Eric Niederhoffer SIU-SOM A 59-year-old man with a history of diabetes and alcohol abuse is brought...

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

Glucose

Glycolysis

Pyruvate

Krebscycle

ElectronTransport

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

Tissues Overview

Blood GlucoseSerum Triglycerides

GlycolysisGluconeogenesi

sβ-Oxidation

LiverAdiposeTissue

Kidney

HeartSkeletalMuscle

Glucose Homeostasis

Glycogenesis and Glycogenolysis

Insulin (ML)

Ep (ML)

βARcAMP

Glucagon (L)

GS GSPn

AKT PDK-1

PKA PKA

PPK PPKP

GSK-3P

PPb PPaP

PKA PPKP

PrPase1P

PrPase1

Glycogenesis

Glycogen

UDP-GlcGlycogenolysis

Glycolysis

TCAETC

Insulin (ML)

GS GSPn

AKT PDK-1

GSK-3P

PrPase1P

PrPase1

Glycogenesis

Glycogen

UDP-Glc

Ep (ML)

βARcAMP

Glucagon (L)

GS GSPn

PKA PKA

PPK PPKP

PPb PPaP

PKA PPKP

Glycogenesis

Glycogen

Glycolysis

TCAETC

Insulin (ML)

Ep (ML)

βARcAMP

Glucagon (L)

GS GSPn

AKT PDK-1

PKA PKA

PPK PPKP

GSK-3P

PPb PPaP

PKA PPKP

PrPase1P

PrPase1

Glycogenesis

Glycogen

Glycolysis

TCAETC

Acetyl-CoA

F26BPasePFK-2

Glycolysis: Regulatory Steps

Insulin

Glucagon

Adipose

HeartLiver

Acetyl-CoA

Glycolysis (Liver)

Alanine

PDHPase

PKAPKP

F26BPase-PFK-2

F26BPase-PFK-2P

Insulin

PrPase2A

GlucagonEp

also represses PFK synthesis

ATPNADH

ATPCit

PrPase

Acetyl-CoA

Glycolysis (Liver)

PDHPase

F26BPase-PFK-2

F26BPase-PFK-2P

Insulin

PrPase2A

ATPCit

PrPase

Acetyl-CoA

Glycolysis (Liver)

Alanine

PKAPKP

F26BPase-PFK-2

F26BPase-PFK-2P

GlucagonEp

ATPCit

Acetyl-CoA

Glycolysis (Liver)

Alanine

PDHPase

PKAPKP

F26BPase-PFK-2

F26BPase-PFK-2P

Insulin

PrPase2A

GlucagonEp

ATPNADH

ATPCit

PrPase

Acetyl-CoA

Glycolysis (Skeletal Muscle)

PDHPase

ATPNADH

ATPCit

F26BPase-PFK-2

F6P↑F6P↓

Acetyl-CoA

PDHPase

ATPNADH

ATPCit

F26BPaseP-PFK-2

F26BPase-PFK-2PKA

Insulin

AKT/WISK???

Glycolysis (Heart)

F26BPase-PFK-2 Regulation Comparison

F26BPase-PFK-2

F26BPase-PFK-2P

Insulin

PrPase2A

GlucagonEp

PKALiver

F26BPase-PFK-2

F6P↑F6P↓Skeletal Muscle

F26BPaseP-PFK-2

F26BPase-PFK-2

???PKA

Insulin

AKT/WISKHeart

Acetyl-CoA

Fructose Metabolism (Liver)

PDHPase

F26BPF26BPase-PFK-2

F26BPase-PFK-2P

Insulin

PrPase2A

GlucagonEp

ATPNADH

ATPCit

GAP DHAP

Fructose

Glyceraldehyde

FK (KHK)

Aldolase B

Triose kinase

Gluconeogenesis (Liver)

Glucagon

PKAPKP

F26BPase-PFK-2

F26BPase-PFK-2P

GKG6Pase

F16BPase

PDHKPDHPPDH

ATPNADH

Protein

MDHMal

PrPase2A

Insulin

Cortisol

CREBGR

Acetyl-CoA

HSLEp, Glucagon, CortisolInsulin

Glucagon

PKAPKP

F26BPase-PFK-2

F26BPase-PFK-2P

GKG6Pase

F16BPase

PDHKPDHPPDH

ATPNADH

Protein

MDHMal

Cortisol

CREBGR

Acetyl-CoA

HSLEp, Glucagon, Cortisol

F26BPase-PFK-2

F26BPase-PFK-2P

GKG6Pase

F16BPase

PDHPPDHPPDH

PEPCKOAA

PrPase2A

Insulin

Acetyl-CoA

TAGHSLInsulin

Glucagon

PKAPKP

F26BPase-PFK-2

F26BPase-PFK-2P

GKG6Pase

F16BPase

PDHKPDHPPDH

ATPNADH

Protein

MDHMal

PrPase2A

Insulin

Cortisol

CREBGR

Acetyl-CoA

Lipogenesis and Lipolysis (Adipose)

Acetyl-CoA

PKAPKP

F26BPase-PFK-2

F26BPase-PFK-2P

ATPNADH

PrPase2A

InsulinGlc

(NADPH)

Glycerol

Acetyl-CoA

Esterification

HSLHSLP

PrPase2A

Insulin

PrPase2A

PKAAMPK

GlucagonCortisol

PKAPKP

F26BPase-PFK-2

F26BPase-PFK-2P

Acetyl-CoA

(NADPH)

Glycerol

Acetyl-CoA

TAGHSLHSLP

ATPNADH

PKAAMPK

GlucagonCortisol

Acetyl-CoA

F26BPase-PFK-2

F26BPase-PFK-2P

PrPase2A

InsulinGlc

(NADPH)

Glycerol

Acetyl-CoA

Esterification

HSLHSLP

PrPase2A

Insulin

PrPase2A

Acetyl-CoA

PKAPKP

F26BPase-PFK-2

F26BPase-PFK-2P

ATPNADH

PrPase2A

InsulinGlc

(NADPH)

Glycerol

Acetyl-CoA

Esterification

HSLHSLP

PrPase2A

Insulin

PrPase2A

PKAAMPK

GlucagonCortisol

Impact of Diabetes on Metabolism

Acetyl-CoALactate

Production of ATP

Glucose

Glycolysis

Pyruvate

Krebscycle

ElectronTransport

Glycogen

Glycogenolysis

Fatty acids(TAG)

β-Oxidation

Ketone bodies

Glycogenesis

Gluconeogenesis

Lipogenesis

Amino acids

(Protein)

Lipolysis

Impact of Diabetes on Glycogen

Glycogenolysis

Glycogenesis

Insulin (ML)

Ep (ML)

βARcAMP

Glucagon (L)

GS GSPn

AKT PDK-1

PKA PKA

PPK PPKP

GSK-3PPPb PPaP

PKA PPKP

PrPase1P

PrPase1

Glycogen

UDP-Glc

Glycolysis

TCAETC

Glycogen breakdown

Impact of Diabetes on Glycolysis (L)

Acetyl-CoA

Alanine

PDHPase

PKAPKP

F26BPase-PFK-2

F26BPase-PFK-2P

Insulin

PrPase2A

Glucagon

ATPNADH

ATPCit

Glycolysis inhibition

PrPase

Impact of Diabetes on Glycolysis (M)

Acetyl-CoA

PDHPase

ATPNADH

ATPCit

F26BPase-PFK-2

F6P↑F6P↓

Only impact is on GLUT4

Impact of Diabetes on Glycolysis (H)

Acetyl-CoA

PDHPase

ATPNADH

ATPCit

F26BPaseP-PFK-2

F26BPase-PFK-2

???PKA

Insulin

AKT/WISK

Heart uses more fatty acids

Impact of Diabetes on Gluconeogenesis (L)

Glucagon

PKAPKP

F26BPase-PFK-2

F26BPase-PFK-2P

GKG6Pase

F16BPase

PDHKPDHPPDH

ATPNADH

Protein

MDHMal

PrPase2A

Insulin

Cortisol

CREBGR

Acetyl-CoA

More glucose, fatty acids, ketone bodies

Impact of Diabetes on Lipogenesis/Lypolysis (A)

Acetyl-CoA

PKAPKP

F26BPase-PFK-2

F26BPase-PFK-2P

ATPNADH

PrPase2A

InsulinGlc

(NADPH)

Glycerol

Acetyl-CoA

Esterification

HSLHSLP

PrPase2A

Insulin

PrPase2A

PKAAMPK

GlucagonCortisol

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?

Eric Niederhoffer SIU-SOM A 59-year-old man with a history of diabetes and alcohol abuse is brought...

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