Insulin Signaling Pathways That Regulate Glucose

Metabolism in Muscle Cells and Adipocytes

INSULIN RESISTANCE
SYNDROME
Mechanisms
Role of Muscles Expression of Cytokines
in Insulin Resistance Syndrome Saghizadeh, JCI 1996
Role of Muscles Expression of Cytokines
in Insulin Resistance Syndrome Saghizadeh, JCI 1996

(triangles) Insulin sensitive

(circles) Insulin resistant
(squares) Diabetic
Tumor Necrosis Factor-–Induced Insulin
Resistance in Adipocytes Qi, Exp Biol Med 2000
LPS Regulates Proinflammatory Cytokine Expression
in Skeletal Muscle Frost, A J P Regul Integr Comp Physiol, 2002
Marked Reduction of GLUT4 in Muscle or Adipose
Tissue Causes Insulin Resistance Minokoshi, JBC, 2003
INSULIN RESISTANCE
SYNDROME
Clinical significance
Hyperglycemia and Outcome in the Acutely Ill
Umpierrez, JCEM 2002
Hyperglycemia and Outcome in the Acutely
van den Berghe, CCM 2003

<110
110-150
>150
Glucose Control and Mortality in Critically Ill Patients
Finney et al JAMA 2003
Effects of Intensive Insulin Therapy on Survival in
Surgical ICU patients. Van den Berghe, NEJM 2002
Effects of Intensive Insulin Therapy on Morbidity in
Surgical ICU patients. Van den Berghe, NEJM 2002

Polyneuropathy *

Bacteremia *
*
Renal Replacement

No vasopressors

MV duration Experimental Group

ICU LOS Control Group

0 10 20 30 40 50 60
 THE ACTORS?

• HYPOTHALAMIC PITUITARY ADRENAL AXIS

• NORADRENERGIC SYSTEM
• GLUCOSE / INSULINE DUO
• VASOPRESSIN
 VASOPRESSIN SYNTHESIS
Magnocellular nucleus
Parvocellular nucleus

Hypothalamus

Anterior
hypophysis

PRL
ADH
GH
TSH ACTH Neurohypophysis
LH FSH
MSH
 OSMOTIC ADAPTATION
PLASMA URINE
VASSOPRESIN (pg/ml)

14 14
12 12
10 10
8 8
6 6
4 4
2 2
0 0
260 270 280 290 300 310 0 300 600 900 1200 1500 1800

OSMOLALITY (mOsm/kg)
 HEMODYNAMIC ADAPTATION
25
VASOPRESSIN (pg/ml)

pression
20
volemia
osmolality
15

10

0
-28 -25 -20 -15 -12 -10 -8 -2 0 4 10 18

VARIATIONS (%)
 VASOPRESSIN
INSUFFICIENCY
Mechanisms
 AVP KINETICS IN SEPTIC
SHOCK
1000
ANIMAL MODELS

100
ENDOTOXIN

10
CONTROLS

1
C 1 2 3 4
 VASOPRESSIN IN LATE
SEPTIC SHOCK
35

30 SBP = 92±2
VASOPRESSIN (pg/ml)

25 Sodium = 140±2 22.7±2.2

20

15
SBP = 101±3
10 Sodium = 139±1
3.1±0.4
5

0
SEPTIC CARDIOGENIC
SHOCK SHOCK
Landry 1997
 AVP IN LATE SEPTIC SHOCK:
OSMOTIC ADAPTATION
25
VASOPRESSIN (pg/ml)

20
15
PATIENTS
10
5 CONTROLS

0
250 270 290 310 330 350
PLASMA OSMOLALITY mOsmol/L
 AVP IN LATE SEPTIC SHOCK:
HEMODYNAMIC ADAPTATION
Hypotensive Normotensive
VASOPRESSIN (pg/ml)

20

15

10

0
20 40 60 80 100 120 140 160 180 200

Systolic Blood Pressure (mm Hg)

AVP AS A FUNCTION OF TIME
IN HUMAN SEPTIC SHOCK
18

16

14
Vasopressin pg/ml

12

10

0
Baseline Hour-6 Hour-24 Hour-48 Hour-96
Vasopressin Deficiency Contributes to the
Vasodilation of Septic Shock .
Donald W. Landry, et al Circulation 1997
 VASOPRESSIN IN LATE
SEPTIC SHOCK
35
33
30 30
VASOPRESSIN (pg/ml)

25

20

15

10
7
5 5,9

0 Before AVP 0.01 UI of AVP

infusion infusion
Landry 1997
IMPAIRED BAROREFLEX MEDIATED
SYNTHESIS
VASOPRESSIN (pg/ml)

20

15

10

0
20 40 60 80 100 120 140 160 180 200

Systolic Blood Pressure (mm Hg)

Normal Baroreflex Impaired Baroreflex

 NEUROHYPOPHYSIS
IN SEPTIC SHOCK

NORMAL SUBJECT ACUTE PHASE RECOVERY

 Astrocytic and Microglial Reactions

• Nucleus Supra-Opticus
 VASOPRESSIN
INSUFFICIENCY
Clinical significance
 Arginine Vasopressin in Advanced Vasodilatory Shock
A Prospective, Randomized, Controlled Study
Dünser, Circulation 2003

90
PAM mmHg

* *
80 * *
70

AVP
60
NE

50
2
0 1h 12 24 48

AVP
NE

1
*
* *

0
0 1h 12 24 48
 Arginine Vasopressin in Advanced Vasodilatory Shock
A Prospective, Randomized, Controlled Study
Dünser, Circulation 2003

5
CI L/min/m2

* *
4
*

3
AVP
NE

2
1800
0 1h 12 24 48
1700
AVP
1600
NE
1500
1400
1300
1200
1100
0 1 h 12 24 48
 TAKE HOME MESSAGE

• HORMONES ARE ESSENTIAL TO SURVIVE TO A STRESS

• ANIMAL MODELS CONSISTENTLY SHOWED THAT
SEPSIS IS ASSOCIATED WITH FAILURE OF THE
VARIOUS HORMONAL SYSTEMS
• OVERALL CLINICAL STUDIES IN SEVERE SEPSIS
CONFIRMED BAD OUTCOMES ASSOCIATED WITH
FAILING HORMONAL SYSTEMS
• HORMONE REPLACEMENT THERAPY MAY BE THE
FUTURE OF SEVERE SEPSIS MANAGEMENT