Biomedical subjects

T Kodama

Publications and source records attributed to T Kodama.

At least 19 recordsLinked to original sources

PubMed1999

Characterization of cleavage enzymes for sterol regulatory element binding protein in hamster liver microsomes.

Sterol regulatory element binding proteins (SREBP-1 and SREBP-2) are the key transcription factors for the regulation of the cellular cholesterol level. To identify proteolytic enzymes for SREBPs, a fluorogenic peptide substrate, MOCAc-GRSVLSFK(Dnp)rr-NH2, was synthesized according to the proposed cleavage site of human SREBP-2. In microsome fractions from hamster liver, we found a peptidase activity inhibitable by the synthetic inhibitor Ac-GRSVL-aldehyde with an IC50 of 40 nM. This peptidase separated into three peaks of approximately 400 kDa, 60 kDa, and 30 kDa (Mp400, Mp60 and Mp30 respectively) upon gel permeation chromatography. Mp30 was purified to apparent homogeneity with an Mr of 32 kDa. The partial amino acid sequence of Mp30 possessed homology to cathepsin B (EC 3.4.22.1). A 109 kDa protein band on SDS-PAGE which corresponded to Mp400 exhibited homology to neprilysin (EC 3.4.24.11) in partial amino acid sequence. These findings suggest several degradative pathways for SREBP in liver microsome membranes.

Amino Acid Sequence↗

PubMed1999

Role of the scavenger receptor MARCO in alveolar macrophage binding of unopsonized environmental particles.

Alveolar macrophages (AMs) avidly bind and ingest unopsonized environmental particles and bacteria through scavenger-type receptors (SRs). AMs from mice with a genetic deletion of the major macrophage SR (types AI and AII; SR-/-) showed no decrease in particle binding compared with SR+/+ mice, suggesting that other SRs are involved. To identify these receptors, we generated a monoclonal antibody (mAb), PAL-1, that inhibits hamster AM binding of unopsonized particles (TiO2, Fe2O3, and latex beads; 66 +/- 5, 77 +/- 2, and 85 +/- 2% inhibition, respectively, measured by flow cytometry). This antibody identifies a protein of approximately 70 kD on the AM surface (immunoprecipitation) that is expressed by AMs and other macrophages in situ. A cDNA clone encoding the mAb PAL-1-reactive protein isolated by means of COS cell expression was found to be 84 and 77% homologous to mouse and human scavenger receptor MARCO mRNA, respectively. Transfection of COS cells with MARCO cDNA conferred mAb-inhibitable TiO2 binding. Hamster MARCO also mediates AM binding of unopsonized bacteria (67 +/- 5 and 47 +/- 4% inhibition of Escherichia coli and Staphylococcus aureus binding by mAb PAL-1). A polyclonal antibody to human MARCO identified the expected approximately 70-kD band on Western blots of lysates of normal bronchoalveolar lavage (BAL) cells (>90% AMs) and showed strong immunolabeling of human AMs in BAL cytocentrifuge preparations and within lung tissue specimens. In normal mouse AMs, the anti-MARCO mAb ED31 also showed immunoreactivity and inhibited binding of unopsonized particles (e.g., TiO2 approximately 40%) and bacteria. The novel function of binding unopsonized environmental dusts and pathogens suggests an important role for MARCO in the lungs' response to inhaled particles.

Amino Acid Sequence↗

PubMed1999

Assembly of the CotSA coat protein into spores requires CotS in Bacillus subtilis.

The CotSA protein, encoded by cotSA (ytxN) of Bacillus subtilis, was detected from the cells at 5 h after the onset of sporulation (T5) and in the spore coat of wild-type cells, but not in cotE, cotS, gerE, or cotSA mutant spores. CotSA was also detected in the sporangium at T5 to T7 but not in the sporangium at T18 of cotS mutant cells, while the incorporation of CotS into the coat was not dependent upon CotSA. These results suggested that CotSA was synthesized simultaneously with CotS during T5 to T7 of sporulation and assembled into the coat dependent upon CotS.

Bacillus subtilis↗

PubMed1999

Alcohol-induced biphasic inhibition of myosin subfragment 1 K-EDTA-ATPase.

Butanol-induced inhibition of K-EDTA-ATPase of myosin subfragment 1 proceeded by biphasic kinetics, consisting of rapid and slow inactivations. The extent of the rapid inactivation, which was estimated by extrapolating the process of slow inactivation to zero time of the incubation period, was saturated with butanol concentration. Recovery of activity by dilution in the rapid phase indicates that the rapid process is reversible. The slow inactivation was concomitant with a partial denaturation of the 50 kDa domain of S1, which was detected by limited tryptic digestion. Other alcohols (methanol, ethanol, propanol and hexanol) also inhibited the K-EDTA-ATPase in the rapid phase. The Ki decreased with an increase in the number of methylene groups of alcohol. When K-EDTA-ATPase activity in the rapid phase was plotted against viscosity, surface tension or dielectric constant, the curves were different for each of the various alcohol solutions. The rapid inactivation appears to be caused by a binding of the alkyl group to S1, rather than by solvent effects. The kinetics of rapid butanol inhibitions indicate that butanol reduces the maximum activity of ATPase but enhances an apparent affinity of S1 with ATP. These indications suggest that alcohol stabilizes S1.KATP intermediate. The rapid K-EDTA-ATPase inhibition was observed at the same alcohol concentration where S1 Mg-ATPase was activated.

1-Butanol↗

PubMed1999

Enhancement of chemotactic peptide-induced activation of phosphoinositide 3-kinase by granulocyte-macrophage colony-stimulating factor and its relation to the cytokine-mediated priming of neutrophil superoxide-anion production.

Incubation of human neutrophils with a chemotactic peptide [N-formylmethionyl-leucylphenylalanine (fMLP)] gave rise to an increase in the phosphoinositide 3-kinase (PI3K) activity, phosphorylation of p47phox and superoxide-anion (O2(-)) generation in the same fMLP-concentration-dependent manner. These responses to fMLP were markedly enhanced when the cells had been incubated for 10 min before the addition of fMLP with increasing concentrations of granulocyte-macrophage colony-stimulating factor (GM-CSF) that were only slightly effective themselves. Wortmannin, an inhibitor of PI3K, suppressed all of these fMLP actions in the same concentration-dependent manner in either GM-CSF-primed or non-primed cells. Sustained activation of protein kinase C by the addition of PMA caused marked phosphorylation of p47phox and respiratory burst itself without activation of PI3K. This strong action of PMA was not primed by GM-CSF. The chemotactic peptide was without effect in pertussis-toxin-treated cells, indicating that its actions are mediated by betagamma-subunits liberated from toxin-susceptible heterotrimeric Gi proteins (Gbetagamma). Thus one of the mechanisms of GM-CSF-mediated priming of fMLP-induced respiratory burst is synergistic activation of wortmannin-sensitive PI3K by Gbetagamma in the presence of tyrosine-phosphorylated proteins in GM-CSF-treated cells, as recently indicated in a cell-free system [Kurosu, Maehama, Okada, Yamamoto, Hoshino, Fukui, Ui, Hazeki and Katada (1997) J. Biol. Chem. 272, 24252-24256]. GM-CSF primed fMLP-induced MAP (mitogen-activated protein) kinase activation enormously as well. The MAP kinase activation was primed even in the presence of wortmannin, indicating that PI3K was not the sole site where tyrosine kinase-related and Gbetagamma-mediated intracellular signals converge to elicit the priming. The GM-CSF priming of fMLP-induced PI3K activation and O2(-) generation was much smaller in magnitude in neutrophils in which cAMP accumulated upon incubation with prostaglandin E1 than in the cells without the nucleotide accumulation. Thus the GM-CSF priming site, in addition to PI3K, might be just the target of cAMP-dependent protein kinase A in fMLP-initiated signalling cascades or could be localized immediately downstream thereof.

Androstadienes↗

PubMed1999

New DNA polymorphisms of human MMH/OGG1 gene: prevalence of one polymorphism among lung-adenocarcinoma patients in Japanese.

MMH/OGG1 is an 8-hydroxyguanine-specific DNA glycosylase/AP-lyase, one of the mutator enzymes for the excision repair of 8-hydroxyguanine. DNA polymorphisms in human MMH/OGG1 gene were newly identified and analyzed to examine a possible association with lung-cancer risk by a population-based study. Polymorphic allele 3 in hMMH/OGG1 exon 1 was significantly prevalent among Japanese patients with adenocarcinoma of the lung [odds ratio (OR): 3.152, 95% confidence interval (CI): 1.266-7.845], indicating that the excision repair of 8-hydroxyguanine may play a role in predisposition to lung cancer.

Adenocarcinoma↗

PubMed1999

The physiological role of sterol regulatory element-binding protein-2 in cultured human cells.

To clarify the role of the sterol regulatory element-binding protein-2 (SREBP-2), we established cell lines in which human SREBP-2(1-481) could be induced by isopropyl-beta-D-thiogalactopyranoside (IPTG). The range of IPTG-induced changes in SREBP-2(1-481) levels in '23-11' cells, one of these cell lines, was almost the same as that of sterol-induced changes in the levels of mature SREBP-2, indicating that IPTG was able to regulate the expression of SREBP-2(1-481) within the normal physiological range in this cell line. Sterols regulate the expression of the LDL receptor, HMG-CoA reductase, squalene synthase and fatty acid synthase in 23-11 cells as they also do in the parental cell line HeLa S3. IPTG increased mRNA levels of the LDL receptor and HMG-CoA reductase but not squalene synthase both in the presence or absence of excess sterols. Fatty acid synthase mRNA was increased 2 h after the IPTG addition in the absence of excess sterol (10% FBS), but was slightly increased 6 h after the IPTG addition in the presence of excess sterols. In the absence of excess sterols, both SREBP-2(1-481) and endogenous mature SREBP-2 exist in the nucleus. This suggests that an increased amount of SREBP-2 over the normal physiological range is required for the regulation of fatty acid synthase. IPTG increased both the surface binding of 125I-LDL and cholesterol biosynthesis from [14C]acetate significantly in a similar time course. In contrast, fatty acid biosynthesis from [14C]acetate was almost unchanged by IPTG during the same incubation period. These results suggest that physiological amounts of SREBP-2 play a key role in the regulation of cholesterol but not fatty acid metabolism.

Cell Line↗

PubMed1999

Effect of nitrogen oxides on expression of the nir and nor genes for denitrification in Pseudomonas aeruginosa.

The activity of the promoters involved in transcription of the genes (nirS, nirQ and norC) required for anaerobic reduction of nitrite and nitric oxide was investigated in NIR- and NOR-deficient mutants of Pseudomonas aeruginosa. The transcriptional activity of these three promoters was induced by nitrite in a wild-type strain and the activity was low in an nirS mutant. In norCBD and nirQOP mutants, which were expected to accumulate nitric oxide because of a lack of nitric oxide reductase activity, the norC and nirQ promoters showed significantly enhanced activity in promoting transcription relative to the parental strain, even at low nitrite concentrations. These results suggest that the nirQ and norC promoters are regulated by the concentration of endogenous nitric oxide rather than that of nitrite.

Gene Expression Regulation, Bacterial↗

PubMed1999

The macrophage scavenger receptor type A directs modified proteins to antigen presentation.

Scavenger receptors constitute a family of cell surface receptors that internalize endotoxins, oxidized low-density lipoproteins (oxLDL) and other proteins with clustered negative charges for degradation in macrophages. They were recently proposed to play a role in antigen presentation but the type of scavenger receptor involved in this process has not been known. In this report, we have examined the cellular immune responses to modified proteins in mice lacking the SR-A scavenger receptor (SRAKO) and their wild-type (ICR) controls. While spleen cells of ICR mice immunized with maleylated murine serum albumin (Mal-MSA) exhibit strong proliferative responses to the antigen, no such responses were found in SRAKO mice. However, addition of SR-A+ antigen-presenting cells from ICR mice unmasked proliferative responses to Mal-MSA in spleen cultures of immunized SRAKO mice. Similarly, addition of SR-A+ antigen-presenting cells was necessary to detect T cell responses in spleen cultures of oxLDL-immunized SRAKO mice. This indicates that SR-A can mediate uptake of modified antigens for presentation to antigen-specific T cells. The fact that cellular immunity developed in SRAKO mice implies that other scavenger receptor(s) also internalize modified antigens for presentation in vivo. These observations show that scavenger receptors participate in immune recognition of oxidized protein antigens; this system may be important for recognition of damaged macromolecules but could also play a role in autoimmunity.

Animals↗

PubMed1999

Perforin-dependent NK cell cytotoxicity is sufficient for anti-metastatic effect of IL-12.

IL-12 exerts a potent anti-tumor effect, which is possibly mediated by multiple mechanisms including activation of NK and NKT cells, induction of cytotoxic T lymphocytes, and inhibition of angiogenesis. In the present study, we characterized the cytotoxic effector cells and mechanisms responsible for the anti-metastatic effect of IL-12. Administration of IL-12 had a comparable inhibitory effect on experimental lung metastasis of B16 melanoma cells in wild-type C57BL/6 mice and RAG-2-/- mice that lack T and NKT cells, which was abolished by depletion of NK cells. Cytotoxic activity of liver and splenic mononuclear cells against B16 was induced by IL-12 administration in RAG-2-/- mice at a level comparable to that in wild-type mice, which was also abolished by depletion of NK cells. Moreover, the anti-metastatic effect of IL-12 was abrogated by perforin deficiency, but not by Fas ligand deficiency, in association with a lack of IL-12-induced cytotoxic activity of liver and splenic mononuclear cells against B16. These results suggest that perforin-dependent cytotoxicity of IL-12-activated NK cells is sufficient for the anti-metastatic effect of IL-12.

Animals↗

PubMed1999

Surgical approaches for pancreatic ascites: report of three cases.

Pancreatic ascites can occur in association with the rupture of a pseudocyst or the disruption of a pancreatic duct during the natural course of chronic pancreatitis. We report herein the successful treatment of three patients with pancreatic ascites by performing a surgical procedure after 4-6 weeks of total parenteral nutrition (TPN) proved ineffective. The principles of our surgical procedure for pancreatic ascites are as follows: (1) minimum pancreatic tissue is resected; (2) surgical intervention to repair leaking sites is not necessary; (3) pancreatic duct drainage is facilitated by an intestinal Roux-en-Y loop; (4) An external drainage tube is inserted through the Roux-en-Y loop into the main pancreatic duct. All three patients who underwent our surgical procedure had a good outcome. Although the mean follow-up time is still only 18.3 months, their condition has improved, with no evidence of recurrent ascites. Thus, our surgical procedure should be considered as an appropriate treatment for pancreatic ascites because it can be applied for all types of leakage, including leakage from the posterior wall of pancreas; it preserves pancreatic function, especially endocrine function; and it enables preservation of the spleen.

Aged↗

PubMed1999

Monoclonality of atypical adenomatous hyperplasia of the lung.

Atypical adenomatous hyperplasia (AAH) of the lung has been postulated as a possible precursor lesion of bronchioloalveolar carcinoma (BAC). The clonality of AAHs from seven female patients was analyzed to determine whether AAH is a monoclonal expansion. All AAHs were identified in lungs surgically resected for BAC. The clonality of the BAC and bronchiolar metaplasia in each case was also analyzed. Approximately 500 cells in each lesion were precisely microdissected from methanol-fixed sections. Adjacent normal lung tissue was collected as a normal control. DNA was extracted for clonal analysis based on an X-chromosome-linked polymorphic marker, the human androgen receptor gene (HUMARA). HUMARA was found to be amplified with or without previous digestion by the methylation-sensitive restriction endonuclease Hpa II. Five cases were informative. All 10 AAHs and 7 BACs obtained from the informative cases showed monoclonality, whereas the control cells showed polyclonality. Three different AAH lesions in a single case showed both possible patterns of monoclonality. BAC and contiguous AAH showed identical monoclonality in two cases. Two lesions of bronchiolar metaplasia, which was considered reactive, were polyclonal. Our results demonstrated the monoclonal nature of AAH, and this finding suggests that AAH is a precursor of BAC or a preneoplastic condition.

Adenocarcinoma, Bronchiolo-Alveolar↗

PubMed1999

Role of macrophage scavenger receptors in hepatic granuloma formation in mice.

In mice homozygous for the gene mutation for type I and type II macrophage scavenger receptors (MSR-A), MSR-A-/-, the formation of hepatic granulomas caused by a single intravenous injection of heat-killed Corynebacterium parvum was delayed significantly for 10 days after injection, compared with granuloma formation in wild-type (MSR-A+/+) mice. In the early stage of granuloma formation, numbers of macrophages and their precursor cells were significantly reduced in MSR-A-/- mice compared with MSR-A+/+ mice. In contrast to MSR-A+/+ mice, no expression of monocyte chemoattractant protein-1, tumor necrosis factor-alpha, and interferon-gamma mRNA was observed in MSR-A-/- mice by 3 days after injection. Also in MSR-A-/- mice, uptake of C. parvum by Kupffer cells and monocyte-derived macrophages in the early stage of granuloma formation was lower and elimination of C. parvum from the liver was slower than in MSR-A+/+ mice. In the livers of MSR-A+/+ mice, macrophages and sinusoidal endothelial cells possessed MSR-A, but this was not seen in the livers of MSR-A-/- mice. In both MSR-A-/- and MSR-A+/+ mice, expression of other scavenger receptors was demonstrated. These data suggest that MSR-A deficiency impairs the uptake and elimination of C. parvum by macrophages and delays hepatic granuloma formation, particularly in the early stage.

Animals↗

PubMed1999

Young lung cancer patients in Japan: different characteristics between the sexes.

BACKGROUND: Lung cancer in younger people is uncommon and has characteristics that distinguish it from cancer in older patients. The percentage of smokers among younger patients ranges from 40% to 50% in Asia to 90% in Western countries. The prognosis for young patients with this disease is controversial. METHODS: Medical records of 91 young (40 years of age or younger) and 3,221 older (more than 40 years of age) Japanese patients with lung cancer were reviewed to compare smoking habits, distribution of histopathologic types, clinical stage, and survival. RESULTS: Among female patients, only 39% were smokers in both age groups, whereas smokers were less common among the young male patients (84%) than the older male patients (95%) (p < 0.0001). Adenocarcinomas were diagnosed in 92% of the young and 73% of the older female patients (p = 0.021) versus only 71% and 42% of the corresponding male patients (p < 0.0001). There was no difference in tumor extent or survival between the two groups of female patients. In the male groups, advanced disease (stages IIIB and IV) was more common in the young patients (75%) than in the older patients (54%) (p = 0.0031), but there was no survival difference between the two groups. CONCLUSIONS: Young male and female lung cancer patients in Japan have different characteristics from each other and from older patients of the same sex. Their survival did not differ from that of older patients.

Adenocarcinoma↗

PubMed1999

Pancreatoscopy for the next generation: development of the peroral electronic pancreatoscope system.

BACKGROUND: To improve visualization of the pancreatic duct with a pancreatoscope, we have developed the smallest known electronic endoscope, that is, the peroral electronic pancreatoscope. METHODS: This instrument (2.1 mm, external diameter) was developed with a 50k-pixel interline charge coupled device. A peroral fiberoptic pancreatoscope was used as control, connected to a video converter. The visibility of both systems was studied with a test chart. The model pancreatic duct, the oral mucosa, and the pancreatic ducts of a healthy control subject and patients with chronic pancreatitis were examined with both systems. RESULTS: The smallest visible interval (with a 5 mm distance between the object and the distal end of the endoscope) was 0.07 mm with the peroral electronic pancreatoscope and 0.2 mm with the peroral fiberoptic pancreatoscope. The electronic instrument produced better images of the model pancreatic duct than the fiberoptic endoscope. A clear image of the small vessels of the oral mucosa was obtained with the electronic but not with the fiberoptic instrument. The fine vessel network of the pancreatic duct was visualized only with the electronic instrument; pancreatic duct stones and rough-surfaced pancreatic duct were shown more precisely with the electronic endoscope. CONCLUSIONS: The peroral electronic pancreatoscope provides images of the fine detail of the pancreatic duct and will contribute to the diagnosis of pancreatic diseases.

Calculi↗

PubMed1999

Evaluation of the inner ear by 3D fast asymmetric spin echo (FASE) MR imaging: phantom and volunteer studies.

The 3D fast asymmetric spin echo (FASE) method combines the half-Fourier technique and 3D fast spin echo (FSE) sequence. The advantage of this method is that it maintains the same spatial resolution as FSE while markedly reducing the imaging time. The purpose of the present study was to evaluate the usefulness of the 3D FASE technique in displaying the inner ear structure using phantom and volunteer studies. 3D FSE sequence images were obtained for comparison, and the optimum 3D FASE sequence was investigated on a 1.5T MR scanner. The results of phantom experiments showed increased signal-to-noise ratio (SNR) with prolonging repetition time (TR) on both 3D FASE and 3D FSE sequences. Although the SNR of 3D FASE images was 20-25% lower than that of 3D FSE images with the same TR, the SNR per minute with 3D FASE was about twice that with 3D FSE. On 3D FASE images, a higher spatial resolution was obtained with 2- or 4-shot images than with single-shot images. However, no significant difference was observed between 2-shot and 4-shot images. In the volunteer study, 3D FASE images using a TR of 5000 ms and an effective echo time (TEeff) of 250 ms showed a high SNR and spatial resolution and provided excellent contrast between cerebrospinal fluid and nerves in the internal auditory canal. The highest contrast was achieved in the 2-shot/2 number of excitations sequence. 3D FASE provides the same image quality as 3D FSE with a significant reducing in imaging time, and gives strong T2-weighted images. This method enables detailed visualization of the tiny structures of the inner ear.

Adult↗

PubMed1999

Characterization of plasmid DNA binding and uptake by peritoneal macrophages from class A scavenger receptor knockout mice.

PURPOSE: Plasmid DNA (pDNA) has become an important class of macromolecular agent suitable for non-viral gene therapy as well as DNA vaccination. Our recent study has suggested that pDNA is taken up by mouse peritoneal macrophages via a specific mechanism mediated by a receptor similar to the scavenger receptor (SR). This study was designed to further characterize the pDNA uptake by macrophages in order to elucidate the mechanism. METHODS: The binding and uptake of pDNA labeled with 32P or a fluorescent marker were studied in vitro using cultured Chinese hamster ovary (CHO) cells expressing the class A scavenger receptor (SRA) and peritoneal macrophages from SRA-knockout mice. RESULTS: pDNA binding and uptake by CHO(SRA) cells were minimal and almost identical to that by wild-type CHO cells. Macrophages from the knockout mice showed pronounced pDNA binding and uptake as did the control macrophages. In both types of macrophage, pDNA binding was significantly inhibited by cold pDNA, polyinosinic acid and dextran sulfate but not by polycytidylic acid or Ac-LDL. These results provide direct evidence that SRA is not responsible for the significant binding and subsequent uptake of pDNA by mouse peritoneal macrophages. Further binding experiments revealed that, in addition to polyinosinic acid and dextran sulfate, heparin was a potent inhibitor among a variety of polyanionic compounds such as polynucleotides, anionic polysaccharides and modified proteins including Ox-LDL. CONCLUSIONS: The present study suggest that pDNA binding and uptake by mouse peritoneal macrophages are mediated by a specific mechanism to some defined polyanions not by scavenger receptors. The finding would be an important basis for further studies to elucidate the mechanism(s) of pDNA uptake by macrophages.

Animals↗

PubMed1999

Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 alpha subunit of phosphoinositide 3-kinase.

The hallmark of type 2 diabetes, the most common metabolic disorder, is a defect in insulin-stimulated glucose transport in peripheral tissues. Although a role for phosphoinositide-3-kinase (PI3K) activity in insulin-stimulated glucose transport and glucose transporter isoform 4 (Glut4) translocation has been suggested in vitro, its role in vivo and the molecular link between activation of PI3K and translocation has not yet been elucidated. To determine the role of PI3K in glucose homeostasis, we generated mice with a targeted disruption of the gene encoding the p85alpha regulatory subunit of PI3K (Pik3r1; refs 3-5). Pik3r1-/- mice showed increased insulin sensitivity and hypoglycaemia due to increased glucose transport in skeletal muscle and adipocytes. Insulin-stimulated PI3K activity associated with insulin receptor substrates (IRSs) was mediated via full-length p85 alpha in wild-type mice, but via the p50 alpha alternative splicing isoform of the same gene in Pik3r1-/- mice. This isoform switch was associated with an increase in insulin-induced generation of phosphatidylinositol(3,4,5)triphosphate (PtdIns(3,4,5)P3) in Pik3r1-/- adipocytes and facilitation of Glut4 translocation from the low-density microsome (LDM) fraction to the plasma membrane (PM). This mechanism seems to be responsible for the phenotype of Pik3r1-/- mice, namely increased glucose transport and hypoglycaemia. Our work provides the first direct evidence that PI3K and its regulatory subunit have a role in glucose homeostasis in vivo.

Animals↗