Metabolic dysfunction in women with bipolar disorder: the potential influence of family history of type 2 diabetes mellitus

Over the last decade, metabolic dysfunction [i.e., overweight/obesity, insulin resistance (IR), and dyslipidemia] has become increasingly important in clinical medicine in general and in psychiatry in particular (1, 2). Despite intense scientific focus on this topic, risk factors for developing metabolic dysfunction as well as its pathophysiology among patients with mental illness remain to be elucidated. IR is recognized as central to the pathophysiology of many metabolic abnormalities and is a known precursor condition for type 2 diabetes mellitus (DM2), obesity, cardiovascular illness (3), and neurocognitive disorders (4). With respect to its prevalence in mood disorders, IR is hypothesized to be (i) an underlying state predisposing toward both mood disorders and metabolic disorders, (ii) a side effect of the psychotropic medications used to treat mood disorders, and/or (iii) a consequence of mood disorders themselves (e.g., lifestyle changes or stress). While our group and others have previously reported high rates of overweight/obesity and surrogate biomarkers of IR in samples of women with bipolar disorder (BD) (5–9), there are no controlled studies utilizing direct measures of insulin sensitivity and glucose utilization in BD patients. The question of trait versus state vulnerability remains unanswered, as the effects of illness per se on glucose handling in these patients are difficult to disentangle from the effects of medications used to treat the illness. Metabolic dysfunction has been routinely considered a consequence of overweight/obesity among psychiatric patients (1, 2). Weight gain leading to overweight/obesity has been viewed as a culprit in the development of IR. Weight gain in patients with BD may relate to mood state per se (i.e., altered eating patterns and energy expenditure during depressive states) and/or may be a result of treatment and number of psychotropic agents used in treatment (10, 11). Nevertheless, a significant proportion of patients with BD do not gain weight on psychotropic medications that are associated with weight gain (11). Further, it has been shown in nonpsychiatric populations that IR develops even in lean individuals (12), suggesting other potential (genetic) mechanisms for IR unrelated to weight gain. The ultimate negative outcome of a longstanding IR occurs when insulin-resistant individuals cannot secrete the amount of insulin needed to overcome the IR, and DM2 ensues (13). Familial transmission of DM2 has been widely reported (14), and some studies have shown family history of DM2 to be a risk factor for IR/DM2 (15), especially among women (16). A recent U.S. population study found that family history of DM2 was associated with risk for metabolic syndrome (17). However, it is unclear whether such history may underlie metabolic dysfunction among patients with mental illness receiving psychotropic medications, as only a handful of studies have examined metabolic function in case-controlled design in patients with affective disorders. The overall aims of the present study were to evaluate metabolic and reproductive function in women with BD in comparison to age-matched healthy controls. Reproductive data are described elsewhere [Rasgon NL, Kenna HA, Reynolds MF et al. Reproductive function in women with bipolar disorder and controls (under review)]. The current manuscript is focused only on the metabolic function assessment. Metabolic biomarkers included fasting plasma insulin (FPI), fasting plasma glucose (FPG), the homeostatic assessment of IR (HOMA-IR), body mass index (BMI), waist circumference (WC), and hip (HC) circumference, which were analyzed for group differences (BD versus controls). Within the women with BD, metabolic biomarkers were tested for differences by use of weight-liable psychotropic medications (WLM). Lastly, differences between groups with respect to the metabolic biomarkers were examined in relation to presence of DM2 in at least one first-degree female relative (FamHxDM2), which is a factor related to metabolic dysfunction in the general population (17).