Endogenous Opioid Activity and Affective State in Insulin Resistant Women

Insulin resistance, a primary component of the metabolic syndrome, is an escalating phenomenon in the United States, and confers an increased risk of depression and mood disorder, particularly in women. The relationship between metabolic and mood disorders may be mediated by endogenous opioid activity in limbic brain regions. We propose to examine affective state and μ- opioid system function in insulin resistant women, and change in response to insulin sensitizing treatment, through the following specific aims and hypotheses: Establish relationship between insulin resistance, affective state, and μ-opioid receptor function. Insulin resistant women will have greater μ-opioid receptor availability at baseline, and a larger response to stress challenge than non-insulin resistant women Insulin resistant women will have greater negative affective state at baseline, and a greater emotional response to stress challenge than non-insulin resistant women. Mediational analyses will reveal that the relationship between insulin resistance and negative affect is mediated by μ-opioid receptor function and neural activation in the amygdala and nucleus accumbens affect-regulating regions. Examine effects of insulin regulation on μ-opioid receptor function and affective state. Improved insulin sensitivity will be accompanied by decreased μ-opioid receptor availability at baseline and a reduced response to stress challenge. Degree of change in baseline receptor availability and response to stress challenge after treatment will correlate with degree of insulin regulation. Improved insulin sensitivity will be associated with improved affective state at baseline, and with a reduced emotional response to stress challenge. Degree of change in affective state and emotional response to stress challenge after treatment will correlate with degree of insulin regulation. Mediational analyses will reveal that the change in affective state after insulin regulation is mediated by change in μ-opioid receptor function and neural activation in the amygdala and nucleus accumbens. The expected results would suggest a role for the endogenous μ-opioid system in mediating the relationship between metabolic function and emotional processes.

The objective of this study is to examine the role of the endogenous mu-opioid system in mediating the relationship between metabolic dysfunction and depressive symptoms in reproductive aged women. PET image data was unable to be analyzed due to PET equipment replacement midway through study, leaving PET images collected at beginning of study incompatible with PET images collected later in study. Due to insufficient enrollment in treatment arms, the 20 or 40 week data was unusable for analytic goals, so the study was re-framed for what could usefully be learned about baseline characteristics among the study populations and the originally planned outcome measures were amended to only to those that related to understanding the baseline population.

metabolically healthy controls will participate in baseline assessments only, and will not be randomized to the placebo and metformin treatment arms.

Women classified as insulin resistant will participate in both a placebo and a metformin treatment arm, each lasting about 16 weeks. Women will be randomized to order of treatment arms.

Mu-opioid neurotransmission in limbic brain regions at baseline and change from baseline after metformin treatment

Mu-opioid neurotransmission in limbic brain regions at baseline and change from baseline after metformin treatment

Mu-opioid neurotransmission in limbic regions at baseline and change from baseline after metformin treatment

Mu-opioid neurotransmission in limbic brain regions at baseline and change from baseline after metformin treatment

Compare positive affective state between controls and insulin resistant women. Positive and Negative Affect Schedule - positive affective state. Scores can range from 10-50, with higher scores representing more positive affective state (better outcome)

Measure of overall negative affective state at baseline in controls and insulin resistant women. Positive and Negative Affect Schedule - negative affective state. Scores can range from 10-50, with higher scores representing more negative affective state (worse outcome)

Measure of overall negative mood at baseline in controls and insulin resistant women; Profile of Mood States are standardized to a relative score where a higher score is a worse mood state. Standardized cores generally ranged from - 11 to 52.

Measure of depression symptoms at baseline in controls and insulin resistant women. The Beck Depression Index runs on a scale from 0 to 63 where low scores mean less depression and high scores mean greater depression. Clinically, scores of 14 or higher are considered mild depression; 20 is moderate and 29 is severe.

Inclusion Criteria: Women 18-40 years old metabolically healthy or insulin resistant (insulin sensitivity > 1.89x10-4 (min-1 x µU-1 x mL-1; calculated by minimal model assessment of glucose tolerance test) body mass index (BMI = weight (kg) / height2 (m2)) between 18 kg/m2 and 35 kg/m2. Women with mild or moderate depressive symptoms not meeting the criteria for Major Depressive Disorder will be included. Exclusion Criteria: men left handed acute medical illness uncorrected thyroid disease diabetes (fasting glucose ≥126 mg/dL)\ neurological disease major depression substance abuse MRI contraindications (claustrophobia, pacemakers, pumps, metallic agents or devices) severe calorie restriction intense physical exercise ≥1 hour/day smoking within 6 months hormonal, insulin sensitizing, or centrally acting medications within 2 months pregnancy within 6 months lactation cardiac or pulmonary insufficiency liver or renal insufficiency (>2.5 x normal transaminases levels, plasma creatinine ≥1.4 mg/dL) history of lactic acidosis BMI ≥35 kg/m2 opioid allergy