Regulation of Metabolism and Diabetes

Report
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
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
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
Pathways Overview
Ketone
bodies
Glucose
Glycogen
Glycogenolysis
Glycolysis
G6P
Glycogenesis
Lipolysis
Pyruvate
Amino
acids
(Protein)
β-Oxidation
Lipogenesis
Gluconeogenesis
Lactate
Fatty acids
(TAG)
Krebs
cycle
Acetyl-CoA
Electron
Transport
Chain
Production of ATP
Tissues Overview
Glycogenesis
Glycogenolysis
Glycolysis
Gluconeogenesis
Lipogenesis
Lipolysis
β-Oxidation
Ketogenesis
Liver
Glycogenesis
Glycogenolysis
Glycolysis
Lipogenesis
Lipolysis
β-Oxidation
Adipose
Tissue
Blood Glucose
Serum Triglycerides
Kidney
Glycogenesis
Glycogenolysis
Glycolysis
β-Oxidation
Glycogenesis
Glycogenolysis
Glycolysis
β-Oxidation
Heart
Glycogenesis
Glycogenolysis
Glycolysis
Gluconeogenesis
β-Oxidation
Skeletal
Muscle
Glucose Homeostasis
Glycogenesis and Glycogenolysis
Ep (ML) Glucagon (L)
Insulin (ML)
βAR
cAMP
PKA
PKA
IR
AKT PDK-1
PPKP
PPK
PPaP
PPb
GSK-3P
AKTP
PKA
Glycogen
GS
PPaP
UDP-Glc
Glycogenolysis
PPKP GSK-3
Glycogenesis
PrPase1P
G1P
Glc
PrPase1
G6P
ETC
Glycolysis
TCA
GSPn
Glycogenesis and Glycogenolysis
Insulin (ML)
IR
AKT PDK-1
GSK-3P
AKTP
GSK-3
Glycogen
GS
UDP-Glc
G1P
Glc
Glycogenesis
PrPase1P
PrPase1
G6P
GSPn
Glycogenesis and Glycogenolysis
Ep (ML) Glucagon (L)
βAR
cAMP
PKA
PKA
PPKP
PPK
PPaP
PPb
PKA
Glycogen
PPKP GSK-3
GS Glycogenesis
PPaP
UDP-Glc
Glycogenolysis
G1P
Glc
G6P
ETC
Glycolysis
TCA
GSPn
Glycogenesis and Glycogenolysis
Ep (ML) Glucagon (L)
Insulin (ML)
βAR
cAMP
PKA
PKA
IR
AKT PDK-1
PPKP
PPK
PPaP
PPb
GSK-3P
AKTP
PKA
Glycogen
GS
PPaP
UDP-Glc
Glycogenolysis
PPKP GSK-3
Glycogenesis
PrPase1P
G1P
Glc
PrPase1
G6P
ETC
Glycolysis
TCA
GSPn
Glycolysis: Regulatory Steps
Glucagon
Liver
Glc
GK
HK
G6P
F6P
PFK-1
Insulin
Liver
Ep
Heart
Liver
F26BPase
PFK-2
Heart
F16BP
PEP
PK
Pyr
Liver
Adipose
PDH
Acetyl-CoA
Glycolysis (Liver)
Glc
Glucagon
also represses PFK synthesis
Ep
Insulin
GK
G6P
F26BPase-PFK-2P
PKA
F6P
PrPase2A
F26BPase-PFK-2
PFK-1
F26BP
F16BP
ATP
Cit
Alanine
PEP
PK
PKA
PKP
Pyr
PDHK
PDH
PDHP
PDHPase
Acetyl-CoA
PrPase
ATP
NADH
Glycolysis (Liver)
Insulin
Glc
GK
G6P
F26BPase-PFK-2P
PrPase2A
F6P
F26BPase-PFK-2
PFK-1
F26BP
F16BP
ATP
Cit
PEP
PK
Pyr
PDHK
PDH
PDHP
PDHPase
Acetyl-CoA
PrPase
Glycolysis (Liver)
Glucagon
also represses PFK synthesis
Ep
Glc
GK
G6P
F26BPase-PFK-2P
PKA
F6P
F26BPase-PFK-2
PFK-1
F26BP
F16BP
Alanine
PEP
PKA
PK
PKP
Pyr
PDHK
PDH
Acetyl-CoA
PDHP
ATP
Cit
Glycolysis (Liver)
Glc
Glucagon
also represses PFK synthesis
Ep
Insulin
GK
G6P
F26BPase-PFK-2P
PKA
F6P
PrPase2A
F26BPase-PFK-2
PFK-1
F26BP
F16BP
ATP
Cit
Alanine
PEP
PK
PKA
PKP
Pyr
PDHK
PDH
PDHP
PDHPase
Acetyl-CoA
PrPase
ATP
NADH
Glycolysis (Skeletal Muscle)
Glc
HK
G6P
F26BPase-PFK-2
F6P↑
F6P↓
F6P
F26BPase-PFK-2
PFK-1
F26BP
F16BP
ATP
Cit
PEP
PK
Pyr
PDHK
PDH
PDHP
PDHPase
Acetyl-CoA
ATP
NADH
Glycolysis (Heart)
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
PDHPase
Acetyl-CoA
ATP
NADH
F26BPase-PFK-2
Regulation Comparison
Glucagon
Ep
Insulin
F26BPase-PFK-2P
Liver
PKA
PrPase2A
F26BPase-PFK-2
F26BPase-PFK-2
Skeletal
Muscle
F6P↓
F6P↑
F26BPase-PFK-2
Ep
F26BPase-PFK-2
Heart
???
PKA
AKT/WISK
F26BPaseP-PFK-2
Insulin
Fructose Metabolism (Liver)
Glucagon
Ep
Glc
Fructose
Insulin
GK
FK (KHK)
G6P
F26BPase-PFK-2P
PKA
F6P
PFK-1
F26BPase-PFK-2
F26BP
F1P
Aldolase B
ATP
Cit
F16BP
DHAP
GAP
PEP
PrPase2A
Triose kinase
PK
Pyr
PDHK
PDH
PDHP
PDHPase
Acetyl-CoA
ATP
NADH
Glyceraldehyde
Gluconeogenesis (Liver)
Insulin
Glucagon
Glc
G6Pase
GK
G6P
Cortisol
F26BPase-PFK-2
PKA
F6P
PFK-1
F16BPase
GR
F26BPase-PFK-2P
F26BP
F16BP
CREB
Protein
PEPCK
OAA
Ala
PEP
PKA
PK
MDH
Mal
Cyt
PrPase2A
PKP
Pyr
PDHK
PDHP
PDH
Mit
PDHP
PC
Acetyl-CoA
OAA
Mal
MDH
Ep, Glucagon, Cortisol
Insulin
KB
FA
HSL
ATP
NADH
Lipolysis
β-Oxidation
TAG
Gluconeogenesis (Liver)
Glucagon
Glc
G6Pase
GK
G6P
Cortisol
F26BPase-PFK-2
PKA
F6P
PFK-1
F16BPase
F26BP
F16BP
CREB
GR
F26BPase-PFK-2P
Protein
PEPCK
OAA
PKA
PK
MDH
Mal
Cyt
Ala
PEP
PKP
Pyr
PDHK
PDHP
PDH
Mit
PC
Acetyl-CoA
OAA
Mal
MDH
Ep, Glucagon, Cortisol
KB
FA
HSL
ATP
NADH
Lipolysis
β-Oxidation
TAG
Gluconeogenesis (Liver)
Insulin
Glc
G6Pase
GK
G6P
F26BPase-PFK-2
PrPase2A
F6P
F16BPase
PFK-1
F26BPase-PFK-2P
F26BP
F16BP
PEPCK
OAA
PEP
PK
Cyt
Pyr
PDH
Mit
PDHP
PDHP
Acetyl-CoA
Insulin
HSL
TAG
Gluconeogenesis (Liver)
Insulin
Glucagon
Glc
G6Pase
GK
G6P
Cortisol
F26BPase-PFK-2
PKA
F6P
PFK-1
F16BPase
GR
F26BPase-PFK-2P
F26BP
F16BP
CREB
Protein
PEPCK
OAA
Ala
PEP
PKA
PK
MDH
Mal
Cyt
PrPase2A
PKP
Pyr
PDHK
PDHP
PDH
Mit
PDHP
PC
Acetyl-CoA
OAA
Mal
MDH
Ep, Glucagon, Cortisol
Insulin
KB
FA
HSL
ATP
NADH
Lipolysis
β-Oxidation
TAG
Lipogenesis and Lipolysis
(Adipose)
Glc
Glucagon
Insulin Cortisol
Ep
PPP
(NADPH)
GK
G6P
F26BPase-PFK-2
PFK-1
PKA
Glycerol
PrPase2A
F26BPase-PFK-2P
G3P
PK
PKA
Pyr
TAG
Esterification
PKP
ATP
NADH
PrPase2A
HSLP
PA
PKA
PDHK
PDH
Acetyl-CoA
PDHP
MCoA
AMPK PKA
PDHP
ACC
Acetyl-CoA
ACCP
FA
PrPase2A
Acetyl-CoA
Cit
KB
Insulin
HSL
Lipogenesis and Lipolysis
(Adipose)
Glc
Glucagon
Cortisol
Ep
PPP
(NADPH)
GK
G6P
F26BPase-PFK-2
PFK-1
Glycerol
PKA
F26BPase-PFK-2P
PK
PKA
TAG
PKP
Pyr
HSLP
ATP
NADH
PKA
PDHK
PDH
PDHP
MCoA
AMPK PKA
Acetyl-CoA
ACC
ACCP
FA
Acetyl-CoA
Acetyl-CoA
KB
HSL
Lipogenesis and Lipolysis
(Adipose)
Glc
Insulin
PPP
(NADPH)
GK
G6P
F26BPase-PFK-2
PFK-1
Glycerol
PrPase2A
F26BPase-PFK-2P
G3P
PK
TAG
Esterification
Pyr
PrPase2A
PA
PDH
Acetyl-CoA
PDHP
MCoA
PDHP
ACC
Acetyl-CoA
Cit
Insulin
ACCP
PrPase2A
HSLP
HSL
Lipogenesis and Lipolysis
(Adipose)
Glc
Glucagon
Insulin Cortisol
Ep
PPP
(NADPH)
GK
G6P
F26BPase-PFK-2
PFK-1
PKA
Glycerol
PrPase2A
F26BPase-PFK-2P
G3P
PK
PKA
Pyr
TAG
Esterification
PKP
ATP
NADH
PrPase2A
HSLP
PA
PKA
PDHK
PDH
Acetyl-CoA
PDHP
MCoA
AMPK PKA
PDHP
ACC
Acetyl-CoA
ACCP
FA
PrPase2A
Acetyl-CoA
Cit
KB
Insulin
HSL
Impact of Diabetes on Metabolism
Ketone
bodies
Glucose
Glycogen
Glycogenolysis
Glycolysis
G6P
Glycogenesis
Lipolysis
Pyruvate
Amino
acids
(Protein)
β-Oxidation
Lipogenesis
Gluconeogenesis
Lactate
Fatty acids
(TAG)
Krebs
cycle
Acetyl-CoA
Electron
Transport
Chain
Production of ATP
Impact of Diabetes on Glycogen
Glycogen breakdown
Ep (ML) Glucagon (L)
Insulin (ML)
βAR
cAMP
PKA
PKA
IR
AKT PDK-1
PPKP
PPK
PPaP
PPb
GSK-3P
AKTP
PKA
Glycogen
GS
PPaP
UDP-Glc
Glycogenolysis
PPKP GSK-3
Glycogenesis
PrPase1P
G1P
Glc
PrPase1
G6P
ETC
Glycolysis
TCA
GSPn
Impact of Diabetes on Glycolysis (L)
Glycolysis inhibition
also represses PFK synthesis
Glucagon
Insulin
Glc
GK
G6P
F26BPase-PFK-2P
PKA
F6P
PrPase2A
F26BPase-PFK-2
PFK-1
F26BP
F16BP
ATP
Cit
Alanine
PEP
PK
PKA
PKP
Pyr
PDHK
PDH
PDHP
PDHPase
Acetyl-CoA
PrPase
ATP
NADH
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
PDHPase
Acetyl-CoA
ATP
NADH
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
PDHPase
Acetyl-CoA
ATP
NADH
Impact of Diabetes on Gluconeogenesis (L)
More glucose, fatty acids, ketone bodies
Insulin
Glucagon
Glc
G6Pase
GK
G6P
Cortisol
F26BPase-PFK-2
PKA
F6P
PFK-1
F16BPase
GR
F26BPase-PFK-2P
F26BP
F16BP
CREB
Protein
PEPCK
OAA
Ala
PEP
PKA
PK
MD
Mal H
Cyt
PrPase2A
PKP
Pyr
PDHK
PDHP
PDH
Mit
PDHP
PC
Acetyl-CoA
OAA
Mal
MDH
Ep, Glucagon, Cortisol
Insulin
KB
FA
HSL
ATP
NADH
Lipolysis
β-Oxidation
TAG
Impact of Diabetes on Lipogenesis/Lypolysis (A)
Increased fatty acids, ketone bodies, cholesterol
Glucagon
Glc
PPP
Insulin Cortisol
GK
Ep
(NADPH)
G6P
F26BPase-PFK-2
PFK-1
PKA
Glycerol
PrPase2A
F26BPase-PFK-2P
G3P
PK
PKA
Pyr
TAG
Esterification
PKP
ATP
NADH
PrPase2A
HSLP
PA
PKA
PDHK
PDH
Acetyl-CoA
PDHP
MCoA
AMPK PKA
PDHP
ACC
Acetyl-CoA
ACCP
FA
PrPase2A
Acetyl-CoA
Cit
KB
Insulin
HSL
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 and glycerol from triacyglycerols
Diabetes
•Fatty acids and glycerol from triacylglycerols
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
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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