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
Medical Biochemistry
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
• Multiple acid-base disorders
• Cellular processing of alcohols
• 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
Glucose bodies
Glycogen Glycolysis Fatty acids
Glycogenolysis (TAG)
G6P β-Oxidation
Glycogenesis Lipogenesis

Gluconeogenesis Lipolysis

Lactate Pyruvate Acetyl-CoA

Amino Electron
Krebs Transport
acids
cycle Chain
(Protein)

Production of ATP
 Tissues Overview
Glycogenesis Glycogenesis
Glycogenolysis Glycogenolysis Glycogenesis
Glycolysis Glycolysis Glycogenolysis
Gluconeogenesis Lipogenesis Glycolysis
Lipogenesis Lipolysis Gluconeogenesis
Lipolysis β-Oxidation β-Oxidation
β-Oxidation
Ketogenesis

~80% Glc provided to body ~20% Glc provided

-50% by glycogenolysis to body by
-30% by gluconeogenesis gluconeogenesis

Adipose
Liver Kidney
Tissue
Blood Glucose
Serum Triglycerides

Glycogenesis Glycogenesis
Glycogenolysis Glycogenolysis
Glycolysis Glycolysis
β-Oxidation β-Oxidation

Skeletal
Heart
Muscle
Glucose Homeostasis
Glycogenesis and Glycogenolysis

Ep (ML) Glucagon (L) Insulin (ML)

βAR IR
cAMP
PKA PKA
AKT PDK-1
PPK PPKP
PPb PPaP GSK-3P
AKTP

PKA PPKP GSK-3

Glycogen
GS Glycogenesis GSPn
PPaP UDP-Glc PrPase1P
Glycogenolysis

G1P PrPase1

Glc G6P Glycolysis

ETC TCA
Glycogenesis and Glycogenolysis

Insulin (ML)

IR

AKT PDK-1

GSK-3P
AKTP

GSK-3
Glycogen
GS Glycogenesis GSPn

UDP-Glc PrPase1P

G1P PrPase1

Glc G6P
Glycogenesis and Glycogenolysis

Ep (ML) Glucagon (L)

βAR
cAMP
PKA PKA
PPK PPKP
PPb PPaP

PKA PPKP GSK-3

Glycogen
GS Glycogenesis GSPn
PPaP UDP-Glc
Glycogenolysis

G1P

Glc G6P Glycolysis

ETC TCA
Glycogenesis and Glycogenolysis

Ep (ML) Glucagon (L) Insulin (ML)

βAR IR
cAMP
PKA PKA
AKT PDK-1
PPK PPKP
PPb PPaP GSK-3P
AKTP

PKA PPKP GSK-3

Glycogen
GS Glycogenesis GSPn
PPaP UDP-Glc PrPase1P
Glycogenolysis

G1P PrPase1

Glc G6P Glycolysis

ETC TCA
Glycolysis: Regulatory Steps

Glucagon
Liver
Insulin
Glc Liver
GK Ep
HK
G6P Heart
Liver

F6P
F26BPase
PFK-1
PFK-2
Heart
F16BP

PEP
Liver
PK

Pyr
Adipose
PDH

Acetyl-CoA
 Glycolysis (Liver)
Glucagon
also represses PFK synthesis Ep
Insulin
Glc
GK
G6P F26BPase-PFK-2P
PKA PrPase2A

F6P F26BPase-PFK-2

PFK-1 F26BP
F16BP
ATP
Alanine Cit
PEP PKA
PK PKP

Pyr
PDHK

PDH PDHP

ATP
PDHPase
Acetyl-CoA PrPase 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
ATP
Alanine Cit
PEP PKA
PK
PKP
Pyr
PDHK

PDH
PDHP

Acetyl-CoA
 Glycolysis (Liver)
Glucagon
also represses PFK synthesis Ep
Insulin
Glc
GK
G6P F26BPase-PFK-2P
PKA PrPase2A

F6P F26BPase-PFK-2

PFK-1 F26BP
F16BP
ATP
Alanine Cit
PEP PKA
PK PKP

Pyr
PDHK

PDH PDHP

ATP
PDHPase
Acetyl-CoA PrPase 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

ATP
PDHPase
Acetyl-CoA 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

ATP
PDHPase
Acetyl-CoA NADH
 F26BPase-PFK-2
Regulation Comparison

Glucagon
Ep
Insulin

F26BPase-PFK-2P
Liver PKA PrPase2A

F26BPase-PFK-2

F26BPase-PFK-2
Skeletal F6P↓ F6P↑
Muscle F26BPase-PFK-2

Ep

Insulin
F26BPase-PFK-2
PKA
Heart ??? AKT/WISK
F26BPaseP-PFK-2
Fructose Metabolism (Liver)
Glucagon
Ep
Glc Insulin Fructose
GK
FK (KHK)
G6P
F26BPase-PFK-2P

PKA PrPase2A F1P

F6P F26BPase-PFK-2 Aldolase B
F26BP
PFK-1

F16BP ATP
Cit

GAP DHAP

Glyceraldehyde
Triose kinase
PEP
PK

Pyr
PDHK

PDH PDHP

PDHPase
ATP
Acetyl-CoA NADH
Glucokinase (Liver)

GLUT2 GLUT2,5,8
Glucose Fructose
GK
FK
G6P Cytosol (KHK)
PGI
F6P F1P

nucleus
GK GK

GKRP GKRP
 Gluconeogenesis (Liver)
Insulin Glucagon
Glc
G6Pase GK

G6P
Cortisol F26BPase-PFK-2

PKA PrPase2A
F6P
F26BPase-PFK-2P
F16BPase PFK-1
F26BP
F16BP
GR CREB
Protein
PEPCK
OAA PEP Ala
PKA
PK PKP
Cyt MDH
Mal Pyr
PDHK
Mit PDH PDHP
↓[Acetyl-CoA] PC PDHP
↓[Glc]
β-oxidation defect Acetyl-CoA ATP
NADH
OAA KB

MDH Lipolysis
Mal FA β-Oxidation

Ep, Glucagon, Cortisol HSL TAG

Insulin
Gluconeogenesis (Liver)
TAG
HSL
Odd-chain
Glycerol + FA
FA oxidation/
AA metabolism
PCoA

MMCoA mutase
TCA
L-MMCoA SCoA
Vit B12 cycle

Glc
AA
Glycerol
G6P

GlK Lactate
F6P

Pyr
Gl3P
F16BP
Gl3PDH

DHAP G3P
Gluconeogenesis (Liver)
Glucagon
Glc
G6Pase GK

G6P
Cortisol F26BPase-PFK-2

PKA
F6P
F26BPase-PFK-2P
F16BPase PFK-1
F26BP
F16BP
GR CREB
Protein
PEPCK
OAA PEP Ala
PKA
PK PKP
Cyt MDH
Mal Pyr
PDHK
Mit PDH PDHP
PC
Acetyl-CoA ATP
NADH
OAA KB

MDH Lipolysis
Mal FA β-Oxidation

Ep, Glucagon, Cortisol HSL TAG

Gluconeogenesis (Liver)
Insulin Glc
G6Pase GK

G6P
F26BPase-PFK-2

PrPase2A
F6P
F26BPase-PFK-2P
F16BPase PFK-1
F26BP
F16BP

PEPCK
OAA PEP
PK
Cyt
Pyr

PDH PDHP
Mit
PDHP

Acetyl-CoA

Insulin HSL TAG

Gluconeogenesis (Liver)
Insulin Glucagon
Glc
G6Pase GK

G6P
Cortisol F26BPase-PFK-2

PKA PrPase2A
F6P
F26BPase-PFK-2P
F16BPase PFK-1
F26BP
F16BP
GR CREB
Protein
PEPCK
OAA PEP Ala
PKA
PK PKP
Cyt MDH
Mal Pyr
PDHK
Mit PDH PDHP
PC PDHP

Acetyl-CoA ATP
NADH
OAA KB

MDH Lipolysis
Mal FA β-Oxidation

Ep, Glucagon, Cortisol HSL TAG

Insulin
 Lipogenesis and Lipolysis (Adipose)

Glucagon
Glc PPP Insulin Cortisol
GK (NADPH) Ep
G6P F26BPase-PFK-2
Glycerol
PFK-1 PKA PrPase2A

F26BPase-PFK-2P
G3P
PrPase2A
PKA
PK PKP Esterification TAG
HSLP HSL
Pyr ATP
NADH PA PKA
PDHK

PDH PDHP
MCoA

AMPK PKA
PDHP
Acetyl-CoA
ACC ACCP
FA
PrPase2A
Acetyl-CoA

Cit Acetyl-CoA
KB
Insulin
 Lipogenesis and Lipolysis (Adipose)

Glucagon
Glc PPP Cortisol
GK (NADPH) Ep
G6P F26BPase-PFK-2
Glycerol
PFK-1 PKA

F26BPase-PFK-2P

PKA
PK PKP TAG
HSLP HSL
Pyr ATP
NADH PKA
PDHK

PDH MCoA
PDHP
AMPK PKA
Acetyl-CoA
ACC ACCP
FA

Acetyl-CoA

Acetyl-CoA
KB
 Lipogenesis and Lipolysis (Adipose)

Glc Insulin
PPP
GK (NADPH)
G6P F26BPase-PFK-2 Glycerol
PFK-1 PrPase2A

F26BPase-PFK-2P
G3P
PrPase2A

PK Esterification TAG
HSLP HSL
Pyr
PA

PDH PDHP
MCoA

PDHP
Acetyl-CoA
ACC ACCP

PrPase2A
Acetyl-CoA

Cit

Insulin
 Lipogenesis and Lipolysis (Adipose)

Glucagon
Glc PPP Insulin Cortisol
GK (NADPH) Ep
G6P F26BPase-PFK-2
Glycerol
PFK-1 PKA PrPase2A

F26BPase-PFK-2P
G3P
PrPase2A
PKA
PK PKP Esterification TAG
HSLP HSL
Pyr ATP
NADH PA PKA
PDHK

PDH PDHP
MCoA

AMPK PKA
PDHP
Acetyl-CoA
ACC ACCP
FA
PrPase2A
Acetyl-CoA

Cit Acetyl-CoA
KB
Insulin
Impact of Diabetes on Metabolism

Ketone
Glucose bodies
Glycogen Glycolysis Fatty acids
Glycogenolysis (TAG)
G6P β-Oxidation
Glycogenesis Lipogenesis

Gluconeogenesis Lipolysis

Lactate Pyruvate Acetyl-CoA

Amino Electron
Krebs Transport
acids
cycle Chain
(Protein)

Production of ATP
Impact of Diabetes on Glycogen
Glycogen breakdown
Ep (ML) Glucagon (L) Insulin (ML)
βAR IR
cAMP
PKA PKA
AKT PDK-1
PPK PPKP
PPb PPaP
GSK-3P
AKTP

PKA PPKP GSK-3

Glycogen
GS Glycogenesis GSPn
PPaP UDP-Glc PrPase1P
Glycogenolysis

G1P PrPase1

Glc G6P Glycolysis

ETC TCA
 Impact of Diabetes on Glycolysis (L)
Glycolysis inhibition
Glucagon
also represses PFK synthesis
Insulin
Glc
GK
G6P F26BPase-PFK-2P
PKA PrPase2A

F6P F26BPase-PFK-2

PFK-1
F26BP
F16BP
ATP
Alanine Cit
PEP PKA
PK PKP

Pyr
PDHK

PDH PDHP

ATP
PDHPase
Acetyl-CoA PrPase
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

ATP
PDHPase
Acetyl-CoA 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

ATP
PDHPase
Acetyl-CoA NADH
 Impact of Diabetes on Gluconeogenesis (L)
More glucose, fatty acids, ketone bodies
Insulin Glucagon
Glc
G6Pase GK

G6P
Cortisol F26BPase-PFK-2

PKA PrPase2A
F6P
F26BPase-PFK-2P
F16BPase PFK-1
F26BP
F16BP
GR CREB
Protein
PEPCK
OAA PEP Ala
PKA
PK PKP
Cyt MD
Mal H Pyr
PDHK
Mit PDH PDHP
PC PDHP

Acetyl-CoA ATP
NADH
OAA KB

MDH Lipolysis
Mal FA β-Oxidation

Ep, Glucagon, Cortisol HSL TAG

Insulin
Impact of Diabetes on Lipogenesis/Lypolysis (A)

Increased fatty acids, ketone bodies, cholesterol

Glucagon
Glc PPP Insulin Cortisol
GK (NADPH) Ep
G6P F26BPase-PFK-2
Glycerol
PFK-1 PKA PrPase2A

F26BPase-PFK-2P
G3P
PrPase2A
PKA
PK PKP Esterification TAG
HSLP HSL
Pyr ATP
NADH PA PKA
PDHK

PDH PDHP
MCoA

AMPK PKA
PDHP
Acetyl-CoA
ACC ACCP
FA
PrPase2A
Acetyl-CoA

Cit Acetyl-CoA
KB
Insulin
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)
•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)
 Multiple Acid-Base Disorders
A 59-year-old man with a history of alcohol abuse
and diabetes is brought to the emergency
department after being found at home
semiconscious, and minimally responsive. His blood
pressure is 100/60 mm Hg. His breath smells of
acetone; skin turgor is decreased. Chest is
symmetric; anterior/posterior (AP) ratio 1:1;
auscultation shows few scattered expiratory
wheezes. He is given 100% O2 by mask.
Na+ 125 mEq/L pH 7.06
K+ 6.9 mEq/L PCO2 25 mm Hg
Cl- 78 mEq/L PO2 288 mm Hg
CO2, total 8 mEq/L HCO3- 7 mEq/L
Glucose 1600 mg/dL Urea 66 mg/dL
Albumin 2.9 g/dL Ethanol 20 mg/dL
Osmolality 376 mOsm/kg water
History/PE suggest electrolyte imbalance. Increased
AG and increased BG. Increased (A-a)PO2
difference
Mixed acid-base disorders, potentially metabolic
acidosis and metabolic alkalosis with respiratory
acidosis.
 Description
Na+ 125 mEq/L pH 7.06
K+ 6.9 mEq/L PCO2 25 mm Hg
Cl- 78 mEq/L PO2 288 mm Hg
CO2, total 8 mEq/L HCO3- 7 mEq/L
Glucose 1600 mg/dL Urea 66 mg/dL
Albumin 2.9 g/dL Ethanol 20 mg/dL
Osmolality 376 mOsm/kg water
AG = 39 mEq/L BG = 8 mEq/L
OG = 8 mOsm/kg water
1.2 mm Hg decrease in PCO2 for every 1 mEq/L
decrease in [HCO3-].
[HCO3-] decrease = 24-7 = 17 mEq/L
PCO2 decrease predicted = 1.2 x 17 = 20.4 mm Hg.
Subtract from 40 mm Hg (reference point) = 19.6
mm Hg
Observed PCO2 is 5 mm Hg higher, suggesting
decreased ventilation, presence of respiratory
acidosis.
 Cellular Processing of Alcohols

Propylene Ethylene
Ethanol Methanol Isopropanol
glycol glycol

Alcohol dehydrogenase

Glycoaldehyde Formaldehyde

Lactaldehyde Acetaldehyde Acetone

Aldehyde dehydrogenase

Glycolic acid Formic acid

Glycolate (formate)
Lactic acid Acetic acid
(lactate) (acetate)
Glyoxylic acid
(glyoxylate)

α-Hydroxy-β- Oxalic acid

Glycine
ketoadipate (oxalate)
 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?
• What is this patient’s acid-base status?
• How are alcohols processed?