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regulation of metabolism and diabetes

Regulation of Metabolism and Diabetes. Clinical focus of glucose metabolismPathways overviewTissues overviewGlucose homeostasisInsulin, glucagon, AMP kinase, PPAR signalingRegulation of carbohydrate metabolismGlycogenesis, glycogenolysis, glycolysis, gluconeogenesisRegulation of fats metabolismLipogenesis, lypolysisImpact of diabetes on metabolismPathway pearlsDrug classesReview questions.

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regulation of metabolism and diabetes

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    2. Regulation of Metabolism and Diabetes Clinical focus of glucose metabolism Pathways overview Tissues overview Glucose homeostasis Insulin, glucagon, AMP kinase, PPAR signaling Regulation of carbohydrate metabolism Glycogenesis, glycogenolysis, glycolysis, 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 Type 1: autoimmune origin (ß-cell destruction), DKA common Type 2: later onset, multiple causes MODY: at least 9 types involving (1) hepatocyte nuclear factor 4a, (2) glucokinase, (3) hepatocyte nuclear factor 1a, (4) insulin promoter factor-1, (5) hepatocyte nuclear factor 1ß = transcription factor-2, (6) neurogenic differentiation 1, (7) Kruppel-like factor 11, (8) Bile salt dependent lipase, (9) PAX4 = transcription factors.Type 1: autoimmune origin (ß-cell destruction), DKA common Type 2: later onset, multiple causes MODY: at least 9 types involving (1) hepatocyte nuclear factor 4a, (2) glucokinase, (3) hepatocyte nuclear factor 1a, (4) insulin promoter factor-1, (5) hepatocyte nuclear factor 1ß = transcription factor-2, (6) neurogenic differentiation 1, (7) Kruppel-like factor 11, (8) Bile salt dependent lipase, (9) PAX4 = transcription factors.

    4. Pathways Overview G6P: glucose-6-phosphate TGA: triacylglycerol ATP: adenosine triphosphate Color coding on pathway slides: red lettering or line arrow indicates inhibition, green lettering or line arrow indicates activationG6P: glucose-6-phosphate TGA: triacylglycerol ATP: adenosine triphosphate Color coding on pathway slides: red lettering or line arrow indicates inhibition, green lettering or line arrow indicates activation

    5. Tissues Overview Liver is primarily responsible for glucose maintenance. Skeletal muscle contributes alanine to liver for gluconeogenesis. Adipose tissue donates fatty acids to liver for ketogenesis. Red blood cells, retina, and kidney donate lactate to liver for gluconeogenesis (Cori cycle).Liver is primarily responsible for glucose maintenance. Skeletal muscle contributes alanine to liver for gluconeogenesis. Adipose tissue donates fatty acids to liver for ketogenesis. Red blood cells, retina, and kidney donate lactate to liver for gluconeogenesis (Cori cycle).

    6. Glucose Homeostasis Absorptive phase I: first 3 hours Post absorptive phase: 3 to 14 hours Early starvation III: 14 to 28 hours Intermediate starvation IV: 28 hours to 16 days Prolonged starvation V: more than 16 days Note that gluconeogenesis and ketone body formation occur simultaneouslyAbsorptive phase I: first 3 hours Post absorptive phase: 3 to 14 hours Early starvation III: 14 to 28 hours Intermediate starvation IV: 28 hours to 16 days Prolonged starvation V: more than 16 days Note that gluconeogenesis and ketone body formation occur simultaneously

    7. Insulin Signaling For more information concerning the insulin signaling pathway see: http://www.abcam.com/index.html?pageconfig=resource&rid=10602&pid=7.For more information concerning the insulin signaling pathway see: http://www.abcam.com/index.html?pageconfig=resource&rid=10602&pid=7.

    8. Glucagon Signaling Glucagon and insulin are peptide hormones released from the pancreas into the blood, that normally act in complementary fashion to stabilize blood glucose concentration. For more information see: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&FOCUS_SPECIES=Homo%20sapiens&ID=163359&.Glucagon and insulin are peptide hormones released from the pancreas into the blood, that normally act in complementary fashion to stabilize blood glucose concentration. For more information see: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&FOCUS_SPECIES=Homo%20sapiens&ID=163359&.

    9. AMP Kinase Signaling AMP-activated protein kinase (AMPK) plays a key role as a master regulator of cellular energy homeostasis (turns up energy production, down energy consumption). Phosphorylates (inhibits) glycogen synthase, acetyl-CoA carboxylase, 3-hydroxy-3-methylglutaryl-CoA reductase; (activates) phosphofructokinase-2 (liver-opposite of PKA action and heart; serves to increase glycolysis). For more information see: http://www.cellsignal.com/reference/pathway/AMPK.html.AMP-activated protein kinase (AMPK) plays a key role as a master regulator of cellular energy homeostasis (turns up energy production, down energy consumption). Phosphorylates (inhibits) glycogen synthase, acetyl-CoA carboxylase, 3-hydroxy-3-methylglutaryl-CoA reductase; (activates) phosphofructokinase-2 (liver-opposite of PKA action and heart; serves to increase glycolysis). For more information see: http://www.cellsignal.com/reference/pathway/AMPK.html.

    10. PPAR Signaling PPARs (Peroxisome Proliferator-Activated Receptors) are ligand-inducible transcription factors that belong to the nuclear hormone receptor superfamily, together with the receptors for thyroid hormone, retinoids, steroid hormones and vitamin D that act as ligand-activated transcription factors. For more information see: http://www.sabiosciences.com/pathway.php?sn=PPAR_PathwayPPARs (Peroxisome Proliferator-Activated Receptors) are ligand-inducible transcription factors that belong to the nuclear hormone receptor superfamily, together with the receptors for thyroid hormone, retinoids, steroid hormones and vitamin D that act as ligand-activated transcription factors. For more information see: http://www.sabiosciences.com/pathway.php?sn=PPAR_Pathway

    11. Glycogenesis and Glycogenolysis Activated Inhibited M: muscle L: liver Ep: epinephrine ßAR: ß adrenergic receptor PKA: protein kinase A cAMP: cyclic adenosine monophosphate PPK: phosphorylase kinase PP: phosphorylase UDP: uridinediphosphate Glc: glucose G6P: glucose-6-phosphate G1P: glucose-1-phosphate GS: glycogen synthase GSK: glycogen synthase kinase PrPase: protein phosphatase TCA: tricarboxylic acid cycle ETC: electron transport chain Glycogen stored in muscles (low % but high total), liver (high %), erythrocytes, white blood cells, glial cells, kidneys, uterus. Two genes, GYS1 (muscle), GYS2 (liver) G6P regulates GSP (inactive form) AMPK phosphorylates (inhibits) GS PrPase1p will inactivate PPKp and Ppap. Cortisol preserves glycogen stores in liver but not muscle.Activated Inhibited M: muscle L: liver Ep: epinephrine ßAR: ß adrenergic receptor PKA: protein kinase A cAMP: cyclic adenosine monophosphate PPK: phosphorylase kinase PP: phosphorylase UDP: uridinediphosphate Glc: glucose G6P: glucose-6-phosphate G1P: glucose-1-phosphate GS: glycogen synthase GSK: glycogen synthase kinase PrPase: protein phosphatase TCA: tricarboxylic acid cycle ETC: electron transport chain Glycogen stored in muscles (low % but high total), liver (high %), erythrocytes, white blood cells, glial cells, kidneys, uterus. Two genes, GYS1 (muscle), GYS2 (liver) G6P regulates GSP (inactive form) AMPK phosphorylates (inhibits) GS PrPase1p will inactivate PPKp and Ppap. Cortisol preserves glycogen stores in liver but not muscle.

    12. Glycolysis: Regulatory Steps Glc: glucose G6P: glucose-6-phosphate F6P: fructose-6-phosphate F16BP: fructose-1,6-bisphosphate PEP: phosphoenolpyruvate Pyr: pyruvate PDH: pyruvate dehydrogenase GK: glucokinase HK: hexokinase PFK: phosphofructokinase F26BPase: fructose-2,6-bisphosphatase PK: pyruvate kinase PDH: pyruvate dehdrogenase Ep: epinephrine Glc: glucose G6P: glucose-6-phosphate F6P: fructose-6-phosphate F16BP: fructose-1,6-bisphosphate PEP: phosphoenolpyruvate Pyr: pyruvate PDH: pyruvate dehydrogenase GK: glucokinase HK: hexokinase PFK: phosphofructokinase F26BPase: fructose-2,6-bisphosphatase PK: pyruvate kinase PDH: pyruvate dehdrogenase Ep: epinephrine

    13. Glycolysis (Liver) PKA: protein kinase A Glc: glucose GK: glucokinase F6P: fructose-6-phosphate G6P: glucose-6-phosphate Cit: citrate PDH: pyruvate dehydrogenase ATP: adenosine triphosphate PFK: phosphofructokinase F16BP: fructose-1,6-bisphosphate F26BP: fructose-2,6-bisphosphate PEP: phosphoenolpyruvate Pyr: pyruvate PK: pyruvate kinase Ep: epinephrine NADH: nicotinamide adenine dinucleotide .Activated Inhibited PDHPase (or K): pyruvate dehdrogenase phosphatase (or kinase) GK regulatory protein (GKRP) anchors GK in nucleus in presence of fructose-6-phosphate, released by fructose-1-phosphate or high glucose, AMPK inhibits GKRP. In adipose and hepatic tissue, insulin activates PDHPase PrPase: protein phosphatasePKA: protein kinase A Glc: glucose GK: glucokinase F6P: fructose-6-phosphate G6P: glucose-6-phosphate Cit: citrate PDH: pyruvate dehydrogenase ATP: adenosine triphosphate PFK: phosphofructokinase F16BP: fructose-1,6-bisphosphate F26BP: fructose-2,6-bisphosphate PEP: phosphoenolpyruvate Pyr: pyruvate PK: pyruvate kinase Ep: epinephrine NADH: nicotinamide adenine dinucleotide .Activated Inhibited PDHPase (or K): pyruvate dehdrogenase phosphatase (or kinase) GK regulatory protein (GKRP) anchors GK in nucleus in presence of fructose-6-phosphate, released by fructose-1-phosphate or high glucose, AMPK inhibits GKRP. In adipose and hepatic tissue, insulin activates PDHPase PrPase: protein phosphatase

    14. Glycolysis (Skeletal Muscle) Activated Inhibited Glc: glucose HK: hexokinase G6P: glucose-6-phosphate F6P: fructose-6-phosphate PEP: phosphoenolpyruvate Cit: citrate PDH: pyruvate dehydrogenase ATP: adenosine triphosphate PFK: phosphofructokinase F16BP: fructose-1,6-bisphosphate F26BP: fructose-2,6-bisphosphate Pyr: pyruvate PK: pyruvate kinase NADH: nicotinamide adenine dinucleotide PDHPase (or K): pyruvate dehdrogenase phosphatase (or kinase)Activated Inhibited Glc: glucose HK: hexokinase G6P: glucose-6-phosphate F6P: fructose-6-phosphate PEP: phosphoenolpyruvate Cit: citrate PDH: pyruvate dehydrogenase ATP: adenosine triphosphate PFK: phosphofructokinase F16BP: fructose-1,6-bisphosphate F26BP: fructose-2,6-bisphosphate Pyr: pyruvate PK: pyruvate kinase NADH: nicotinamide adenine dinucleotide PDHPase (or K): pyruvate dehdrogenase phosphatase (or kinase)

    15. Glycolysis (Heart) Activated Inhibited Glc: glucose HK: hexokinase G6P: glucose-6-phosphate F6P: fructose-6-phosphate PEP: phosphoenolpyruvate Cit: citrate PDH: pyruvate dehydrogenase ATP: adenosine triphosphate PFK: phosphofructokinase F16BP: fructose-1,6-bisphosphate F26BP: fructose-2,6-bisphosphate Pyr: pyruvate PK: pyruvate kinase Ep: epinephrine PKA: protein kinase A PDHPase (or K): pyruvate dehdrogenase phosphatase (or kinase) NADH: nicotinamide adenine dinucleotide ???: protein phosphatase 2A possiblyActivated Inhibited Glc: glucose HK: hexokinase G6P: glucose-6-phosphate F6P: fructose-6-phosphate PEP: phosphoenolpyruvate Cit: citrate PDH: pyruvate dehydrogenase ATP: adenosine triphosphate PFK: phosphofructokinase F16BP: fructose-1,6-bisphosphate F26BP: fructose-2,6-bisphosphate Pyr: pyruvate PK: pyruvate kinase Ep: epinephrine PKA: protein kinase A PDHPase (or K): pyruvate dehdrogenase phosphatase (or kinase) NADH: nicotinamide adenine dinucleotide ???: protein phosphatase 2A possibly

    16. F26BPase-PFK-2 Regulation Comparison Activated Inhibited F6P: fructose-6-phosphate PFK: phosphofructokinase F26BPase: fructose-2,6-bisphosphatase Ep: epinephrine PKA: protein kinase A ???: protein phosphatase possibly PrPase: protein phosphatase Activated Inhibited F6P: fructose-6-phosphate PFK: phosphofructokinase F26BPase: fructose-2,6-bisphosphatase Ep: epinephrine PKA: protein kinase A ???: protein phosphatase possibly PrPase: protein phosphatase

    17. Gluconeogenesis Glc: glucose GK: glucokinase G6Pase: glucose-6-phosphatase F6P: fructose-6-phosphate PFK: phosphofructokinase F16BP: fructose-1,6-bisphosphate PEP: phosphoenolpyruvate PK: pyruvate kinase Pyr: pyruvate PDH: pyruvate dehydrogenase NAD+/NADH: nicotinamide adenine dinucleotide MDH: malate dehydrogenase OAA: oxaloacetate PC: pyruvate carboxylase LDH: lactate dehydrogenase PEPCK: phosphoenolpyruvate carboxykinase F16BPase: fructose-1,6-bisphosphatase G6Pase: glucose-6-phosphatase Ala: alanine TGA: triacylglycerol HSL: hormone sensitive lipase FA: fatty acid KB: ketone bodies Mal: malate PDHPase (or K): pyruvate dehdrogenase phosphatase (or kinase) MDH: malate dehydrogenase GR: glucocorticoid receptor CREB: cAMP response element-binding PrPase: protein phosphatase PKA: protein kinase A Insulin inhibits gene expression of PEPCK, glucagon (CREB), cortisol, (GR) retinoic acid enhance gene expression of PEPCK. Glycerol from TGA and lactate from glycolysis can be used for Glc synthesis in liver. Activated InhibitedGlc: glucose GK: glucokinase G6Pase: glucose-6-phosphatase F6P: fructose-6-phosphate PFK: phosphofructokinase F16BP: fructose-1,6-bisphosphate PEP: phosphoenolpyruvate PK: pyruvate kinase Pyr: pyruvate PDH: pyruvate dehydrogenase NAD+/NADH: nicotinamide adenine dinucleotide MDH: malate dehydrogenase OAA: oxaloacetate PC: pyruvate carboxylase LDH: lactate dehydrogenase PEPCK: phosphoenolpyruvate carboxykinase F16BPase: fructose-1,6-bisphosphatase G6Pase: glucose-6-phosphatase Ala: alanine TGA: triacylglycerol HSL: hormone sensitive lipase FA: fatty acid KB: ketone bodies Mal: malate PDHPase (or K): pyruvate dehdrogenase phosphatase (or kinase) MDH: malate dehydrogenase GR: glucocorticoid receptor CREB: cAMP response element-binding PrPase: protein phosphatase PKA: protein kinase A Insulin inhibits gene expression of PEPCK, glucagon (CREB), cortisol, (GR) retinoic acid enhance gene expression of PEPCK. Glycerol from TGA and lactate from glycolysis can be used for Glc synthesis in liver. Activated Inhibited

    18. Lipogenesis and Lipolysis Glc: glucose G6P: glucose-6-phosphate Pyr: pyruvate Cit: citrate GK: glucokinase PK: pyruvate kinase PFK: phosphofructokinase PDH: pyruvate dehydrogenase F26BPase: fructose-2,6-bisphosphatase PKA: protein kinase A Ep: epinephrine HSL: hormone sensitive lipase PrPase: protein phosphatase TGA: triacylglycerol G3P: glycerol-3-phosphate PA: palmitic acid MCoA: malonyl-CoA AMPK: AMP kinase ACC: acetyl-CoA carboxylase KB: ketone bodies ATP: adenosine triphosphate FA: fatty acid NADH: nicotinamide adenine dinucleotide PDHPase (or K): pyruvate dehdrogenase phosphatase (or kinase) 6-Phosphgluconate from PPP will activate pyruvate kinase Activated InhibitedGlc: glucose G6P: glucose-6-phosphate Pyr: pyruvate Cit: citrate GK: glucokinase PK: pyruvate kinase PFK: phosphofructokinase PDH: pyruvate dehydrogenase F26BPase: fructose-2,6-bisphosphatase PKA: protein kinase A Ep: epinephrine HSL: hormone sensitive lipase PrPase: protein phosphatase TGA: triacylglycerol G3P: glycerol-3-phosphate PA: palmitic acid MCoA: malonyl-CoA AMPK: AMP kinase ACC: acetyl-CoA carboxylase KB: ketone bodies ATP: adenosine triphosphate FA: fatty acid NADH: nicotinamide adenine dinucleotide PDHPase (or K): pyruvate dehdrogenase phosphatase (or kinase) 6-Phosphgluconate from PPP will activate pyruvate kinase Activated Inhibited

    19. Impact of Diabetes on Metabolism G6P: glucose-6-phosphate TGA: triacylglycerol ATP: adenosine triphosphate High glucose leads to sorbitol production, osmotic stress leading to neuropathy, nephropathy, retinopathy High lipids cycling leads to high cholesterolG6P: glucose-6-phosphate TGA: triacylglycerol ATP: adenosine triphosphate High glucose leads to sorbitol production, osmotic stress leading to neuropathy, nephropathy, retinopathy High lipids cycling leads to high cholesterol

    20. Impact of Diabetes on Glycogen M: muscle L: liver Ep: epinephrine ßAR: ß adrenergic receptor cAMP: cyclic adenosine monophosphate PKA: protein kinase A PPK: phosphorylase kinase PP: phosphorylase UDP: uridinediphosphate Glc: glucose G6P: glucose-6-phosphate G1P: glucose-1-phosphate GS: glycogen synthase GSK: glycogen synthase kinase PrPase: protein phosphatase TCA: tricarboxylic acid cycle ETC: electron transport chain Glycogen stored in muscles (low % but high total), liver (high %), erythrocytes, white blood cells, glial cells, kidneys, uterus. Activated Inhibited Two genes, GYS1 (muscle), GYS2 (liver) G6P regulates GSP (inactive form)M: muscle L: liver Ep: epinephrine ßAR: ß adrenergic receptor cAMP: cyclic adenosine monophosphate PKA: protein kinase A PPK: phosphorylase kinase PP: phosphorylase UDP: uridinediphosphate Glc: glucose G6P: glucose-6-phosphate G1P: glucose-1-phosphate GS: glycogen synthase GSK: glycogen synthase kinase PrPase: protein phosphatase TCA: tricarboxylic acid cycle ETC: electron transport chain Glycogen stored in muscles (low % but high total), liver (high %), erythrocytes, white blood cells, glial cells, kidneys, uterus. Activated Inhibited Two genes, GYS1 (muscle), GYS2 (liver) G6P regulates GSP (inactive form)

    21. Impact of Diabetes on Glycolysis (L) PKA: protein kinase A Glc: glucose GK: glucokinase F6P: fructose-6-phosphate G6P: glucose-6-phosphate Cit: citrate PDH: pyruvate dehydrogenase ATP: adenosine triphosphate PFK: phosphofructokinase F16BP: fructose-1,6-bisphosphate F26BP: fructose-2,6-bisphosphate PEP: phosphoenolpyruvate Pyr: pyruvate PK: pyruvate kinase NADH: nicotinamide adenine dinucleotide PDHPase (or K): pyruvate dehdrogenase phosphatase (or kinase) PrPPase: protein phosphatase GK regulatory protein (GKRP) anchors GK in nucleus in presence of fructose-6-phosphate, released by fructose-1-phosphate or high glucose, AMPK inhibits GKRP. In adipose and hepatic tissue, insulin activates PDHPase. Activated InhibitedPKA: protein kinase A Glc: glucose GK: glucokinase F6P: fructose-6-phosphate G6P: glucose-6-phosphate Cit: citrate PDH: pyruvate dehydrogenase ATP: adenosine triphosphate PFK: phosphofructokinase F16BP: fructose-1,6-bisphosphate F26BP: fructose-2,6-bisphosphate PEP: phosphoenolpyruvate Pyr: pyruvate PK: pyruvate kinase NADH: nicotinamide adenine dinucleotide PDHPase (or K): pyruvate dehdrogenase phosphatase (or kinase) PrPPase: protein phosphatase GK regulatory protein (GKRP) anchors GK in nucleus in presence of fructose-6-phosphate, released by fructose-1-phosphate or high glucose, AMPK inhibits GKRP. In adipose and hepatic tissue, insulin activates PDHPase. Activated Inhibited

    22. Impact of Diabetes on Glycolysis (SM) Activated Inhibited Glc: glucose HK: hexokinase G6P: glucose-6-phosphate F6P: fructose-6-phosphate PEP: phosphoenolpyruvate Cit: citrate PDH: pyruvate dehydrogenase ATP: adenosine triphosphate PFK: phosphofructokinase F16BP: fructose-1,6-bisphosphate F26BP: fructose-2,6-bisphosphate Pyr: pyruvate PK: pyruvate kinase NADH: nicotinamide adenine dinucleotide PDHPase (or K): pyruvate dehdrogenase phosphatase (or kinase)Activated Inhibited Glc: glucose HK: hexokinase G6P: glucose-6-phosphate F6P: fructose-6-phosphate PEP: phosphoenolpyruvate Cit: citrate PDH: pyruvate dehydrogenase ATP: adenosine triphosphate PFK: phosphofructokinase F16BP: fructose-1,6-bisphosphate F26BP: fructose-2,6-bisphosphate Pyr: pyruvate PK: pyruvate kinase NADH: nicotinamide adenine dinucleotide PDHPase (or K): pyruvate dehdrogenase phosphatase (or kinase)

    23. Impact of Diabetes on Glycolysis (H) Glc: glucose HK: hexokinase G6P: glucose-6-phosphate F6P: fructose-6-phosphate PEP: phosphoenolpyruvate Cit: citrate PDH: pyruvate dehydrogenase ATP: adenosine triphosphate PFK: phosphofructokinase F16BP: fructose-1,6-bisphosphate F26BP: fructose-2,6-bisphosphate Pyr: pyruvate PK: pyruvate kinase Ep: epinephrine PKA: protein kinase A Activated Inhibited PDHPase (or K): pyruvate dehdrogenase phosphatase (or kinase) NADH: nicotinamide adenine dinucleotide ???: protein phosphatase possiblyGlc: glucose HK: hexokinase G6P: glucose-6-phosphate F6P: fructose-6-phosphate PEP: phosphoenolpyruvate Cit: citrate PDH: pyruvate dehydrogenase ATP: adenosine triphosphate PFK: phosphofructokinase F16BP: fructose-1,6-bisphosphate F26BP: fructose-2,6-bisphosphate Pyr: pyruvate PK: pyruvate kinase Ep: epinephrine PKA: protein kinase A Activated Inhibited PDHPase (or K): pyruvate dehdrogenase phosphatase (or kinase) NADH: nicotinamide adenine dinucleotide ???: protein phosphatase possibly

    24. Impact of Diabetes on Gluconeogenesis Glc: glucose GK: glucokinase G6Pase: glucose-6-phosphatase F6P: fructose-6-phosphate PFK: phosphofructokinase F16BP: fructose-1,6-bisphosphate PEP: phosphoenolpyruvate PK: pyruvate kinase Pyr: pyruvate PDH: pyruvate dehydrogenase NAD+/NADH: nicotinamide adenine dinucleotide MDH: malate dehydrogenase OAA: oxaloacetate PC: pyruvate carboxylase LDH: lactate dehydrogenase PEPCK: phosphoenolpyruvate carboxykinase F16BPase: fructose-1,6-bisphosphatase G6Pase: glucose-6-phosphatase Ala: alanine TGA: triacylglycerol HSL: hormone sensitive lipase FA: fatty acid KB: ketone bodies Mal: malate PDHPase (or K): pyruvate dehdrogenase phosphatase (or kinase) MDH: malate dehydrogenase GR: glucocorticoid receptor CREB: cAMP response element-binding PrPase: protein phosphatase PKA: protein kinase A Insulin inhibits gene expression of PEPCK, glucagon (CREB), cortisol, (GR) retinoic acid enhance gene expression of PEPCK. Glycerol from TGA and lactate from glycolysis can be used for Glc synthesis in liver. Activated InhibitedGlc: glucose GK: glucokinase G6Pase: glucose-6-phosphatase F6P: fructose-6-phosphate PFK: phosphofructokinase F16BP: fructose-1,6-bisphosphate PEP: phosphoenolpyruvate PK: pyruvate kinase Pyr: pyruvate PDH: pyruvate dehydrogenase NAD+/NADH: nicotinamide adenine dinucleotide MDH: malate dehydrogenase OAA: oxaloacetate PC: pyruvate carboxylase LDH: lactate dehydrogenase PEPCK: phosphoenolpyruvate carboxykinase F16BPase: fructose-1,6-bisphosphatase G6Pase: glucose-6-phosphatase Ala: alanine TGA: triacylglycerol HSL: hormone sensitive lipase FA: fatty acid KB: ketone bodies Mal: malate PDHPase (or K): pyruvate dehdrogenase phosphatase (or kinase) MDH: malate dehydrogenase GR: glucocorticoid receptor CREB: cAMP response element-binding PrPase: protein phosphatase PKA: protein kinase A Insulin inhibits gene expression of PEPCK, glucagon (CREB), cortisol, (GR) retinoic acid enhance gene expression of PEPCK. Glycerol from TGA and lactate from glycolysis can be used for Glc synthesis in liver. Activated Inhibited

    25. Impact of Diabetes on Lipogenesis/Lypolysis Activated Inhibited Glc: glucose G6P: glucose-6-phosphate Pyr: pyruvate Cit: citrate GK: glucokinase PK: pyruvate kinase PFK: phosphofructokinase PDH: pyruvate dehydrogenase F26BPase: fructose-2,6-bisphosphatase PKA: protein kinase A Ep: epinephrine HSL: hormone sensitive lipase PrPase: protein phosphatase TGA: triacylglycerol G3P: glycerol-3-phosphate PA: palmitic acid MCoA: malonyl-CoA AMPK: AMP kinase ACC: acetyl-CoA carboxylase KB: ketone bodies ATP: adenosine triphosphate FA: fatty acid NADH: nicotinamide adenine dinucleotide PDHPase (or K): pyruvate dehdrogenase phosphatase (or kinase) PrPase: protein phosphataseActivated Inhibited Glc: glucose G6P: glucose-6-phosphate Pyr: pyruvate Cit: citrate GK: glucokinase PK: pyruvate kinase PFK: phosphofructokinase PDH: pyruvate dehydrogenase F26BPase: fructose-2,6-bisphosphatase PKA: protein kinase A Ep: epinephrine HSL: hormone sensitive lipase PrPase: protein phosphatase TGA: triacylglycerol G3P: glycerol-3-phosphate PA: palmitic acid MCoA: malonyl-CoA AMPK: AMP kinase ACC: acetyl-CoA carboxylase KB: ketone bodies ATP: adenosine triphosphate FA: fatty acid NADH: nicotinamide adenine dinucleotide PDHPase (or K): pyruvate dehdrogenase phosphatase (or kinase) PrPase: protein phosphatase

    26. Pathway Pearls DKA: diabetic ketoacidosisDKA: diabetic ketoacidosis

    27. Drug Classes Thiazolidinediones (glitazones) appear to act through PPAP? pathway Metformin appears to act through AMPK activating tuberous sclerosis complex (TSC) proteins, which disables mammalian target of rapamycin (mTOR) or newer theory has AMPK acting through RAG GTPase to disable mTORThiazolidinediones (glitazones) appear to act through PPAP? pathway Metformin appears to act through AMPK activating tuberous sclerosis complex (TSC) proteins, which disables mammalian target of rapamycin (mTOR) or newer theory has AMPK acting through RAG GTPase to disable mTOR

    28. 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?

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