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?