Objective (1) Evaluate feasibility and acceptability of a mindfulness-based group in adolescent girls at-risk for type 2 diabetes (T2D) with depressive symptoms, and (2) compare efficacy of a mindfulness-based versus cognitive-behavioral group for decreasing depressive symptoms and improving insulin resistance. Design and setting Parallel-group, randomized controlled pilot trial conducted at a university. Participants Thirty-three girls 12-17y with overweight/obesity, family history of diabetes, and elevated depressive symptoms were randomized to a six-week mindfulness-based (n=17) or cognitive-behavioral program (n=16). Interventions Both interventions included six, one-hour weekly group sessions. The mindfulness-based program included guided mindfulness awareness practices. The cognitive-behavioral program involved cognitive restructuring and behavioral activation. Main outcome measures Adolescents were evaluated at baseline, post-intervention, and six-months. Feasibility/acceptability were measured by attendance and program ratings. Depressive symptoms were assessed by validated survey. Insulin resistance was determined from fasting insulin and glucose, and dual energy x-ray absorptiometry was used to assess body composition. Results Most adolescents attended ≥80% sessions (mindfulness:92% versus cognitive-behavioral:87%, p=1.00). Acceptability ratings were strong. At post-treatment and six-months, adolescents in the mindfulness condition had greater decreases in depressive symptoms than adolescents in the cognitive-behavioral condition (ps<.05). Compared to the cognitive-behavioral condition, adolescents in the mindfulness-based intervention also had greater decreases in insulin resistance and fasting insulin at post-treatment, adjusting for fat mass and other covariates (ps<.05). Conclusions A mindfulness-based intervention shows feasibility and acceptability in girls at-risk for T2D with depressive symptoms. Compared to a cognitive-behavioral program, after the intervention, adolescents who received mindfulness showed greater reductions in depressive symptoms and better insulin resistance.

SUMMARY Hepatic lipid accumulation in obesity correlates with the severity of hyperinsulinemia and systemic insulin resistance. Obesity-induced hepatocellular lipid accumulation results in hepatocyte depolarization. We have established that hepatocyte depolarization depresses hepatic afferent vagal nerve firing, increases GABA release from liver slices, and causes hyperinsulinemia. Preventing hepatic GABA release or eliminating the ability of the liver to communicate to the hepatic vagal nerve ameliorates the hyperinsulinemia and insulin resistance associated with diet-induced obesity. In people with obesity, hepatic expression of GABA transporters is associated with glucose infusion and disposal rates during a hyperinsulinemic euglycemic clamp. Single-nucleotide polymorphisms in hepatic GABA re-uptake transporters are associated with an increased incidence of type 2 diabetes mellitus. Herein, we identify GABA as a neuro-hepatokine that is dysregulated in obesity and whose release can be manipulated to mute or exacerbate the glucoregulatory dysfunction common to obesity.

Geisler et al. show that GABAtransaminase catalyzes GABA synthesis in the liver of obese mice, resulting in hyperinsulinemia, insulin resistance, and hyperphagia. In people with obesity, liver GABA-transaminase expression is positively associated with hyperinsulinemia. Thus, GABAtransaminase inhibitors may be effective at restoring glucose homeostasis in obese, hyperinsulinemic, insulinresistant individuals.

Mice are a valuable model for elegant studies of complex, systems-dependent diseases, including pulmonary diseases. Current tools to assess lung function in mice are either terminal or lack accuracy. We set out to develop a low-cost, accurate, head-out variable-pressure plethysmography system to allow for repeated, non-terminal measurements of lung function in mice. Current head-out plethysmography systems are limited by air leaks that prevent accurate measures of volume and flow. We designed an inflatable cuff that encompasses the mouse's neck preventing air leak. We wrote corresponding software to collect and analyze the data, remove movement artifacts, and automatically calibrate each dataset. This software calculates inspiratory/expiratory volume, inspiratory/expiratory time, breaths per minute, mid-expiratory flow, and end-inspiratory pause. To validate the use, we established that our plethysmography system accurately measured tidal breathing, the bronchoconstrictive response to methacholine, sex and age associated changes in breathing, and breathing changes associated with house dust mite sensitization. Our estimates of volume, flow, and timing of breaths are in line with published estimates, we observed dose-dependent decreases in volume and flow in response to methacholine (P < 0.05), increased lung volume and decreased breathing rate with aging (P < 0.05), and that house dust mite sensitization decreased volume and flow (P <0.05) while exacerbating the methacholine induced increases in inspiratory and expiratory time (P < 0.05). We describe an accurate, sensitive, low-cost, head-out plethysmography system that allows for longitudinal studies of pulmonary disease in mice.

Hepatic lipid accumulation is a hallmark of type II diabetes (T2D) and associated with hyperinsulinemia, insulin resistance, and hyperphagia. Hepatic synthesis of GABA, catalyzed by GABAtransaminase (GABA-T), is upregulated in obese mice. To assess the role of hepatic GABA production in obesity-induced metabolic and energy dysregulation, we treated mice with two pharmacologic GABA-T inhibitors and knocked down hepatic GABA-T expression using an antisense oligonucleotide. Hepatic GABA-T inhibition and knockdown decreased basal hyperinsulinemia and hyperglycemia, and improved glucose intolerance. GABA-T knockdown improved insulin sensitivity assessed by hyperinsulinemiceuglycemic clamps in obese mice. Hepatic GABA-T knockdown also decreased food intake and induced weight loss without altering energy expenditure in obese mice. Data from people with obesity support the notion that hepatic GABA production and transport are associated with serum insulin, HOMA-IR, T2D, and BMI. These results support a key role for hepatocyte GABA production in the dysfunctional glucoregulation and feeding behavior associated with obesity.However, in the liver, GABA-T mediates GABA synthesis 12 . We have proposed that hepatic lipids activate reversed GABA shunt activity in hepatocytes, and that hepatic GABA and glucose production are metabolically linked ). It remains completely untested whether manipulating this GABA shunt can prevent hepatic steatosis derived metabolic disease. Thus, GABA-T represents a promising target to decrease hyperinsulinemia and insulin resistance by limiting hepatic GABA production. Accordingly, in the current manuscript, we employed two novel models to limit hepatic GABA production: 1) pharmacologic inhibition of GABA-T activity, and 2) antisense oligonucleotide (ASO) mediated knockdown of hepatic specific GABA-T expression. Using these models for the first time we assessed systemic glucose homeostasis to strengthen the causative role between hepatic GABA production and hyperinsulinemia / insulin resistance. We also assessed food intake and energy expenditure to understand the role of hepatic GABA production in the dysregulation of energy homeostasis in obesity. Results GABA-Transaminase Inhibition Improves Glucose Homeostasis in ObesityTo directly assess the effect of GABA-T in obesity-induced metabolic dysfunction we treated high fat diet-induced obese mice with one of two irreversible GABA-T inhibitors, ethanolamine-Osulphate (EOS) or vigabatrin (8 mg/day). Both reduce hepatic GABA-T activity by over 90% within two days 13 . Through 5 days of treatment, body weight remained similar among EOS, vigabatrin, and saline injected mice (Fig. 1A). Four days of EOS or vigabatrin treatment decreased serum insulin and glucose concentrations and increased the glucose:insulin ratio relative to pre-treatment ( Figs. 1B-1D). Two-weeks washout from EOS or vigabatrin resulted in a return of serum insulin and the glucose:insulin ratio to pretreatment levels (Figs. 1B-1D). EOS treatment (5 days) decreased serum glucagon relat...