why are diabetes and depression associated? connecting …€¦ · why are diabetes and depression...
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Why Are Diabetes and Depression
Associated?
Connecting the Brain to the Pancreas
Sherita Hill Golden, MD, MHSHugh P. McCormick Family Professor of Endocrinology and MetabolismExecutive Vice-Chair, Department of Medicine
Division of Endocrinology, Diabetes, and MetabolismWelch Center for Prevention, Epidemiology, and Clinical Research
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Birth of a Research
Career
San Antonio, TX
American Diabetes Association
Meeting 2000
Dr. Fred Brancati
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STRESS
STRESS
Edvard Munch,
1893
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• You added bleach to the
color load by accident!
• You woke up at the time
you were supposed to be
leaving for work!
• Most of your writers have
not submitted their
articles for a pending
deadline!
6/6/2016 4
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William Osler, MD
First Chairman of Medicine
Johns Hopkins University
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Risk Factors for Type 2 Diabetes
Osler’s Principles & Practice of Medicine,
1892
• Heredity
• Ethnicity
• Social Class
• Adiposity
• Sedentary life
• Overindulgence
• Nervous strain
• Worry
STRESSSTRESS
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Diabetes and Depression: A Common
Association In Adults
• Aggregate odds ratio of depression in adults
with diabetes compared to those without
diabetes: 2.0 (95% CI: 1.8, 2.2)
• Lifetime prevalence of major depression
higher in individuals with diabetes (17.5%)
compared to those without diabetes (6.8%)
Anderson et al. Diabetes Care, 2001
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Diabetes and Depression: A Common
Association in Adolescents
• 15-20% of adolescents with type 1 diabetes
have elevated depressive symptoms
• 23% have subclinical depressive symptoms
• SEARCH Study: rates similar for type 1 and
type 2 diabetes, but slightly higher in type 2
Kovacs et al., 1997; Grey et al, 2002; Hood et al., 2006; McGrady et al., 2009;
Lawrence et al., 2006
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Average Ages of Onset for
Diabetes and Depression
Type 1 DM
5-14
Depression
18 - 39
Type 2 DM
40-60
Age
10 20 30 40 50 60 700
Depression
45 - 64
From Dr. Mercedes Carnethon
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Diabetes mellitus DEPRESSION
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Psychological demands imposed by
diabetes
New complications
Multiple complicationsVisual impairment
Impotence
Impaired physical/cognitive
functioning
Lack of
social support
Passive
coping skills
DEPRESSION
DIABETES
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Hyperglycemia associated with
diabetes
• Adverse effects on
hippocampus
– Atrophy
– Neuronal apoptosis
• Brain region that
controls mood and
cognition
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HYPERGLYCEMIA
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Description of the Multi-Ethnic
Study of Atherosclerosis (MESA)• Multi-center, longitudinal cohort study of occurrence and
correlates of subclinical CVD and factors influencing its progression
• Six centers: Northwestern University, Wake Forest University, University of Minnesota, Columbia University, Johns Hopkins University, University of California-Los
• 6,000 men and women aged 45-85 years– 40% non-Hispanic White
– 10% Chinese American
– 30% African American
– 20% Hispanic American
– No history of clinical CVD
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MESA: Diabetes Depression
Visit 1
00-02Visit 2
02-04
Visit 3
04-05
4, 847 adults
ages 45 to 84 w/o
prevalent
depression or
CHD
Depression
CES-D16 and/or
anti-depressant use
Glucose Status
Normal fasting glucose (NGT)
Impaired fasting glucose (IFG)
Untreated DM
Treated DM
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• Individuals with diabetes at baseline had a
50% higher risk of developing depression
during follow-up compared to those without
diabetes
• Independent of differences in diabetes
complications, socioeconomic status, and
obesity
Golden et al, JAMA, 2008
Diabetes Predict Development of
Depression
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DepressionDIABETES
MELLITUS
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DEPRESSION
TreatmentSerotonin reuptake inhibitors
Tricyclics
Psychosocialburden of illness,
social support
Behavioralsmoking, diet, physical
activity,
treatment adherence
Neurohormonalcortisol, catecholamines,
inflammatory markers
OBESITY
INSULIN RESISTANCE
TYPE 2 DIABETES
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MESA: Depression Diabetes
Visit 1
00-02Visit 2
02-04
Visit 3
04-05
5,201 adults ages
45 to 84 w/o
prevalent
diabetes or CHD
Depression
CES-D16 and/or
anti-depressant use
TYPE 2 DM
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Depression Predicts Development of
Diabetes
Depression was associated with type 2 diabetes risk
factors:
• Less physical activity
• Greater calorie intake
• Higher likelihood of current smoking
• Higher body mass index
• High levels of inflammatory markers
After controlling for these factors, depression was
associated with a 21% higher risk of developing type 2
diabetesGolden et al, JAMA, 2008
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Linking the Brain
and Pituitary to
the Pancreas?
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Stress affects hormonal factors that increase
diabetes risk
INSULIN RESISTANCE
TYPE 2 DM
(+)
(+)
(-)(-)
(+)
Harrison’s Textbook
of Internal Medicine
(+)
Depression/Stress
HPA axis
hyperactivity
SNS
activation
cortisol
catecholamines
interleukin-6
CENTRAL OBESITY
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Metabolic Perils of Central Obesity
• glucose and insulin
resistance
• blood pressure
• dyslipidemia (high
triglycerides, low HDL)
• Risk for developing type 2
diabetes
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Insulin Regulates Glucose Metabolism
Glucose,
other food
moleculesInsulin
Energy
CELL
Normal insulin action Abnormal insulin action
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Cortisol Hypothesis: Animal Data
Transgenic mouse
model of 11-HSD1
overexpression
• Insulin resistance
• Obesity
• High cortisol in liver
circulation
11 -HDS 1 inactive active cortisol
Masuzaki et al. Science, 2001
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Cortisol Hypothesis: Clinical and
Human Research Data
• Overt hypercortisolism
– Cushings’ Syndrome
– Steroid-induced
diabetes
• Cortisol axis dysfunction
independent of depression
– Type 2 diabetes
– Obesity
faculty.plattsburgh.edu
Champaneri et al, Metabolism, 2012
Champaneri et al, Obesity, 2013;
Joseph et al, Psychoneuroendocrinology, 2015
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So What? Significance and Future
Directions
• Modification of the neurohormonalresponse: a novel approach to primary prevention of Type 2 diabetes (complementary to established measures)
• Collaborative care models that simultaneously treat depression and diabetes will likely improve outcomes for both conditions
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Acknowledgements MESA Stress
• Shivam Champaneri, MD
• Elias Spanakis, MD
• Joshua Joseph, MD
• Steven Xu, MS
• Steven Wang, MS
• Ana Diez Roux, MD, PhD
• Mercedes Carnethon, PhD
• Alain Bertoni, MD, MPH
• Teresa Seeman, PhD
• Sandi Shrager, MSW
Neuroendocrine Study
• Gary Wand, MD
• Saurabh Malhotra, MD, MPH
• Sarah Casagrande, PhD
• Frederick Brancati, MD, MHS
• Dan Ford, MD, MPH
• Karen Horton, MD
• Ihab Kamel, MD, PhD
Funding Agencies
• NHLBI (ADR)
– RO1 HL076831: Stress I
– RO1 HL101161: Stress II
• RWJ Harold Amos Faculty Award (SHG)
• NIDDK
– K23 DK071565 (SHG)
– T32 DK062707 (Champaneri, Spanakis, Joseph)
• Johns Hopkins General Clinical Research Center