A critical role of hepatic GABA in the metabolic dysfunction and hyperphagia of obesity.

Hepatic lipid accumulation is a hallmark of type II diabetes (T2D) associated with hyperinsulinemia, insulin resistance, and hyperphagia. Hepatic synthesis of GABA, catalyzed by GABA-transaminase (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 hyperinsulinemic-euglycemic 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, homeostatic model assessment for insulin resistance (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.

Hepatocyte membrane potential regulates serum insulin and insulin sensitivity by altering hepatic GABA release.

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.

Insulin Sensitivity, Depression/Anxiety, and Physical Fitness in At-Risk Adolescents.

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.

Mindfulness-based Group Intervention for an Adolescent Girl at Risk for Type 2 Diabetes: A Case Report.

CONTEXT: Behavioral lifestyle interventions to lower body mass index (BMI; kg/m2) are the standard approach for preventing adolescent-onset type 2 diabetes (T2D). Unfortunately, existing programs have had limited long-term success of lessening insulin resistance, the key physiological risk indicator for T2D. Underlying psychosocial factors, particularly depressive symptoms, have been related to insulin resistance, independent of BMI or body fat. Preliminary evidence indicates that mindfulness-based programs show promise for intervening with depression and T2D; yet, this approach is novel and data in adolescents are scarce. OBJECTIVE: The objectives of this study were (1) to evaluate the benefits, and potential underlying mechanisms, of a mindfulness-based intervention in adolescents at-risk for T2D with depressive symptoms and (2) to consider clinical implementation with this specific, psychologically, and medically at-risk adolescent population. DESIGN AND SETTING: The research team conducted a case study report. The setting was an outpatient therapy clinic and research laboratory at a university. PARTICIPANT: The participant was a 16-y-old female with elevated depressive symptoms, obesity, and insulin resistance, and a family history of T2D. INTERVENTION AND OUTCOMES: The intervention was a 6-wk mindfulness-based group program. The key outcomes were patterns of change in trait mindfulness, depression, and insulin resistance in the course of a 1-y follow-up. Secondary outcomes were patterns of change in reported-overeating patterns and cortisol awakening response. RESULTS: Compared with her scores at baseline, the participant displayed a pattern of increased trait mindfulness, decreased depressive symptoms, and lessening of insulin resistance immediately following the group program and at 1 y. BMI and body fat were stable. There was a remission in reported-overeating and a pattern of declining cortisol awakening response 1 y later. Participant feedback on the intervention was generally positive but also provided potential modifications to strengthen acceptability and effectiveness. CONCLUSIONS: The current case results suggest that teaching mindfulness skills to adolescent girls at risk for T2D with depressive symptoms may offer distinctive advantages for treating depression and T2D risk. Clinical implications for increasing the success of implementing mindfulness-based programs in this population include a focus on promotion of social connectedness within the group, implementation of strategies to increase adherence to home practice activities, and the use of facilitation techniques to promote concrete understanding of abstract mindfulness concepts. Future, adequately powered clinical trial data are required to test therapeutic mechanisms and recommended adaptations.