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...
Poor physical fitness contributes to the early progression of cardiometabolic disease, yet the physiological and psychological factors underpinning poor fitness in at-risk adolescents are not well understood. In this study, we sought to determine the relationship of physical fitness with two developmental phenomena of adolescence, insulin resistance and depression/anxiety symptoms among at-risk youth. We conducted secondary data analyses of 241 overweight or obese adolescents (12–17 years), drawn from two study cohorts. Insulin sensitivity index was derived from oral glucose tolerance tests. Adolescents self-reported depressive symptoms and anxiety symptoms on validated surveys. A walk/run test was administered to determine perceived exertion and physical fitness (distance traveled). Insulin sensitivity was positively associated with walk/run distance (b=0.16, P<0.01), even after accounting for all covariates. Anxiety symptoms were inversely related to perceived exertion (b=–0.11, P<0.05), adjusting for covariates. These findings suggest that insulin resistance and anxiety symptoms are associated with different dimensions of physical fitness in overweight or obese adolescents and could both potentially contribute to declining fitness and worsening metabolic outcomes in at-risk youth.
In the U.S., one in thirteen individuals have been diagnosed with asthma. Obesity increases the incidence of asthma by 56%. The degree of obesity is associated with the severity of reduction in lung volume and lung volume can be restored with weight loss. Obesity also increases the risk of hospitalization by 460%. Although asthma and altered lung function is commonly assessed with spirometry in humans, plethysmography is recommended by the American Thoracic Society for assessing lung volume. The most common and effective method for assessing lung function in mice, forced ventilation, is terminal and limited to assessing lower airway function, preventing repeated measures. We aimed to develop a head‐out, variable pressure plethysmography system that would allow for repeated sensitive assessment of lung function and volume in lean and diet‐induced obese mice while mimicking the measures in human clinical practice. Preventing air leak from the chamber is vital for recording accurate measurements in a variable pressure plethysmography system. To eliminate air leak, we created an inflatable cuff that encompassed the mouse’s neck. This allowed us to repeatedly and accurately assess airway function in mice. To validate the head‐out, variable pressure plethysmography system, we used a series of models with altered muscarinic signaling. First, we assessed the response to a nebulized bronchoconstrictor, methacholine, establishing that methacholine resulted in the expected decreased breaths/minute, increased expiratory and inspiratory time, and decreased the rate of air flow at 50% of exhalation (EF50). To assess chronic muscarinic signaling, we used an adeno‐associated viral delivery to induce expression of a mutated constitutively active muscarinic 3 receptor (Q409L M3R) in airway smooth muscle, creating a model of chronic bronchoconstriction. In mice that expressed the Q490L M3R, we similarly found a decrease in breaths/minute and an increase in expiratory and inspiratory time at tidal breathing. Finally, we observed a decrease in breaths per minute at tidal breathing in muscarinic 3 receptor knock‐out mice. In our model of diet‐induced obesity we showed that obesity increased breaths per minute and decreased expiratory time at tidal breathing relative to that observed in lean mice. We have developed a reliable tool to repeatedly assess lung function in mice using the same clinically relevant measure applied in human asthmatics. Future research will apply this tool to better understand the mechanism by which obesity alters lung function and tidal breathing volume in mice. Support or Funding Information ABRC ADHS14‐082986ABRC ADHS17‐00002043T32 HL 007249
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, enhanced pause, mid-expiratory flow, and end-inspiratory pause. To validate the use, we established 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 tidal 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.New & NoteworthyWe describe a variable-pressure head-out plethysmography system that can be used to assess lung function in mice. A balloon cuff that inflates around the mouse’s neck prevents air leak, allowing for accurate measurements of lung volume and air flow. Custom software facilitates system calibration, removes movement artifacts, and eases data analysis. The system was validated by measuring tidal breathing, responses to methacholine, and changes associated with house dust mite sensitization, sex, and aging.Contributions to StudyStephanie Bruggink: development of head-out plethysmography chamber, measurement of breathing, data analysis, prepared manuscriptKyle Kentch: development of head-out plethysmography chamber, programmed software to collect and analyze data, prepared manuscriptJason Kronenfeld: development of tools to analyze data, analysis of dataBenjamin Renquist: development of head-out plethysmography chamber, statistical analysis, prepared manuscript
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