The Regulation of Liver Glucose Production and Uptake

Transcription

1 The Regulation of Liver Glucose Production and Uptake Vanderbilt University Medical Center Nashville, TN USA Dale Edgerton, PhD An Organ Systems Approach to Experimental Targeting of the Metabolic Syndrome July 1, 11

2 DAILY PROFILE Ordinary Daily Life OGTT Diabetes Technol Ther. 9 Jul;11(7):57-6.

3 Int J Obes Relat Metab Disord. Sep;6 Suppl 3:S9-17. DAILY PROFILE

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5 MEASUREMENT OF PRODUCTION IN VIVO Tracer Method 3-3 H Glucose infusion Data analysis with two compartment model A-V Difference Method Blood glucose difference across organ Blood flow across organ

6 CALCULATIONS ([Portal]*BF P ) + ([Hepatic]*BF Total ) ([Arterial]*BF A )

7 MEASUREMENT OF GLUCONEOGENESIS AND GLYCOGENOLYSIS IN VIVO Glucose Production = Glycogenolysis + Gluconeogenesis Lactate Production Glucose Oxidation

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10 15 ARTERIAL ( mg/dl ) 1 5 ARTERIAL INSULIN ( U/ml ) 3 1 Glucagon Insulin ARTERIAL GLUCAGON ( pg/ml ) PRODUCTION ( mg/kg/min ) 3 1 } } GLY GNG

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12 EFFECT OF A SELECTIVE INCREASE IN INSULIN 1 Saline 1 Insulin Portal INSULIN ( U/ml ) 5 5 Arterial 1 1 GLUCAGON ( pg/ml ) 5 5 Portal Arterial

13 EFFECT OF A SELECTIVE INCREASE IN INSULIN +/- Insulin +/- Insulin 3 ARTERIAL ( mg/dl ) 1 GLY ( mg/kg/min) HEPATIC OUTPUT ( mg/kg/min) 1 Control Insulin GNG FLUX ( mg/kg/min)

14 EFFECT OF SELECTIVE INSULIN DEFICIENCY Saline Insulin INSULIN ( U/ml ) Art Portal 1 1 Portal GLUCAGON ( pg/ml ) 5 5 Arterial

15 EFFECT OF SELECTIVE INSULIN DEFICIENCY 3 +/- Insulin +/- Insulin 6 ARTERIAL ( mg/dl ) 1 GLY ( mg/kg/min) HEPATIC OUTPUT ( mg/kg/min) Control Insulin GNG FLUX ( mg/kg/min)

16 INSULIN AND PRODUCTION HEPATIC OUTPUT ( mg/kg/min ) PRODUCTION ( mg.m -.min -1 ) Dog 8 1 Basal HEPATIC SINUSOIDAL INSULIN ( U/ml ) ** Man 8 1 Basal ESTIMATED HEPATIC SINUSOIDAL INSULIN ( U/ml ) ** ( Redrawn from Holther-Nielsen et al.: Metabolism 5: 8-91, 1996 ) + ( Sherwin et al.: Journal of Clinical Endocrinology and Metabolism 5: , 1977 )

17 EFFECT OF A SELECTIVE INCREASE IN GLUCAGON Saline Glucagon 3 3 Portal INSULIN ( U/ml ) 1 1 Arterial Portal GLUCAGON ( pg/ml ) Arterial

18 EFFECT OF A SELECTIVE INCREASE IN GLUCAGON +/- Glucagon 8 +/- Glucagon ARTERIAL ( mg/dl ) GLY ( mg/kg/min) HEPATIC OUTPUT ( mg/kg/min) 8 6 Control Glucagon GNG FLUX ( mg/kg/min)

19 EFFECT OF SELECTIVE GLUCAGON DEFICIENCY 3 Saline 3 Glucagon INSULIN ( U/ml ) 1 1 Portal Arterial 1 1 GLUCAGON ( pg/ml ) 8 8 Portal Arterial

20 EFFECT OF SELECTIVE GLUCAGON DEFICIENCY +/- Glucagon 3 +/- Glucagon ARTERIAL ( mg/dl ) GLY ( mg/kg/min) 1 HEPATIC OUTPUT ( mg/kg/min) 3 1 Control Glucagon GNG FLUX ( mg/kg/min)

21 GLUCAGON VS PRODUCTION ( INSULIN BASAL AND FIXED ) PRODUCTION ( mg/kg/min ) 8 6 Human Dog Basal Level HEPATIC SINUSOIDAL GLUCAGON ( pg/ml )

22 CATECHOLAMINES AND STRESS 3 ARTERIAL EPINEPHRINE ( pg/ml ) ARTERIAL NOREPINEPHRINE ( pg/ml ) 8 6 Overnight Fast Moderate Exercise Infection Ketoacidosis Hypoglycemia ( mg/dl)

23 EFFECT OF A SELECTIVE INCREASE IN EPINEPHRINE 15 Saline 15 Epinephrine EPI ( pg/ml ) Arterial Portal 6 6 NOREPI ( pg/ml )

24 EFFECT OF A SELECTIVE INCREASE IN EPINEPHRINE ARTERIAL ( mg/dl ) 1 8 +/- Epinephrine +/- Epinephrine 3 GLY ( mg/kg/min) 1 HEPATIC OUTPUT ( mg/kg/min) 6 Epinephrine Control 3 GNG FLUX ( mg/kg/min)

25 EFFECT OF A SELECTIVE INCREASE IN SINUSOIDAL NOREPINEPHRINE Saline Norepinephrine EPI ( pg/ml ) Arterial Portal 6 6 NOREPI ( pg/ml ) Portal Arterial

26 EFFECT OF A SELECTIVE INCREASE IN SINUSOIDAL NOREPINEPHRINE +/- Portal Norepi +/- Portal Norepi ARTERIAL ( mg/dl ) GLY ( mg/kg/min) 3 1 HEPATIC OUTPUT ( mg/kg/min) 3 1 Portal Norepi Control GNG FLUX ( mg/kg/min)

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29 INSULIN AND AS STIMULATORS OF HEPATIC UPTAKE Peripheral Glucose Infusion BLOOD ( mg/dl ) Arterial Portal ARTERIAL INSULIN ( U/ml ) 6 Glucagon Insulin 6 ARTERIAL GLUCAGON ( pg/ml ) HEPATIC BALANCE ( mg/kg/min ) - - Output Uptake

30 OGTT IN THE CONSCIOUS DOG 5 Oral Glucose BLOOD ( mg/dl ) Arterial Portal ARTERIAL INSULIN ( U/ml ) Glucagon Insulin ARTERIAL GLUCAGON ( pg/ml ) HEPATIC BALANCE ( mg/kg/min ) - - Output Uptake

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32 EFFECT OF THE ROUTE OF ADMINISTRATION ON DISPOSITION IN THE BODY min Tracers and Indocyanine Green SRIF + Basal Portal Glucagon Basal Portal Insulin X Basal Portal Insulin + Peripheral Glucose Portal Glucose or Portal Glucose Peripheral Glucose

33 EFFECT OF THE ROUTE OF ADMINISTRATION ON DISPOSITION IN IN THE BODY 15 Artery Portal BLOOD ( mg/dl ) 1 5 C Pe Po Treatment Period

34 EFFECT EFFECT OF THE OF ROUTE THE ROUTE OF OF ADMINISTRATION DELIVERY ON DISPOSITION IN THE BODY ON HEPATIC UPTAKE 75 ARTERIAL INSULIN ( U/ml ) 3 1 HEPATIC LOAD ( mg/kg/min ) 5 5 ARTERIAL GLUCAGON ( pg/ml ) HEPATIC BALANCE ( mg/kg/min ) - - Uptake Output -6 Control Pe Po Control Pe Po

35 HEPATIC LOAD VS HEPATIC UPTAKE HEPATIC UPTAKE ( mg/kg/min ) HEPATIC Portal Signal Active Portal Signal Inactive HEPATIC LOAD

36 INSULIN VS HEPATIC UPTAKE IN THE PRESENCE OF BASAL GLUCAGON AND A X BASAL HEPATIC LOAD HEPATIC UPTAKE ( mg/kg/min ) 8 6 Portal Signal Active Portal Signal Inactive HEPATIC SINUSOIDAL INSULIN ( U/ml )

37 ARTERIAL-PORTAL GRADIENT VS HEPATIC UPTAKE IN THE PRESENCE OF BASAL GLUCAGON, X BASAL INSULIN AND X BASAL HEPATIC LOAD 8 HEPATIC UPTAKE ( mg/kg/min ) ARTERIAL - PORTAL BLOOD GRADIENT ( mg/dl )

38 EFFECT OF GLUCAGON ON HEPATIC UPTAKE Min Peripheral Somatostatin Basal Portal Ins+GGN Portal Insulin (-Fold Basal ) Portal Glucose ( 3.8 mg/kg/min ) Peripheral Glucose ( to double HGL ) Hi GGN ( n=6 ) Lo GGN ( n=6 ) + Portal Glucagon ( ng/kg/min ) 1. Or Portal Glucagon ( ng/kg/min ).3.5.

39 ARTERIAL BLOOD ( mg/dl ) ARTERIAL INSULIN ( U/ml ) ARTERIAL GLUCAGON ( pg/ml ) Glucose Infusion Hormone Manipulation High GGN Low GGN

40 HEPATIC LOAD ( mg/kg/min ) TOTAL INFUSION ( mg/kg/min ) HEPATIC BALANCE ( mg/kg/min ) High GGN Low GGN Output Uptake Glucose Infusion Hormone Manipulation