Elsevier

Psychoneuroendocrinology

Volume 82, August 2017, Pages 91-97
Psychoneuroendocrinology

Biological predictors of insulin resistance associated with posttraumatic stress disorder in young military veterans

https://doi.org/10.1016/j.psyneuen.2017.04.016Get rights and content

Highlights

Abstract

Posttraumatic stress disorder (PTSD) is associated with increased risk for Type 2 diabetes and cardiovascular disease (cardiometabolic disease), warranting research into targeted prevention strategies. In the present case–control study of 160 young (mean age 32.7 years) male military veterans, we aimed to assess whether PTSD status predicted increased markers of cardiometabolic risk in otherwise healthy individuals, and further, to explore biological pathways between PTSD and these increased markers of cardiometabolic risk. Toward these aims, we compared measures of cardiometabolic risk, namely insulin resistance (IR) (HOMA-IR), metabolic syndrome (MetS) and prediabetes, between 80 PTSD cases and 80 controls without PTSD. We then determined whether PTSD-associated increases in HOMA-IR were correlated with select biological variables from pathways previously hypothesized to link PTSD with cardiometabolic risk, including systemic inflammation (increased C-reactive protein, interleukin-6, and tumor necrosis factor α), sympathetic over-activity (increased resting heart rate), and neuroendocrine dysregulation (increased plasma cortisol or serum brain-derived neurotrophic factor (BDNF)). We found PTSD diagnosis was associated with substantially higher HOMA-IR (cases 4.3 ± 4.3 vs controls 2.4 ± 2.0; p < 0.001), and a higher frequency of MetS (cases 21.3% vs controls 2.5%; p < 0.001), but not prediabetes (cases 20.0% vs controls 18.8%; p > 0.05). Cases also had increased pro-inflammatory cytokines (p < 0.01), heart rate (p < 0.001), and BDNF (p < 0.001), which together predicted increased HOMA-IR (adjusted R2 = 0.68, p < 0.001). Results show PTSD diagnosis in young male military veterans without cardiometabolic disease is associated with increased IR, predicted by biological alterations previously hypothesized to link PTSD to increased cardiometabolic risk. Findings support further research into early, targeted prevention of cardiometabolic disease in individuals with PTSD.

Introduction

Posttraumatic stress disorder (PTSD) in susceptible individuals follows traumatic exposure frequently involving actual or threatened physical harm. The lifetime prevalence in the United States is 7.8% (Kessler et al., 2005), with a higher lifetime prevalence (12–30%) in combat veteran populations (Seal et al., 2009). In addition to distressing psychological symptoms, individuals with PTSD are at increased risk for medical health problems. In particular, PTSD substantially increases risk for cardiovascular disease (CVD) (Boscarino, 2012, Edmondson et al., 2013, Kubzansky et al., 2007, Vaccarino et al., 2013) and Type 2 diabetes (T2D) (Roberts et al., 2015, Vancampfort et al., 2016), (collectively referred to as cardiometabolic disease), even after controlling for comorbid major depressive disorder (MDD), which may also increase this risk (Vancampfort et al., 2015). Cardiometabolic disease and its sequelae lead to diminished quality of life, and also contribute substantially to the PTSD-associated excess mortality rate, which is 2–3 times higher than the general population (Ahmadi et al., 2011, Schlenger et al., 2015).

In the general population, prevention of cardiometabolic disease is facilitated by screening for markers of increased risk including insulin resistance (IR), prediabetes, and metabolic syndrome (MetS) (Knowler et al., 2002, Rutter et al., 2005, Tabak et al., 2009). Insulin resistance is defined as the reduced capacity of target cells to take up glucose in response to insulin, leading to elevated blood glucose and compensatory increases in insulin (Reaven, 1988). Measures of IR obtainable in the clinical setting include fasting insulin and HOMA-IR (a fasting insulin and glucose product), both of which show good correlation with gold standard measures such as the hyperinsulinemic-euglycemic clamp (Matthews et al., 1985, ter Horst et al., 2015). ‘Prediabetes’ is defined by elevations in fasting glucose and or HbA1c that are below the threshold for T2D, and is employed by the American Diabetes Association to target T2D prevention (Association, 2016). MetS, also used in clinical practice, is a cluster of features including hyperglycemia, central obesity, dyslipidemia and hypertension, with IR as a source of pathogenesis (Reaven, 1988).

Cross-sectional evidence suggests PTSD is associated with an increase in these markers of cardiometabolic risk, consistent with an increased prevalence of cardiometabolic disease in individuals with PTSD. Multiple studies of MetS exist, largely of older individuals (>45 years), showing roughly twice the prevalence of MetS in individuals with PTSD compared to healthy controls in this age group (Bartoli et al., 2013, Rosenbaum et al., 2015). Recent studies of insulin function suggest PTSD is associated with increased fasting insulin and impaired glucose tolerance (Rao et al., 2014, Farr et al., 2015). Current limitations include few studies of insulin function and prediabetes, limited control for relevant medications and current cardiometabolic disease, and a lack of studies in military veteran populations. The latter issue is important because combat associated PTSD may be associated with substantially higher cardiometabolic risk, compared to non-combat related PTSD (Vancampfort et al., 2016). To determine whether a diagnosis of combat-associated PTSD is associated with increased markers of cardiometabolic risk prior to disease onset, we assessed data from a case–control study of young male combat veterans returning from the Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) conflicts. We compared IR (HOMA-IR) between combat-exposed veterans with, and without PTSD, whilst controlling for potential confounds including age, ethnicity, comorbid major depressive disorder (MDD), smoking, and medication use–in particular antidepressants, and atypical antipsychotics. To relate findings to clinical practice and previous studies in PTSD, we also compared on prediabetes and MetS status.

Biological mediators between PTSD and increased cardiometabolic risk remain unknown. Candidate biological mediators have been proposed, largely based on their observed occurrence both in individuals with PTSD, as well as in individuals with IR/MetS or prospectively at risk for cardiometabolic disease: these hypothesized mediators include increased systemic inflammation, increased sympathetic tone, and dysregulation in neuroendocrine pathways involved in glucose regulation, namely the glucocorticoid and brain derived neurotrophic factor (BDNF) signaling pathways (Dedert et al., 2010, Farr et al., 2014, Kubzansky et al., 2014, Levine et al., 2014, Michopoulos et al., 2016b). However, very few studies have directly linked these proposed mediators to cardiometabolic risk or markers of cardiometabolic risk in patients with PTSD. Longitudinal studies that may establish causal pathways are similarly lacking. In the current cross-sectional study, we assessed whether increased insulin resistance (HOMA-IR) associated with PTSD correlates with increased inflammatory cytokines, namely C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), increased resting heart rate, increased plasma cortisol, and increased serum BDNF.

Section snippets

Participants

One hundred and sixty-seven OIF and OEF veterans were recruited at New York University (NYU) (90 subjects) and the Icahn School of Medicine at Mount Sinai and the James J. Peters Veterans Affairs Medical Center (JJPVAMC) (77 subjects). Recruitment sites included Mental Health Services of the Manhattan, Bronx and Brooklyn Veterans Affairs Medical Centers; other regional VA medical centers; Veterans Service Organizations; National Guard; reservist agencies, and the general community. Recruitment

Participant characteristics

Eighty-three combat-exposed men with PTSD (cases), and 84 combat-exposed age-matched men without a lifetime history of PTSD (controls) were recruited. Data were not collected for one control subject, resulting in a total of 166 subjects (see Table 1). The average symptom severity (past-month total CAPS score) in PTSD cases was 69.7, (within the severe range, i.e. CAPS 60–79), and ranged between 44 (moderate) to 113 (extreme), whereas controls were asymptomatic. The average duration of PTSD

Discussion

In the present case–control study we examined whether PTSD diagnosis in young male military veterans without cardiometabolic disease is associated with increased cardiometabolic risk markers including HOMA-IR, MetS and prediabetes. To our knowledge, few studies have addressed this question in a wholly military veteran sample whilst controlling for relevant confounds and medication use. The current subjects (cases and controls) were mostly overweight and obese, with cases having slightly higher

Conflict of interest

The authors declare no conflict of interest.

Funding

The funding sources had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.

Acknowledgements

This study was supported by the following grants: U. S. Department of Defense, W81XWH-11-2-0223 (PI: Charles Marmar); U. S. Department of Defense, W81XWH-10-1-0021 (PI: Owen M. Wolkowitz); The Mental Illness Research, Education and Clinical Center (MIRECC). Daniel Lindqvist was supported by the Swedish Research Council (2015-00387), Marie Sklodowska Curie Actions, Cofund (Project INCA 600398), the Swedish Society of Medicine, the Söderström-Königska Foundation, the Sjöbring Foundation, OM

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