Depression and insulin resistance: applications to polycystic ovary syndrome.
Clin Obstet Gynecol. 2004 Sep;47(3):592-6.
Duke University Medical Center, Durham, North Carolina.
Insulin resistance in depressive disorders and Alzheimer's disease: revisiting the missing link hypothesis.
Rasgon NL, Kenna HA.
Neurobiol Aging. 2005 Dec;26 Suppl 1:103-7. Epub 2005 Oct 11.
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine.
Several lines of evidence suggest an association between depressive disorders and Alzheimer's disease
(AD). We previously suggested central nervous system (CNS) effects of insulin resistance (IR) to
be an important link between depressive disorders and AD. Although the exact mechanism of central
IR is not known, it is thought that central IR results in inadequate glucose metabolism in the brain.
According to our hypothesis, inadequate glucose utilization resulting from IR underlies neuronal
changes in crucial brain regions (i.e. limbic system) observed among patients with depressive disorders,
the same brain regions affected in AD. Further, in patients with undetected and/or untreated IR,
such changes in glucose utilization, if unresolved, may lead to neurodegeneration. Our studies
have demonstrated a high prevalence of IR in patients with depressive disorders, and reciprocally,
a high prevalence of depression in patients with the primary IR disorder polycystic ovary syndrome
(PCOS), and we believe these populations have significantly increased risk of cognitive decline.
Herein, we review the IR link in depressive disorders and AD and describe the results of our studies
and others in support of this hypothesis.
Insulin resistance after oral glucose tolerance testing in patients with major depression.
A Winokur, G Maislin, JL Phillips and JD Amsterdam.
Am J Psychiatry. 1988 Mar;145(3):325-30.
Department of Psychiatry, School of Medicine, University of Pennsylvania, Philadelphia 19104.
An association between affective disorders and alterations in glucose utilization has been recognized.
The authors administered a 5-hour oral glucose tolerance test (GTT) to 28 depressed patients and 21 healthy
volunteer control subjects and measured serum glucose as well as plasma insulin and glucagon responses. Depressed
patients demonstrated significantly higher basal glucose levels, greater cumulative glucose responses
after the GTT, and larger cumulative insulin responses after the GTT than control subjects. Values
for cumulative glucagon did not significantly differ between groups. These findings indicate the presence
of a functional state of insulin resistance during major depressive illness and suggest the presence
of a more generalized biological disturbance in some depressed patients.
A biochemical and functional characterization of diet-induced brain insulin resistance.
Mielke JG, Taghibiglou C, Liu L, Zhang Y, Jia Z, Adeli K, Wang YT.
J Neurochem. 2005 Jun;93(6):1568-78.
Brain and Behaviour Program, Hospital for Sick Children, Toronto, Ontario, Canada.
While considerable research has examined diminished insulin responses within peripheral tissues, comparatively
little has been done to examine the effects of this metabolic disruption upon the CNS. The present study
employed biochemical and electrophysiological assays of acutely prepared brain slices to determine whether
neural insulin resistance is a component of the metabolic syndrome observed within the fructose-fed (FF)
hamster. The tyrosine phosphorylation levels of the insulin receptor (IR) and insulin receptor substrate
1 (IRS-1) in response to insulin were significantly reduced within FF hamsters. Also, insulin-mediated
phosphorylation of both residues necessary for activation of the serine-threonine kinase Akt/PKB, a key
effector of insulin signaling, was markedly decreased. Elevated levels of the protein tyrosine phosphatase
1B, which dephosphorylates the IR and IRS-1, were also observed within the cerebral cortex and hippocampus
of FF hamsters. Examination of whether a nutritionally induced compromise of neural insulin signaling
altered synaptic function revealed a significant attenuation of insulin-induced long-term depression,
but no effect upon either paired-pulse facilitation or electrically induced long-term potentiation. Collectively,
our results demonstrate, for the first time, that nutritionally induced insulin resistance significantly
affects the neural insulin signaling pathway, and suggest that brain insulin resistance may contribute
to cognitive impairment.
The relationship between central serotonergic activity and insulin sensitivity in healthy volunteers.
Horacek J, Kuzmiakova M, Hoschl C, Andel M, Bahbonh R.
Psychoneuroendocrinology. 1999 Nov;24(8):785-97.
3rd Faculty of Medicine, Charles University, Prague, Czech Republic.
In order to determine whether central serotonin (5-HT) activity is related to sensitivity of insulin
receptors, 19 healthy volunteers with normal basal glycemia and HbAlc were studied. The relationship
between prolactin response to D-fenfluramine (delta PRL) in a challenge test and metabolic clearance
rates (MCR) of glucose during the hyperinsulinemic-euglycemic clamp technique was evaluated. delta PRL
had been chosen as a correlate of central 5-HT activity. Two levels of insulin concentration of approximately
70 mU/l (MCRsubmax) and 2000 mU/l (MCRmax) were used in a clamp, each for a duration of 120 min. A negative
correlation was found between delta PRL and MCRsubmax (r = -0.55, P < 0.02) and between delta PRL
and MCRmax (r = -0.51, P < 0.03). We did not find any correlation between the prolactin response to
D-fenfluramine and body weight, body mass index (BMI) or waist and hip circumference (WHR). The data
support the hypothesis of a close connection between 5-HT activity in the brain and peripheral sensitivity
to insulin. The possible physiological mechanisms of this connection are discussed.
The metabolic syndrome is associated with reduced central serotonergic responsivity in healthy community
Muldoon MF, Mackey RH, Korytkowski MT, Flory JD, Pollock BG,Manuck SB.
J Clin Endocrinol Metab. 2006 Feb;91(2):718-21. Epub 2005 Nov 22.
Division of Clinical Pharmacology, Departments of Medicine and Epidemiology, University of Pittsburgh.
CONTEXT: The pathobiology of the metabolic syndrome remains unclear. The central nervous system is
likely to be involved via regulation of eating, physical activity, blood pressure, and metabolism.
OBJECTIVE: The objective of this study was to test the hypothesis that low central serotonergic
activity is associated with the metabolic syndrome. DESIGN, SETTING, PARTICIPANTS: This was a cross-sectional
study of 345 healthy community volunteers, aged 30-55 yr, not taking medications for hypertension,
lipid disorders, or diabetes. OUTCOME MEASURES: Central serotonergic responsivity was assessed with
the iv citalopram challenge test. The serum prolactin area under the curve (AUC) over 150 min was
calculated, and all analyses were adjusted for age, sex, plasma citalopram concentration, and baseline
prolactin. The metabolic syndrome was defined according to the National Cholesterol Education Program
(NCEP) and International Diabetes Federation (IDF) criteria. Insulin resistance was estimated by
homeostasis model assessment. RESULTS: Compared with other individuals, persons meeting either NCEP
or IDF criteria for the metabolic syndrome had lower mean prolactin responses (P < 0.05 for both).
Using logistic regression, a decrease in prolactin AUC of 1 sd (-13.6 ng/ml.h) more than doubled
the odds of having the metabolic syndrome (NCEP criteria: odds ratio, 2.38; 95% confidence interval,
1.14-4.97; P = 0.02; IDF criteria: odds ratio, 2.80; 95% confidence interval, 1.48-5.30; P = 0.002).
Finally, the prolactin AUC was negatively associated with insulin resistance (beta = -0.03, P =
0.02). CONCLUSIONS: Corroborating previous evidence, the metabolic syndrome
was associated with diminished brain serotonergic activity as reflected in a comparative blunting of the prolactin response
to a selective serotonergic challenge. This association may have implications for the etiology,
prevention, and treatment of the metabolic syndrome.
Low central nervous system serotonergic responsivity is associated with the metabolic syndrome
and physical inactivity.
Muldoon MF, Mackey RH, Williams KV, Korytkowski MT, Flory JD, Manuck SB.
J Clin Endocrinol Metab. 2004 Jan;89(1):266-71.
Divisions of Clinical Pharmacology, Department of Medicine, University of Pittsburgh School
The metabolic syndrome, recognized by the co-occurrence of general or abdominal obesity, hypertension,
dyslipidemia, insulin resistance, and dysglycemia, appears to involve disturbances in metabolism,
autonomic function, and health-related behaviors. However, physiological processes linking the
components of the metabolic syndrome remain obscure. The current study examined associations
of central nervous system serotonergic function with each metabolic syndrome risk variable,
the metabolic syndrome, and physical activity. The subjects were 270 adult volunteers who participated
in a study of cardiovascular disease risk factors and neurobehavioral functioning. Central serotonergic
responsivity was indexed as the prolactin (PRL) response evoked by the serotonin-releasing agent,
fenfluramine. Across the sample, low PRL response was associated with greater body mass index,
higher concentrations of triglycerides, glucose, and insulin, higher systolic and diastolic
blood pressure, greater insulin resistance, and less physical activity (P < 0.03-0.001).
There also existed an inverse linear relationship between PRL response and the number of metabolic
syndrome risk factors individuals possessed (P for trend = 0.002). Finally, a 1 SD decline in
PRL response was associated with an odds ratio for the metabolic syndrome of 2.05 (95% confidence
interval, 1.10-3.83; P = 0.002) and 5.70 (95% confidence interval, 1.69-19.25; P = 0.005), according
to the definitions of the National Cholesterol Education Program and the World Health Organization,
respectively. These findings reveal a heretofore unrecognized association between reduced central
serotonergic responsivity and the metabolic syndrome.
Depressive symptoms, insulin resistance, and risk of diabetes in women at midlife.
Everson-Rose SA, Meyer PM, Powell LH, Pandey D, Torrens JI, Kravitz HM, Bromberger JT, Matthews KA.
Diabetes Care. 2004 Dec;27(12):2856-62.
Department of Preventive Medicine, Rush University Medical Center, Chicago.
OBJECTIVE: To examine depression and 3-year change in insulin resistance and risk of diabetes and whether
associations vary by race. RESEARCH DESIGN AND METHODS: We analyzed data from 2,662 Caucasian, African-American,
Hispanic, Japanese-American, and Chinese-American women without a history of diabetes from the Study
of Women's Health Across the Nation. We estimated regression coefficients and odds ratios to determine
whether depression (Center for Epidemiological Studies Depression Scale score > or =16) predicted
increases in homeostasis model assessment of insulin resistance (HOMA-IR) and greater risk of incident
diabetes, respectively, over 3 years. RESULTS: Mean baseline HOMA-IR was 1.31 (SD 0.86) and increased
0.05 units per year for all women (P <0.0001). A total of 97 incident cases of diabetes occurred.
Depression was associated with absolute levels of HOMA-IR (P <0.04) but was unrelated to changes in
HOMA-IR; associations did not vary by race. The association between depression and HOMA-IR was eliminated
after adjustment for central adiposity (P=0.85). Depression predicted a 1.66-fold greater risk of diabetes
(P <0.03), which became nonsignificant after adjustment for central adiposity (P=0.12). We also observed
a depression-by-race interaction (P <0.05) in analyses limited to Caucasians and African Americans,
the only groups with enough diabetes cases to reliably test this interaction. Race-stratified models
showed that depression predicted 2.56-fold greater risk of diabetes in African Americans only, after
risk factor adjustment (P=0.008). CONCLUSIONS: Depression is associated with higher HOMA-IR values
and incident diabetes in middle-aged women. These associations are mediated largely through
However, African-American women with depression experience increased risk of diabetes independent of
central adiposity and other risk factors.
Insulin resistance: a metabolic link between depressive disorder and atherosclerotic vascular diseases.
Med Hypotheses. 2002 Nov;59(5):537-51.
Department of Psychiatry, University of Calgary, Foothills Hospital, Canada.
The association of depression with insulin resistance (IR) and athersclerotic vascular diseases has been
well documented. This review examines the relevance of IR as a link between depressive disorder and atherosclerotic
vascular diseases. Relevant articles collected from Medline database over the period of 1966-2001 were
reviewed. Studies have shown that IR is a state-dependent abnormality in depression and depression
increases the risk of vascular morbidity and mortality. Given that IR is a central component of cardiovascular
risk factors, depression-related IR might play a role in the development and progression of coronary
and cerebral atherosclerosis in chronic-resistant depression. Further, IR may contribute to the pathophysiology
of depressive disorder. In conclusion IR could account for the linkage between depression and atherosclerotic
vascular diseases. More studies are needed to examine the importance of improving insulin sensitivity
in the treatment of chronic-resistant depression and prevention of depression-related vascular morbidity
Metabolism, mood and cognition in aging: the importance of lifestyle and dietary intervention.
Hendrickx H, McEwen BS, Ouderaa F.
Neurobiol Aging. 2005 Dec;26 Suppl 1:1-5. Epub 2005 Nov 14.
Unilever Corporate Research, Colworth House, Sharnbrook MK44 1LQ, UK.
We are witnessing an unprecedented rise in obesity and Type 2 diabetes. Until recently, study of the
relation between metabolic dysregulation and higher brain function was limited. This paper summarizes
the findings of a Spark workshop that focussed on the impact of obesity and diabetes on mood and cognition.
in peripheral glucose regulation are associated with cognitive impairment and depressed mood, especially
in older adults. Multiple mechanisms and mediators underlie this association including insulin, glucose,
neurotropic factors, glucocorticoids, inflammatory agents and reactive oxygen species. Importantly, prevention
and even reversal of diabetes and obesity related cognitive impairment and depressive mood can be brought
about by lifestyle modification. In particular, increasing physical fitness and moderating/changing food
intake will have beneficial effects. Prevention of obesity and hyperglycemia by adopting a healthy lifestyle
will contribute to the maintenance of functional integrity and mental health later in life.
Alpha lipoic acid: a novel treatment for depression.
Med Hypotheses. 2000 Dec;55(6):510-2.
Amherst College, Amherst, Massachusetts.
Insulin resistance has been associated with people diagnosed with depression. Conversely, it has
also been documented that diabetics have an increased risk of depression. Evidence suggests that insulin
activity plays a role in serotonergic activity by increasing the influx of tryptophan into the brain.
This increased influx of tryptophan has been shown to result in an increase in serotonin synthesis. In
accordance with the serotonin theory of depression, it may be possible to treat depression by increasing
insulin activity. The antioxidant alpha lipoic acid has been shown to increase insulin sensitivity and
is used to treat people with diabetes. Therefore, the nutrient alpha lipoic acid should be clinically
tested as an adjunct treatment for depression. Copyright 2000 Harcourt Publishers Ltd.