Post on 24-Feb-2016
description
transcript
Eric NiederhofferSIU-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?
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 metabolismLipogenesis, lypolysis
• Impact of diabetes on metabolism• Pathway pearls• Drug classes• Review questions
Clinical Focus of Glucose Metabolism
• Glucose intoleranceType 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
Acetyl-CoALactate
Production of ATP
G6P
Glucose
Glycolysis
Pyruvate
Krebscycle
ElectronTransport
Chain
GlycogenGlycogenolysis
Fatty acids(TAG)
β-Oxidation
Ketone bodies
Pathways Overview
Glycogenesis
Gluconeogenesis
Lipogenesis
Amino acids
(Protein)
Lipolysis
GlycogenesisGlycogenolysis
GlycolysisLipogenesis
Lipolysisβ-Oxidation
GlycogenesisGlycogenolysis
GlycolysisGluconeogenesi
sLipogenesis
Lipolysisβ-OxidationKetogenesis
GlycogenesisGlycogenolysis
Glycolysisβ-Oxidation
GlycogenesisGlycogenolysis
Glycolysisβ-Oxidation
Tissues Overview
Blood GlucoseSerum Triglycerides
GlycogenesisGlycogenolysis
GlycolysisGluconeogenesi
sβ-Oxidation
Liver AdiposeTissue Kidney
Heart SkeletalMuscle
Glucose Homeostasis
Glycogenesis and GlycogenolysisInsulin (ML)
IR
Ep (ML)βAR
cAMP
Glucagon (L)
GS GSPn
GSK-3
AKT PDK-1
AKTP
PKA PKAPPK PPKP
GSK-3P
PPaP
PPb PPaP
PKA PPKP
PrPase1P
PrPase1
Glycogenesis
Glc
Glycogen
G6P
G1P
UDP-GlcGlycogenolysis
Glycolysis
TCAETC
Glycogenesis and GlycogenolysisInsulin (ML)
IR
GS GSPn
GSK-3
AKT PDK-1
AKTP
GSK-3P
PrPase1P
PrPase1
Glycogenesis
Glc
Glycogen
G6P
G1P
UDP-Glc
Glycogenesis and GlycogenolysisEp (ML)
βARcAMP
Glucagon (L)
GS GSPn
GSK-3
PKA PKAPPK PPKP
PPaP
PPb PPaP
PKA PPKP
Glycogenesis
Glc
Glycogen
G6P
G1P
UDP-GlcGlycogenolysis
Glycolysis
TCAETC
Glycogenesis and GlycogenolysisInsulin (ML)
IR
Ep (ML)βAR
cAMP
Glucagon (L)
GS GSPn
GSK-3
AKT PDK-1
AKTP
PKA PKAPPK PPKP
GSK-3P
PPaP
PPb PPaP
PKA PPKP
PrPase1P
PrPase1
Glycogenesis
Glc
Glycogen
G6P
G1P
UDP-GlcGlycogenolysis
Glycolysis
TCAETC
PK
PFK-1
Glc
Acetyl-CoA
Pyr
F6P
F16BP
PEP
G6P
PDH
F26BPasePFK-2
Glycolysis: Regulatory Steps
HK
InsulinGlucagon
Ep
Adipose
HeartLiver
GK
Liver
Liver
Liver
Heart
PK
PFK-1
Glc
Acetyl-CoA
Pyr
F6P
F16BP
PEP
G6P
PDH
Glycolysis (Liver)
Alanine
PDHPase
PDHK
PDHP
PKAPKP
F26BP
F26BPase-PFK-2
F26BPase-PFK-2P
Insulin
PrPase2A
GlucagonEp
PKA
also represses PFK synthesis
GK
ATPNADH
ATPCit
PrPase
PK
PFK-1
Glc
Acetyl-CoA
Pyr
F6P
F16BP
PEP
G6P
PDH
Glycolysis (Liver)
PDHPase
PDHK
PDHP
F26BP
F26BPase-PFK-2
F26BPase-PFK-2P
Insulin
PrPase2A
GK
ATPCit
PrPase
PK
PFK-1
Glc
Acetyl-CoA
Pyr
F6P
F16BP
PEP
G6P
PDH
Glycolysis (Liver)
Alanine
PDHK
PDHP
PKAPKP
F26BP
F26BPase-PFK-2
F26BPase-PFK-2P
GlucagonEp
PKA
also represses PFK synthesis
GK
ATPCit
PK
PFK-1
Glc
Acetyl-CoA
Pyr
F6P
F16BP
PEP
G6P
PDH
Glycolysis (Liver)
Alanine
PDHPase
PDHK
PDHP
PKAPKP
F26BP
F26BPase-PFK-2
F26BPase-PFK-2P
Insulin
PrPase2A
GlucagonEp
PKA
also represses PFK synthesis
GK
ATPNADH
ATPCit
PrPase
PK
PFK-1
Glc
Acetyl-CoA
Pyr
F6P
F16BP
PEP
G6P
PDH
Glycolysis (Skeletal Muscle)
PDHPase
PDHK
PDHP
F26BP
HK
ATPNADH
ATPCit
F26BPase-PFK-2
F26BPase-PFK-2F6P↑F6P↓
PK
PFK-1
Glc
Acetyl-CoA
Pyr
F6P
F16BP
PEP
G6P
PDH
PDHPase
PDHK
PDHP
F26BP
HK
ATPNADH
ATPCit
F26BPaseP-PFK-2
F26BPase-PFK-2PKA
Ep
Insulin
AKT/WISK???
Glycolysis (Heart)
F26BPase-PFK-2 Regulation Comparison
F26BPase-PFK-2
F26BPase-PFK-2P
Insulin
PrPase2A
GlucagonEp
PKALiver
F26BPase-PFK-2
F26BPase-PFK-2F6P↑F6P↓Skeletal
Muscle
F26BPaseP-PFK-2
F26BPase-PFK-2
???PKA
Ep
Insulin
AKT/WISKHeart
PK
PFK-1
Glc
Acetyl-CoA
Pyr
F6P
F16BP
PEP
G6P
PDH
Fructose Metabolism (Liver)
PDHPase
PDHK
PDHP
F26BPF26BPase-PFK-2
F26BPase-PFK-2P
Insulin
PrPase2A
GlucagonEp
PKA
GK
ATPNADH
ATPCit
GAP DHAP
Fructose
F1P
Glyceraldehyde
FK (KHK)
Aldolase B
Triose kinase
Gluconeogenesis (Liver)
Glucagon
PKAPKP
F26BPase-PFK-2
F26BPase-PFK-2P
PKA
PK
PFK-1
GKG6Pase
F16BPase
PDHP
PDHKPDHPPDH
ATPNADH
Glc
Pyr
F6P
F16BP
PEP
G6P
Protein
MDH
PEPCK
Mal
OAA
PC
MDHMal
OAA
Mit
Cyt
PrPase2A
Insulin
Ala
KB
F26BP
Cortisol
CREBGR
Acetyl-CoA
TAG
Lipolysisβ-OxidationFA
HSLEp, Glucagon, CortisolInsulin
Gluconeogenesis (Liver)Glucagon
PKAPKP
F26BPase-PFK-2
F26BPase-PFK-2P
PKA
PK
PFK-1
GKG6Pase
F16BPase
PDHKPDHPPDH
ATPNADH
Glc
Pyr
F6P
F16BP
PEP
G6P
Protein
MDH
PEPCK
Mal
OAA
PC
MDHMal
OAA
Mit
Cyt
Ala
KB
F26BP
Cortisol
CREBGR
Acetyl-CoA
TAG
Lipolysisβ-OxidationFA
HSLEp, Glucagon, Cortisol
Gluconeogenesis (Liver)
F26BPase-PFK-2
F26BPase-PFK-2P
PK
PFK-1
GKG6Pase
F16BPase
PDHPPDHPPDH
Glc
Pyr
F6P
F16BP
PEP
G6P
PEPCKOAA
Mit
Cyt
PrPase2A
Insulin
F26BP
Acetyl-CoA
TAGHSLInsulin
Gluconeogenesis (Liver)Glucagon
PKAPKP
F26BPase-PFK-2
F26BPase-PFK-2P
PKA
PK
PFK-1
GKG6Pase
F16BPase
PDHP
PDHKPDHPPDH
ATPNADH
Glc
Pyr
F6P
F16BP
PEP
G6P
Protein
MDH
PEPCK
Mal
OAA
PC
MDHMal
OAA
Mit
Cyt
PrPase2A
Insulin
Ala
KB
F26BP
Cortisol
CREBGR
Acetyl-CoA
TAG
Lipolysisβ-OxidationFA
HSLEp, Glucagon, CortisolInsulin
Lipogenesis and Lipolysis (Adipose)
Acetyl-CoA
Pyr
PK
PFK-1
PDH
PKA PKP
F26BPase-PFK-2
F26BPase-PFK-2P
PKA
PDHK
ATPNADH
PrPase2A
InsulinGlc
G6P
GKPPP
(NADPH)
ACC
MCoA
FA
Glycerol
Acetyl-CoAKB
Cit
Acetyl-CoA
PA
TAG
G3P
EsterificationHSLHSLP
PrPase2A
PDHP
PDHP
Insulin
ACCP
PrPase2A
PKAAMPK
GlucagonCortisol
Ep
PKA
Lipogenesis and Lipolysis (Adipose)
PK
PFK-1
PDH
PKAPKP
F26BPase-PFK-2
F26BPase-PFK-2P
PKA
Acetyl-CoA
Pyr
Glc
G6P
GKPPP
(NADPH)
FA
Glycerol
Acetyl-CoAKB
ACC
MCoA
Acetyl-CoA
TAGHSLHSLP
PDHK
ATPNADH
PDHP
ACCP
PKAAMPK
GlucagonCortisol
Ep
PKA
Lipogenesis and Lipolysis (Adipose)
Acetyl-CoA
Pyr
PK
PFK-1
PDH
F26BPase-PFK-2
F26BPase-PFK-2P
PrPase2A
InsulinGlc
G6P
GKPPP
(NADPH)
ACC
MCoA
Glycerol
Cit
Acetyl-CoA
PA
TAG
G3P
EsterificationHSLHSLP
PrPase2A
PDHP
PDHP
Insulin
ACCP
PrPase2A
Lipogenesis and Lipolysis (Adipose)
Acetyl-CoA
Pyr
PK
PFK-1
PDH
PKA PKP
F26BPase-PFK-2
F26BPase-PFK-2P
PKA
PDHK
ATPNADH
PrPase2A
InsulinGlc
G6P
GKPPP
(NADPH)
ACC
MCoA
FA
Glycerol
Acetyl-CoAKB
Cit
Acetyl-CoA
PA
TAG
G3P
EsterificationHSLHSLP
PrPase2A
PDHP
PDHP
Insulin
ACCP
PrPase2A
PKAAMPK
GlucagonCortisol
Ep
PKA
Impact of Diabetes on Metabolism
Acetyl-CoALactate
Production of ATP
G6P
Glucose
Glycolysis
Pyruvate
Krebscycle
ElectronTransport
Chain
GlycogenGlycogenolysis
Fatty acids(TAG)
β-Oxidation
Ketone bodies
Glycogenesis
Gluconeogenesis
Lipogenesis
Amino acids
(Protein)
Lipolysis
Impact of Diabetes on Glycogen
GlycogenolysisPPaP
Glycogenesis
Insulin (ML)
IR
Ep (ML)βAR
cAMP
Glucagon (L)
GS GSPn
GSK-3
AKT PDK-1
AKTP
PKA PKAPPK PPKP
GSK-3PPPb PPaP
PKA PPKP
PrPase1P
PrPase1
Glc
Glycogen
G6P
G1P
UDP-Glc
Glycolysis
TCAETC
Glycogen breakdown
Impact of Diabetes on Glycolysis (L)
PK
PFK-1
Glc
Acetyl-CoA
Pyr
F6P
F16BP
PEP
G6P
PDH
Alanine
PDHPase
PDHK
PDHP
PKAPKP
F26BP
F26BPase-PFK-2
F26BPase-PFK-2P
Insulin
PrPase2A
Glucagon
PKA
also represses PFK synthesis
GK
ATPNADH
ATPCit
Glycolysis inhibition
PrPase
Impact of Diabetes on Glycolysis (M)
PK
PFK-1
Glc
Acetyl-CoA
Pyr
F6P
F16BP
PEP
G6P
PDH
PDHPase
PDHK
PDHP
F26BP
HK
ATPNADH
ATPCit
F26BPase-PFK-2
F26BPase-PFK-2F6P↑F6P↓
Only impact is on GLUT4
Impact of Diabetes on Glycolysis (H)
PK
PFK-1
Glc
Acetyl-CoA
Pyr
F6P
F16BP
PEP
G6P
PDH
PDHPase
PDHK
PDHP
F26BP
HK
ATPNADH
ATPCit
F26BPaseP-PFK-2
F26BPase-PFK-2
???PKA
Ep
Insulin
AKT/WISK
Heart uses more fatty acids
Impact of Diabetes on Gluconeogenesis (L)
Glucagon
PKAPKP
F26BPase-PFK-2
F26BPase-PFK-2P
PKA
PK
PFK-1
GKG6Pase
F16BPase
PDHP
PDHKPDHPPDH
ATPNADH
Glc
Pyr
F6P
F16BP
PEP
G6P
Protein
MDH
PEPCK
Mal
OAA
PC
MDHMal
OAA
Mit
Cyt
PrPase2A
Insulin
Ala
KB
F26BP
Cortisol
CREBGR
Acetyl-CoA
TAG
Lipolysisβ-OxidationFA
HSLEp, Glucagon, CortisolInsulin
More glucose, fatty acids, ketone bodies
Impact of Diabetes on Lipogenesis/Lypolysis (A)
Acetyl-CoA
Pyr
PK
PFK-1
PDH
PKA PKP
F26BPase-PFK-2
F26BPase-PFK-2P
PKA
PDHK
ATPNADH
PrPase2A
InsulinGlc
G6P
GKPPP
(NADPH)
ACC
MCoA
FA
Glycerol
Acetyl-CoAKB
Cit
Acetyl-CoA
PA
TAG
G3P
EsterificationHSLHSLP
PrPase2A
PDHP
PDHP
Insulin
ACCP
PrPase2A
PKAAMPK
GlucagonCortisol
Ep
PKA
Increased fatty acids, ketone bodies, cholesterol
LiverWell-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)
MuscleWell-fed• Glucose to glycogen and triacylglycerols
Starvation• Glucose from glycogen• Alanine from protein
Diabetes• Alanine from protein (muscle wasting)
AdipocytesWell-fed• Glucose to glycogen and triacylglycerols
Starvation• Fatty acids and glycerol from triacyglycerols
Diabetes• Fatty acids and glycerol from triacylglycerols
Pathway Pearls
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
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
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?