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)

-Oxidation
Lipogenesis

Gluconeogenesis

Lactate

Fatty acids
(TAG)

Krebs
cycle

Acetyl-CoA

Electron
Transport
Chain

Production of ATP

Tissues Overview
Glycogenesis
Glycogenolysis
Glycolysis
Gluconeogenesi
s
Lipogenesis
Lipolysis
-Oxidation
Ketogenesis

Glycogenesis
Glycogenolysis
Glycolysis
Lipogenesis
Lipolysis
-Oxidation

Adipose
Liver
Tissue
Blood Glucose
Serum Triglycerides

Kidney

Glycogenesis
Glycogenolysis
Glycolysis
-Oxidation

Glycogenesis
Glycogenolysis
Glycolysis
-Oxidation

Heart

Glycogenesis
Glycogenolysis
Glycolysis
Gluconeogenesi
s
-Oxidation

Skeletal
Muscle

Glucose Homeostasis

Glycogenesis and Glycogenolysis

Ep (ML) Glucagon (L)

Insulin (ML)

AR
cAMP
PKA
PKA

IR

AKT PDK-1

PPK

PPK

PPaP

PPb

GSK-3P
AKTP

PKA

Glycogen

GS
PPaP

UDP-Glc

Glycogenolysis

PPKP

Glycogenesis

PrPase1P

G1P

Glc

GSK-3

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)
AR
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)

AR
cAMP
PKA
PKA

IR

AKT PDK-1

PPK

PPK

PPaP

PPb

GSK-3P
AKTP

PKA

Glycogen

GS
PPaP

UDP-Glc

Glycogenolysis

PPKP

Glycogenesis

PrPase1P

G1P

Glc

GSK-3

PrPase1

G6P
ETC

Glycolysis
TCA

GSPn

Glycolysis: Regulatory Steps

Glucagon

Liver

Glc

GK
HK
G6P
F6P
PFK-1
F16BP
PEP
PK
Pyr
PDH
Acetyl-CoA

Insulin

Liver

Ep
Heart
Liver

F26BPase
PFK-2

Heart

Liver

Adipose

Glycolysis (Liver)
Glucagon
also represses PFK synthesis
Ep
Insulin

Glc
GK
G6P

F26BPase-PFK-2P
PKA

F6P

PrPase2A

F26BPase-PFK-2

PFK-1

F26BP

F16BP

ATP
Cit

Alanine
PEP
PK
Pyr

PKA
PKP

PDHK

PDH
Acetyl-CoA

PDHP
PDHPase
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
Acetyl-CoA

PDHP
PDHPase
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
PK

Pyr

PKA
PKP
PDHK

PDH

Acetyl-CoA

PDHP

ATP
Cit

Glycolysis (Liver)
Glucagon
also represses PFK synthesis
Ep
Insulin

Glc
GK
G6P

F26BPase-PFK-2P
PKA

F6P

PrPase2A

F26BPase-PFK-2

PFK-1

F26BP

F16BP

ATP
Cit

Alanine
PEP
PK
Pyr

PKA
PKP

PDHK

PDH
Acetyl-CoA

PDHP
PDHPase
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
Acetyl-CoA

PDHP
PDHPase

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
Acetyl-CoA

PDHP
PDHPase

ATP
NADH

F26BPase-PFK-2
Regulation Comparison
Glucagon
Ep
Insulin
F26BPase-PFK-2P
Liver

PKA

PrPase2A

F26BPase-PFK-2

Skeletal
Muscle

F26BPase-PFK-2
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

Mit

PDH

PC

PDHP

Acetyl-CoA

OAA
Mal

MDH

Ep, Glucagon, Cortisol

Insulin

KB
FA
HSL

PDHP
ATP
NADH

Lipolysis
-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

Mit

PDHP

PDH

PC

Acetyl-CoA

OAA
Mal

MDH

Ep, Glucagon, Cortisol

KB
FA
HSL

ATP
NADH

Lipolysis
-Oxidation

TAG

Gluconeogenesis (Liver)
Insulin

Glc
G6Pase

GK

G6P

F26BPase-PFK-2
PrPase2A

F6P
F16BPase

PFK-1

F26BPase-PFK-2P

F16BP

F26BP

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

Mit

PDH

PC

PDHP

Acetyl-CoA

OAA
Mal

MDH

Ep, Glucagon, Cortisol

Insulin

KB
FA
HSL

PDHP
ATP
NADH

Lipolysis
-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)

-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)

AR
cAMP
PKA
PKA

IR

PPK

PPK

AKT PDK-1

PPaP

PPb

GSK-3P
AKTP

PKA

Glycogen

GS
PPaP

UDP-Glc

Glycogenolysis

PPKP

Glycogenesis

PrPase1P

G1P

Glc

GSK-3

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
Pyr

PKA
PKP

PDHK

PDH
Acetyl-CoA

PDHP
PDHPase
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
Acetyl-CoA

PDHP
PDHPase

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
Acetyl-CoA

PDHP
PDHPase

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

Mit

PDH

PC

PDHP

Acetyl-CoA

OAA
Mal

MDH

Ep, Glucagon, Cortisol

Insulin

KB
FA
HSL

PDHP
ATP
NADH

Lipolysis
-Oxidation

TAG

Impact of Diabetes on Lipogenesis/Lypolysis (A)

Increased fatty acids, ketone bodies,
Glucagon
cholesterol
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
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)
-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)

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?