regulation of blood sugar level at the whole animal owen m c guinness january 11, 2010 course: mpb...

Regulation of Blood Sugar Level Regulation of Blood Sugar Level at the Whole Animalat the Whole Animal

Owen MOwen MccGuinnessGuinness

January 11, 2010January 11, 2010

Course: MPB 333

Contact info:Phone: 343-4473Office: 831C Light Halle-mail:Owen.mcguinness@vanderbilt.edu

Regulation of Glucose Regulation of Glucose Homeostasis: the Metabolic Homeostasis: the Metabolic

Challenge of Insulin ResistanceChallenge of Insulin Resistance

What is a normal fasting What is a normal fasting Glucose concentration?Glucose concentration?

Normal fasting Normal fasting level=<110 mg/dllevel=<110 mg/dl

Impaired glucose Impaired glucose intolerance=110-intolerance=110-125 mg/dl125 mg/dl

Diabetes Diabetes mellitus>125mg/dlmellitus>125mg/dl

Where is glucose?Where is glucose?

ISF CellCapillary

DiffusionGlucose

=100 mg/dl

Glucose=? mg/dl

Glucose diffuses down a Glucose diffuses down a concentration gradientconcentration gradient

If the arterial glucose=100 mg/dl and insulin is If the arterial glucose=100 mg/dl and insulin is at a basal concentration, what is the glucose at a basal concentration, what is the glucose

concentration in a muscle cell?concentration in a muscle cell?

1.1. 100 mg/dl100 mg/dl

2.2. Slightly less than 100 mg/dl Slightly less than 100 mg/dl (~98 mg/dl)(~98 mg/dl)

3.3. Very low ~2 mg/dlVery low ~2 mg/dl

4.4. Greater than 100 mg/dlGreater than 100 mg/dl

Blood flow

Cell

Glu-6P

Glu

A VGLU= 100 mg/dl GLU= 98 mg/dl

3. Very low ~2 mg/dl

Glucose

Glucose-6 P

Glycogen

Pyruvate

Lactate

CO2 + H2O

GLUT

HK II

Multiple Metabolic Fates of Glucose

GSPFK

PDH

If arterial glucose=100 mg/dl ,what is the If arterial glucose=100 mg/dl ,what is the interstitialinterstitial glucose concentration outside a glucose concentration outside a

muscle cell?muscle cell?

1.1. 100 mg/dl100 mg/dl

2.2. Slightly less than 98 mg/dlSlightly less than 98 mg/dl

3.3. Very low ~2 mg/dlVery low ~2 mg/dl

4.4. Greater than 100 mg/dlGreater than 100 mg/dl

A V

Blood flow

Cell

GLU= 100 mg/dl GLU= 98 mg/dl

Glu-6P

Glu

#2. Slightly less than 98 mg/dl

Steady StateSteady State

In=Out

Out=Clearance x Concentration

Plasma Glucose

Relationship between Mass and Relationship between Mass and ConcentrationConcentration

Volume

Injected MassC ononcentrati

Glucose mass (70 kg individual)Glucose mass (70 kg individual)

Total body water (TBW)=60% Body WeightTotal body water (TBW)=60% Body Weight 42 L TBW (=0.60 *70 kg)42 L TBW (=0.60 *70 kg) Extracellular fluid volume (ECF)=1/3 TBWExtracellular fluid volume (ECF)=1/3 TBW 14 L ECF {~volume of distribution of glucose}14 L ECF {~volume of distribution of glucose} Glucose 100 mg/dl=1 mg/ml=1 g/LGlucose 100 mg/dl=1 mg/ml=1 g/L 14 grams glucose in ECF14 grams glucose in ECF 9 g/hr flux rate= rate of liver glucose production9 g/hr flux rate= rate of liver glucose production

Glucose Ingestion (75 g)Glucose Ingestion (75 g)

In=Out=9 g/h

Out=Clearance x Concentration

Plasma Glucose(14 g)

Ingest 75 grams glucoseIngest 75 grams glucose

75 grams in 300 ml water (~2 cokes)75 grams in 300 ml water (~2 cokes) Assuming it takes about 20 min to Assuming it takes about 20 min to

absorb the glucose (225 g/h)absorb the glucose (225 g/h) By 180 minutes the glucose By 180 minutes the glucose

concentration returns to normalconcentration returns to normal Removed 5.3 times the mass of Removed 5.3 times the mass of

glucose in the body in 180 minglucose in the body in 180 min

Time (min)

0 60 120 180

Glu

co

se (

mg

/dl)

0

100

200

300

400

NormalDiabetic

75 grams

75 g glucose load75 g glucose load

If you did nothingIf you did nothing glucose level exceed 500 mg/dlglucose level exceed 500 mg/dl

Liver9 g/hr

Glucose=90 mg/dl

CNS

Brain6 g/hr

MuscleFat

3 g/hr

Insulin++

GlucagonInsulin

Overnight fasted state

? ?

Liver 12 g/hrGlucose=~130 mg/dl

CNS

Brain6 g/hr

MuscleFat32 g/hr

Insulin

++

or GlucagonInsulin

Fed state

Intestine50 g/hr

Cholinergic

Liver7 g/hr

Glucose=~70 mg/dl

CNS

Brain~5 g/hr

MuscleFat2 g/hr

Insulin

++

GlucagonInsulin

Prolonged fasted state

Ketones

Liver46 g/hr

Glucose=~90 mg/dl

CNS

Brain6 g/hr

MuscleFat

40 g/hr

Insulin

++

GlucagonInsulin

“Fight or Flight” state

Adrenergic

Increased Muscle Energy

Demand

Liver26 g/hr

Glucose>~300 mg/dl

CNS

Brain6 g/hr

MuscleFat<1 g/hr

+

Glucagon

Type I Diabetic state ( loss of insulin secretion)

Kidney~19 g/hrKetones

Net Organ UptakeNet Organ Uptake

(A-V) * flow = uptake

Hepatic vein

Net Splanchnic uptakeNet Splanchnic uptake

(Artery-HepaticVein) * flow = uptake

Splanchnic bed:liverIntestineSpleenpancreas

Splanchnic BedSplanchnic Bed

Producer and/or glucose consumerLiverIntestine

Splanchnic metabolism during hyperglycemiaSplanchnic metabolism during hyperglycemia

Persistent glucose Persistent glucose production in diabetic production in diabetic (i.e. negative balance)(i.e. negative balance)

Failure to take up Failure to take up glucose with glucose with additional insulinadditional insulin

The failure to activate The failure to activate uptake and suppress uptake and suppress production both production both contributecontribute

DiabeticNon-Diabetic

Low insulin High insulin

Individuals with type II diabetes Individuals with type II diabetes The liver produces glucose The liver produces glucose despite high glucose levels despite high glucose levels

Glucose Concentration(mg/dl)

50 100 150 200

Glucose Uptake(mg/kg/min)

2

4

6

8

10

12

50 100 150 2000

2

4

6

8

10

12

Glucose Uptake(mg/kg/min)

Glucose Concentration(mg/dl)

4x insulin

basal insulin

4x insulin

basal insulin

Tissue glucose uptake Tissue glucose uptake increases in proportion increases in proportion to the available glucoseto the available glucose

Insulin facilitates this Insulin facilitates this process in tissues that process in tissues that respond to insulinrespond to insulin transporttransport phosphorylationphosphorylation– ↑↑Glycogen synthesisGlycogen synthesis– ↑↑Glucose oxidationGlucose oxidation

Insulin resistance Insulin resistance impairs this processimpairs this process

Insulin Resistant

Normal

Steady StateSteady State

In=Out

Out=Clearance x Concentration

Plasma Glucose

Source: www.cdc.gov.

Diabetes Trends* Among Adults in the Diabetes Trends* Among Adults in the U.S.,U.S.,

(Includes Gestational Diabetes)BRFSS,(Includes Gestational Diabetes)BRFSS, 1990,1995 and 20011990,1995 and 20011990 1995

2001

No Data <4% 4%-6% 6%-8% 8%-10% >10%

Liver9 g/hr

Glucose=120 mg/dl

CNS

Brain6 g/hr

MuscleFat

3 g/hr

Insulin

++

GlucagonInsulin

Overnight Fasted Insulin Resistant state

Compensation for insulin Compensation for insulin resistanceresistance

Increase insulin secretionIncrease insulin secretion Mild to severe hyperglycemia Mild to severe hyperglycemia

(Diabetes Type II; NIDDM) because (Diabetes Type II; NIDDM) because of inadequate pancreas compensationof inadequate pancreas compensation

Glucose production by liver and Glucose production by liver and uptake by peripheral tissues can be uptake by peripheral tissues can be normal or increasednormal or increased

Tools used in vivo to assess Tools used in vivo to assess glucose homeostasis and insulin glucose homeostasis and insulin

actionaction

MEASUREMENT OF GLUCOSE PRODUCTION IN VIVO

Tracer Method ( dilution principle)

3-3H Glucose infusion

Data analysis with two compartment model

A-V Difference Method

Blood glucose difference across organ

Blood flow across organ

x

-40

-20

0

20

40

0

100

200

300

-40 0 60 120 180

0

50

100

150

200

TIME ( MIN )

SENSITIVITY OF & CELLS TO GLUCOSE IN VIVO

ARTERIALPLASMAINSULIN

% BASAL

ARTERIALPLASMA

GLUCAGON

% BASAL

ARTERIALPLASMA

( mg/dl )

GLUCOSE

Gly Inhibitor + Glucose

0

2

4

ARTERIAL PLASMA GLUCOSE

( mg/dl )

EFFECT OF GLUCOSE ON INSULIN AND GLUCAGON

INSULIN

SECRETION

( pmol/kg/min )

50 75 100 125 150

0.0

0.4

0.8

GLUCAGON

SECRETION

( ng/kg/min )

SECRETION IN THE CONSCIOUS DOG

Flattem et al.: Diabetes 50, February 2001: 367-375

FastingGlucose

FastingGlucose

Sampling site: Portal Vein and Sampling site: Portal Vein and ArteryArtery

If you infuse a substance into the If you infuse a substance into the portal vein, the concentration of the portal vein, the concentration of the substance in the portal vein will be substance in the portal vein will be greater than in any other vesselgreater than in any other vessel

0

50

100

0

50

100

-40 0 60 120 180

0

50

100

TIME ( Min )

EFFECT OF A SELECTIVE INCREASE IN INSULIN

-40 0 60 120 180

0

50

100

TIME ( Min )

Pancreatic ClampInsulin

Pancreatic ClampSaline

Portal

Arterial

Portal

Arterial

PLASMA

INSULIN

( U/ml )

PLASMA

GLUCAGON

( pg/ml )

Impact of insulin on tissuesImpact of insulin on tissues

Enhance muscle glucose uptakeEnhance muscle glucose uptake Decrease liver glucose productionDecrease liver glucose production Decrease arterial glucose levelDecrease arterial glucose level Inhibit lipolysisInhibit lipolysis To prevent hypoglycemia exogenous To prevent hypoglycemia exogenous

glucose is givenglucose is given

The “gold standard” for The “gold standard” for quantifying insulin sensitivity quantifying insulin sensitivity in in

vivovivo

Primed-constantInsulin Infusion

VariableGlucose Infusion

Insulin

Glucose

RadioactiveGlucose Tracers

EndogenousGlucose Production (basal and clamp)

GlucoseDisappearance (Rd)

ExogenousGlucose Infusion rate (GIR)

Defronzo RA et al AJP E214,1979

Peripheral insulin sensitivityPeripheral insulin sensitivity

Insulin (U/ml)

0 100 200 300 700

Glu

cose

uti

liza

tio

n(m

g/k

g/m

in)

0

2

4

6

8

10

12

14

0

1

2

3

0

100

200

-40 0 60 120 180

0

1

2

3

TIME ( Min )

EFFECT OF A SELECTIVE INCREASE IN INSULIN

-40 0 60 120 180

0

1

2

3

Control

GLY

( mg/kg/min )

NET

GNG

( mg/kg/min )

FLUX

GLUCOSEPLASMA

( mg/dl )

ARTERIAL

OUTPUTGLUCOSE

( mg/kg/min )

HEPATICNET

TIME ( Min )

Pancreatic Clamp Pancreatic Clamp

+/- Insulin +/- Insulin

Insulin

Hepatic Insulin SensitivityHepatic Insulin Sensitivity

Insulin (U/ml)

0 25 50 75

Glu

cose

Pro

duct

ion

(mg/

kg/m

in)

0

1

2

3

4

5

Human

Basal Insulin

Peripheral vein

Diabetes and insulin resistanceDiabetes and insulin resistance

Insulin resistanceInsulin resistance– Normal or elevated insulin levelsNormal or elevated insulin levels– Inappropriately increased lipolysisInappropriately increased lipolysis– Insulin ineffective and in many cases Insulin ineffective and in many cases

pancreatic defects limit adaptationpancreatic defects limit adaptation– Underlying inflammation can aggravate Underlying inflammation can aggravate

defectsdefects

The EndThe End