PEP G6P Protein MDH PEPCK Mal OAA PC MDH Mal OAA Mit Cyt PrPase2A Insulin Ala KB F26BP Cortisol CREB GR Acetyl-CoA TAG Lipolysis β-Oxidation FA HSL Ep, Glucagon, Cortisol Insulin

24. Lipogenesis and Lipolysis (Adipose) Acetyl-CoA Pyr PK PFK-1 PDH PKA PK P F26BPase - PFK-2 F26BPase - PFK-2 P PKA PDHK ATP NADH PrPase2A Insulin Glc G6P GK PPP (NADPH) ACC MCoA FA Glycerol Acetyl-CoA KB Cit Acetyl-CoA PA TAG G3P Esterification HSL HSL P PrPase2A PDHP Insulin ACC P PrPase2A PKAAMPK Glucagon Cortisol Ep PKA

25. Lipogenesis and Lipolysis (Adipose) PK PFK-1 PDH PKA PK P F26BPase - PFK-2 F26BPase - PFK-2 P PKA Acetyl-CoA Pyr Glc G6P GK PPP (NADPH) FA Glycerol Acetyl-CoA KB ACC MCoA Acetyl-CoA TAG HSL HSL P PDHK ATP NADH PDH P ACC P PKAAMPK Glucagon Cortisol Ep PKA

26. Lipogenesis and Lipolysis (Adipose) Acetyl-CoA Pyr PK PFK-1 PDH F26BPase - PFK-2 F26BPase - PFK-2 P PrPase2A Insulin Glc G6P GK PPP (NADPH) ACC MCoA Glycerol Cit Acetyl-CoA PA TAG G3P Esterification HSL HSL P PrPase2A PDHP Insulin ACC P PrPase2A

27. Lipogenesis and Lipolysis (Adipose) Acetyl-CoA Pyr PK PFK-1 PDH PKA PK P F26BPase - PFK-2 F26BPase - PFK-2 P PKA PDHK ATP NADH PrPase2A Insulin Glc G6P GK PPP (NADPH) ACC MCoA FA Glycerol Acetyl-CoA KB Cit Acetyl-CoA PA TAG G3P Esterification HSL HSL P PrPase2A PDHP Insulin ACC P PrPase2A PKAAMPK Glucagon Cortisol Ep PKA

28. Impact of Diabetes on Metabolism Acetyl-CoALactate Production of ATP G6P Glucose Glycolysis Pyruvate Krebs cycle Electron Transport Chain Glycogen Glycogenolysis Fatty acids (TAG) β- Oxidation Ketone bodies Glycogenesis Gluconeogenesis Lipogenesis Amino acids (Protein) Lipolysis

29. Impact of Diabetes on Glycogen Glycogenolysis PPa P Glycogenesis Insulin (ML) IR Ep (ML) βAR cAMP Glucagon (L) GSGS Pn GSK-3 AKTPDK-1 AKT P PKA PPK PPK P GSK-3 P PPb PPa P PKAPPK P PrPase1 P PrPase1 Glc Glycogen G6P G1P UDP-Glc Glycolysis TCAETC Glycogen breakdown

30. Impact of Diabetes on Glycolysis (L) PK PFK-1 Glc Acetyl-CoA Pyr F6P F16BP PEP G6P PDH Alanine PDHPase PDHK PDH P PKA PK P F26BP F26BPase- PFK-2 F26BPase -PFK-2 P Insulin PrPase2A Glucagon PKA also represses PFK synthesis GK ATP NADH ATP Cit Glycolysis inhibition PrPase

31. Impact of Diabetes on Glycolysis (M) PK PFK-1 Glc Acetyl-CoA Pyr F6P F16BP PEP G6P PDH PDHPase PDHK PDH P F26BP HK ATP NADH ATP Cit F26BPase- PFK-2 F6P↑ F6P↓ Only impact is on GLUT4

32. Impact of Diabetes on Glycolysis (H) PK PFK-1 Glc Acetyl-CoA Pyr F6P F16BP PEP G6P PDH PDHPase PDHK PDH P F26BP HK ATP NADH ATP Cit F26BPase P - PFK-2 F26BPase -PFK-2 ??? PKA Ep Insulin AKT/WISK Heart uses more fatty acids

33. Impact of Diabetes on Gluconeogenesis (L) Glucagon PKA PK P F26BPase - PFK-2 F26BPase - PFK-2 P PKA PK PFK-1 GK G6Pase F16BPase PDHP PDHK PDH P PDH ATP NADH Glc Pyr F6P F16BP PEP G6P Protein MD H PEPCK Mal OAA PC MDH Mal OAA Mit Cyt PrPase2A Insulin Ala KB F26BP Cortisol CREB GR Acetyl-CoA TAG Lipolysis β-Oxidation FA HSL Ep, Glucagon, Cortisol Insulin More glucose, fatty acids, ketone bodies

34. Impact of Diabetes on Lipogenesis/Lypolysis (A) Acetyl-CoA Pyr PK PFK-1 PDH PKA PK P F26BPase - PFK-2 F26BPase - PFK-2 P PKA PDHK ATP NADH PrPase2A Insulin Glc G6P GK PPP (NADPH) ACC MCoA FA Glycerol Acetyl-CoA KB Cit Acetyl-CoA PA TAG G3P Esterification HSL HSL P PrPase2A PDHP Insulin ACC P PrPase2A PKAAMPK Glucagon Cortisol Ep PKA Increased fatty acids, ketone bodies, cholesterol

35. Liver  Well-fed Glucose to glycogen and triacylglycerols  Starvation Glucose from glycogen and gluconeogenesis Ketone bodies from amino acids and fatty acids  Diabetes Glucose from gluconeogenesis (muscle wasting) Ketone bodies from amino acids and fatty acids (DKA) Muscle  Well-fed Glucose to glycogen and triacylglycerols  Starvation Glucose from glycogen Alanine from protein  Diabetes Alanine from protein (muscle wasting) Adipocytes  Well-fed Glucose to glycogen and triacylglycerols  Starvation Fatty acids and glycerol from triacyglycerols  Diabetes Fatty acids and glycerol from triacylglycerols Pathway Pearls

36. Type 1 Insulins Amylinomimetics - postprandial glucagon release (Pramlintide acetate) Hypoglycemic antidotes – glycogenolysis and gluconeogenesis (Glucagon) Type 2 Biguanides - gluconeogenesis (Metformin) AMPK/AC Sulfonylureas - insulin secretion (Glyburide, Glipizide, Glimepiride) Meglitinides - insulin secretion (Repaglinide, Nateglinide) α-Glucosidase inhibitors - glucose absorption (Acarbose, Miglitol) Thiazolidinediones (glitazones) - fat cell differentiation/fatty acid metabolism (Rosiglitazone, Pioglitazone) PPAR Drug Classes

37. Type 2 Glucagonlike peptide-1 agonists - insulin release (Exenatide, Liraglutide, Albiglutide, Dulaglutide) Dipeptidyl peptidase IV inhibitors - insulin release (Sitagliptin, Saxagliptin, Linagliptin, Alogliptin) Amylinomimetics - postprandial glucagon release (Pramlintide acetate) Insulins Selective sodium-glucose transporter-2 inhibitors – renal glucose threshold (Canagliflozin, Dapagliflozin, Empagliflozin) Bile acid sequestrants – unknown glycemic mechanism (Colesevelam) Dopamine agonists – reset abnormally increased hypothalamic drive (Bromocriptine) Drug Classes

38. Review Questions Which steps in carbohydrate metabolism are regulated by glucagon, insulin, epinephrine, and cortisol? What are the roles of protein kinase A and protein phosphatase in regulating carbohydrate metabolism? Which steps in lipid metabolism are regulated by glucagon, insulin, epinephrine, and cortisol? What are the roles of AMPK, protein kinase A, and protein phosphatase in regulating lipid metabolism? What are the tissue differences in the regulation of metabolism? What are some key features associated with defects in glucose homeostasis?