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Kosheleva L, Koshelev D, Lagunas-Rangel FA, Levit S, Rabinovitch A, Schiöth HB. Disease-modifying pharmacological treatments of type 1 diabetes: Molecular mechanisms, target checkpoints, and possible combinatorial treatments. Pharmacol Rev 2025; 77:100044. [PMID: 40014914 PMCID: PMC11964952 DOI: 10.1016/j.pharmr.2025.100044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 01/10/2025] [Indexed: 03/01/2025] Open
Abstract
After a century of extensive scientific investigations, there is still no curative or disease-modifying treatment available that can provide long-lasting remission for patients diagnosed with type 1 diabetes (T1D). Although T1D has historically been regarded as a classic autoimmune disorder targeting and destroying pancreatic islet β-cells, significant research has recently demonstrated that β-cells themselves also play a substantial role in the disease's progression, which could explain some of the unfavorable clinical outcomes. We offer a thorough review of scientific and clinical insights pertaining to molecular mechanisms behind pathogenesis and the different therapeutic interventions in T1D covering over 20 possible pharmaceutical intervention treatments. The interventions are categorized as immune therapies, treatments targeting islet endocrine dysfunctions, medications with dual modes of action in immune and islet endocrine cells, and combination treatments with a broader spectrum of activity. We suggest that these collective findings can provide a valuable platform to discover new combinatorial synergies in search of the curative disease-modifying intervention for T1D. SIGNIFICANCE STATEMENT: This research delves into the underlying causes of T1D and identifies critical mechanisms governing β-cell function in both healthy and diseased states. Thus, we identify specific pathways that could be manipulated by existing or new pharmacological interventions. These interventions fall into several categories: (1) immunomodifying therapies individually targeting immune cell processes, (2) interventions targeting β-cells, (3) compounds that act simultaneously on both immune cell and β-cell pathways, and (4) combinations of compounds simultaneously targeting immune and β-cell pathways.
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Affiliation(s)
- Liudmila Kosheleva
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, Uppsala, Sweden
| | - Daniil Koshelev
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, Uppsala, Sweden
| | - Francisco Alejandro Lagunas-Rangel
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, Uppsala, Sweden; Laboratory of Pharmaceutical Pharmacology, Latvian Institute of Organic Synthesis, Riga, Latvia
| | - Shmuel Levit
- Diabetes and Metabolism Institute, Assuta Medical Centers, Tel Aviv, Israel
| | | | - Helgi B Schiöth
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, Uppsala, Sweden; Laboratory of Pharmaceutical Pharmacology, Latvian Institute of Organic Synthesis, Riga, Latvia.
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Li Y, Zhen S, Sun F, Cao L, Wang L. Effects of γ-Aminobutyric Acid on Growth Performance, Immunity, Antioxidant Capacity, and Intestinal Microbiota of Growing Minks. Vet Sci 2024; 11:398. [PMID: 39330777 PMCID: PMC11435872 DOI: 10.3390/vetsci11090398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 07/16/2024] [Accepted: 08/27/2024] [Indexed: 09/28/2024] Open
Abstract
The present experiment was conducted to investigate the effects of γ-aminobutyric acid (GABA) on the growth performance, immunity, antioxidant capacity, and intestinal microbiota of growing minks. One hundred minks were evenly allocated across five groups, with each group consisting of 10 males and 10 females. The minks in these groups were fed a basal diet supplemented with γ-aminobutyric acid (GABA) at 0 (control), 10, 20, 30, and 40 mg/kg of diet, respectively. The experiment lasted for eight weeks. The results showed that GABA significantly affected immunity, antioxidant capacity, and intestinal microbiota (p < 0.05). Compared to the control minks, minks in 20, 30, and 40 mg/kg GABA group had greater total protein quantitative (TP), immunoglobulin A (IgA), immunoglobulin M (IgM) content, total antioxidant capacity (T-AOC), and glutathione peroxidase (GSH-Px) activities in serum as well as interleukin-4 (IL-4) level in jejunal mucosa (p < 0.05), and had less serum blood urea nitrogen (BUN) content (p < 0.05). Furthermore, compared with the control, the supplementation of GABA at 30 mg/kg of diet improved average daily feed intake (ADFI) (p < 0.05), increased immunoglobulin G (IgG) content in serum, interleukin-10 (IL-10) and secreted immunoglobulin A (SIgA) levels in jejunal mucosa, and decreased jejunal mucosal interleukin-2 (IL-2), interleukin-12 (IL-12), and interferon-γ (IFN-γ) levels (p < 0.05). The weight and feed intake of males were higher than females, and the feed/gain ratio (F/G) was lower than females (p < 0.05). Males also had greater serum superoxide dismutase (SOD) and GSH-Px activities, and jejunal mucosa IL-2, IL-4, IL-12, SIgA, and IFN-γ levels (p < 0.05), and males had less serum IgA, IgM, and T-AOC contents, and jejunal mucosal tumor necrosis factor-α (TNF-α) level (p < 0.05). The results suggest that the supplementation of GABA at 30 mg/kg of diet can improve immune status and antioxidant capacity, and modulate the intestinal microbiota abundance of growing minks.
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Affiliation(s)
- Yalin Li
- College of Animal Science and Technology, Qingdao Agricultural University, Qingdao 266109, China
| | - Shibo Zhen
- College of Animal Science and Technology, Qingdao Agricultural University, Qingdao 266109, China
| | - Fengxue Sun
- College of Animal Science and Technology, Qingdao Agricultural University, Qingdao 266109, China
| | - Lin Cao
- College of Animal Science and Technology, Qingdao Agricultural University, Qingdao 266109, China
| | - Lihua Wang
- College of Animal Science and Technology, Qingdao Agricultural University, Qingdao 266109, China
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Shirey KA, Lai W, Sunday ME, Cuttitta F, Blanco JCG, Vogel SN. Novel neuroendocrine role of γ-aminobutyric acid and gastrin-releasing peptide in the host response to influenza infection. Mucosal Immunol 2023; 16:302-311. [PMID: 36965691 PMCID: PMC10330014 DOI: 10.1016/j.mucimm.2023.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 03/16/2023] [Accepted: 03/20/2023] [Indexed: 03/27/2023]
Abstract
Gastrin-releasing peptide (GRP), an evolutionarily conserved neuropeptide, significantly contributes to influenza-induced lethality and inflammation in rodent models. Because GRP is produced by pulmonary neuroendocrine cells (PNECs) in response to γ-aminobutyric acid (GABA), we hypothesized that influenza infection promotes GABA release from PNECs that activate GABAB receptors on PNECs to secrete GRP. Oxidative stress was increased in the lungs of influenza A/PR/8/34 (PR8)-infected mice, as well as serum glutamate decarboxylase 1, the enzyme that converts L-glutamic acid into GABA. The therapeutic administration of saclofen, a GABAB receptor antagonist, protected PR8-infected mice, reduced lung proinflammatory gene expression of C-C chemokine receptor type 2 (Ccr2), cluster of differentiation 68 (Cd68), and Toll like receptor 4 (Tlr4) and decreased the levels of GRP and high-mobility group box 1 (HMGB1) in sera. Conversely, baclofen, a GABAB receptor agonist, significantly increased the lethality and inflammatory responses. The GRP antagonist, NSC77427, as well as the GABAB antagonist, saclofen, blunted the PR8-induced monocyte infiltration into the lung. Together, these data provide the first report of neuroregulatory control of influenza-induced disease.
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Affiliation(s)
- Kari Ann Shirey
- Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, Maryland, USA.
| | - Wendy Lai
- Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, Maryland, USA
| | - Mary E Sunday
- Duke University Medical Center, Durham, North Carolina, USA
| | - Frank Cuttitta
- Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland, USA
| | | | - Stefanie N Vogel
- Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, Maryland, USA
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GABA promotes gastrin-releasing peptide secretion in NE/NE-like cells: Contribution to prostate cancer progression. Sci Rep 2018; 8:10272. [PMID: 29980692 PMCID: PMC6035255 DOI: 10.1038/s41598-018-28538-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 06/22/2018] [Indexed: 01/10/2023] Open
Abstract
In prostate cancer (PCa), neuroendocrine cells (NE) have been associated with the progression of the disease due to the secretion of neuropeptides that are capable of diffusing and influence surrounding cells. The GABAergic system is enriched in NE-like cells, and contributes to PCa progression. Additionally, γ-aminobutyric acid (GABA) stimulates the secretion of gastrin-releasing peptide (GRP) in peripheral organs. For the first time, in this study we show the role of GABA and GABAB receptor 1 (GABBR1) expression in GRP secretion in NE-like prostate cancer cells. We demonstrated an increase in GRP levels in NE-like cell medium treated with GABAB receptor agonist. Moreover, the blocking of this receptor inhibited GABA-induced GRP secretion. The invasive potential of PC3 cells was enhanced by either GRP or conditioned medium of NE-like cells treated with GABA. Additionally, we confirmed a positive correlation between GABA and GRP levels in the serum of PCa patients with NE markers. Finally, using public available data sets, we found a negative correlation between GABBR1 and androgen receptor (AR) expression, as well as a strong positive correlation between GABBR1 and enolase 2. These results suggest that GABA via GABBR1 induces GRP secretion in NE like cells involved in PCa progression.
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Xie WY, Hou XY, Yan FB, Sun GR, Han RL, Kang XT. Effect of γ-aminobutyric acid on growth performance and immune function in chicks under beak trimming stress. Anim Sci J 2012; 84:121-9. [PMID: 23384353 DOI: 10.1111/j.1740-0929.2012.01051.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
This experiment was undertaken to examine the effect of beak trimming stress on the growth performance and immune system, and to consider possible roles of γ-aminobutyric acid (GABA) in this stress response. Results showed that body weight, feed intake and relative spleen weight were significantly increased by GABA at 80 mg/kg (P < 0.05) under beak trimming stress, whereas the relative organ weights of the bursa of fabricius and thymus were not significantly affected (P > 0.05). Adrenocorticotropic hormone concentration in serum was highest for chicks fed the GABA-deficient water and was significantly decreased by the supplement of GABA at days 1, 3 and 5 after beak trimming (P < 0.05). The supplement of GABA significantly increased the proportions of CD4(+) and CD8(+) lymphocytes, especially at the dose of 60 mg/kg (P < 0.05). The levels of interleukin (IL)-1β, lipopolysaccharide-induced tumor necrosis factor-α and IL-6 in serum were significantly decreased by GABA at 80 mg/kg (P < 0.05). All the three cytokines expressed in the spleen were significantly decreased by GABA at 80 mg/kg when birds were under beak trimming stress (P < 0.05). It is concluded that beak trimming suppressed the immune response of chicks, whereas the immune response of chicks could be improved by GABA supplementation.
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Affiliation(s)
- Wan-ying Xie
- Department of Animal Science and Veterinary Medicine, Henan Agricultural University, Henan Research Center of Breeding Resources for Poultry, Zhengzhou, China
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Ericsson P, Håkanson R, Norlén P. Gastrin response to candidate messengers in intact conscious rats monitored by antrum microdialysis. ACTA ACUST UNITED AC 2010; 163:24-30. [DOI: 10.1016/j.regpep.2010.03.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2009] [Revised: 01/25/2010] [Accepted: 03/16/2010] [Indexed: 11/29/2022]
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Zong YF, Chen WH, Zhang YS, Zou SX. Effects of intra-gastric beta-casomorphin-7 on somatostatin and gastrin gene expression in rat gastric mucosa. World J Gastroenterol 2007; 13:2094-9. [PMID: 17465454 PMCID: PMC4319131 DOI: 10.3748/wjg.v13.i14.2094] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the in vivo effect of beta-casomorphin-7 on the regulation of gastric somatostatin and gastrin messenger RNA in rat gastric mucosa.
METHODS: Somatostatin and gastrin mRNA were quantified by RT-PCR and in situ hybridization (ISH) in 24 rats. The rats were divided into three treatment groups: basal diet + physiological saline (n = 8), basal diet + beta-casomorphin-7 (7.5 × 10-7 mol) (n = 8), and basal diet + poly-Gly-7 (containing equal mol of N with 7.5 × 10-7 mol beta-casomorphin-7) (n = 8). After oral administration for 30 days, rats were killed by exsanguinations.
RESULTS: After intra-gastric administration of beta-casomorphin-7 for 30 d, gastrin mRNA increased by 52.8% (P < 0.05, n = 8), and somatostatin mRNA levels decreased by 30.7% compared with the controls (P < 0.01, n = 8). No significant differences in the expression of the two genes were observed in the poly-Gly-treated group, although gastrin mRNA expression was elevated by 35.6% as against the control group (P = 0.15, n = 8). The long-term oral administration of a casomorphin solution significantly decreased the even gray of D-cells, but did not lower the number of D-cells both in the antrum and fundus. Interestingly, the number of G-cells increased in the antrum and fundus, but its average density was augmented only in the antrum.
CONCLUSION: Beta-casomorphin-7 is capable of modulating gene expression of the regulatory peptides from G and D cells. Data from in situ hybridization studies indicate that beta-casomorphin-7 affects gastrin gene expression indirectly by means of the paracrine action of somatostatin, and depends on its intrinsic molecular function.
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Affiliation(s)
- Ya-Feng Zong
- Department of Animal Physiology and Biochemistry, Nanjing Agricultural University, Nanjing 210095, Jiangshu Province, China
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Ligon B, Yang J, Morin SB, Ruberti MF, Steer ML. Regulation of pancreatic islet cell survival and replication by gamma-aminobutyric acid. Diabetologia 2007; 50:764-73. [PMID: 17318626 DOI: 10.1007/s00125-007-0601-8] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2006] [Accepted: 12/17/2006] [Indexed: 10/23/2022]
Abstract
AIMS/HYPOTHESIS Pancreatic islets have evolved remarkable, though poorly understood mechanisms to modify beta cell mass when nutrient intake fluctuates or cells are damaged. We hypothesised that appropriate and timely adjustments in cell number occur because beta cells release proliferative signals to surrounding cells when stimulated by nutrients and 'bleed' these growth factors upon injury. MATERIALS AND METHODS In rat pancreatic islets, we measured DNA content, insulin content, insulin secretion after treatment, immunoblots of apoptotic proteins and the uptake of nucleoside analogues to assess the ability of gamma-aminobutyric acid (GABA), which is highly concentrated in beta cells, to act as a growth and survival factor. This focus is supported by work from others demonstrating that GABA increases cell proliferation in the developing nervous system, acts as a survival factor for differentiated neurons and, interestingly, protects plants under stress. RESULTS Our results show that DNA, insulin content and insulin secretion are higher in freshly isolated islets treated with GABA or GABA B receptor agonists. Exposure to GABA upregulated the anti-apoptotic protein B-cell chronic lymphocytic leukaemia XL and limited activation of caspase 3 in islets. The cellular proliferation rate in GABA-treated islets was twice that of untreated controls. CONCLUSIONS/INTERPRETATION We conclude that GABA serves diverse purposes in the islet, meeting a number of functional criteria to act as an endogenous co-regulator of beta cell mass.
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Affiliation(s)
- B Ligon
- Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111, USA.
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Simcock DC, Lawton DEB, Scott I, Simpson HV. Abomasal bacteria produce an inhibitor of gastrin secretion in vitro. Res Vet Sci 2006; 81:152-7. [PMID: 16352323 DOI: 10.1016/j.rvsc.2005.10.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2005] [Revised: 08/02/2005] [Accepted: 10/25/2005] [Indexed: 12/01/2022]
Abstract
Previously, proliferating microflora transferred with abomasal nematodes, were suspected to be the source of the gastrin inhibitor in some parasite excretory/secretory products. Aerobic cultures in HBSS of abomasal fluid from uninfected sheep became inhibitory during the static growth phase, unless antibiotics were present. Basal gastrin secretion was reduced by up to 90%. Rumen fluid and incubates and medium in which Streptococcus bovis and ovine rumen Actinomycete spp. had been grown also contained the inhibitor. Unlike abomasal cultures, rumen fluid and incubates also reduced the measurement of gastrin standards. Rumen incubates were less potent after exposure to pH 2-3, suggesting that inactivation normally occurs in the unparasitised abomasum. Contaminating bacteria which generate the gastrin inhibitor in parasite ES products are probably rumen organisms which survive in the abomasum and proliferate during subsequent incubation. Significantly, rumen bacteria have been shown to be capable of affecting the secretory activity of the gastric mucosa.
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Affiliation(s)
- D C Simcock
- Institute of Food, Nutrition and Human Health, Massey University, Private Bag 11-222, Palmerston North, New Zealand
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Simcock DC, Scott I, Przemeck SMC, Simpson HV. Abomasal contents of parasitised sheep contain an inhibitor of gastrin secretion in vitro. Res Vet Sci 2006; 81:225-30. [PMID: 16530238 DOI: 10.1016/j.rvsc.2006.01.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2005] [Revised: 12/14/2005] [Accepted: 01/12/2006] [Indexed: 11/24/2022]
Abstract
Serum gastrin concentrations are typically elevated in parasitised sheep; however, in some animals serum gastrin concentrations may fall abruptly despite a very high abomasal pH. Although proliferating abomasal bacteria in culture generate a potent inhibitor of in vitro gastrin secretion, this inhibitor has not been detected in abomasal contents of unparasitised sheep. In sheep parasitised by O. circumcincta, all abomasal fluid samples of pH 5 and above were inhibitory to gastrin release in vitro. Inhibitory activity and abomasal pH were correlated in two separate experiments; the model best fitting the data being sigmoidal in each case, with zero activity at pH 3.6 and 4.6, respectively. There was no clear evidence that the presence of a gastrin inhibitor in the abomasal contents reduced the serum gastrin concentration in parasitised sheep. Serum gastrin was correlated with abomasal pH (log(10) serum gastrin concentrations conformed to log-linear sigmoidal models).
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Affiliation(s)
- D C Simcock
- Institute of Food, Nutrition and Human Health, Massey University, Private Bag 11-222, Palmerston North, New Zealand
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Piqueras L, Martinez V. Peripheral GABAB agonists stimulate gastric acid secretion in mice. Br J Pharmacol 2004; 142:1038-48. [PMID: 15210585 PMCID: PMC1575121 DOI: 10.1038/sj.bjp.0705876] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
1 We characterized the effects of intravenous GABA and preferential GABAA (muscimol), GABAB (R-baclofen and SKF-97541) and GABAC agonists (imidazole-4-acetic acid) on gastric acid secretion in urethane-anesthetized mice implanted with a gastric cannula, and determined the role of vagal cholinergic mechanisms, and gastrin and somatostatin by using peptide immunoneutralization, the SSTR2 antagonist, PRL-2903, and SSTR2 knockout mice. 2 The selective GABA(B) agonists R-baclofen (0.1-3 mg kg(-1), i.v.) and SKF-97541 (0.01-0.3 mg kg(-1), i.v.) induced a dose-related stimulation of gastric acid secretion. SKF-97541 was about 10 times more potent than R-baclofen stimulating gastric acid secretion. Neither GABA (0.1-100 mg kg(-1), i.v.) nor muscimol (0.1-3 mg kg(-1)) nor imidazole-4-acetic acid (0.1-10 mg kg(-1)) affected basal gastric acid secretion. 3 Stimulatory effects of SKF-97541 (0.1 mg kg(-1), i.v.) were blocked by the selective GABAB antagonist, 2-hydroxysaclofen, cholinergic blockade with atropine, subdiaphragmatic vagotomy or gastrin immunoneutralization. 4 Somatostatin immunoneutralization or SSTR2 blockade with PRL-2903 enhanced the secretory response to SKF-97541 (0.1 mg kg(-1), i.v.) by 78 and 105%, respectively. 5 In SSTR2 knockout mice, SKF-97541 (0.1 mg kg(-1), i.v.) increased basal gastric acid secretion by 48%. Neither GABA nor muscimol nor imidazole-4-acetic acid modified basal gastric acid secretion in SSTR2 knockout mice. 6 These results indicate that, in mice, stimulation of GABAB receptors increases gastric acid secretion through vagal- and gastrin-dependent mechanisms. Somatostatin implication might be secondary to the release of gastrin and the increase in gastric luminal acidity.
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MESH Headings
- Animals
- Antibodies, Monoclonal/pharmacology
- Atropine/pharmacology
- Baclofen/analogs & derivatives
- Baclofen/pharmacology
- Deoxyglucose/pharmacology
- Dose-Response Relationship, Drug
- GABA Agonists/pharmacology
- GABA Antagonists/pharmacology
- GABA-A Receptor Agonists
- GABA-B Receptor Agonists
- Gastric Acid/metabolism
- Gastrins/immunology
- Imidazoles/pharmacology
- Injections, Intravenous
- Male
- Mice
- Mice, Knockout
- Muscimol/pharmacology
- Organophosphorus Compounds/pharmacology
- Pentagastrin/pharmacology
- Peptides, Cyclic/pharmacology
- Receptors, GABA/drug effects
- Receptors, GABA/physiology
- Receptors, GABA-A/physiology
- Receptors, GABA-B/physiology
- Receptors, Somatostatin/antagonists & inhibitors
- Receptors, Somatostatin/genetics
- Receptors, Somatostatin/physiology
- Somatostatin/immunology
- Time Factors
- Vagotomy
- gamma-Aminobutyric Acid/pharmacology
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Affiliation(s)
- Laura Piqueras
- Department of Physiology, Pharmacology and Toxicology, Cardenal Herrera CEU University, Valencia, Spain
| | - Vicente Martinez
- Department of Physiology, Pharmacology and Toxicology, Cardenal Herrera CEU University, Valencia, Spain
- Author for correspondence:
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Li YY. Mechanisms for regulation of gastrin and somatostatin release from isolated rat stomach during gastric distention. World J Gastroenterol 2003; 9:129-33. [PMID: 12508367 PMCID: PMC4728226 DOI: 10.3748/wjg.v9.i1.129] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the intragastric mechanisms for regulation of gastric neuroendocrine functions during gastric distention in isolated vascularly perfused rat stomach.
METHODS: Isolated vascularly perfused rat stomach was prepared, then the gastric lumen was distended with either 5, 10 or 15 mL pH7 isotonic saline during a period of 20 min. During the distention, the axonal blocker tetrodotoxin (TTX), the cholinergic antagonist atropine, or the putative somatostatin-antagonist cyclo [7-aminoheptanoyl-Phe-D-Trp-Lys-Thr(Bzl)] were applied by vascular perfusion. The releases of gastrin and somatostatin were then examined by radioimmunoassay.
RESULTS: The graded gastric distention caused a significant volume-dependent decrease in gastrin secretion [-183 ± 75 (5 mL), -385 ± 86 (10 mL) and -440 ± 85 (15 mL) pg/20 min] and a significant increase of somatostatin secretion [260 ± 102 (5 mL), 608 ± 148 (10 mL) and 943 ± 316 (15 mL) pg/20 min]. In response to 10 mL distention, the infusion of either axonal blocker TTX (10-6 M) or cholinergic blocker atropine (10-7 M) had a similar affect. They both attenuated the decrease of gastrin release by approximately 50%, and attenuated the increase of somatostatin release by approximately 40%. The infusion of somatostatin-antagonist cyclo [7-aminoheptanoyl-Phe-D-Trp-Lys-Thr(Bzl)] (10-6 M) attenuated the decrease of gastrin release by about 60%. Furthermore, combined infusion of the somatostatin-antagonist and atropine completely abolished distention-induced inhibition of gastrin release.
CONCLUSION: The present data suggest that distention of isolated rat stomach stimulates somatostatin release via cholinergic and non-cholinergic TTX-insensitive pathways. Both somatostatin and intrinsic cholinergic pathways are responsible for distention-induced inhibition of gastrin release.
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Affiliation(s)
- Yong-Yu Li
- Department of Pathophysiology, Medical College of Tongji University, Shanghai 200331, China.
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Abstract
AIM: To investigate the relationship among gastrin, somatostatin, G and D cells in gastric ulcer and in its healing process in rats.
METHODS: Fourty-nine Wistar rats were divided into 7 groups. The gastric ulcer model was induced by acetic acid successfully. The gastrin and the somatostatin in rat plasma, gastric fluid and antral tissue were measured by radioimmunoassay (RIA). G and D cells in antral mucosa were analyzed with polyclonal antibody of gastrin and somatostatin by immunohistochemical method and Quantimet 500 image analysis system.
RESULTS: In gastric ulcer, the level of gastrin in plasma, gastric fluid, and antral tissue increased, that of somatostatin declined, and the disorder gradually recovered to the normal level in the healing process. Immunohistochemical technique of G and D cells in antral mucosa demonstrated that the number of G cells increased and that of D cells decreased, both areas of G and D cells declined, the ratio of number and area of G/D increased in gastric ulcer, and the disorder gradually recovered in the healing process.
CONCLUSION: In gastric ulcer, the increased gastrin secreted by G cells, the declined somatostatin secreted by D cells, and the disordered G/D cell ratio can lead to gastrointestinal dysfunction.
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Affiliation(s)
- Feng-Peng Sun
- Department of Gastroenterology, Zhujiang Hospital, First Military Medical University, Guangzhou 510282, Guangdong Province, China.
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Norlén P, Bernsand M, Konagaya T, Håkanson R. ECL-cell histamine mobilization in conscious rats: effects of locally applied regulatory peptides, candidate neurotransmitters and inflammatory mediators. Br J Pharmacol 2001; 134:1767-77. [PMID: 11739254 PMCID: PMC1572899 DOI: 10.1038/sj.bjp.0704419] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
1. The ECL cells control gastric acid secretion by mobilizing histamine in response to circulating gastrin. In addition, the ECL cells are thought to operate under nervous control and to be influenced by local inflammatory processes. 2. The purpose of the present study was to monitor histamine mobilization from ECL cells in conscious rats in response to locally applied regulatory peptides, candidate neurotransmitters and inflammatory mediators. 3. Microdialysis probes were implanted in the submucosa of the acid-producing part of the rat stomach. Three days later, the agents to be tested were administered via the microdialysis probe and their effects on basal (48 h fast) and stimulated (intravenous infusion of gastrin-17, 3 nmol kg(-1) h(-1)) mobilization of ECL-cell histamine was monitored by continuous measurement of histamine in the perfusate (radioimmunoassay). 4. Locally administered gastrin-17 and sulfated cholecystokinin-8 mobilized histamine as did pituitary adenylate cyclase-activating peptide-27, vasoactive intestinal peptide, peptide YY, met-enkephalin, endothelin and noradrenaline, adrenaline and isoprenaline. 5. While gastrin, sulfated-cholecystokinin-8, met-enkephalin and isoprenaline induced a sustained elevation of the submucosal histamine concentration, endothelin, peptide YY, pituitary adenylate cyclase activating peptide, vasoactive intestinal peptide, noradrenaline and adrenaline induced a transient elevation. 6. Calcitonin gene-related peptide, galanin, somatostatin and the prostanoid misoprostol inhibited gastrin-stimulated histamine mobilization. 7. The gut hormones neurotensin and secretin and the neuropeptides gastrin-releasing peptide, neuropeptide Y and substance P failed to affect ECL-cell histamine mobilization, while motilin and neuromedin U-25 had weak stimulatory effects. Also acetylcholine, carbachol, serotonin and the amino acid neurotransmitters aspartate, gamma-aminobutyric acid, glutamate and glycine were inactive or weakly active as was bradykinin. 8. In summary, a range of circulating hormones, local hormones, catecholamines, neuropeptides and inflammatory mediators participate in controlling the activity of rat stomach ECL cells in situ.
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Affiliation(s)
- P Norlén
- Department of Pharmacology, Institute of Physiological Sciences, University of Lund BMC F13, S-221 84 Lund, Sweden
| | - M Bernsand
- Department of Pharmacology, Institute of Physiological Sciences, University of Lund BMC F13, S-221 84 Lund, Sweden
| | - T Konagaya
- Department of Pharmacology, Institute of Physiological Sciences, University of Lund BMC F13, S-221 84 Lund, Sweden
| | - R Håkanson
- Department of Pharmacology, Institute of Physiological Sciences, University of Lund BMC F13, S-221 84 Lund, Sweden
- Author for correspondence:
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Hardt J, Larsson LI, Hougaard DM. Immunocytochemical evidence suggesting that diamine oxidase catalyzes biosynthesis of gamma-aminobutyric acid in antropyloric gastrin cells. J Histochem Cytochem 2000; 48:839-46. [PMID: 10820157 DOI: 10.1177/002215540004800612] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
gamma-Aminobutyric acid (GABA) is a neurotransmitter that also occurs in a few non-neuronal cell types, where it may serve as a paracrine modulator. GABA is biosynthesized from glutamate by glutamate decarboxylase (GAD) and from putrescine via diamine oxidase (DAO). GAD is demonstrable in several GABA-positive cell types but is undetectable in the GABA-containing gastrin cells and somatostatin cells of the antropyloric mucosa of the stomach. Using two antisera raised against synthetic peptides corresponding to two different regions of rat DAO, we now demonstrate strong reactivity for DAO in gastrin-positive cells of the rat antropyloric mucosa, whereas somatostatin-positive cells as well as other structures of the antrum are unreactive. Western blotting analysis of antrum and colon demonstrate that both antisera react with a single band of 85 kD, consistent with the predicted molecular weight of DAO. Expression of DAO mRNA in the antrum is demonstrated by reverse transcriptase polymerase chain reaction (RT-PCR). Our results strongly indicate that gastrin cells produce GABA via DAO-catalyzed oxidation of putrescine, and experimental data moreover suggest that the biosynthesis of GABA is regulated by the prandial state. Because GABA modulates release of somatostatin, these results point to a new mechanism of paracrine interaction between gastrin cells and somatostatin cells.
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Affiliation(s)
- J Hardt
- Department of Clinical Biochemistry, Statens Serum Institut, Copenhagen, Denmark
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