Regulation of Metabolism and Diabetes
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Transcript Regulation of Metabolism and Diabetes
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?