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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?. Eric Niederhoffer SIU-SOM.

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Eric Niederhoffer SIU-SOM

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  1. 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? Eric Niederhoffer SIU-SOM

  2. 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 Regulation of Metabolism and Diabetes

  3. 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 Clinical Focus of Glucose Metabolism

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

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

  6. Glucose Homeostasis

  7. Ep(ML) Insulin (ML) βAR cAMP IR PKA PKA AKT PDK-1 PPKP PPK PPaP PPb GSK-3P AKTP PKA PPKP GSK-3 Glycogen GS Glycogenesis GSPn PPaP UDP-Glc PrPase1P Glycogenolysis G1P PrPase1 Glc G6P Glycolysis ETC TCA Glycogenesis and Glycogenolysis Glucagon (L)

  8. Insulin (ML) IR AKT PDK-1 GSK-3P AKTP GSK-3 Glycogen GS Glycogenesis GSPn UDP-Glc PrPase1P G1P PrPase1 Glc G6P Glycogenesis and Glycogenolysis

  9. Ep(ML) βAR cAMP PKA PKA PPKP PPK PPaP PPb PKA PPKP GSK-3 Glycogen GS Glycogenesis GSPn PPaP UDP-Glc Glycogenolysis G1P Glc G6P Glycolysis ETC TCA Glycogenesis and Glycogenolysis Glucagon (L)

  10. Ep(ML) Insulin (ML) βAR cAMP IR PKA PKA AKT PDK-1 PPKP PPK PPaP PPb GSK-3P AKTP PKA PPKP GSK-3 Glycogen GS Glycogenesis GSPn PPaP UDP-Glc PrPase1P Glycogenolysis G1P PrPase1 Glc G6P Glycolysis ETC TCA Glycogenesis and Glycogenolysis Glucagon (L)

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

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

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

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

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

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

  17. Ep Glc Insulin G6P F26BPase-PFK-2 PKA ??? AKT/WISK F6P F26BPaseP-PFK-2 F26BP F16BP ATP Cit PEP Pyr PDHK PDHP ATP NADH PDHPase Acetyl-CoA Glycolysis (Heart) HK PFK-1 PK PDH

  18. Glucagon Ep Insulin F26BPase-PFK-2P Liver PKA PrPase2A F26BPase-PFK-2 F26BPase-PFK-2 Skeletal Muscle F6P↑ F6P↓ F26BPase-PFK-2 Ep Insulin F26BPase-PFK-2 PKA Heart ??? AKT/WISK F26BPaseP-PFK-2 F26BPase-PFK-2 Regulation Comparison

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

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

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

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

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

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

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

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

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

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

  29. Impact of Diabetes on Glycogen Glycogen breakdown Ep(ML) Glucagon (L) Insulin (ML) βAR cAMP IR PKA PKA AKT PDK-1 PPKP PPK PPaP PPb GSK-3P AKTP PKA PPKP GSK-3 Glycogen GS Glycogenesis GSPn PPaP UDP-Glc PrPase1P Glycogenolysis G1P PrPase1 Glc G6P Glycolysis ETC TCA

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

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

  32. Impact of Diabetes on Glycolysis (H) Heart uses more fatty acids Ep Glc Insulin HK G6P F26BPase-PFK-2 PKA ??? AKT/WISK F6P F26BPaseP-PFK-2 PFK-1 F26BP F16BP ATP Cit PEP PK Pyr PDHK PDH PDHP ATP NADH PDHPase Acetyl-CoA

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

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

  35. Pathway Pearls • 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 from triacyglycerols • Diabetes • Fatty acids and glycerol from triacylglycerols

  36. Drug Classes • Type 1 • Insulins • Amylin analogs - postprandial glucagon release (Pramlintide acetate) • Type 2 • Sulfonylureas - insulin secretion (Glyburide, Glipizide, Glimepiride) • Meglitinides - insulin secretion (Repaglinide, Nateglinide) • Biguanides - gluconeogenesis (Metformin) AMPK/AC • α-Glucosidase inhibitors - glucose absorption (Acarbose, Miglitol) • Thiazolidinediones (glitazones) - fat cell differentiation/fatty acid metabolism (Rosiglitazone, Pioglitazone) PPAR • Incretin-mimetics - insulin release (Exenatide, Liraglutide • Dipeptidyl peptidase IV inhibitors - insulin release (Sitagliptin, Saxagliptin) • Insulins

  37. 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? Review Questions

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