The TAS1R2 G-protein-coupled receptor is an ambient glucose sensor in skeletal muscle that regulates NAD homeostasis and mitochondrial capacity.

The bioavailability of nicotinamide adenine dinucleotide (NAD) is vital for skeletal muscle health, yet the mechanisms or signals regulating NAD homeostasis remain unclear. Here, we uncover a pathway connecting peripheral glucose sensing to the modulation of muscle NAD through TAS1R2, the sugar-sensing G protein-coupled receptor (GPCR) initially identified in taste perception. Muscle TAS1R2 receptor stimulation by glucose and other agonists induces ERK1/2-dependent phosphorylation and activation of poly(ADP-ribose) polymerase1 (PARP1), a major NAD consumer in skeletal muscle. Consequently, muscle-specific deletion of TAS1R2 (mKO) in male mice suppresses PARP1 activity, elevating NAD levels and enhancing mitochondrial capacity and running endurance. Plasma glucose levels negatively correlate with muscle NAD, and TAS1R2 receptor deficiency enhances NAD responses across the glycemic range, implicating TAS1R2 as a peripheral energy surveyor. These findings underscore the role of GPCR signaling in NAD regulation and propose TAS1R2 as a potential therapeutic target for maintaining muscle health.

The TAS1R2 sweet taste receptor regulates skeletal muscle mass and fitness.

Muscle fitness and mass deteriorate under the conditions of obesity and aging for reasons yet to be fully elucidated. Herein, we describe a novel pathway linking peripheral nutrient sensing and skeletal muscle function through the sweet taste receptor TAS1R2 and the involvement of ERK2-PARP1-NAD signaling axis. Muscle-specific deletion of TAS1R2 (mKO) in mice produced elevated NAD levels due to suppressed PARP1 activity, improved mitochondrial function, increased muscle mass and strength, and prolonged running endurance. Deletion of TAS1R2 in obese or aged mice also ameliorated the decline in muscle mass and fitness arising from these conditions. Remarkably, partial loss-of-function of TAS1R2 (rs35874116) in older, obese humans recapitulated the healthier muscle phenotype displayed by mKO mice in response to exercise training. Our findings show that inhibition of the TAS1R2 signaling in skeletal muscle is a promising therapeutic approach to preserve muscle mass and function.

The Ile191Val Variant of the TAS1R2 Subunit of Sweet Taste Receptors Is Associated With Reduced HbA1c in a Human Cohort With Variable Levels of Glucose Homeostasis.

The Ile191Val variant of the TAS1R2 gene of sweet taste receptors causes a partial loss-of-function and is associated with reduced glucose excursions in a healthy lean cohort. However, it is unclear whether this polymorphism contributes to the regulation of glucose homeostasis in metabolically unhealthy individuals. Thus, we used participants with variable glycemic profiles and obesity to assess the effects of the TAS1R2-Ile191Val variant. We found that the Val minor allele carriers had lower HbA1c at all levels of fasting glucose and glucose tolerance. These effects were not due to differences in beta-cell function or insulin sensitivity assessed with a frequently sampled intravenous glucose tolerance test. This study extends our previous findings and provides further evidence that sweet taste receptor function may contribute to glucose regulation in humans.

BALF and BLOOD NK- cells in different stages of pulmonary sarcoidosis.

BACKGROUND AND OBJECTIVE: Data on natural killer (NK)- and natural killer T (NKT)- like cells in the immunopathogenesis of sarcoidosis remain limited. The aim was to assess NK- and NKT-like cells across different stages in bronchoalveolar lavage (BALF) versus peripheral blood (PB) in comparison to controls. METHODS: Forty four patients (32 women and 12 men, mean age 46.6±14.4 years) with biopsy-proven sarcoidosis and 10 healthy individuals (6 women, 4 men mean age 52.6±19.1 years) were submitted to BALF. Total cells and cell differentials were counted, while CD45+, CD3+, CD4+, CD8+, CD19+, CD3-CD16/56 (NK cells) and CD3+CD16/56+ (NKT-like cells) were determined by dual flow cytometry in BALF and PB. RESULTS: A significantly lower percentage of both NK and NKT-like cells was observed in BALF of controls and sarcoid patients (SP) compared to PB. Both BALF NK and NKT-cell counts were significantly higher in SP than in controls (NK: p=0.046, NKT-like: p=0.012) In addition BALF NK cell percentage differed among sarcoidosis stages (p=0.005). In PB NK-cell count was lower in sarcoidosis patients but the difference did not reach statistical significance. Also, in sarcoid patients' BALF NK-cell percentage negatively correlated with lymphocyte percentage (r=-0.962, p<0.001). CONCLUSIONS: The increased count of BALF NK and NKT-like cells in sarcoidosis compared to controls along with the increase of NK cells with stage progression are in line with a growing number of investigations suggesting the involvement of NK- and NKT-like cells in the pathogenesis of sarcoidosis.

Saccharin Stimulates Insulin Secretion Dependent on Sweet Taste Receptor-Induced Activation of PLC Signaling Axis.

BACKGROUND: Saccharin is a common artificial sweetener and a bona fide ligand for sweet taste receptors (STR). STR can regulate insulin secretion in beta cells, so we investigated whether saccharin can stimulate insulin secretion dependent on STR and the activation of phospholipase C (PLC) signaling. METHODS: We performed in vivo and in vitro approaches in mice and cells with loss-of-function of STR signaling and specifically assessed the involvement of a PLC signaling cascade using real-time biosensors and calcium imaging. RESULTS: We found that the ingestion of a physiological amount of saccharin can potentiate insulin secretion dependent on STR. Similar to natural sweeteners, saccharin triggers the activation of the PLC signaling cascade, leading to calcium influx and the vesicular exocytosis of insulin. The effects of saccharin also partially require transient receptor potential cation channel M5 (TRPM5) activity. CONCLUSIONS: Saccharin ingestion may transiently potentiate insulin secretion through the activation of the canonical STR signaling pathway. These physiological effects provide a framework for understanding the potential health impact of saccharin use and the contribution of STR in peripheral tissues.

Cardiac-derived TGF-ß1 confers resistance to diet-induced obesity through the regulation of adipocyte size and function.

Regulation of organismal homeostasis in response to nutrient availability is a vital physiological process that involves inter-organ communication. Understanding the mechanisms controlling systemic cross-talk for the maintenance of metabolic health is critical to counteract diet-induced obesity. Here, we show that cardiac-derived transforming growth factor beta 1 (TGF-ß1) protects against weight gain and glucose intolerance in mice subjected to high-fat diet. Secretion of TGF-ß1 by cardiomyocytes correlates with the bioavailability of this factor in circulation. TGF-ß1 prevents adipose tissue inflammation independent of body mass and glucose metabolism phenotypes, indicating protection from adipocyte dysfunction-driven immune cell recruitment. TGF-ß1 alters the gene expression programs in white adipocytes, favoring their fatty acid oxidation and consequently increasing their mitochondrial oxygen consumption rates. Ultimately, subcutaneous and visceral white adipose tissue from cadiac-specific TGF-ß1 transgenic mice fail to undergo cellular hypertrophy, leading to reduced overall adiposity during high-fat feeding. Thus, TGF-ß1 is a critical mediator of heart-fat communication for the regulation of systemic metabolism.

The Ile191Val is a partial loss-of-function variant of the TAS1R2 sweet-taste receptor and is associated with reduced glucose excursions in humans.

OBJECTIVE: Sweet taste receptors (STR) are expressed in the gut and other extra-oral tissues, suggesting that STR-mediated nutrient sensing may contribute to human physiology beyond taste. A common variant (Ile191Val) in the TAS1R2 gene of STR is associated with nutritional and metabolic outcomes independent of changes in taste perception. It is unclear whether this polymorphism directly alters STR function and how it may contribute to metabolic regulation. METHODS: We implemented a combination of in vitro biochemical approaches to decipher the effects of TAS1R2 polymorphism on STR function. Then, as proof-of-concept, we assessed its effects on glucose homeostasis in apparently healthy lean participants. RESULTS: The Ile191Val variant causes a partial loss of function of TAS1R2 through reduced receptor availability in the plasma membrane. Val minor allele carriers have reduced glucose excursions during an OGTT, mirroring effects previously seen in mice with genetic loss of function of TAS1R2. These effects were not due to differences in beta-cell function or insulin sensitivity. CONCLUSIONS: Our pilot studies on a common TAS1R2 polymorphism suggest that STR sensory function in peripheral tissues, such as the intestine, may contribute to the regulation of metabolic control in humans.

High-dose saccharin supplementation does not induce gut microbiota changes or glucose intolerance in healthy humans and mice.

BACKGROUND: Non-caloric artificial sweeteners (NCAS) are widely used as a substitute for dietary sugars to control body weight or glycemia. Paradoxically, some interventional studies in humans and rodents have shown unfavorable changes in glucose homeostasis in response to NCAS consumption. The causative mechanisms are largely unknown, but adverse changes in gut microbiota have been proposed to mediate these effects. These findings have raised concerns about NCAS safety and called into question their broad use, but further physiological and dietary considerations must be first addressed before these results are generalized. We also reasoned that, since NCAS are bona fide ligands for sweet taste receptors (STRs) expressed in the intestine, some metabolic effects associated with NCAS use could be attributed to a common mechanism involving the host. RESULTS: We conducted a double-blind, placebo-controlled, parallel arm study exploring the effects of pure saccharin compound on gut microbiota and glucose tolerance in healthy men and women. Participants were randomized to placebo, saccharin, lactisole (STR inhibitor), or saccharin with lactisole administered in capsules twice daily to achieve the maximum acceptable daily intake for 2 weeks. In parallel, we performed a 10-week study administering pure saccharin at a high dose in the drinking water of chow-fed mice with genetic ablation of STRs (T1R2-KO) and wild-type (WT) littermate controls. In humans and mice, none of the interventions affected glucose or hormonal responses to an oral glucose tolerance test (OGTT) or glucose absorption in mice. Similarly, pure saccharin supplementation did not alter microbial diversity or composition at any taxonomic level in humans and mice alike. No treatment effects were also noted in readouts of microbial activity such as fecal metabolites or short-chain fatty acids (SCFA). However, compared to WT, T1R2-KO mice were protected from age-dependent increases in fecal SCFA and the development of glucose intolerance. CONCLUSIONS: Short-term saccharin consumption at maximum acceptable levels is not sufficient to alter gut microbiota or induce glucose intolerance in apparently healthy humans and mice. TRIAL REGISTRATION: Trial registration number NCT03032640 , registered on January 26, 2017. Video abstract.

NIH Workshop Report: sensory nutrition and disease.

In November 2019, the NIH held the "Sensory Nutrition and Disease" workshop to challenge multidisciplinary researchers working at the interface of sensory science, food science, psychology, neuroscience, nutrition, and health sciences to explore how chemosensation influences dietary choice and health. This report summarizes deliberations of the workshop, as well as follow-up discussion in the wake of the current pandemic. Three topics were addressed: A) the need to optimize human chemosensory testing and assessment, B) the plasticity of chemosensory systems, and C) the interplay of chemosensory signals, cognitive signals, dietary intake, and metabolism. Several ways to advance sensory nutrition research emerged from the workshop: 1) refining methods to measure chemosensation in large cohort studies and validating measures that reflect perception of complex chemosensations relevant to dietary choice; 2) characterizing interindividual differences in chemosensory function and how they affect ingestive behaviors, health, and disease risk; 3) defining circuit-level organization and function that link and interact with gustatory, olfactory, homeostatic, visceral, and cognitive systems; and 4) discovering new ligands for chemosensory receptors (e.g., those produced by the microbiome) and cataloging cell types expressing these receptors. Several of these priorities were made more urgent by the current pandemic because infection with sudden acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the ensuing coronavirus disease of 2019 has direct short- and perhaps long-term effects on flavor perception. There is increasing evidence of functional interactions between the chemosensory and nutritional sciences. Better characterization of this interface is expected to yield insights to promote health, mitigate disease risk, and guide nutrition policy.

Th2/Th17 cytokine profile in phenotyped Greek asthmatics and relationship to biomarkers of inflammation.

OBJECTIVE: The aim of the present study was to investigate the Th2/Th17 pathway in asthmatic patients and also the relationship to asthma severity and biomarkers of inflammation. METHODS: 90 asthmatic patients, 51 patients with severe, 39 patients with mild asthma and 98 healthy controls were included. Skin prick tests, blood eosinophils, total serum IgE and exhaled FeNO were evaluated. Serum levels of IL-4, IL-5, IL-13, IL-6, IL-17A, IL-23 and TGFß1 were determined by Flow Cytometry using a panel kit (AimPlex Biosciences). The SNP of IL17A (rs17880588) was genotyped using reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: The genotype of the SNP in IL17A (rs 17880588) was similar among all three groups. Serum levels of IL-4, IL-5, IL-13, IL-6, IL-17A and IL-23 were higher in asthmatics compared to controls (p < 0.05). In addition, IL-17A and IL-4 serum levels were found significantly elevated in patients with allergic asthma (p < 0.05). Furthermore, IL-4, IL-5, IL-13 and IL-23 were found significantly higher in patients with eosinophil cut off values above 300 cells/µl (p < 0.05). IL-17A levels were positively correlated with FeNO values in severe asthmatics with eosinophils>400 cells/µl. CONCLUSIONS: The above findings suggest the coexistence of Th2/Th17 pathway in severe, eosinophilic and in allergic asthma.

T1R2 receptor-mediated glucose sensing in the upper intestine potentiates glucose absorption through activation of local regulatory pathways.

OBJECTIVE: Beyond the taste buds, sweet taste receptors (STRs; T1R2/T1R3) are also expressed on enteroendocrine cells, where they regulate gut peptide secretion but their regulatory function within the intestine is largely unknown. METHODS: Using T1R2-knock out (KO) mice we evaluated the role of STRs in the regulation of glucose absorption in vivo and in intact intestinal preparations ex vivo. RESULTS: STR signaling enhances the rate of intestinal glucose absorption specifically in response to the ingestion of a glucose-rich meal. These effects were mediated specifically by the regulation of GLUT2 transporter trafficking to the apical membrane of enterocytes. GLUT2 translocation and glucose transport was dependent and specific to glucagon-like peptide 2 (GLP-2) secretion and subsequent intestinal neuronal activation. Finally, high-sucrose feeding in wild-type mice induced rapid downregulation of STRs in the gut, leading to reduced glucose absorption. CONCLUSIONS: Our studies demonstrate that STRs have evolved to modulate glucose absorption via the regulation of its transport and to prevent the development of exacerbated hyperglycemia due to the ingestion of high levels of sugars.

Inhibition of sweet chemosensory receptors alters insulin responses during glucose ingestion in healthy adults: a randomized crossover interventional study.

Background: Glucose is a natural ligand for sweet taste receptors (STRs) that are expressed on the tongue and in the gastrointestinal tract. Whether STRs directly contribute to the regulation of glucose homeostasis in response to glucose ingestion is unclear.Objective: We sought to determine the metabolic effects of the pharmacologic inhibition of STRs in response to an oral glucose load in healthy lean participants.Design: Ten healthy lean participants with a body mass index (in kg/m2) of 22.4 ± 0.8 were subjected to an oral-glucose-tolerance test (OGTT) on 4 separate days with the use of a randomized crossover design. Ten minutes before the 75-g OGTT, participants consumed a preload solution of either 300 parts per million (ppm) saccharin or water with or without the addition of 500 ppm lactisole, a human-specific inhibitor of STRs. When present, lactisole was included in both the preload and OGTT solutions. We assessed plasma responses of glucose, insulin, C-peptide, glucagon, glucagon-like peptides 1 and 2, gastric inhibitory peptide, acetaminophen, and 3-O-methylglucose. With the use of mathematical modeling, we estimated gastric emptying, glucose absorption, ß-cell function, insulin sensitivity and clearance, and the portal insulin:glucagon ratio.Results: The addition of lactisole to the OGTT caused increases in the plasma responses of insulin (P = 0.012), C-peptide (P = 0.004), and the insulin secretory rate (P = 0.020) compared with the control OGTT. The addition of lactisole also caused a slight reduction in the insulin sensitivity index independent of prior saccharin consumption (P < 0.025). The ingestion of saccharin before the OGTT did not alter any of the measured variables but eliminated the effects of lactisole on the OGTT.Conclusion: The pharmacologic inhibition of STRs in the gastrointestinal tract alters insulin responses during an oral glucose challenge in lean healthy participants. This trial was registered at clinicaltrials.gov as NCT02835859.

Disruption of the sugar-sensing receptor T1R2 attenuates metabolic derangements associated with diet-induced obesity.

Sweet taste receptors (STRs) on the tongue mediate gustatory sweet sensing, but their expression in the gut, pancreas, and adipose tissue suggests a physiological contribution to whole body nutrient sensing and metabolism. However, little is known about the function and contribution of these sugar sensors during metabolic stress induced by overnutrition and subsequent obesity. Here, we investigated the effects of high-fat/low-carbohydrate (HF/LC) diet on glucose homeostasis and energy balance in mice with global disruption of the sweet taste receptor protein T1R2. We assessed body composition, energy balance, glucose homeostasis, and tissue-specific nutrient metabolism in T1R2 knockout (T1R2-KO) mice fed a HF/LC diet for 12 wk. HF/LC diet-fed T1R2-KO mice gained a similar amount of body mass as did WT mice, but had reduced fat mass and increased lean mass relative to WT mice. T1R2-KO mice were also hyperphagic and hyperactive. Ablation of the T1R2 sugar sensor protected mice from HF/LC diet-induced hyperinsulinemia and altered substrate utilization, including increased rates of glucose oxidation and decreased liver triglyceride (TG) accumulation, despite normal intestinal fat absorption. Finally, STRs (T1r2/T1r3) were upregulated in the adipose tissue of WT mice in response to HF/LC diet, and their expression positively correlated with fat mass and glucose intolerance. The chemosensory receptor T1R2, plays an important role in glucose homeostasis during diet-induced obesity through the regulation of yet to be identified molecular mechanisms that alter energy disposal and utilization in peripheral tissues.

Could Somatostatin Enhance the Outcomes of Chemotherapeutic Treatment in SCLC?

PURPOSE: Somatostatin is a peptide with a potent and broad antisecretory action, which makes it an invaluable drug target for the pharmacological management of pituitary adenomas and neuroendocrine tumors. Furthermore, somatostatin (SST) receptors (SSTR1, 2A and B, 3, 4 and 5) belong to the G protein coupled receptor family and are overexpressed in tumors. Since, human small-cell lung cancer overexpresses somatostatin receptors (STTR), they could be legitimate targets for treating SCLC.The aim of this study was the evaluation of cytotoxicity of somatostatin in combination with several anticancer drugs in HTB-175 cell line (Small Cell Lung Cancer Cell line that expresses neuron specific enolase). METHODS: Docetaxel, Paclitaxel, Carboplatin, Cisplatin, Etoposide, Gemzar, Navelbine, Fluorouracil, Farmorubicin are the chemotherapeutic drugs that we used for the combination before and after adding somatostatin in SCLC cell culture. HTB-175 cell line was purchased from ATCC LGC Standards.At indicated time-point, 48h after the combination, cell viability and apoptosis were measured with Annexin V staining by flow cytometry. RESULTS: Flow cytometry showed that Docetaxel, Paclitaxel, Gemzar and Cisplatin induced apoptosis more when they were added before somatostatin, whereas etoposide induced apoptosis more after somatostatin treatment. Navelbine alone or in combination with somatostatin showed no differences in apoptosis. Farmorubicin showed equal toxicity in all combinations. Fluorouracil and Carboplatin induced apoptosis more when added alone in HTB-175 cell line. However, increased apoptosis was also observed when Carboplatin was administered before somatostatin in higher concentrations. CONCLUSION: Our results indicated that depending on the drug, somatostatin treatment before or after chemotherapeutic drugs increased apoptosis in small cell lung cancer cells. We suggest that long acting somatostatin analogues could be used as additive and maintenance therapy in combination to antineoplastic agents in SCLC patients.

Bronchoalveolar lavage fluid and blood natural killer and natural killer T-like cells in cryptogenic organizing pneumonia.

BACKGROUND AND OBJECTIVE: Natural killer (NK) cells appear to be involved in the development of interstitial lung diseases (ILD). The purpose of this study was to investigate the involvement of NK and natural killer T (NKT)-like cells in two recognized cytotoxic ILD with systemic character, hypersensitivity pneumonitis (HP) and cryptogenic organizing pneumonia (COP), compared with idiopathic pulmonary fibrosis (IPF) and controls. METHODS: Bronchoalveolar lavage fluid (BALF) and peripheral blood (PBL) cells and lymphocyte subsets of 83 patients (26 with COP, 19 with HP and 38 with IPF) and 10 controls were prospectively studied by flow cytometry. RESULTS: The percentage of NK and NKT-like cells was lower in BALF than in PBL in all patient groups and controls. Patients with COP presented with statistically significantly higher NK and NKT-like cell counts in BALF compared with controls (P = 0.044 and P = 0.05 respectively) and IPF (P = 0.049 and P = 0.045 respectively). BALF NKT-like cell count correlated with PBL NKT-like cell count only in COP (r = 0.627, P = 0.002). In addition, a significant positive correlation between BALF NKT-like cell and PBL cytotoxic T CD8+ cell count was observed in COP (r = 0.562, P = 0.006) but not in HP, IPF or controls. CONCLUSIONS: Our study provides for the first time evidence for the implication of NKT-like cells in the pathogenesis of COP, as part of both localized and systemic cytotoxicity.

A multifactoral analysis of 1452 patients for smoking sensation. An outpatient lab experience.

Smoking habit is held responsible for several respiratory and metabolic diseases. Data from 1452 patients were recorded from our outpatient laboratory. The following parameters were recorded within several follow ups of our patients; smoking habit, respiratory functions, smoking cessation questionnaires, and administered drugs. The treatment administered to smokers throughout the period of inspection seems to also have a significant effect on dependence. In fact, varelicline causes a 50% reduction in smoking dependence in regards to nicotine substitutes (odds ratio: 0.48 (0.31-0,74), p=0.001) so displaying a substantial preponderance on the choice to fight smoking dependence.

Sweet taste receptors regulate basal insulin secretion and contribute to compensatory insulin hypersecretion during the development of diabetes in male mice.

ß-Cells rapidly secrete insulin in response to acute increases in plasma glucose but, upon further continuous exposure to glucose, insulin secretion progressively decreases. Although the mechanisms are unclear, this mode of regulation suggests the presence of a time-dependent glucosensory system that temporarily attenuates insulin secretion. Interestingly, early-stage ß-cell dysfunction is often characterized by basal (ie, fasting) insulin hypersecretion, suggesting a disruption of these related mechanisms. Because sweet taste receptors (STRs) on ß-cells are implicated in the regulation of insulin secretion and glucose is a bona fide STR ligand, we tested whether STRs mediate this sensory mechanism and participate in the regulation of basal insulin secretion. We used mice lacking STR signaling (T1R2(-/-) knockout) and pharmacologic inhibition of STRs in human islets. Mouse and human islets deprived of STR signaling hypersecrete insulin at short-term fasting glucose concentrations. Accordingly, 5-hour fasted T1R2(-/-) mice have increased plasma insulin and lower glucose. Exposure of isolated wild-type islets to elevated glucose levels reduced STR expression, whereas islets from diabetic (db/db) or diet-induced obese mouse models show similar down-regulation. This transcriptional reprogramming in response to hyperglycemia correlates with reduced STR function in these mouse models, leading to insulin hypersecretion. These findings reveal a novel mechanism by which insulin secretion is physiologically regulated by STRs and also suggest that, during the development of diabetes, STR function is compromised by hyperglycemia leading to hyperinsulinemia. These observations further suggest that STRs might be a promising therapeutic target to prevent and treat type 2 diabetes.

Hyperleptinemia is associated with CRP, but not apolipoprotein E, and is reduced by exercise training.

The purpose of this study was to examine whether leptin levels affect the response of leptin to exercise training (ET) and whether this is also affected by C-reactive protein (CRP) or the three common Apolipoprotein E genotypes (APOE). Ninety-seven (male = 45, female = 52) sedentary individuals underwent 6 months of supervised ET. Blood was sampled before the initiation of ET, and again 24 and 72 hr after completion of the final training session. ET resulted in a small reduction in body mass (80.47 ± 18.03 vs 79.42 ± 17.34 kg, p < .01). Leptin was reduced 24 hr after the final exercise session (p < .01), but returned to normal after 72 hr (p > .05)--Pre: 13.51 ± 12.27, 24hr: 12.14 ± 12.34, 72 hr: 12.98 ± 11.40 ng/ml. The most hyperleptinemic individuals had a greater initial response, which was sustained through to 72 hr after the final session in the pooled study population (p < .01), and in both males (p < .05) and females (p < .05) separately. CRP was related to leptin independently of body weight and positively related to the reductions in leptin. APOE genotype was not related to leptin levels and did not affect the response to ET. Leptin levels may only be reduced by ET in those with hyperleptinemia. In addition, both the initial extent of hyperleptinemia and the subsequent reduction in leptin may be related to low grade chronic systemic inflammation.

NK cell populations in collagen vascular disease.

OBJECTIVES: Pulmonary involvement of varying etiology is common in collagen vascular diseases (CVDs). Bronchoalveolar lavage fluid (BALF) cell differentials reveal information on the immune mechanisms involved in the CVDs. The aim of the present study was to evaluate BALF cell populations in CVD-associated ILD and to investigate possible correlation with pulmonary function. METHODS: Fifty-seven patients (26 male and 31 female, mean age ± SD: 54.68±12.18 years) with CVD-associated interstitial lung disease were studied. Patients were divided into 6 groups based on underlying CVD. The study population also included a group of 10 healthy controls. BALF was examined in all individuals. Cell density, total cell number and differential cell count were recorded. BALF lymphocyte subsets were analysed by dual flow cytometry. Pulmonary function was assessed in all patients. RESULTS: BALF differential cell count did not differ significantly among the different groups. Scleroderma patients showed the highest percentage of CD19 cells (p<0.001). The NK and NKT cell percentages were significantly higher in systemic lupus erythematosus and in Sjögren, respectively, compared to other CVDs and controls (p=0.001 and p<0.001). Also BALF neutrophil percentage correlated negatively with FVC (r=-0.356, p=0.011) and FEV1 (r=-0.336, p=0.017) and BALF NKT cell percentage correlated negatively with pO2 (r=-0.415, p=0.003). CONCLUSIONS: Important variations observed in BALF cell populations suggest the implication of NK and NKT cells in the pathogenesis of lung involvement in CVDs.

Sweet taste receptor signaling in beta cells mediates fructose-induced potentiation of glucose-stimulated insulin secretion.

Postprandial insulin release is regulated by glucose, but other circulating nutrients may target beta cells and potentiate glucose-stimulated insulin secretion via distinct signaling pathways. We demonstrate that fructose activates sweet taste receptors (TRs) on beta cells and synergizes with glucose to amplify insulin release in human and mouse islets. Genetic ablation of the sweet TR protein T1R2 obliterates fructose-induced insulin release and its potentiating effects on glucose-stimulated insulin secretion in vitro and in vivo. TR signaling in beta cells is triggered, at least in part, in parallel with the glucose metabolic pathway and leads to increases in intracellular calcium that are dependent on the activation of phospholipase C (PLC) and transient receptor potential cation channel, subfamily M, member 5 (TRPM5). Our results unveil a pathway for the regulation of insulin release by postprandial nutrients that involves beta cell sweet TR signaling.