Figure 1 - available via license: Creative Commons Attribution 4.0 International
Content may be subject to copyright.
GABA-transaminase inhibition improves glucose homeostasis in obesity HFD-induced obese mice were treated with GABA-transaminase inhibitors ethanolamine-O-sulfate (EOS) or vigabatrin (8 mg/day) or phosphate-buffered saline (PBS) (control) for 5 days. (A and B) Bars that do not share a common letter differ significantly within injection treatment (p < 0.05; number below bar denotes n per group) (A) Body weight during treatment. (B-D) Basal serum insulin (B), glucose (C), and glucose:insulin ratio (D) pre-treatment, on treatment day 4, and after a 2-week washout. (E) Serum glucagon in response to EOS. (F and G) Oral glucose tolerance (OGTT) (F) and OGTT area under the curve (AUC) (G) on treatment day 4. (legend continued on next page)
Source publication
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 mi...
Contexts in source publication
Context 1
... inhibitors reduce hepatic GABA-T activity by over 90% within 2 days (Qume and Fowler, 1996). Through 5 days of treatment, body weight remained similar among EOS-, vigabatrin-, and saline-injected mice ( Figure 1A). 4 days of EOS or vigabatrin treatment decreased serum insulin and glucose concentrations and increased the glucose:insulin ratio relative to pre-treatment (Fig- ures 1B-1D). ...
Context 2
... 5 days of treatment, body weight remained similar among EOS-, vigabatrin-, and saline-injected mice ( Figure 1A). 4 days of EOS or vigabatrin treatment decreased serum insulin and glucose concentrations and increased the glucose:insulin ratio relative to pre-treatment (Fig- ures 1B-1D). 2-week washout from EOS or vigabatrin resulted in a return of serum insulin and the glucose:insulin ratio to pretreatment levels ( Figures 1B-1D). ...
Context 3
... days of EOS or vigabatrin treatment decreased serum insulin and glucose concentrations and increased the glucose:insulin ratio relative to pre-treatment (Fig- ures 1B-1D). 2-week washout from EOS or vigabatrin resulted in a return of serum insulin and the glucose:insulin ratio to pretreatment levels ( Figures 1B-1D). EOS treatment (5 days) decreased serum glucagon relative to control mice ( Figure 1E). ...
Context 4
... washout from EOS or vigabatrin resulted in a return of serum insulin and the glucose:insulin ratio to pretreatment levels ( Figures 1B-1D). EOS treatment (5 days) decreased serum glucagon relative to control mice ( Figure 1E). Blood glucose concentrations during an oral glucose tolerance test (OGTT) (raw area under the curve [AUC]), but not relative glucose clearance (delta AUC) was improved by 4 days of GABA-T inhibition (Figures 1F and 1G). ...
Context 5
... glucose concentrations during an oral glucose tolerance test (OGTT) (raw area under the curve [AUC]), but not relative glucose clearance (delta AUC) was improved by 4 days of GABA-T inhibition (Figures 1F and 1G). Coincident with this improved clearance, glucose-stimulated serum insulin was decreased by vigabatrin and tended to be decreased by EOS relative to pre-treatment concentrations ( Figure 1H). 2-week washout from EOS and vigabatrin markedly increased glucose-stimulated serum insulin ( Figure 1H). ...
Context 6
... with this improved clearance, glucose-stimulated serum insulin was decreased by vigabatrin and tended to be decreased by EOS relative to pre-treatment concentrations ( Figure 1H). 2-week washout from EOS and vigabatrin markedly increased glucose-stimulated serum insulin ( Figure 1H). Both GABA-T inhibitors improved insulin sensitivity assessed by insulin tolerance test (ITT) within 4 days of initiating treatment ( Figures 1I and 1J). ...
Context 7
... washout from EOS and vigabatrin markedly increased glucose-stimulated serum insulin ( Figure 1H). Both GABA-T inhibitors improved insulin sensitivity assessed by insulin tolerance test (ITT) within 4 days of initiating treatment ( Figures 1I and 1J). As oral drug delivery is preferred in clinic, we conducted another series of studies with EOS provided in the drinking water (3 g/L) for 4 days. ...
Context 8
... oral drug delivery is preferred in clinic, we conducted another series of studies with EOS provided in the drinking water (3 g/L) for 4 days. EOS in the drinking water similarly improved measures of glucose homeostasis, and the response washed out after 2 weeks without EOS in the drinking water ( Figure S1). ...
Context 9
... treatment increased 2DG uptake by the soleus (22%) but did not affect 2DG clearance by the quadriceps femoris (quad) or gonadal white adipose tissue (WAT) ( Figure 1K). Given that blood perfusion is a key regulator of insulin action and glucose clearance, we subsequently measured cyclic guanosine monophosphate (cGMP), a key second messenger downstream of nitric oxide (NO) signaling that regulates blood flow (Archer et al., 1994). ...
Context 10
... that blood perfusion is a key regulator of insulin action and glucose clearance, we subsequently measured cyclic guanosine monophosphate (cGMP), a key second messenger downstream of nitric oxide (NO) signaling that regulates blood flow (Archer et al., 1994). EOS increased cGMP in the soleus (59%) but had no effect in quad ( Figure 1L). ...
Context 11
... lean mice, which have low hepatic GABA production (Fig- ures 4A and 4B in Geisler et al., 2021), there was no effect of EOS or vigabatrin (8 mg/day i.p.) on serum insulin concentrations or insulin sensitivity ( Figures S1I, S1O, and S1P). In lean mice, GABA-T inhibition decreased glucose-stimulated serum insulin ( Figure S1N). ...
Context 12
... lean mice, which have low hepatic GABA production (Fig- ures 4A and 4B in Geisler et al., 2021), there was no effect of EOS or vigabatrin (8 mg/day i.p.) on serum insulin concentrations or insulin sensitivity ( Figures S1I, S1O, and S1P). In lean mice, GABA-T inhibition decreased glucose-stimulated serum insulin ( Figure S1N). ...
Context 13
... (4-week) GABA-T knockdown did not affect body weight or glucoregulatory measures in lean mice ( Figures S3C-S3K). This agrees with our observations that acute GABA-T inhibition with EOS does not alter glucose homeostasis in lean mice ( Figures S1I-S1P). Instead, beneficial effects of GABA-T inhibition are specific to obesity, due to an increase in the GABA shunt activity and subsequent hepatic GABA production. ...
Context 14
... 4 weeks of GABA-T ASO injections, serum glucagon oral glucose tolerance, glucose-stimulated serum insulin, and insulin sensitivity were not different between surgical treatments (Figures S2K-S2P). Hepatic vagotomy protects against obesity-induced glucose intolerance and insulin resistance ( Figure 1 in Geisler et al., 2021). Here, we show that GABA-T knockdown allowed shamoperated animals to achieve similar glucose tolerance, glucose-stimulated serum insulin, and insulin sensitivity to that measured in hepatic vagotomized mice. ...
Context 15
... had previously reported that hepatic vagotomy decreased weight gain on a HFD ( Figure 1B in Geisler et al., 2021). Here, we show that hepatic vagotomy decreases 1-week cumulative light cycle food intake by 22% in diet-induced obese mice, resulting in a 5.3% decrease in cumulative 24-h food intake (Fig- ure S8A). ...
Context 16
... hepatic GABA production improves insulin sensitivity primarily by increasing skeletal muscle glucose clearance (Fig- ures 1K and 3G). Our results propose that some of the improvements in glucose clearance may be mediated by increased blood flow. ...
Context 17
... microvascular vasodilatory response is reduced in obesity, directly contributing to systemic insulin resistance (Cleland et al., 1999;Indumathy et al., 2015;Van Guilder et al., 2006). We showed that EOS treatment increased soleus muscle cGMP concentrations ( Figure 1L). Future work will focus on understanding how hepatic GABA signaling at the HVAN regulates endothelial NO production and muscle perfusion. ...
Context 18
... report that diet-induced obese, hepatic vagotomized mice eat less during the light cycle than sham-operated controls, suggesting that hepatic vagotomy protects against the obesity-induced increase in daytime feeding. We hypothesize that preventing the GABA-mediated depression of HVAN activity from reaching the hindbrain not only improves glycemic control (Figure 1 in Geisler et al., 2021) but decreases light cycle food intake, possibly explaining the decreased weight gain with HFD feeding in hepatic vagotomized mice (Figure 1B in Geisler et al., 2021). Further supporting a role of hepatic GABA in HFD-induced weight gain, we previously observed that inducing hepatic Kir2.1 expression limited hepatic GABA release and HFD-induced weight gain ( Figure 3C in Geisler et al., 2021). ...
Context 19
... hypothesize that preventing the GABA-mediated depression of HVAN activity from reaching the hindbrain not only improves glycemic control (Figure 1 in Geisler et al., 2021) but decreases light cycle food intake, possibly explaining the decreased weight gain with HFD feeding in hepatic vagotomized mice (Figure 1B in Geisler et al., 2021). Further supporting a role of hepatic GABA in HFD-induced weight gain, we previously observed that inducing hepatic Kir2.1 expression limited hepatic GABA release and HFD-induced weight gain ( Figure 3C in Geisler et al., 2021). ...
Similar publications
![Extracted ion chromatograms of oxalate and [¹³C2]‐oxalate internal...](publication/362094647/figure/fig2/AS:11431281180641964@1691660662232/Extracted-ion-chromatograms-of-oxalate-and-C2-oxalate-internal-standard-IS-and_Q320.jpg)
Ob/ob mice have recently emerged as a model for obesity-related hyperoxaluria as they are obese and excrete more urine oxalate compared to wild type mice. Ob/ob mice are deficient of leptin and develop obesity with hyperphagia and hyperinsulinemia. We hypothesized that insulin resistance and the gut microbiome contribute to hyperoxaluria in ob/ob m...
Citations
... While commonly known as a neurotransmitter in the brain, GABA (a glutamate metabolite), can have effects in other metabolic organs including the liver (54). Hepatic GABA signaling is involved in mechanisms such as glucoregulation via insulin signaling and membrane transport, oxidative stress damage, and lipid metabolism (55)(56)(57). Gene pathways altered in our study that reflected such mechanisms were found in continuous DCA exposures (e.g., Nrf2 oxidative stress), persistent effects (e.g., insulin pathway signaling), and both (e.g., cholesterol biosynthesis), and were modulated by age and exposure length. Since DCA exposure increases glutamate production (58) and GABAtransaminase activity is increased through the TCA cycle which mediates GABA synthesis (54), likely there is an increase in GABA availability after early DCA exposure, impacting a variety of pathways, and leaving an indelible mark in the methylome. ...
Background
Mechanistic understanding of transient exposures that lead to adverse health outcomes will enhance our ability to recognize biological signatures of disease. Here, we measured the transcriptomic and epigenomic alterations due to exposure to the metabolic reprogramming agent, dichloroacetic acid (DCA). Previously, we showed that exposure to DCA increased liver tumor incidence in B6C3F1 mice after continuous or early life exposures significantly over background level.
Methods
Using archived formalin-fixed liver samples, we utilized modern methodologies to measure gene expression and DNA methylation levels to link to previously generated phenotypic measures. Gene expression was measured by targeted RNA sequencing (TempO-seq 1500+ toxicity panel: 2754 total genes) in liver samples collected from 10-, 32-, 57-, and 78-week old mice exposed to deionized water (controls), 3.5 g/L DCA continuously in drinking water (“Direct” group), or DCA for 10-, 32-, or 57-weeks followed by deionized water until sample collection (“Stop” groups). Genome-scaled alterations in DNA methylation were measured by Reduced Representation Bisulfite Sequencing (RRBS) in 78-week liver samples for control, Direct, 10-week Stop DCA exposed mice.
Results
Transcriptomic changes were most robust with concurrent or adjacent timepoints after exposure was withdrawn. We observed a similar pattern with DNA methylation alterations where we noted attenuated differentially methylated regions (DMRs) in the 10-week Stop DCA exposure groups compared to the Direct group at 78-weeks. Gene pathway analysis indicated cellular effects linked to increased oxidative metabolism, a primary mechanism of action for DCA, closer to exposure windows especially early in life. Conversely, many gene signatures and pathways reversed patterns later in life and reflected more pro-tumorigenic patterns for both current and prior DCA exposures. DNA methylation patterns correlated to early gene pathway perturbations, such as cellular signaling, regulation and metabolism, suggesting persistence in the epigenome and possible regulatory effects.
Conclusion
Liver metabolic reprogramming effects of DCA interacted with normal age mechanisms, increasing tumor burden with both continuous and prior DCA exposure in the male B6C3F1 rodent model.
... Steatosis was observed in the liver of DM-TB and DM mice, indicating the development of insulin resistance and hyperinsulinemia, which was absent in the TB mice group. Increased hepatic lipid accumulation correlated with higher GABA levels in the liver of DM and DM-TB mice, thus corroborating an earlier report (23). Increased hepatic GABA production and release in DM conditions regulate insulin release and sensitivity in a paracrine manner thereby driving the development of metabolic disorders (23). ...
... Increased hepatic lipid accumulation correlated with higher GABA levels in the liver of DM and DM-TB mice, thus corroborating an earlier report (23). Increased hepatic GABA production and release in DM conditions regulate insulin release and sensitivity in a paracrine manner thereby driving the development of metabolic disorders (23). Nephropathy, a common complication reported in DM, was also observed in the DM-TB mice with higher glomerular and tubulointerstitial degeneration. ...
Diabetes mellitus (DM) is a risk factor for developing active tuberculosis (TB) with a 3-fold increase in susceptibility and a 4-fold higher relapse rate. With increasing DM prevalence in TB endemic regions, understanding pathophysiological changes associated with DM-TB comorbidity is imperative. In this study, streptozotocin (STZ)-induced DM C57BL/6 mice were aerosol infected with low dose (100–120 CFU) Mycobacterium tuberculosis H37Rv. At 3 weeks post infection (w.p.i.), multiple tissue mycobacterial load and metabolites were profiled. The liver proteome of DM-TB and controls were analyzed using quantitative proteomics, and multi-omics data were integrated. DM-TB mice showed dysregulated multi-tissue (lungs, liver, brain, kidney and thigh muscle) metabolism. In contrast, the mycobacterial burden in the lung, spleen and liver was similar at 3 w.p.i. in DM-TB and TB groups. Enrichment analysis of deregulated liver metabolites (n = 20; log2DM-TB/TB>±1.0) showed significant perturbation in cysteine-methionine, glycine-serine, BCAA and fatty acid metabolism. 60 out of 1660 identified liver proteins showed deregulation (log2DM-TB/TB>±1.0) and contributed from perturbed cysteine-methionine metabolism corroborating metabolomics data. In addition, amino acid biosynthesis, retinol metabolism and polyol biosynthetic process were also differentially enriched in the livers of DM-TB groups. Global correlation analysis of liver metabolome and proteome data showed a strong association between aspartic acid, pyruvic acid, leucine and isoleucine with CYP450 enzymes involved in retinol metabolism, while iminodiacetic acid, isoleucine and γ-aminobutyric acid (GABA) strong positive correlation involved in cysteine metabolism. Targeting perturbed cysteine metabolism using micro molecules, like DL-Propargylglycine, might help prevent liver damage in DM-TB comorbid conditions.
... After knocking down GABA transaminase (GABA-T, a catabolic GABA protease) in the livers of diet-induced obese (DIO) mice, Geisler et al. (2021) observed the alleviation of insulin resistance and impaired glucose tolerance in mice, indicating that GABA plays an important role in glucose metabolism. Moreover, compared to GABA alone, the combined therapy of GABA and glibenclamide not only significantly improved circulating insulin levels and glucose utilization in diabetic rats but also demonstrated therapeutic effects on a range of diabetes-induced complications (Zhu et al. 2021). ...
... One clinical study found that GABA stimulated insulin secretion in healthy volunteers, leading to a 1.4-1.6 times increase in circulating insulin, while concurrently reducing the level of glycosylated proteins among the volunteers (Li et al. 2015). Moreover, another clinical data showed that the expression of GABA-T in the liver of obese patients was inversely proportional to the hepatic insulin sensitivity index, suggesting that GABA may increase insulin sensitivity in the liver (Geisler et al. 2021). Therefore, for future research, more clinical trials need to be conducted to confirm the anti-diabetic capacity of GABA and to unravel its underlying mechanism of action. ...
... Numerous studies have ----the expression of GaBa-t is inversely proportional to insulin sensitivity, indicating that GaBa is a potential target for the treatment of diabetes. (Geisler et al. 2021) b GaBa: gamma-aminobutyric acid; GaBa-t: GaBa transaminase; -: denote no information provided. a data source from https://clinicaltrials.gov b data source from journal. ...
Diabetes is a metabolic disease due to impaired or defective insulin secretion and is considered one of the most serious chronic diseases worldwide. Gamma-aminobutyric acid (GABA) is a naturally occurring non-protein amino acid commonly present in a wide range of foods. A number of studies documented that GABA has good anti-diabetic potential. This review summarized the available dietary sources of GABA as well as animal and human studies on the anti-diabetic properties of GABA, while also discussing the underlying mechanisms. GABA may modulate diabetes through various pathways such as inhibiting the activities of α-amylase and α-glucosidase, promoting β-cell proliferation, stimulating insulin secretion from β-cells, inhibiting glucagon secretion from α-cells, improving insulin resistance and glucose tolerance, and increasing antioxidant and anti-inflammatory activities. However, further mechanistic studies on animals and human are needed to confirm the therapeutic effects of GABA against diabetes.
... Damage to liver cells results in increased permeability of cell membranes, which leads to the entry of AST and ALT from the liver into the bloodstream. 20 The HFD triggered high ALT levels in the blood (p < 0.05) while no significant effect was observed for the AST level (p > 0.05). Notably, LJ, FLJ and GABA supplementation could effectively reduce the ALT levels. ...
... Geisler et al. found that hepatocyte GABA production (GABAtransaminase catalyzed synthesis) effectively regulates glucose regulation dysfunction and feeding behavior associated with obesity. 20 Moreover, previous studies have shown that oral treatment with GABA reduced the body weight gain, epididymal fat mass, and adipocyte size of HFD-fed mice, mainly due to the action of GABA on the peripheral GABA receptors, which inhibited insulin resistance and obesity by inhibiting obesityrelated inflammation and up-regulating Treg responses in vivo. 47 In addition, it can be seen in Fig. 4D that the FLJ and GABA groups were closer and similar to the LF group in the structural composition of the intestinal flora. ...
Gamma-aminobutyric acid (GABA) dietary intervention is considered to have therapeutic potential against obesity. Microbial enrichment is an effective strategy to naturally and safely enhance the GABA production of food. As “the king of GABA” in fruits, the retention or enrichment of its content during processing has been a key issue in the litchi industry. This study aimed to investigate the potential of GABA and fermented litchi juice enriched with GABA (FLJ) to protect against obesity in a high-fat diet (HFD) mice model. Supplementation of GABA and FLJ displayed an anti-obesogenic effect by attenuating body weight gain, fat accumulation, oxidative damage, and improving serum lipid profile and hepatic function. Sequencing (16S rRNA) of fecal samples indicated that GABA and FLJ intervention displayed different regulatory effects on HFD-induced gut microbiota dysbiosis at different taxonomic levels. The microbial diversity, the relative abundance of Firmicutes and Bacteroidetes as well as F/B ratio of GABA and FLJ groups were reversed compared to the HFD-induced mice. Our finding broadens the potential mechanisms by which GABA regulates gut flora in the amelioration of obesity and provides guidance for developing FLJ as a functional food to prevent obesity.
... The accumulation of hepatic glucose production in response to insulin resistance (IR) and impaired glucagon signaling inhibition is a major contributor to type 2 diabetes and its complications [1,2]. Defects in insulin signaling, a major feature of IR in obesity [3], disable pathways that normally inhibit hepatic glucose production; the resulting systemic hyperinsulinemia overstimulates hepatic lipid synthesis and storage [4]. In addition to the metabolic derangements of type 2 diabetes, patients have a 2-to 4-fold increased lifetime risk of cardiovascular disease [5], owing largely atherogenic dyslipidemia induced by deranged hepatic lipid metabolism [6]. ...
Objective
To date, therapies for endothelial dysfunction have primarily focused on ameliorating identified atherosclerosis (AS) risk factors rather than explicitly addressing endothelium-based mechanism. An in-depth exploration of the pathological mechanisms of endothelial injury was performed herein.
Methods
Aortic caveolin 1 (Cav1) knockdown was achieved in mice using lentivirus, and AS was induced using a high-fat diet. Mouse body weight, blood glucose, insulin, lipid parameters, aortic plaque, endothelial injury, vascular nitric oxide synthase (eNOS), injury marker, and oxidative stress were examined. The effect of Cav1 knockdown on the content of PKCzeta and PI3K/Akt/eNOS pathway–related protein levels, as well as PKCzeta binding to Akt, was studied. ZIP, a PKCzeta inhibitor, was utilized to treat HUVECs in vitro, and the effect of ZIP on cell viability, inflammatory response, oxidative stress, and Akt activation was evaluated.
Results
Cav1 knockdown had no significant effect on body weight or blood glucose in mice over an 8-week period, whereas drastically reduced insulin, lipid parameters, endothelial damage, E-selectin, and oxidative stress and elevated eNOS levels. Moreover, Cav1 knockdown triggered decreased PKCzeta enrichment and the activation of the PI3K/Akt/eNOS pathway. PKCzeta has a positive effect on cells without being coupled by Cav1, and ZIP had no marked influence on PKCzeta-Akt binding following Cav1/PKCzeta coupling.
Conclusion
Cav1/PKCzeta coupling antagonizes the activation of PI3K on Akt, leading to eNOS dysfunction, insulin resistance, and endothelial cell damage.
... We observed higher infant dietary fat (grams) to be only weakly negatively correlated with GABA concentration (r = − 0.25, p = 0.0762). Also, hepatic GABA synthesis may modulate insulin and glucagon secretion, homeostatic model assessment for insulin resistance (HOMA-IR), type 2 diabetes, and BMI [35]. GABA in the central nervous system has been implicated in regulation of systemic metabolism. ...
Evidence supports a complex interplay of gut microbiome and host metabolism as regulators of obesity. The metabolic phenotype and microbial metabolism of host diet may also contribute to greater obesity risk in children early in life. This study aimed to identify features that discriminated overweight/obese from normal weight infants by integrating gut microbiome and serum metabolome profiles. This prospective analysis included 50 South Asian children living in Canada, selected from the SouTh Asian biRth cohorT (START). Serum metabolites were measured by multisegment injection-capillary electrophoresis-mass spectrometry and the relative abundance of bacterial 16S rRNA gene amplicon sequence variant was evaluated at 1 year. Cumulative body mass index (BMIAUC) and skinfold thickness (SSFAUC) scores were calculated from birth to 3 years as the total area under the growth curve (AUC). BMIAUC and/or SSFAUC >85th percentile was used to define overweight/obesity. Data Integration Analysis for Biomarker discovery using Latent cOmponent (DIABLO) was used to identify discriminant features associated with childhood overweight/obesity. The associations between identified features and anthropometric measures were examined using logistic regression. Circulating metabolites including glutamic acid, acetylcarnitine, carnitine, and threonine were positively, whereas γ-aminobutyric acid (GABA), symmetric dimethylarginine (SDMA), and asymmetric dimethylarginine (ADMA) were negatively associated with childhood overweight/obesity. The abundance of the Pseudobutyrivibrio and Lactobacillus genera were positively, and Clostridium sensu stricto 1 and Akkermansia were negatively associated with childhood overweight/obesity. Integrative analysis revealed that Akkermansia was positively whereas Lactobacillus was inversely correlated with GABA and SDMA, and Pseudobutyrivibrio was inversely correlated with GABA. This study provides insights into metabolic and microbial signatures which may regulate satiety, energy metabolism, inflammatory processes, and/or gut barrier function, and therefore, obesity trajectories in childhood. Understanding the functional capacity of these molecular features and potentially modifiable risk factors such as dietary exposures early in life may offer a novel approach for preventing childhood obesity.
... However, in a study of adult Greeks, it was shown by multivariate analysis that the PNPLA3 variant rs738409, WC and female sex were directly associated with fatty liver disease, whereas the duration of DM had an inverse association [153]. The available data also indicate a key relationship between GABA production and transport in the liver and insulin activity, HOMA-IR, T2DM, and BMI [154]. ...
In clinical practice, we often deal with patients who suffer from non-alcoholic fatty liver disease (NAFLD) concurrent with type 2 diabetes mellitus (T2DM). The etiopathogenesis of NAFLD is mainly connected with insulin resistance (IR) and obesity. Similarly, the latter patients are in the process of developing T2DM. However, the mechanisms of NAFLD and T2DM coexistence have not been fully elucidated. Considering that both diseases and their complications are of epidemic proportions and significantly affect the length and quality of life, we aimed to answer which of these diseases appears first and thereby highlight the need for their diagnosis and treatment. To address this question, we present and discuss the epidemiological data, diagnoses, complications and pathomechanisms of these two coexisting metabolic diseases. This question is difficult to answer due to the lack of a uniform procedure for NAFLD diagnosis and the asymptomatic nature of both diseases, especially at their beginning stages. To conclude, most researchers suggest that NAFLD appears as the first disease and starts the sequence of circumstances leading ultimately to the development of T2DM. However, there are also data suggesting that T2DM develops before NAFLD. Despite the fact that we cannot definitively answer this question, it is very important to bring the attention of clinicians and researchers to the coexistence of NAFLD and T2DM in order to prevent their consequences.
... The inhibition of hepatic GABA production improves insulin sensitivity primarily by increasing the skeletal muscle glucose clearance, which directly affects blood flow. Thus, GABA-T represents a promising target for decreasing hyperinsulinemia and insulin resistance by limiting hepatic GABA production [24], highlighting the importance of understanding hepatic GABA function and the action of GABARs in various disease conditions. We will discuss how GABA metabolism is involved in liver diseases. ...
Gamma-aminobutyric acid (GABA) plays a crucial role in signal transduction and can function as a neurotransmitter. Although many studies have been conducted on GABA in brain biology, the cellular function and physiological relevance of GABA in other metabolic organs remain unclear. Here, we will discuss recent advances in understanding GABA metabolism with a focus on its biosynthesis and cellular functions in other organs. The mechanisms of GABA in liver biology and disease have revealed new ways to link the biosynthesis of GABA to its cellular function. By reviewing what is known about the distinct effects of GABA and GABA-mediated metabolites in physiological pathways, we provide a framework for understanding newly identified targets regulating the damage response, with implications for ameliorating metabolic diseases. With this review, we suggest that further research is necessary to develop GABA’s beneficial and toxic effects on metabolic disease progression.
... GABA also demonstrates the potential for lowing blood pressure in spontaneously hypertensive rats (SHR) and hypertensive humans [9,10]. Furthermore, a previous study reported the key role of GABA production in hepatocytes in the dysregulation of glucose regulation and eating behavior associated with obesity [11][12][13]. There has been an increased demand for GABA due to its widespread use in various industries [14]. ...
Gamma-aminobutyric acid (GABA) is a non-protein amino acid with various physiological functions. Levilactobacillus brevis NPS-QW 145 strains active in GABA catabolism and anabolism can be used as a microbial platform for GABA production. Soybean sprouts can be treated as a fermentation substrate for making functional products. This study demonstrated the benefits of using soybean sprouts as a medium to produce GABA by Levilactobacillus brevis NPS-QW 145 when monosodium glutamate (MSG) is the substrate. Based on this method, a GABA yield of up to 2.302 g L−1 was obtained with a soybean germination time of one day and fermentation of 48 h with bacteria using 10 g L−1 glucose according to the response surface methodology. Research revealed a powerful technique for producing GABA by fermentation with Levilactobacillus brevis NPS-QW 145 in foods and is expected to be widely used as a nutritional supplement for consumers.
... Zooming in on human brain cells, we find a strong signal for dopaminergic cells as well as GABAergic cells. Targeting GABAergic pathways might be a promising therapeutic strategy for improving MetS and associated diseases; GABA knockdown in mice improved insulin sensitivity, decreased food intake, and induced weight loss (39). ...
A quarter of the world’s population is estimated to meet the criteria for metabolic syndrome, a cluster of cardiometabolic risk factors that promote development of coronary artery disease and type II diabetes, leading to increased risk of premature death and significant health costs.1–3 In this study we investigate whether the genetics associated with metabolic syndrome components mirror their phenotypic clustering. A multivariate approach that leverages genetic correlations between fasting glucose, high density lipoprotein, systolic blood pressure, triglycerides, and waist circumference was used; which revealed that these genetic correlations are best captured by a genetic one factor model. The common genetic factor genome-wide association study (GWAS) detects 235 associated loci, 174 more than the largest GWAS on metabolic syndrome to date. Of these loci, 53 (22.5%) overlap with loci identified for two or more metabolic syndrome components, indicating that metabolic syndrome is a complex, heterogeneous disorder. Associated loci harbour genes that show increased expression in the brain, especially in GABAergic and dopaminergic neurons. A polygenic risk score drafted from the metabolic syndrome factor GWAS predicts 5.9% of the variance in metabolic syndrome. These results provide mechanistic insights in the genetics of metabolic syndrome and suggestions for drug targets. especially fenofibrate, which has the promise of tackling multiple metabolic syndrome components.
