Eric Niederhoffer SIU-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

Eric Niederhoffer

SIU-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 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

Acetyl-CoALactate

Production of ATP

G6P

Glucose

Glycolysis

Pyruvate

Krebscycle

ElectronTransport

Chain

Glycogen

Glycogenolysis

Fatty acids(TAG)

β-Oxidation

Ketone bodies

Pathways Overview

Glycogenesis

Gluconeogenesis

Lipogenesis

Amino acids

(Protein)

Lipolysis

GlycogenesisGlycogenolysis

GlycolysisLipogenesis

Lipolysisβ-Oxidation


GlycolysisGluconeogenesi

sLipogenesis

Lipolysisβ-OxidationKetogenesis


Glycolysisβ-Oxidation


Glycolysisβ-Oxidation

Tissues Overview

Blood GlucoseSerum Triglycerides


GlycolysisGluconeogenesi

sβ-Oxidation

LiverAdiposeTissue

Kidney

HeartSkeletalMuscle

Glucose Homeostasis

Glycogenesis and Glycogenolysis

Insulin (ML)

IR

Ep (ML)

βARcAMP

Glucagon (L)

GS GSPn

GSK-3

AKT PDK-1

AKTP

PKA PKA

PPK PPKP

GSK-3P

PPaP

PPb PPaP

PKA PPKP

PrPase1P

PrPase1

Glycogenesis

Glc

Glycogen

G6P

G1P

UDP-GlcGlycogenolysis

Glycolysis

TCAETC


Insulin (ML)

IR

GS GSPn

GSK-3

AKT PDK-1

AKTP

GSK-3P

PrPase1P

PrPase1

Glycogenesis

Glc

Glycogen

G6P

G1P

UDP-Glc


Ep (ML)

βARcAMP

Glucagon (L)

GS GSPn

GSK-3

PKA PKA

PPK PPKP

PPaP

PPb PPaP

PKA PPKP

Glycogenesis

Glc

Glycogen

G6P

G1P


Glycolysis

TCAETC


Insulin (ML)

IR

Ep (ML)

βARcAMP

Glucagon (L)

GS GSPn

GSK-3

AKT PDK-1

AKTP

PKA PKA

PPK PPKP

GSK-3P

PPaP

PPb PPaP

PKA PPKP

PrPase1P

PrPase1

Glycogenesis

Glc

Glycogen

G6P

G1P


Glycolysis

TCAETC

PK

PFK-1

Glc

Acetyl-CoA

Pyr

F6P

F16BP

PEP

G6P

PDH

F26BPasePFK-2

Glycolysis: Regulatory Steps

HK

Insulin

Glucagon

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


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


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-2

F6P↑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-2

F6P↑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


FA

HSLEp, Glucagon, CortisolInsulin


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


FA

HSLEp, Glucagon, Cortisol


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


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


FA


Lipogenesis and Lipolysis (Adipose)

Acetyl-CoA

Pyr

PK

PFK-1

PDH

PKAPKP

F26BPase-PFK-2

F26BPase-PFK-2P

PKA

PDHK

ATPNADH

PrPase2A

InsulinGlc

G6P

GKPPP

(NADPH)

ACC

MCoA

FA

Glycerol

Acetyl-CoA

KBCit

Acetyl-CoA

PA

TAG

G3P

Esterification

HSLHSLP

PrPase2A

PDHP

PDHP

Insulin

ACCP

PrPase2A

PKAAMPK

GlucagonCortisol

Ep

PKA


PK

PFK-1

PDH

PKAPKP

F26BPase-PFK-2

F26BPase-PFK-2P

PKA

Acetyl-CoA

Pyr

Glc

G6P

GKPPP

(NADPH)

FA

Glycerol

Acetyl-CoA

KB

ACC

MCoA

Acetyl-CoA

TAGHSLHSLP

PDHK

ATPNADH

PDHP

ACCP

PKAAMPK

GlucagonCortisol

Ep

PKA


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

Esterification

HSLHSLP

PrPase2A

PDHP

PDHP

Insulin

ACCP

PrPase2A


Acetyl-CoA

Pyr

PK

PFK-1

PDH

PKAPKP

F26BPase-PFK-2

F26BPase-PFK-2P

PKA

PDHK

ATPNADH

PrPase2A

InsulinGlc

G6P

GKPPP

(NADPH)

ACC

MCoA

FA

Glycerol

Acetyl-CoA

KBCit

Acetyl-CoA

PA

TAG

G3P

Esterification

HSLHSLP

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

Glycogen

Glycogenolysis

Fatty acids(TAG)

β-Oxidation

Ketone bodies

Glycogenesis

Gluconeogenesis

Lipogenesis

Amino acids

(Protein)

Lipolysis

Impact of Diabetes on Glycogen

Glycogenolysis

PPaP

Glycogenesis

Insulin (ML)

IR

Ep (ML)

βARcAMP

Glucagon (L)

GS GSPn

GSK-3

AKT PDK-1

AKTP

PKA PKA

PPK 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


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-2

F6P↑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


FA


More glucose, fatty acids, ketone bodies

Impact of Diabetes on Lipogenesis/Lypolysis (A)

Acetyl-CoA

Pyr

PK

PFK-1

PDH

PKAPKP

F26BPase-PFK-2

F26BPase-PFK-2P

PKA

PDHK

ATPNADH

PrPase2A

InsulinGlc

G6P

GKPPP

(NADPH)

ACC

MCoA

FA

Glycerol

Acetyl-CoA

KBCit

Acetyl-CoA

PA

TAG

G3P

Esterification

HSLHSLP

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


Starvation

• Glucose from glycogen

• Alanine from protein

Diabetes

• Alanine from protein (muscle wasting)

AdipocytesWell-fed


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?

Documents

Eric Niederhoffer SIU-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