Hostility, Adiposity and the Adrenal Medulla
Psychological Factors And The Physiology of Glucose Regulation Richard S. Surwit
Richard S. Surwit
Disclosure: This work is supported by R01HL076020 and P01HL36587.
B k
Background
d
• Exaggerated glycemic response to stress and to epinephrine (EPI) have be found in animals and humans predisposed to obesity and diabetes C57BL6J Ob/Ob Mouse
600
GLUCO
OSE (MG//DL)
OBESE
500
400
300
LEAN
200
100
0
0
30
5 15
60
120
TIME (MIN)
Kuhn et al: 1987, PHARMACOLOGY, BIOCHEMISTRY & BEHAVIOR Pima Indians
Se
erum glucose (mM
M)
6.8
6.2
5.6
Caucasian
5.0
4.4
4
4
0
Pima
30
60
Minutes post prandial
120 130 140 150
1
2
3
Stress Test Times
Stress
Test Times
Esposito‐del Puente, 1994, International Journal of Obesity
Personality Factors Have Also Been Related to Glucose Metabolism
• Depressed affect
• Hostility
Hostility
• Hostility is a personality construct that has
been associated with increased risk of
cardiovascular disease and all cause
mortality.
Hostility
y is Commonlyy Measured By
y
The 27 item Cook Medley Hostility
Questionnaire ((CMHOST))
Covers primary cognitive dimensions
reflecting cynicism and mistrust
“I think most people would lie to get ahead.”
“People
People often disappoint me
me.”
“It’s safer to trust nobody”
The Mechanism of Hostility’s Relationship to Disease is Unknown
• Hostility
y has been related to increased
neuroendocrine response to stress.
• Hostility
y has also been associated with
increased food intake, BMI, and decreased
insulin sensitivity.
Does Hostility Impact Glucose Does
Hostility Impact Glucose
Metabolism?
• Fasting glucose and HbA1c are linearly
related to risk for cardiovascular disease,
even throughout the “normal”
normal range.
Hostility Is Correlated with Fasting Glucose in African Americans
Adju
usted BG (mg
g/dl)
120
120
African American
110
R=.44, p<.01
110
100
100
90
90
80
80
70
70
60
60
5
10
15
Hostility Score
20
Caucasian
5
10
15
Hostility Score
Surwit et al 2002, Diabetes Care
20
Relationship of Hostility to Fasting Glucose Was Repeatedly Found in African American Women
Studyy A
N=101
Fasting glucose
*p<.04
.22*
Replication Replication
Studyy B
Studyy C
N=44
N=38
.34*
.34*
Georgiades et al 2009 Psychosomatic Medicine
Georgiades, et al, 2009 Psychosomatic Medicine
How Does Hostility Impact Glucose Metabolism?
• Determine the variables which may
y mediate
Hostility’s impact glucose metabolism in
these populations
– Sympathoadrenal activity
– BMI
– Physical Activity
• Determine the relationship between Hostility
and glucose kinetics in healthy White and
African American men and women
Surwit et al 2009 Psychosomatic Med
Surwit et al, 2009, Psychosomatic Med
The Labeled IVGTT
The Labeled IVGTT
• Enables modeling of glucose kinetics in vivo
• Enables separation of endogenous glucose
(from liver and kidneys) from exogenous
glucose
Method
• 115 African American and White male and
f
female
l volunteers
l
• Glucose bolus (300mg/kg) containing 2mg/kg
(0 7%) 13C6-glucose administered by IV push (1
(0.7%)
min)
• Specimens
p
collected at t= -1, 2, 3, 4, 5, 6, 10,
12, 15, 20, 30, 40, 60, 80, 100, 120, 140, 150,
180, 210, 240 min.
• Total
T t l Glucose
Gl
& Insulin
I
li assayed
d
• Glucose Isotope ratio by mass spec
Minimal Model of Glucose Kinetics
• DI= Glucose Disposition Index, reflects the ability of the
beta cells in the pancreas to compensate for increased
insulin resistance.
• Sg= Glucose effectiveness, is a measure of the ability of
glucose to stimulate its own uptake independent of insulin
insulin.
• AIRg= Glucose-stimulated insulin release.
• Si= Insulin Sensitivity.
• NEFA= Non-esterified fatty acids.
• EGP= Endogenous glucose production, refers to glucose
produced in the liver and kidneys through the process of
gluconeogenesis.
l
i
•Hostility was related to metabolic y
parameters only in African American Women
•Hostility was unrelated to self‐report of •Hostility
was unrelated to self report of
physical activity as measured by the IPAQ.
Hostility and BMI Figure 1. Association of Hostility to BMI in women and men. Blue squares and lines represent African Americans and green circles and lines represent Whites.
Relationship of Hostility to BMI in African American Women 45.00
r=.42, p=.02
BMI kg/m22
40.00
35.00
30.00
25.00
R Sq Linear = 0
0.172
172
20.00
0
5
10
15
20
25
CMHOST
Surwit, R. S. et al. Psychosomatic Medicine, 2009
30
Relationship of Hostility to Epinephrine Change in African American Women
g
r=.40, p=.03
Delta E
EPI
20.00
0.00
-20.00
-40.00
R Sq Linear = 0
0.155
155
0
5
10
15
20
25
CMHOST
Surwit, R. S. et al. Psychosomatic Medicine, 2009
30
Relationship of Hostility to Fasting NEFA in African American Women
African American Women
Non-Esterified Fatty Ac
cids (meq/L)
1.20
r=.44, p=.01
1.00
0.80
0.60
0 40
0.40
0.20
R Sq Linear = 0.193
0.00
0
5
10
15
20
CM HOST
Surwit, R. S. et al. Psychosomatic Medicine
25
30
Relationship of Hostility to DI in Af i
African American Women
A
i
W
10.00
rr=-.44,
.44, p
p=.01
.01
LnDI
9.00
8 00
8.00
7.00
6.00
R Sq Linear = 0
0.19
19
5.00
0
5
10
15
20
25
CM HOST
Surwit, R. S. et al. Psychosomatic Medicine, 2009
30
Relationship of Hostility to Sg in Af i
African American Women
A
i
W
-2.00
2 00
r=.49, p=.008
LnSg
-3.00
-4.00
-5.00
-6.00
R Sq Linear = .24
24
-7.00
0
5
10
15
20
CM HOST
Surwit, R. S. et al. Psychosomatic Medicine, 2009
25
30
Hostility is Related to Hepatic Glucose Production
• Hepatic
Hepatic glucose production was estimated by glucose production was estimated by
assessing the ratio of labeled to unlabeled glucose and then measuring the latency of
glucose and then measuring the latency of suppression of hepatic glucose following the IV bolus
Latency Time of Endogenous Glucose S
Suppression During the IVGTT
i D i
h IVGTT
Endogenous G
Glucose
Latency
Time
EGP laten
ncy time (m
min.)
Hostility Was Associated with Increased Time to Suppression of
pp
Endogenous Glucose in African American Women
American Women
40
r=.50, p=.001
30
20
10
R Sq
q Linear = 0.25
0
0
5
10
15
CMHOST
20
25
30
Endogenous Glucose Latency Time g
y
in Relation to NEFA and Sg
Spearman’s rho
NEFA
.50*
50*
Sg
.50*
* P<.01
How Hostility Appears to Impact Fasting Glucose
Fasting Glucose
Suppression Endogenous
Glucose
Production
EPI
Hostility
NEFA
Central l
C
Adiposity
Fasting Glucose
Pancreatic Beta Cell Function
(DI)
Hostility Metabolism and Serotonin
Hostility, Metabolism and Serotonin
• Recent studies showed that AN SSRI
(citalopram) successfully reduced hostility
and improved metabolic parameters in high
hostile individuals. Kamarck et al,
Psychosomatic Medicine
Medicine, 2009
2009,
Psychoneuroendocrinology, 2011).
Does Serotonin Metabolism Play
a Role in the Relationship of
Hostility
y to Metabolic Function?
Methods
Sample
37 healthy African American women. Mean age 32(9)
years.
Measures
Hostility was assessed by a 27-item version of the
Cook-Medley Hostility Scale. Tryptophan (TRYP), 5OH-tryptophan (5HTP) and 5HIAA was assayed from
cerebrospinal fluid drawn after lumbar puncture.
Glucose and insulin were assayed from blood samples
drawn after an overnight fast.
Associations Among Study Variables
TRYP
TRYP
5HTP
5HIAA
Hostility Glucose
Insulin
1.00
.37*
.01
-.03
.16
1 00
1.00
.52**
52**
.43**
43**
.42**
42** .56**
56**
1.00
.46**
.38*
5HTP
5HIAA
Hostility
Glucose
1.00
-.06
.29
.52** .41**
1.00
Insulin
.68**
1.00
* P<.05, **P<.01
Boyle et al, 2010, Psychosomatic Medicine Common Factor Analysis
A common factor analysis performed on ageadjusted hostility scores, fasting glucose and
insulin, 5HTP and 5HIAA yielded a single
factor (Eigenvalue = 2.31) in which all
variables loaded above .55.
Hypothesized
yp
Interrelations Between Central
Serotonin, Hostility and Glucose Metabolism
CNS
SEROTONIN
H tilit
Hostility
Glucose
metabolism
Do Central Adiposity and
E i
Epinephrine
h i IInteract
t
t tto D
Determine
t
i
Glucose Levels in African
American Women?
Surwit et al, 2010, Obesity
DEXA scan
1
3
2
4
2
5
6
Standard regions
of a DEXA scan:
1. head
2. trunk
3. right arm
4 left arm
4.
5. right leg
6. left leg
Association between % Trunk Fat and Fasting Glucose in African American Women
Fasting Glucose in African American Women
Fasting
g Glucos
se (mg/d
dl)
120.00
r=.45, p<.001
110.00
100.00
90.00
80.00
70.00
R Sq Linear = 0.204
60 00
60.00
10.0
20.0
30.0
40.0
TRUNK FAT
50.0
60.0
Association Between Plasma EPI Levels and Fasting Glucose in African American Women with High Central Adiposity
African American Women with High Central Adiposity African American women, High Trunk fat (>32%) group
Fastting Gluco
ose
110.00
100.00
90.00
80.00
R Sq Linear = 0.361
70.00
1.00
2.00
3.00
ln EPI mean
4.00
5.00
Association Between Plasma EPI Levels and Fasting Glucose in African American Women with Low Central Adiposity
African American Women with Low Central Adiposity African American women, low trunk fat (<32%) group
Fasting Gluco
ose
100 00
100.00
90.00
80.00
70.00
R Sq Linear = 6.57E-4
60.00
1.00
2.00
3.00
ln EPI mean
4.00
5.00
95% CI Faasting Gluccose (mg/ddl)
Fasting Glucose Levels by Trunk Fat Group (Low/High)
and Epinephrine Group (Low/High)
105 00
105.00
100.00
95.00
90.00
85.00
80.00
Low Trunk fat,
Low EPI
High Trunk fat, Low Trunk fat,
Low EPI
High EPI
Surwit et al. 2010, Obesity
High Trunk fat,
High EPI
NEFA levels by EPI and Obesity Group in African American Women
in African American Women
Conclusion
• Epinephrine interacts with central adiposity in d t
determining fasting NEFA and fasting glucose in i i f ti NEFA d f ti
l
i
African American women Does Adrenal Medullary Function Play a Role in Maintaining Euglycemia?
Method
We examined 445 healthy euglycemic individuals (
(159 white women, 156 white men, 75 AA ,
,
women and 55 AA men) who had completed a p
DEXA scan as well as collection of both plasma and urine epinephrine measurements. Plasma Epinephrine Levels In Men and Women With Fasting Glucose <95 mg/dl
Women With Fasting Glucose <95 mg/dl
Urinary Epinephrine Levels in Men and Women With Fasting Glucose < 95 Women With Fasting Glucose 95
mg/dl
Relationship of Urinary Epinephrine to BMI in Chinese Euglycemic Subjecs
BMI in Chinese Euglycemic
BMI
16 20
16‐20
21 23
21‐23
24 25
24‐25
26 28
26‐28
28 38
28‐38
N 577
N=577
Urinary EPI
(nm/dl)
72
67
53
62
41
P<.001
Lee et al, 2001, Metabolism
,
,
Several Smaller Studies Show the Same Phenomenon in Other Populations
Phenomenon in Other Populations
• Caucasian men. Loebig et al, 2010, PloS One.
• Adolescent Boys. Jabbour et al, 2011, Medicine and Science in Sports & Exercise
and Science in Sports & Exercise.
EPI Does Not Decrease With Increasing BMI When Fasting Glucose > 95 mg/dl
BMI When Fasting Glucose > 95 mg/dl
Does Adipose Tissue Mass Feed Back To Limit Adrenal Medullary Function to Maintain Euglyemia
Medullary Function to Maintain Euglyemia
Glucose
Adrenal
Medulla
CNS
?
?
?
Liver
FFAs
Adipose Tissue
Summary
• Hostility is related to body weight, adrenal medullary function, and CNS serotonin metabolism, and fasting glucose. • Adrenal medullary function interacts with central adiposity to determine fasting NEFA and fasting glucose.
adiposity to determine fasting NEFA and fasting glucose.
• Adrenal medullary function decreases with increasing adiposity in euglycemic individuals, but not in individuals with impaired fasting glucose
with impaired fasting glucose.
• Abnormal glucose metabolism could be due, in part, to a failure of the adrenal medulla to adapt to increasing adiposity.
di it
Collaborators
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Anastasia Georgiades
David Millington
James Lane
Mark Feinglos
Sharon Minda
H
Haoyue Zyang
Z
Raymond Boston
Rhonda Merwin
Redford Williams
Redford Williams
Ilene Siegler
John Barefoot
Cynthia Kuhn
Cynthia Kuhn
Stephen Boyle
Rima Kaddurah‐Daouk