2,517 results on '"Secretagogue"'
Search Results
2. Real-World Effects of Second-Generation Versus Earlier Intermediate/Basal Insulin Analogues on Rates of Hypoglycemia in Adults with Type 1 and 2 Diabetes (iNPHORM, US).
- Author
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Black, Jason E., Harris, Stewart B., Ryan, Bridget L., Zou, Guangyong, and Ratzki-Leewing, Alexandria
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TYPE 1 diabetes , *TYPE 2 diabetes , *HYPOGLYCEMIA , *INSULIN , *GENERALIZED estimating equations - Abstract
Introduction: Second-generation basal insulin analogues have been shown to reduce hypoglycemia in several trials and observational studies of select populations; however, it remains unclear whether these results persist in real-world settings. Using self-reported hypoglycemia events, we assessed whether second-generation basal insulin analogues reduce rates of hypoglycemia events (non-severe/severe; overall/daytime/nocturnal) compared to earlier intermediate/basal insulin analogues among people with insulin-treated type 1 or 2 diabetes. Methods: We used prospectively collected data from the Investigating Novel Predictions of Hypoglycemia Occurrence Using Real-World Models (iNPHORM) panel survey. This US-wide, 1-year internet-based survey assessed hypoglycemia experiences and related sociodemographic and clinical characteristics of people with diabetes (February 2020−March 2021). We estimated population-average rate ratios for hypoglycemia comparing second-generation to earlier intermediate/basal insulin analogues using negative binomial regression, adjusting for confounders. Within-person variability of repeated observations was addressed with generalized estimating equations. Results: Among iNPHORM participants with complete data, N = 413 used an intermediate/basal insulin analogue for ≥ 1 month during follow-up. After adjusting for baseline and time-updated confounders, average second-generation basal insulin analogue users experienced a 19% (95% CI 3–32%, p = 0.02) lower rate of overall non-severe hypoglycemia and 43% (95% CI 26–56%, p < 0.001) a lower rate of nocturnal non-severe hypoglycemia compared to earlier intermediate/basal insulin users. Overall severe hypoglycemia rates were similar among second-generation and earlier intermediate/basal insulin users (p = 0.35); however, the rate of severe nocturnal hypoglycemia was reduced by 44% (95% CI 10–65%, p = 0.02) among second-generation insulin users compared to earlier intermediate/basal insulin users. Conclusion: Our real-world results suggest second-generation basal insulin analogues reduce rates of hypoglycemia, especially nocturnal non-severe and severe events. Whenever possible and feasible, clinicians should prioritize prescribing these agents over first-generation basal or intermediate insulin in people with type 1 and 2 diabetes. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
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3. Preptin Deficiency Does Not Protect against High‐Fat Diet‐Induced Metabolic Dysfunction or Bone Loss in Mice.
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Buckels, Emma J., Tan, Joey, Hsu, Huai‐Ling, Zhu, Yuting, Buchanan, Christina M., Matthews, Brya G., and Lee, Kate L.
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METABOLIC disorders ,BONE health ,CANCELLOUS bone ,INSULIN ,LOW-fat diet ,COMPACT bone - Abstract
Preptin is derived from the cleavage of the E‐peptide of pro‐insulin‐like growth factor (IGF)‐II and is an insulin secretagogue. Observational studies have linked elevated circulating preptin to metabolic dysfunction in humans; however, a causal role for preptin in metabolic dysfunction has not been established. Additionally, preptin can promote osteoblast proliferation and differentiation, suggesting a link with skeletal health. We previously described a global preptin knockout (KO) model. In this study, we sought to uncover the impact of preptin KO in mice on the response to a moderately high‐fat diet (HFD) and low‐fat diet (LFD). HFD groups had higher weight and fat mass gain, lower trabecular and cortical bone volume and fracture load, and higher liver triglycerides. In males, preptin deficiency led to lower blood glucose than wild‐type (WT) mice under LFD conditions. This was accompanied by differences in bone microarchitecture, including lower trabecular bone volume fraction, trabecular number, and lower cortical thickness. These differences were absent in female mice, although KO females had a HFD‐driven increase in fat mass and liver triglycerides that was absent in WT mice. Female WT mice had increased glucose‐stimulated insulin secretion under HFD conditions that was absent in female KO mice. Overall, preptin may have a detrimental impact on metabolism and a positive impact on bone health in male mice and may protect against liver fat storage in females while enabling islet compensation under HFD conditions. When we consider that serum preptin levels are elevated in humans of both sexes in pathological states in which insulin levels are elevated, the impact of preptin on comorbidity risk needs to be better understood. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]
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- 2023
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4. Preptin Deficiency Does Not Protect against High‐Fat Diet‐Induced Metabolic Dysfunction or Bone Loss in Mice
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Emma J. Buckels, Joey Tan, Huai‐Ling Hsu, Yuting Zhu, Christina M. Buchanan, Brya G. Matthews, and Kate L. Lee
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DIET ,GLUCOSE TOLERANCE ,INSULIN‐LIKE GROWTH FACTOR‐II ,METABOLIC DYSFUNCTION ,SECRETAGOGUE ,SEXUAL DIMORPHISM ,Orthopedic surgery ,RD701-811 ,Diseases of the musculoskeletal system ,RC925-935 - Abstract
ABSTRACT Preptin is derived from the cleavage of the E‐peptide of pro‐insulin‐like growth factor (IGF)‐II and is an insulin secretagogue. Observational studies have linked elevated circulating preptin to metabolic dysfunction in humans; however, a causal role for preptin in metabolic dysfunction has not been established. Additionally, preptin can promote osteoblast proliferation and differentiation, suggesting a link with skeletal health. We previously described a global preptin knockout (KO) model. In this study, we sought to uncover the impact of preptin KO in mice on the response to a moderately high‐fat diet (HFD) and low‐fat diet (LFD). HFD groups had higher weight and fat mass gain, lower trabecular and cortical bone volume and fracture load, and higher liver triglycerides. In males, preptin deficiency led to lower blood glucose than wild‐type (WT) mice under LFD conditions. This was accompanied by differences in bone microarchitecture, including lower trabecular bone volume fraction, trabecular number, and lower cortical thickness. These differences were absent in female mice, although KO females had a HFD‐driven increase in fat mass and liver triglycerides that was absent in WT mice. Female WT mice had increased glucose‐stimulated insulin secretion under HFD conditions that was absent in female KO mice. Overall, preptin may have a detrimental impact on metabolism and a positive impact on bone health in male mice and may protect against liver fat storage in females while enabling islet compensation under HFD conditions. When we consider that serum preptin levels are elevated in humans of both sexes in pathological states in which insulin levels are elevated, the impact of preptin on comorbidity risk needs to be better understood. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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- 2023
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5. Genetic ablation of the preptin-coding portion of Igf2 impairs pancreatic function in female mice.
- Author
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Buckels, E. J., Hsu, H.-L., Buchanan, C. M., Matthews, B. G., and Lee, K. L.
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HOMEOSTASIS , *GLUCOSE metabolism , *BLOOD sugar measurement , *BODY composition , *WESTERN immunoblotting , *GLUCOSE tolerance tests - Abstract
Preptin is a 34-amino acid peptide derived from the E-peptide of pro-insulin-like growth factor 2 and is co-secreted with insulin from β-cells. Little is understood about the effects of endogenous preptin on whole body glucose metabolism. We developed a novel mouse model in which the preptin portion of Igf2 was genetically ablated in all tissues, hereafter referred to as preptin knockout (KO), and tested the hypothesis that the removal of preptin will lead to a decreased insulin response to a metabolic challenge. Preptin KO and wild-type (WT) mice underwent weekly fasting blood glucose measurements, intraperitoneal insulin tolerance tests (ITT) at 9, 29, and 44 wk of age, and an oral glucose tolerance test (GTT) at 45 wk of age. Preptin KO mice of both sexes had similar Igf2 exon 2-3 mRNA expression in the liver and kidney compared with WT mice, but Igf2 exon 3-4 (preptin) expression was not detectable. Western blot analysis of neonatal serum indicated that processing of pro-IGF2 translated from the KO allele may be altered. Preptin KO mice had similar body weight, body composition, β-cell area, and fasted glucose concentrations compared with WT mice in both sexes up to 47 wk of age. Female KO mice had a diminished ability to mount an insulin response following glucose stimulation in vivo. This effect was absent in male KO mice. Although preptin is not essential for glucose homeostasis, when combined with previous in vitro and ex vivo findings, these data show that preptin positively impacts β-cell function. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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6. Role of Par-4 in EMT
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Faheem, Mir Mohd, Katoch, Archana, Goswami, Anindya, and Rangnekar, Vivek M., editor
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- 2021
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7. Contributions of Astrocyte and Neuronal Volume to CA1 Neuron Excitability Changes in Elevated Extracellular Potassium.
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Walch, Erin, Bilas, Alexander, Bebawy, Valine, Lam, Angelina, Murphy, Thomas R., Sriram, Sandhya, and Fiacco, Todd A.
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ASTROCYTES ,CELL size ,PYRAMIDAL neurons ,CELLULAR control mechanisms ,ACTION potentials ,NEURONS ,METHYL aspartate receptors - Abstract
Rapid increases in cell volume reduce the size of the extracellular space (ECS) and are associated with elevated brain tissue excitability. We recently demonstrated that astrocytes, but not neurons, rapidly swell in elevated extracellular potassium (^[K
+ ]o) up to 26 mM. However, effects of acute astrocyte volume fluctuations on neuronal excitability in ^[K+ ]o have been difficult to evaluate due to direct effects on neuronal membrane potential and generation of action potentials. Here we set out to isolate volume-specific effects occurring in ^[K+ ]o on CA1 pyramidal neurons in acute hippocampal slices by manipulating cell volume while recording neuronal glutamate currents in 10.5 mM [K+ ]o + tetrodotoxin (TTX) to prevent neuronal firing. Elevating [K+ ]o to 10.5 mM induced astrocyte swelling and produced significant increases in neuronal excitability in the form of mixed a-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA)/N-methyl-D-aspartate (NMDA) receptor mEPSCs and NMDA receptor-dependent slow inward currents (SICs). Application of hyperosmolar artificial cerebrospinal fluid (ACSF) by addition of mannitol in the continued presence of 10.5 mM K+ forced shrinking of astrocytes and to a lesser extent neurons, which resisted swelling in ^[K+ ]o. Cell shrinking and dilation of the ECS significantly dampened neuronal excitability in 10.5 mM K+ . Subsequent removal of mannitol amplified effects on neuronal excitability and nearly doubled the volume increase in astrocytes, presumably due to continued glial uptake of K+ while mannitol was present. Slower, larger amplitude events mainly driven by NMDA receptors were abolished by mannitol-induced expansion of the ECS. Collectively, our findings suggest that cell volume regulation of the ECS in elevated [K+ ]o is driven predominantly by astrocytes, and that cell volume effects on neuronal excitability can be effectively isolated in elevated [K+ ]o conditions. [ABSTRACT FROM AUTHOR]- Published
- 2022
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8. Contributions of Astrocyte and Neuronal Volume to CA1 Neuron Excitability Changes in Elevated Extracellular Potassium
- Author
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Erin Walch, Alexander Bilas, Valine Bebawy, Angelina Lam, Thomas R. Murphy, Sandhya Sriram, and Todd A. Fiacco
- Subjects
cell swelling ,extrasynaptic ,NMDA ,slow inward currents ,epilepsy ,secretagogue ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Rapid increases in cell volume reduce the size of the extracellular space (ECS) and are associated with elevated brain tissue excitability. We recently demonstrated that astrocytes, but not neurons, rapidly swell in elevated extracellular potassium (∧[K+]o) up to 26 mM. However, effects of acute astrocyte volume fluctuations on neuronal excitability in ∧[K+]o have been difficult to evaluate due to direct effects on neuronal membrane potential and generation of action potentials. Here we set out to isolate volume-specific effects occurring in ∧[K+]o on CA1 pyramidal neurons in acute hippocampal slices by manipulating cell volume while recording neuronal glutamate currents in 10.5 mM [K+]o + tetrodotoxin (TTX) to prevent neuronal firing. Elevating [K+]o to 10.5 mM induced astrocyte swelling and produced significant increases in neuronal excitability in the form of mixed α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/N-methyl-D-aspartate (NMDA) receptor mEPSCs and NMDA receptor-dependent slow inward currents (SICs). Application of hyperosmolar artificial cerebrospinal fluid (ACSF) by addition of mannitol in the continued presence of 10.5 mM K+ forced shrinking of astrocytes and to a lesser extent neurons, which resisted swelling in ∧[K+]o. Cell shrinking and dilation of the ECS significantly dampened neuronal excitability in 10.5 mM K+. Subsequent removal of mannitol amplified effects on neuronal excitability and nearly doubled the volume increase in astrocytes, presumably due to continued glial uptake of K+ while mannitol was present. Slower, larger amplitude events mainly driven by NMDA receptors were abolished by mannitol-induced expansion of the ECS. Collectively, our findings suggest that cell volume regulation of the ECS in elevated [K+]o is driven predominantly by astrocytes, and that cell volume effects on neuronal excitability can be effectively isolated in elevated [K+]o conditions.
- Published
- 2022
- Full Text
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9. Predicting Real-world Hypoglycemia Risk in American Adults With Type 1 or 2 Diabetes Mellitus Prescribed Insulin and/or Secretagogues: Protocol for a Prospective, 12-Wave Internet-Based Panel Survey With Email Support (the iNPHORM [Investigating Novel Predictions of Hypoglycemia Occurrence Using Real-world Models] Study).
- Author
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Ratzki-Leewing, Alexandria, Ryan, Bridget L., Zou, Guangyong, Webster-Bogaert, Susan, Black, Jason E., Stirling, Kathryn, Timcevska, Kristina, Khan, Nadia, Buchenberger, John D., and Harris, Stewart B.
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HYPOGLYCEMIA ,TYPE 1 diabetes ,TYPE 2 diabetes ,INSULIN ,ADVERSE health care events - Abstract
Background: Hypoglycemia prognostic models contingent on prospective, self-reported survey data offer a powerful avenue for determining real-world event susceptibility and interventional targets. Objective: This protocol describes the design and implementation of the 1-year iNPHORM (Investigating Novel Predictions of Hypoglycemia Occurrence Using Real-world Models) study, which aims to measure real-world self-reported severe and nonsevere hypoglycemia incidence (daytime and nocturnal) in American adults with type 1 or 2 diabetes mellitus prescribed insulin and/or secretagogues, and develop and internally validate prognostic models for severe, nonsevere daytime, and nonsevere nocturnal hypoglycemia. As a secondary objective, iNPHORM aims to quantify the effects of different antihyperglycemics on hypoglycemia rates. Methods: iNPHORM is a prospective, 12-wave internet-based panel survey that was conducted across the United States. Americans (aged 18-90 years) with self-reported type 1 or 2 diabetes mellitus prescribed insulin and/or secretagogues were conveniently sampled via the web from a pre-existing, closed, probability-based internet panel (sample frame). A sample size of 521 baseline responders was calculated for this study. Prospective data on hypoglycemia and potential prognostic factors were self-assessed across 14 closed, fully automated questionnaires (screening, baseline, and 12 monthly follow-ups) that were piloted using semistructured interviews (n=3) before fielding; no face-to-face contact was required as part of the data collection. Participant responses will be analyzed using multivariable count regression and machine learning techniques to develop and internally validate prognostic models for 1-year severe and 30-day nonsevere daytime and nocturnal hypoglycemia. The causal effects of different antihyperglycemics on hypoglycemia rates will also be investigated. Results: Recruitment and data collection occurred between February 2020 and March 2021 (ethics approval was obtained on December 17, 2019). A total of 1694 participants completed the baseline questionnaire, of whom 1206 (71.19%) were followed up for 12 months. Most follow-up waves (10,470/14,472, 72.35%) were completed, translating to a participation rate of 179% relative to our target sample size. Over 70.98% (856/1206) completed wave 12. Analyses of sample characteristics, quality metrics, and hypoglycemia incidence and prognostication are currently underway with published results anticipated by fall 2022. Conclusions: iNPHORM is the first hypoglycemia prognostic study in the United States to leverage prospective, longitudinal self-reports. The results will contribute to improved real-world hypoglycemia risk estimation and potentially safer, more effective clinical diabetes management. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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10. Plasma FGF21 concentrations are regulated by glucose independently of insulin and GLP-1 in lean, healthy humans.
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Solomon, Thomas P. J., Carter, Steven, Haus, Jacob M., Karstoft, Kristian, von Holstein-Rathlou, Stephanie, Nielsen, Mette S., and Gillum, Matthew P.
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HYPERGLYCEMIA ,INSULIN ,FIBROBLAST growth factors ,BLOOD sugar ,GLUCOSE - Abstract
Background. Fibroblast growth factor 21 (FGF21) treatment improves metabolic homeostasis in diverse species, including humans. Physiologically, plasma FGF21 levels increase modestly after glucose ingestion, but it is unclear whether this is mediated by glucose itself or due to a secondary effect of postprandial endocrine responses. A refined understanding of the mechanisms that control FGF21 release in humans may accelerate the development of small-molecule FGF21 secretagogues to treat metabolic disease. This study aimed to determine whether FGF21 secretion is stimulated by elevations in plasma glucose, insulin, or glucagon-like peptide-1 (GLP-1) in humans. Methods. Three groups of ten healthy participants were included in a parallel-group observational study. GroupAunderwent a hyperglycemic infusion; Group B underwent a 40 mU/m2/min hyperinsulinemic euglycemic clamp; Group C underwent two pancreatic clamps (to suppress endogenous insulin secretion) with euglycemic and hyperglycemic stages with an infusion of either saline or 0.5 pmol/kg/min GLP-1. Plasma FGF21 concentrations were measured at baseline and during each clamp stage by ELISA. Results. Plasma FGF21 was unaltered during hyperglycemic infusion and hyperinsulinemic euglycemic clamps, compared to baseline. FGF21 was, however, increased by hyperglycemia under pancreatic clamp conditions (P < 0:05), while GLP-1 infusion under pancreatic clamp conditions did not change circulating FGF21 levels. Conclusion. Increases in plasma FGF21 are likely driven directly by changes in plasma glucose independent of changes in insulin or GLP-1 secretion. Ecologically valid postprandial investigations are now needed to confirm our observations from basic science infusion models. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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11. Plasma FGF21 concentrations are regulated by glucose independently of insulin and GLP-1 in lean, healthy humans
- Author
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Thomas P.J. Solomon, Steven Carter, Jacob M. Haus, Kristian Karstoft, Stephanie von Holstein-Rathlou, Mette S. Nielsen, and Matthew P. Gillum
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Fibroblast growth factor 21 ,Secretagogue ,Incretin hormones ,Clamp methodology ,FGF21 secretion ,Medicine ,Biology (General) ,QH301-705.5 - Abstract
Background Fibroblast growth factor 21 (FGF21) treatment improves metabolic homeostasis in diverse species, including humans. Physiologically, plasma FGF21 levels increase modestly after glucose ingestion, but it is unclear whether this is mediated by glucose itself or due to a secondary effect of postprandial endocrine responses. A refined understanding of the mechanisms that control FGF21 release in humans may accelerate the development of small-molecule FGF21 secretagogues to treat metabolic disease. This study aimed to determine whether FGF21 secretion is stimulated by elevations in plasma glucose, insulin, or glucagon-like peptide-1 (GLP-1) in humans. Methods Three groups of ten healthy participants were included in a parallel-group observational study. Group A underwent a hyperglycemic infusion; Group B underwent a 40 mU/m2/min hyperinsulinemic euglycemic clamp; Group C underwent two pancreatic clamps (to suppress endogenous insulin secretion) with euglycemic and hyperglycemic stages with an infusion of either saline or 0.5 pmol/kg/min GLP-1. Plasma FGF21 concentrations were measured at baseline and during each clamp stage by ELISA. Results Plasma FGF21 was unaltered during hyperglycemic infusion and hyperinsulinemic euglycemic clamps, compared to baseline. FGF21 was, however, increased by hyperglycemia under pancreatic clamp conditions (P
- Published
- 2022
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12. Bisacodyl: A review of pharmacology and clinical evidence to guide use in clinical practice in patients with constipation.
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Corsetti, Maura, Landes, Sabine, and Lange, Robert
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CLINICAL pharmacology , *CONSTIPATION , *LARGE intestine , *LAXATIVES , *OPEN-ended questions - Abstract
Background: Bisacodyl is a member of the diphenylmethane family and is considered to be a stimulant laxative. It has a dual prokinetic and secretory action and needs to be converted into the active metabolite bis‐(p‐hydroxyphenyl)‐pyridyl‐2‐methane (BHPM) in the gut to achieve the desired laxative effect. Bisacodyl acts locally in the large bowel by directly enhancing the motility, reducing transit time, and increasing the water content of the stool. A recent network meta‐analysis concluded that bisacodyl showed similar efficacy to prucalopride, lubiprostone, linaclotide, tegaserod, velusetrag, elobixibat, and sodium picosulfate for the primary endpoint of ≥3 complete spontaneous bowel movements (CSBM)/week and an increase of ≥1 CSBM/week over baseline. The meta‐analysis also found that bisacodyl may be superior to the other laxatives for the secondary endpoint of change from baseline in the number of spontaneous bowel movements per week in patients with chronic constipation. This observation stimulated the authors to review the available literature on bisacodyl, which has been available on the market since the 1950 s. Purpose: The aim of the current review was to provide an overview of the historic background, structure, function, and mechanism of action of bisacodyl. Additionally, we discuss the important features and studies for bisacodyl to understand its peculiar characteristics and guide its use in clinical practice, but also stimulate research on open questions. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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13. A radioligand receptor binding assay for measuring of insulin secreted by MIN6 cells after stimulation with glucose, arginine, ornithine, dopamine, and serotonin.
- Author
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Asai, Seiya, Žáková, Lenka, Selicharová, Irena, Marek, Aleš, and Jiráček, Jiří
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BINDING site assay , *RADIOLIGAND assay , *DOPAMINE receptors , *SEROTONIN receptors , *INSULIN , *ORNITHINE , *SEROTONIN - Abstract
We adapted a radioligand receptor binding assay for measuring insulin levels in unknown samples. The assay enables rapid and accurate determination of insulin concentrations in experimental samples, such as from insulin-secreting cells. The principle of the method is based on the binding competition of insulin in a measured sample with a radiolabeled insulin for insulin receptor (IR) in IM-9 cells. Both key components, radiolabeled insulin and IM-9 cells, are commercially available. The IR binding assay was used to determine unknown amounts of insulin secreted by MIN6 β cell line after stimulation with glucose, arginine, ornithine, dopamine, and serotonin. The experimental data obtained by the IR binding assay were compared to the results determined by RIA kits and both methods showed a very good agreement of results. We observed the stimulation of glucose-induced insulin secretion from MIN6 cells by arginine, weaker stimulation by ornithine, but inhibitory effects of dopamine. Serotonin effects were either stimulatory or inhibitory, depending on the concentration of serotonin used. The results will require further investigation. The study also clearly revealed advantages of the IR binding assay that allows the measuring of a higher throughput of measured samples, with a broader range of concentrations than in the case of RIA kits. The IR binding assay can provide an alternative to standard RIA and ELISA assays for the determination of insulin levels in experimental samples and can be especially useful in scientific laboratories studying insulin production and secretion by β cells and searching for new modulators of insulin secretion. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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14. A High-Throughput Assay for the Pancreatic Islet Beta-Cell Potassium Channel: Use in the Pharmacological Characterization of Insulin Secretagogues Identified from Phenotypic Screening.
- Author
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Song, Luyan, Barrett, David G., Cox, Karen L., Efanov, Alexander M., Syed, Samreen K., Tomandl, Dirk, and Willard, Francis S.
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ISLANDS of Langerhans ,PANCREATIC beta cells ,GHRELIN receptors ,INSULIN ,POTASSIUM channels ,PHARMACOLOGY ,THALLIUM ,ION channels - Abstract
Phenotypic screening is a neoclassical approach for drug discovery. We conducted phenotypic screening for insulin secretion enhancing agents using INS-1E insulinoma cells as a model system for pancreatic beta-cells. A principal regulator of insulin secretion in beta-cells is the metabolically regulated potassium channel Kir6.2/SUR1 complex. To characterize hit compounds, we developed an assay to quantify endogenous potassium channel activity in INS-1E cells. We quantified ligand-regulated potassium channel activity in INS-1E cells using fluorescence imaging and thallium flux. Potassium channel activity was metabolically regulated and coupled to insulin secretion. The pharmacology of channel opening agents (diazoxide) and closing agents (sulfonylureas) was used to validate the applicability of the assay. A precise high-throughput assay was enabled, and phenotypic screening hits were triaged to enable a higher likelihood of discovering chemical matter with novel and useful mechanisms of action. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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15. An animal study on the effect of topically administered ambroxol for dry eye
- Author
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Zixuan Wang, Li Yu, Shaochong Zhang, Zhenhan Wang, and Mingwu Wang
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ambroxol ,secretagogue ,dry eye disease ,rabbit dry eye model ,inflammatory cytokines ,muc5ac ,icam-1 ,lifitegrast ,Biochemistry ,QD415-436 ,Biology (General) ,QH301-705.5 - Abstract
Objective: To evaluate the effect of 0.2% ambroxol eye drop on tear secretion and corneal healing on a rabbit dry eye model, and to delineate potential underlying mechanisms. Materials and method: A mixed mechanism dry eye model was created using 12 healthy New Zealand rabbits by excision of the main lacrimal glands, Harderian gland and nictitating membrane. Establishment of the model was confirmed by the decrease of Schirmer I and increase of corneal fluorescein staining scores. Two weeks after model creation, the rabbits were randomly and evenly divided into NaCl, 0.1% sodium hyaluronate and 0.2% ambroxol groups. Each group was administered the respective eye drops 4 times a day for four weeks. The Schirmer I test and corneal fluorescein staining were performed at two and four weeks. After four weeks of treatment, the animals were sacrificed and the conjunctiva and eyelid specimens collected. Inflammatory factors IL-8, TNF-α, and goblet cell specific mucin MUC5AC were measured by ELISA while the lid meibomian gland was evaluated by oil red O staining. Results: Compared with the baseline, 2 weeks after the surgery, Schirmer I test value decreased significantly (20.35 ± 5.18 mm/5 min vs 13.95 ± 4.64 mm/5 min, p < 0.01), and the fluorescein staining score increased significantly (0.5 ± 0.6 vs 5.5 ± 1.4, p < 0.01). After four weeks of treatment, compared with the NaCl and sodium hyaluronate groups, tear secretion in ambroxol group increased significantly (p < 0.01), while the corneal fluorescence staining score decreased significantly (p < 0.01). In the conjunctival tissue, significant decrease was seen in TNF-α (p < 0.01) and IL-8 [p (unilateral) < 0.05] concentrations in ambroxol group, and significant increase in MUC5AC concentration (p < 0.01) in ambroxol group as well. The lipid content in the lid meibomian glands appeared increased after the administration of ambroxol. Conclusion: The present rabbit dry eye model study demonstrated potentials of topically administered 0.2% ambroxol in stimulating tear and mucin secretion, inhibiting ocular surface inflammation, promoting corneal healing, and possibly augmenting meibomian gland lipid production.
- Published
- 2022
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16. Efficacy of Artificial Tears Based on an Extract of Artemia salina Containing Dinucleotides in a Rabbit Dry Eye Model
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Carlos Carpena-Torres, Jesus Pintor, Fernando Huete-Toral, Alba Martin-Gil, Candela Rodríguez-Pomar, Alejandro Martínez-Águila, and Gonzalo Carracedo
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dry eye ,Artemia salina ,dinucleotides ,secretagogue ,purinergic signaling ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
(1) Background: Artemia salina is a brine shrimp containing high concentrations of dinucleotides, molecules with properties for dry eye treatment. For this reason, the purpose of the study was to evaluate the effect of the artificial tears based on an extract of Artemia salina in a rabbit dry eye model. (2) Methods: A prospective and randomized study was carried out. Twenty rabbits were divided into 4 groups (n = 5, each group): healthy rabbits, dry eye rabbits, dry eye rabbits treated with hypromellose (HPMC), and dry eye rabbits treated with Artemia salina. Dry eye was induced by the topical instillation of 0.2% benzalkonium chloride. The measurements were performed before and after the treatment for 5 consecutive days. (3) Results: The topical instillation of artificial tears containing Artemia salina showed beneficial effects on tear secretion, tear break-up time, corneal staining, the density of Goblet cells, heigh of mucin cloud secreted by these cells, and mRNA levels of IL-1β and MMP9 in conjunctival cells. Compared with the HPMC, there was a statistically significant improvement (p < 0.05) with the Artemia salina in all the variables under study, except for the conjunctival hyperemia, density of Goblet cells, and mRNA levels of IL-6. (4) Conclusions: The potential of artificial tears based on Artemia salina as a secretagogue agent for dry eye treatment was confirmed, opening the door for future clinical trials and studies to extrapolate the findings for dry eye patients.
- Published
- 2021
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17. Family Members: The Forgotten Players in the Diabetes Care Team (The TALK-HYPO Study).
- Author
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Ratzki-Leewing, Alexandria, Parvaresh Rizi, Ehsan, and Harris, Stewart B.
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TYPE 1 diabetes , *TYPE 2 diabetes , *MEDICAL personnel , *DIABETES , *HYPOGLYCEMIA - Abstract
Introduction: The objective of this study was to establish the burden of hypoglycemia on family members of people with diabetes (PWDs) and to gain an understanding of how conversations about hypoglycemia can contribute to diabetes care. Methods: This was a multinational cross-sectional study of family members of people with type 1 or type 2 diabetes taking insulin and/or secretagogues for ≥ 12 months who voluntarily completed an online questionnaire. Results: Overall, 4300 family members of PWDs (type 1 [29%], type 2 [46%], unknown [25%]) were surveyed. Two in three family members (66%) reported thinking about the hypoglycemia of the PWD at least monthly, and 64% felt worried or anxious about the PWD's risk for hypoglycemia. There was general agreement among family members that more conversations about hypoglycemia would have a positive impact on the PWD's life (76%). Conclusions: Hypoglycemia can present a burden on the lives of family members of PWDs. Conversations about hypoglycemia, facilitated by a healthcare professional, may reduce this burden and hypoglycemia risk. Funding: Novo Nordisk A/S. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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18. TH1 and TH2 cytokine data in insulin secretagogues users newly diagnosed with breast cancer
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Zachary A.P. Wintrob, Jeffrey P. Hammel, George K. Nimako, Dan P. Gaile, Alan Forrest, and Alice C. Ceacareanu
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Type 1T helper cytokine ,Type 2T helper cytokine ,TH1 cytokine ,TH2 cytokine ,Cytokine ,Secretagogue ,Breast cancer ,Diabetes ,Cancer outcomes ,Cancer prognosis ,Computer applications to medicine. Medical informatics ,R858-859.7 ,Science (General) ,Q1-390 - Abstract
Stimulation of insulin production by insulin secretagogue use may impact T helper cells’ cytokine production. This dataset presents the relationship between baseline insulin secretagogues use in women diagnosed with breast cancer and type 2 diabetes mellitus, the T-helper 1 and 2 produced cytokine profiles at the time of breast cancer diagnosis, and subsequent cancer outcomes. A Pearson correlation analysis evaluating the relationship between T-helper cytokines stratified by of insulin secretagogues use and controls is also provided.
- Published
- 2017
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19. Insulin secretagogue use and circulating inflammatory C–C chemokine levels in breast cancer patients
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Zachary A.P. Wintrob, Jeffrey P. Hammel, George K. Nimako, Zahra S. Fayazi, Dan P. Gaile, Alan Forrest, and Alice C. Ceacareanu
- Subjects
Inflammation ,Inflammatory cytokines ,Secretagogue ,C–C chemokines ,CCL-2 ,CCL-3 ,CCL-4 ,CCL-5 ,Breast cancer ,Diabetes ,Monocyte infiltration ,Activated macrophage ,Cancer outcomes ,Cancer prognosis ,Computer applications to medicine. Medical informatics ,R858-859.7 ,Science (General) ,Q1-390 - Abstract
Monocytes’ infiltration into the tumor tissue and their activation to tumor-associated macrophages is an essential step in tumor development, also playing a critical role in an eventual metastasis. Stimulation of endogenous insulin production by oral insulin secretagogue treatment has the potential to interfere with the production and release of C–C chemokines, a group of potent inflammatory cytokines acting as monocyte chemo-attractants and influencing their behavior in the tumor microenvironment. Studied plasma samples were collected under a previously reported study design involving a population of women diagnosed with breast cancer presenting with or without type 2 diabetes mellitus at the time of breast cancer diagnosis (Wintrob et al., 2017, 2016) [1,2]. The data presented here shows the relationship between pre-existing use of insulin secretagogue, the inflammatory C–C chemokine profiles at the time of breast cancer diagnosis, and subsequent cancer outcomes. A Pearson correlation analysis stratified by secretagogue use and controls was implemented to evaluate the relationship between the investigated biomarkers and respectively each of these biomarkers and the other relevant reported cytokine datasets derived from the same patient population (Wintrob et al., 2017, 2016) [1,2].
- Published
- 2017
- Full Text
- View/download PDF
20. Dataset on granulopoiesis- and lymphopoiesis-stimulating cytokine levels in insulin secretagogue users with incident breast cancer
- Author
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Zachary A.P. Wintrob, Jeffrey P. Hammel, George K. Nimako, Dan P. Gaile, Alan Forrest, and Alice C. Ceacareanu
- Subjects
Hematopoiesis ,Hematopoietic cytokines ,Secretagogue ,GM-CSF ,G-CSF ,IL-7 ,Breast cancer ,Diabetes ,Cancer outcomes ,Cancer prognosis ,Computer applications to medicine. Medical informatics ,R858-859.7 ,Science (General) ,Q1-390 - Abstract
GM-CSF and G-CSF are widely used for their benefit in reducing chemotherapy-associated neutropenia. However, whether GM- or G-CSF administration could have tumorigenic or pro-metastatic effects or whether insulin resistance could negatively impact such effects is not known. Their ability to stimulate monocyte production at the same time with the highly sought after neutrophils’ production, enables an enhanced potential for activation of tumor-associated macrophages. At the same time, IL-7 remains the main driver of B and T cell differentiation and maturation, a process linked to the development of insulin resistance and response to diabetes pharmacotherapy. Insulin secretagogues have the potential to interfere with the hematopoiesis process, respectively with the formation of lineages that may lead to a tumorigenic or pro-metastatic phenotype, but this relationship has not been yet investigated. The data presented here shows the relationship between pre-existing use of insulin secretagogues in women diagnosed with breast cancer and type 2 diabetes mellitus, the GM-CSF, G-CSF and IL-7 cytokine profiles at the time of breast cancer diagnosis, and subsequent cancer outcomes. A Pearson correlation analysis evaluating the relationship between investigated cytokines stratified by secretagogue use and controls, and interferon is also provided.
- Published
- 2017
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- View/download PDF
21. Circulating adipokines data associated with insulin secretagogue use in breast cancer patients
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Zachary A.P. Wintrob, Jeffrey P. Hammel, George K. Nimako, Zahra S. Fayazi, Dan P. Gaile, Alan Forrest, and Alice C. Ceacareanu
- Subjects
Adipokine ,Insulin ,Secretagogue ,Breast cancer ,Diabetes ,Cancer outcomes ,Cancer prognosis ,Computer applications to medicine. Medical informatics ,R858-859.7 ,Science (General) ,Q1-390 - Abstract
Oral drugs stimulating endogenous insulin production (insulin secretagogues) may have detrimental effects on breast cancer outcomes. The data presented shows the relationship between pre-existing insulin secretagogues use, adipokine profiles at the time of breast cancer (BC) diagnosis and subsequent cancer outcomes in women diagnosed with BC and type 2 diabetes mellitus (T2DM). The Pearson correlation analysis evaluating the relationship between adipokines stratified by T2DM pharmacotherapy and controls is also provided. This information is the extension of the data presented and discussed in “Insulin use, adipokine profiles and breast cancer prognosis” (Wintrob et al., in press) [1].
- Published
- 2017
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22. CRH stimulation improves 18F-FDG-PET detection of pituitary adenomas in Cushing's disease.
- Author
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Boyle, Jacqueline, Patronas, Nicholas J., Smirniotopoulos, James, Herscovitch, Peter, Dieckman, William, Millo, Corina, Maric, Dragan, Chatain, Grégoire P., Hayes, Christina Piper, Benzo, Sarah, Scott, Gretchen, Edwards, Nancy, Ray Chaudhury, Abhik, Lodish, Maya B., Sharma, Susmeeta, Nieman, Lynnette K., Stratakis, Constantine A., Lonser, Russell R., and Chittiboina, Prashant
- Abstract
Objective: In MRI-negative cases Cushing's disease (CD), surgeons perform a more extensive exploration of the pituitary gland, with fewer instances of hormonal remission.
18 F-fluoro-deoxy-glucose (18 F-FDG) positron emission tomography (PET) has a limited role in detecting adenomas that cause CD (corticotropinomas). Our previous work demonstrated corticotropin-releasing hormone (CRH) stimulation leads to delayed, selective glucose uptake in corticotropinomas. Here, we prospectively evaluated the utility of CRH stimulation in improving18 F-FDG-PET detection of adenomas in CD. Methods: Subjects with a likely diagnosis of CD (n = 27, 20 females) each underwent two18 F-FDG-PET studies [without and with ovine-CRH (oCRH) stimulation] on a high-resolution PET platform. Standardized-uptake-values (SUV) in the sella were calculated. Two blinded neuroradiologists independently read18 F-FDG-PET images qualitatively. Adenomas were histopathologically confirmed, analyzed for mutations in the USP8 gene and for glycolytic pathway proteins. Results: The mean-SUV of adenomas was significantly increased from baseline (3.6 ± 1.5) with oCRH administration (3.9 ± 1.7; one-tailed p = 0.003). Neuroradiologists agreed that adenomas were visible on 21 scans, not visible on 26 scans (disagreed about 7, kappa = 0.7). oCRH-stimulation led to the detection of additional adenomas (n = 6) not visible on baseline-PET study. Of the MRI-negative adenomas (n = 5), two were detected on PET imaging (one only after oCRH-stimulation). USP8 mutations or glycolytic pathway proteins were not associated with SUV in corticotropinomas. Conclusions: The results of the current study suggest that oCRH-stimulation may lead to increased18 F-FDG uptake, and increased rate of detection of corticotropinomas in CD. These results also suggest that some MRI invisible adenomas may be detectable by oCRH-stimulated FDG-PET imaging. Clinical trial information:18 F-FDG-PET imaging with and without CRH stimulation was performed under the clinical trial NIH ID 12-N-0007 (clinicaltrials.gov identifier NCT01459237). The transsphenoidal surgeries and post-operative care was performed under the clinical trial NIH ID 03-N-0164 (clinicaltrials.gov identifier NCT00060541). [ABSTRACT FROM AUTHOR]- Published
- 2019
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23. Biological sex modifies aldosterone’s secretion at a cellular level
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Amanda E Garza, Gordon H. Williams, Luminita H. Pojoga, Chee Sin Tay, Jian Yao Wong, Shadi K Gholami, Jose R. Romero, Ezgi Caliskan Guzelce, Jessica Lee, Gail K. Adler, Eleanor Zagoren, and Stephen A. Maris
- Subjects
Male ,endocrine system ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Gene Expression ,Stimulation ,Biology ,Plasma renin activity ,chemistry.chemical_compound ,Endocrinology ,Mineralocorticoid receptor ,Corticosterone ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,Aldosterone ,Cells, Cultured ,Sex Characteristics ,Secretory Pathway ,Angiotensin II ,Rats ,medicine.anatomical_structure ,chemistry ,Zona glomerulosa ,Female ,Zona Glomerulosa ,Secretagogue - Abstract
Inconsistencies have been reported on the effect of sex on aldosterone (ALDO) levels leading to clinical confusion. The reasons for these inconsistencies are uncertain but include estrogen and/or its receptor modulating target gene responses to mineralocorticoid receptor activation and ALDO secretagogues’ levels. This study’s goal was to determine whether ALDO’s biosynthesis also differed by sex. Two approaches were used. First, plasma renin activity and aldosterone were measured in rats. Both were significantly higher in males. Secondly, using rat zona glomerulosa (ZG) cells, we assessed three ex vivo areas: (1) activity/levels of early steps in ALDO’s biosynthesis (StAR and CYP11A1); (2) activity/levels of a late step (CYP11B2); and (3) the status of the mineralocorticoid receptor (MR)-mediated, ultrashort feedback loop. Females had higher expression of CYP11A1 and StAR and increased CYP11A1 activity (increased pregnenolone/corticosterone levels) but did not differ in CYP11B2 expression or activity (ALDO levels). Activating the ZG’s MR (thereby activating the ultrashort feedback loop) reduced CYP11B2’s activity similarly in both sexes. Exvivo, these molecular effects were accompanied, in females, by lower ALDO basally but higher ALDO with angiotensin II stimulation. In conclusion, we documented that not only was there a sex-mediated difference in the activity of ALDO’s biosynthesis but also these differences at the molecular level help explain the variable reports on ALDO’s circulating levels. Basally, both in vivo and ex vivo, males had higher ALDO levels, likely secondary to higher ALDO secretagogue levels. However, in response to acute stimulation, ALDO levels are higher in females because of the greater levels and/or activity of their StAR/CYP11A1.
- Published
- 2022
24. Growth hormone secretagogue peptide-6 enhances oreochromicins transcription and antimicrobial activity in tilapia (Oreochromis sp.)
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Rebeca Martínez, Antonio Morales, Osmany Rodrigo, Liz Hernandez, Mario Pablo Estrada, Soraya Piloto, Liliana Basabe, Adriana Nuñez-Robainas, Janet Velázquez, Fidel Herrera, Daniel O Palenzuela, Adrian Rodriguez-Gabilondo, and Hanlet Camacho
- Subjects
food.ingredient ,Secretagogues ,Growth hormone secretagogue receptor ,Antimicrobial peptides ,Tilapia ,Cichlids ,General Medicine ,Aquatic Science ,Biology ,Antimicrobial ,Ghrelin ,Microbiology ,chemistry.chemical_compound ,food ,Anti-Infective Agents ,chemistry ,Growth hormone secretagogue ,Growth Hormone ,Animals ,Environmental Chemistry ,Secretagogue ,GHRP-6 ,Antimicrobial Peptides - Abstract
Growth Hormone-Releasing Peptide 6 (GHRP-6) (His-(D-Trp)-Ala-Trp-(D-Phe)-Lys-NH2) is an agonist of the growth hormone secretagogue receptor. GHRP-6 mimics the effect of ghrelin. The present study focuses on the immunomodulatory effects of GHRP-6 in tilapia with and without the presence of Pseudomonas aeruginosa infection. GHRP-6 up-regulated the transcription levels of three piscidin-like antimicrobial peptides (Oreochromicins I, II, and III) and granzyme in a tissue-dependent manner. Antimicrobial activity stimulation in serum (lysozyme and anti-protease activity) was also confirmed. Besides, GHRP-6 enhanced the in vitro antimicrobial activity against P. aeruginosa in tilapia gills mucus and serum samples and decreased the bacterial load in vivo after infection with this Gram-negative bacterium. Our results evidenced, for the first time, a direct link between a growth hormone secretagogue ghrelin mimetic in fish and the enhancement of antimicrobial peptides transcription, which suggests that this secretagogue is capable to lead the activation of microbicidal activity in tilapia. Thus, these results open new possibilities for GHRP-6 application in aquaculture to stimulate the teleost immune system as an alternative treatment against opportunistic bacteria.
- Published
- 2021
25. Plasma FGF21 concentrations are regulated by glucose independently of insulin and GLP-1 in lean, healthy humans
- Abstract
Background. Fibroblast growth factor 21 (FGF21) treatment improves metabolic homeostasis in diverse species, including humans. Physiologically, plasma FGF21 levels increase modestly after glucose ingestion, but it is unclear whether this is mediated by glucose itself or due to a secondary effect of postprandial endocrine responses. A refined understanding of the mechanisms that control FGF21 release in humans may accelerate the development of small-molecule FGF21 secretagogues to treat metabolic disease. This study aimed to determine whether FGF21 secretion is stimulated by elevations in plasma glucose, insulin, or glucagon-like peptide-1 (GLP-1) in humans. Methods. Three groups of ten healthy participants were included in a parallel-group observational study. Group A underwent a hyperglycemic infusion; Group B underwent a 40 mU/m2/min hyperinsulinemic euglycemic clamp; Group C underwent two pancreatic clamps (to suppress endogenous insulin secretion) with euglycemic and hyperglycemic stages with an infusion of either saline or 0.5 pmol/kg/min GLP-1. Plasma FGF21 concentrations were measured at baseline and during each clamp stage by ELISA. Results. Plasma FGF21 was unaltered during hyperglycemic infusion and hyperinsulinemic euglycemic clamps, compared to baseline. FGF21 was, however, increased by hyperglycemia under pancreatic clamp conditions (P < 0.05), while GLP-1 infusion under pancreatic clamp conditions did not change circulating FGF21 levels. Conclusion. Increases in plasma FGF21 are likely driven directly by changes in plasma glucose independent of changes in insulin or GLP-1 secretion. Ecologically valid postprandial investigations are now needed to confirm our observations from basic science infusion models.
- Published
- 2022
26. Plasma FGF21 concentrations are regulated by glucose independently of insulin and GLP-1 in lean, healthy humans
- Abstract
Background. Fibroblast growth factor 21 (FGF21) treatment improves metabolic homeostasis in diverse species, including humans. Physiologically, plasma FGF21 levels increase modestly after glucose ingestion, but it is unclear whether this is mediated by glucose itself or due to a secondary effect of postprandial endocrine responses. A refined understanding of the mechanisms that control FGF21 release in humans may accelerate the development of small-molecule FGF21 secretagogues to treat metabolic disease. This study aimed to determine whether FGF21 secretion is stimulated by elevations in plasma glucose, insulin, or glucagon-like peptide-1 (GLP-1) in humans. Methods. Three groups of ten healthy participants were included in a parallel-group observational study. Group A underwent a hyperglycemic infusion; Group B underwent a 40 mU/m2/min hyperinsulinemic euglycemic clamp; Group C underwent two pancreatic clamps (to suppress endogenous insulin secretion) with euglycemic and hyperglycemic stages with an infusion of either saline or 0.5 pmol/kg/min GLP-1. Plasma FGF21 concentrations were measured at baseline and during each clamp stage by ELISA. Results. Plasma FGF21 was unaltered during hyperglycemic infusion and hyperinsulinemic euglycemic clamps, compared to baseline. FGF21 was, however, increased by hyperglycemia under pancreatic clamp conditions (P < 0.05), while GLP-1 infusion under pancreatic clamp conditions did not change circulating FGF21 levels. Conclusion. Increases in plasma FGF21 are likely driven directly by changes in plasma glucose independent of changes in insulin or GLP-1 secretion. Ecologically valid postprandial investigations are now needed to confirm our observations from basic science infusion models.
- Published
- 2022
27. Berberine is an insulin secretagogue targeting the KCNH6 potassium channel
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Qi Li, Sen Li, Haixia Huang, Testuro Izumi, Jing Lu, Xi Cao, Kohichi Matsunaga, Hao Wang, Ting-Ting Shi, Chen Chen, Jin-Kui Yang, and Miao-Miao Zhao
- Subjects
Adult ,Male ,Adolescent ,Berberine ,medicine.medical_treatment ,Science ,General Physics and Astronomy ,Drug development ,Pharmacology ,Hypoglycemia ,Diet, High-Fat ,General Biochemistry, Genetics and Molecular Biology ,Article ,Young Adult ,chemistry.chemical_compound ,Cell Line, Tumor ,Insulin-Secreting Cells ,Diabetes mellitus ,Insulin Secretion ,medicine ,Animals ,Humans ,Secretion ,Author Correction ,Ion transport ,Mice, Knockout ,geography ,Cross-Over Studies ,Multidisciplinary ,geography.geographical_feature_category ,business.industry ,Secretagogues ,Insulin ,Diabetes ,General Chemistry ,Middle Aged ,Islet ,medicine.disease ,Ether-A-Go-Go Potassium Channels ,Potassium channel ,Mice, Inbred C57BL ,HEK293 Cells ,chemistry ,Hyperglycemia ,Secretagogue ,business ,Ion Channel Gating - Abstract
Coptis chinensis is an ancient Chinese herb treating diabetes in China for thousands of years. However, its underlying mechanism remains poorly understood. Here, we report the effects of its main active component, berberine (BBR), on stimulating insulin secretion. In mice with hyperglycemia induced by a high-fat diet, BBR significantly increases insulin secretion and reduced blood glucose levels. However, in mice with hyperglycemia induced by global or pancreatic islet β-cell-specific Kcnh6 knockout, BBR does not exert beneficial effects. BBR directly binds KCNH6 potassium channels, significantly accelerates channel closure, and subsequently reduces KCNH6 currents. Consequently, blocking KCNH6 currents prolongs high glucose-dependent cell membrane depolarization and increases insulin secretion. Finally, to assess the effect of BBR on insulin secretion in humans, a randomized, double-blind, placebo-controlled, two-period crossover, single-dose, phase 1 clinical trial (NCT03972215) including 15 healthy men receiving a 160-min hyperglycemic clamp experiment is performed. The pre-specified primary outcomes are assessment of the differences of serum insulin and C-peptide levels between BBR and placebo treatment groups during the hyperglycemic clamp study. BBR significantly promotes insulin secretion under hyperglycemic state comparing with placebo treatment, while does not affect basal insulin secretion in humans. All subjects tolerate BBR well, and we observe no side effects in the 14-day follow up period. In this study, we identify BBR as a glucose-dependent insulin secretagogue for treating diabetes without causing hypoglycemia that targets KCNH6 channels., Berberine is a compound with glucose-lowering effects in mice and humans. Here, the authors show that in mice berberine has beneficial glycemic effects by promoting insulin secretion, which requires the potassium channel KCNH6 in beta cells, and that berberine can promote insulin secretion in healthy men in a phase 1 clinical trial.
- Published
- 2021
28. Corticotropin releasing hormone can selectively stimulate glucose uptake in corticotropinoma via glucose transporter 1.
- Author
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Lu, Jie, Montgomery, Blake K., Chatain, Grégoire P., Bugarini, Alejandro, Zhang, Qi, Wang, Xiang, Edwards, Nancy A., Ray-Chaudhury, Abhik, Merrill, Marsha J., Lonser, Russell R., and Chittiboina, Prashant
- Subjects
- *
CORTICOTROPIN releasing hormone , *GLUCOSE transporters , *CUSHING'S syndrome diagnosis , *SURGICAL technology , *FLUORODEOXYGLUCOSE F18 - Abstract
Background Pre-operative detection of corticotropin (ACTH) secreting microadenomas causing Cushing's disease (CD) improves surgical outcomes. Current best magnetic resonance imaging fails to detect up to 40% of these microadenomas. 18 F-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography (PET) is specific, but not sensitive in detecting corticotropinomas. Theoretically, secretagogue stimulation with corticotropin releasing hormone (CRH) could improve detection of adenomas with 18 F-FDG PET. Previous attempts with simultaneous CRH stimulation have failed to demonstrate increased 18 F-FDG uptake in corticotropinomas. We hypothesized that CRH stimulation leads to a delayed elevation in glucose uptake in corticotropinomas. Methods Clinical data was analyzed for efficacy of CRH in improving 18 FDG-PET detection of corticotropinomas in CD. Glucose transporter 1 (GLUT1) immunoreactivity was performed on surgical specimens. Ex-vivo, viable cells from these tumors were tested for secretagogue effects (colorimetric glucose uptake), and for fate of intracellular glucose (glycolysis stress analysis). Validation of ex-vivo findings was performed with AtT-20 cells. Results CRH increased glucose uptake in human-derived corticotroph tumor cells and AtT-20, but not in normal murine or human corticotrophs (p < 0.0001). Continuous and intermittent (1 h) CRH exposure increased glucose uptake in AtT-20 with maximal effect at 4 h (p = 0.001). Similarly, CRH and 8-Br-cAMP led to robust GLUT1 upregulation and increased membrane translocation at 2 h, while fasentin suppressed baseline (p < 0.0001) and CRH-mediated glucose uptake. Expectedly, intra-operatively collected corticotropinomas demonstrated GLUT1 overexpression. Lastly, human derived corticotroph tumor cells demonstrated increased glycolysis and low glucose oxidation. Conclusion Increased and delayed CRH-mediated glucose uptake differentially occurs in adenomatous corticotrophs. Delayed secretagogue-stimulated 18 F-FDG PET could improve microadenoma detection. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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29. Les insulinosécréteurs, sulfamides et glinides.
- Author
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Faure, Sébastien
- Abstract
Résumé Les sulfamides hypoglycémiants sont encore largement utilisés par de nombreux patients diabétiques de type 2, principalement en seconde intention et souvent en association avec d’autres molécules antidiabétiques. L’action des glinides, molécules plus récentes, est très proche de celle des sulfamides. Le seul représentant de la classe actuellement sur le marché est le répaglinide. Summary Sulphonylureas are still widely used by many patients with type 2 diabetes, mainly as a second-line treatment and often in combination with other antidiabetic molecules. The action of glinides, more recent molecules, is very similar to that of sulphonylureas. The only representative of the class currently on the market is repaglinide. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
30. An Overview of Sports Supplements
- Author
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Lockwood, Chris, Antonio, Jose, editor, Kalman, Douglas, editor, Stout, Jeffrey R., editor, Greenwood, Mike, editor, Willoughby, Darryn S., editor, and Haff, G. Gregory, editor
- Published
- 2008
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31. Hyphaene thebaica (doum)-derived extract alleviates hyperglycemia in diabetic rats: a comprehensive in silico, in vitro and in vivo study
- Author
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Ahmed M. Sayed, Heba Ali Hassan, Mohamed Kamel, Entesar Ali Saber, Mahmoud A. El-Rehany, Shereen S. Gaber, Fatma A Abo-Elsoud, Nourhan Hisham Shady, Sherif A. Maher, and Usama Ramadan Abdelmohsen
- Subjects
biology ,Insulin ,medicine.medical_treatment ,General Medicine ,Pharmacology ,biology.organism_classification ,chemistry.chemical_compound ,chemistry ,In vivo ,Apigenin ,medicine ,Secretagogue ,Myricetin ,Hyphaene thebaica ,Mode of action ,Luteolin ,Food Science - Abstract
In the present study, we investigated the hypoglycemic effect of different extracts (i.e. organic and aqueous) derived from the fruits of Hyphaene thebaica (doum) on male streptozotocin-induced diabetic rats. Blood glucose levels as well as the relative gene expression of insulin, TNF-α, and TGF-β were determined in the pancreatic tissue of the experimental animals. Treatment of STZ-induced diabetic rats with aqueous extracts of the plant fruit over 7 weeks significantly reduced the elevated blood glucose and increased the relative expression of insulin, while the relative expression of inflammatory mediators (i.e. TNF-α and TGF-β) was significantly reduced. Histopathological investigation also revealed that the aqueous extract treatment effectively reversed the β-cell necrosis induced by STZ and restored its normal morphology. Furthermore, liquid chromatography high resolution mass spectrometry (LC-HRMS) and in silico chemical investigation of the aqueous extract elucidated its major bioactive phytochemicals (i.e. flavonoids) and putatively determined the pancreatic KATP channel as a target for these bioactive components. In vitro insulin secretion assay revealed that myricetin, luteolin, and apigenin were able to induce insulin secretion by human pancreatic cells (insulin production = 20.9 ± 1.3, 13.74 ± 1.8, and 11.33 ± 1.1 ng mL-1, respectively). Using molecular docking and dynamics simulations, we were able to shed the light on the insulin secretagogue's mode of action through these identified bioactive compounds and to determine the main structural elements required for its bioactivity. This comprehensive investigation of this native fruit will encourage future clinical studies to recommend edible and widely available fruits like doum to be a part of DM treatment plans.
- Published
- 2021
32. Bitter Melon Extract Yields Multiple Effects on Intestinal Epithelial Cells and Likely Contributes to Anti-diabetic Functions
- Author
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Shi-Yie Cheng, Chi-I Chang, Jing-Hong Tu, Annisa Oktafianti Nurlatifah, Wei-Wen Sung, Hsueh-Ling Cheng, and Lin-Lee Lee
- Subjects
Momordica charantia ,Enterocyte ,Enteroendocrine Cells ,medicine.medical_treatment ,Enteroendocrine cell ,Pharmacology ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,Insulin resistance ,AMP-activated protein kinase ,medicine ,Humans ,Insulin ,Intestinal Mucosa ,intestine ,diabetes ,biology ,Plant Extracts ,Chemistry ,food and beverages ,General Medicine ,medicine.disease ,bitter-taste receptor ,Glucagon-like peptide-1 ,glucagon-like peptide 1 ,Diabetes Mellitus, Type 1 ,Enterocytes ,Glucose ,medicine.anatomical_structure ,Diabetes Mellitus, Type 2 ,Cell culture ,biology.protein ,030211 gastroenterology & hepatology ,Secretagogue ,Insulin Resistance ,Research Paper - Abstract
The intestines have been recognized as important tissues for metabolic regulation, including glycemic control, but their vital role in promoting the anti-diabetic effects of bitter melon, the fruit of Momordica charantia L, has seldom been characterized, nor acknowledged. Evidence suggests that bitter melon constituents can have substantial interactions with the intestinal epithelial cells before circulating to other tissues. We therefore characterized the effects of bitter melon extract (BME) on intestinal epithelial cells. BME was found to contain substantial amounts of carbohydrates, proteins, and triterpenoids. TNF-α induced insulin resistance in an enterocyte cell line of IEC-18 cells, and BME promoted glucose utilization of the insulin-resistant cells. Further analysis suggested that the increased glucose consumption was a result of the combined effects of insulin sensitizing and insulin substitution functions of BME. The functions of insulin substitution were likely generated due to the activation of AMP-activated protein kinase. Meanwhile, BME acted as a glucagon-like peptide 1 (GLP-1) secretagogue on enteroendocrine cells, which may be mediated by the activation of bitter-taste receptors. Therefore, BME possesses insulin sensitizing, insulin substitution, and GLP-1 secretagogue functions upon intestinal cells. These effects of BME on intestinal cells likely play a significant part in the anti-diabetic action of bitter melon.
- Published
- 2021
33. FGF21 Is an Exocrine Pancreas Secretagogue.
- Author
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Coate, Katie C., Hernandez, Genaro, Thorne, Curtis A., Sun, Shengyi, Le, Thao D.V., Vale, Kevin, Kliewer, Steven A., and Mangelsdorf, David J.
- Abstract
Summary The metabolic stress hormone FGF21 is highly expressed in exocrine pancreas, where its levels are increased by refeeding and chemically induced pancreatitis. However, its function in the exocrine pancreas remains unknown. Here, we show that FGF21 stimulates digestive enzyme secretion from pancreatic acinar cells through an autocrine/paracrine mechanism that requires signaling through a tyrosine kinase receptor complex composed of an FGF receptor and β-Klotho. Mice lacking FGF21 accumulate zymogen granules and are susceptible to pancreatic ER stress, an effect that is reversed by administration of recombinant FGF21. Mice carrying an acinar cell-specific deletion of β-Klotho also accumulate zymogen granules but are refractory to FGF21-stimulated secretion. Like the classical post-prandial secretagogue, cholecystokinin (CCK), FGF21 triggers intracellular calcium release via PLC-IP 3 R signaling. However, unlike CCK, FGF21 does not induce protein synthesis, thereby preventing protein accumulation. Thus, pancreatic FGF21 is a digestive enzyme secretagogue whose physiologic function is to maintain acinar cell proteostasis. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
34. Insulin use, adipokine profiles and breast cancer prognosis.
- Author
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Wintrob, Zachary A.P., Hammel, Jeffrey P., Khoury, Thaer, Nimako, George K., Fu, Hsin-Wei, Fayazi, Zahra S., Gaile, Dan P., Forrest, Alan, and Ceacareanu, Alice C.
- Subjects
- *
TYPE 2 diabetes , *BODY mass index , *CYTOKINES , *TUMORS , *BREAST cancer - Abstract
Background Type-2 diabetes mellitus (T2DM) and breast cancer (BC) share common cytokine signaling changes resultant from adipose tissue dysfunction. This modified adipokine signaling was shown to be directly associated with changes in the body mass index (BMI) and diet and it is expected to also be influenced by T2DM pharmacotherapy. We evaluated the relationship between pre-existing diabetes treatment, circulating adipokine levels at cancer diagnosis, and long-term outcomes. Methods All incident BC cases were reviewed (01/01/2003-12/31/2009, N = 2194). Each of the subjects with baseline T2DM (cases) was matched with two other subjects without T2DM (controls) based on the following criteria: age, BMI, ethnicity, menopausal status and tumor stage. All cases and controls with available baseline plasma and tumor biopsies, and being surgery and BC treatment naïve, were included (N 1 = 97, N 2 = 194). Clinical history and vital status were documented. Adipokine levels (adiponectin, leptin, TNF-α, CRP, IL-1β, IL-1Ra, IL-6, and C-peptide) were assessed by either ELISA or Luminex® assays. Cancer outcomes were assessed by Kaplan-Meier analysis; associations between categorical variables were assessed by Fisher’s exact test, categorical and continuous variables by Kruskal-Wallis or Wilcoxon Rank-Sum test, where appropriate. Multivariate adjustments (MVP, multivariate p-value) were performed accounting for age, tumor stage, BMI, estrogen receptor (ER) status and cumulative comorbidity. All biomarker correlations were assessed by the Pearson method. Utilization of insulin and insulin secretagogues was associated with ER (−) phenotype (p = 0.008, p = 0.043) and poorer BC outcomes (p = 0.012, p = 0.033). Insulin users were found to have lower C-peptide and higher IL-6, TNF-α and CRP levels, of which elevated CRP and TNF-α were associated with poorer BC outcomes (p = 0.003, MVP = 0.210). Insulin remarked by higher leptin levels as compared to controls (p = 0.052), but did not differ significantly from non-users. Although lower adiponectin levels were observed among non-insulin users as compared to controls (p < 0.001, MVP = 0.006), insulin use seemed to have restored adiponectin production. C-peptide levels were lower among insulin users as compared to non-users (p < 0.001, MVP < 0.001) and approached levels comparable with those of the controls. In the overall dataset, C-peptide lower than 0.75 ng/ml were strongly associated with poorer survival (p = 0.007, MVP = 0.002). Among insulin users, C-peptide levels were inversely correlated with IL-1β and IL-1Ra levels only after full adjustment (p = 0.012, p = 0.030); the correlation was unremarkable in other groups. Conclusion Insulin use is associated with elevated leptin, CRP, TNFα, and lower C-peptide and also linked to poor BC outcomes. More research is needed to verify these findings; however, we are among the first to correlate pharmacotherapy use, measures of adipose tissue dysfunction and cancer outcomes. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
35. Comparison of nocturnal and morning ghrelin concentration in children with growth hormone deficiency and with idiopathic short stature
- Author
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Marzena Kolasa-Kicińska, Andrzej Lewiński, Maciej Hilczer, Renata Stawerska, and Anna Łupińska
- Subjects
Male ,medicine.medical_specialty ,Adolescent ,Physiology ,030209 endocrinology & metabolism ,Nocturnal ,Growth hormone ,Growth hormone deficiency ,03 medical and health sciences ,0302 clinical medicine ,Physiology (medical) ,Internal medicine ,medicine ,Humans ,Circadian rhythm ,Insulin-Like Growth Factor I ,Child ,Growth Disorders ,Morning ,Human Growth Hormone ,business.industry ,digestive, oral, and skin physiology ,medicine.disease ,Ghrelin ,Circadian Rhythm ,Idiopathic short stature ,Endocrinology ,Growth Hormone ,Female ,Secretagogue ,business ,hormones, hormone substitutes, and hormone antagonists ,030217 neurology & neurosurgery - Abstract
Ghrelin - a growth hormone (GH) secretagogue - presents a circadian rhythm with higher nocturnal than diurnal concentration (similar to GH). However, daily ghrelin production depends on food intake and nutritional state; it is increased in the fasting state and decreased after a meal. Since most past research concerning short stature children has relied on the morning ghrelin concentration for analyses, we decided to assess ghrelin concentration at the 60
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- 2020
36. Effects of Lubiprostone, an Intestinal Secretagogue, on Electrolyte Homeostasis in Chronic Idiopathic and Opioid-induced Constipation
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Satish S.C. Rao, Peter Lichtlen, and Sepideh Habibi
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medicine.medical_specialty ,Constipation ,irritable bowel syndrome with constipation ,lubiprostone ,Renal function ,chronic idiopathic constipation ,Placebo ,electrolyte homeostasis ,Gastroenterology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Homeostasis ,Humans ,Medicine ,Blood urea nitrogen ,Irritable bowel syndrome ,Creatinine ,business.industry ,Secretagogues ,medicine.disease ,Lubiprostone ,opioid-induced constipation ,Analgesics, Opioid ,chemistry ,030220 oncology & carcinogenesis ,Alimentary Tract: Original Articles ,Female ,030211 gastroenterology & hepatology ,Secretagogue ,medicine.symptom ,business ,medicine.drug - Abstract
Goals To assess short-term and long-term effects of lubiprostone, a type-2 chloride channel activator, on electrolyte homeostasis. Background Conventional laxatives are associated with electrolyte imbalances. Lubiprostone is a type-2 chloride channel activator approved for treating chronic idiopathic constipation (CIC), opioid-induced constipation (OIC), and constipation-predominant irritable bowel syndrome in women. It induces intestinal fluid secretion, possibly affecting water and electrolyte homeostasis. We investigated short-term and long-term effects of lubiprostone on electrolyte, blood urea nitrogen (BUN), and creatinine levels using pooled data from CIC and OIC patients. Study Data were pooled from 10 CIC and OIC studies-6 double-blind, randomized, placebo-controlled studies and 4 open-label, long-term studies. Total duration of lubiprostone exposure was from 3 weeks (short-term: CIC, 3 to 4 wk; OIC, placebo-controlled, 12 wk) to 48 weeks (long-term: CIC, 24 to 48 wk; OIC, 48 wk). Sodium, chloride, potassium, magnesium, BUN, and creatinine levels were examined at baseline and final assessment. Results Overall, 3209 patients were assessed. In the double-blind, placebo-controlled studies, there were no clinically meaningful differences in levels of electrolytes, BUN, and creatinine between lubiprostone and placebo groups, and in changes from baseline levels with long-term use of lubiprostone. Analyses of shifts in laboratory values (low/normal/high) at baseline and final assessment showed minimal effects on electrolytes, BUN, and creatinine. Conclusions Lubiprostone did not cause clinically meaningful electrolyte imbalances or affect markers of renal function in either the short-term or long-term treatment of CIC or OIC.
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- 2020
37. Pregnancy, but not dietary octanoic acid supplementation, stimulates the ghrelin-pituitary growth hormone axis in mice
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Georgia S Clarke, Lili Huang, Amanda J. Page, Kathryn L. Gatford, Beverly S. Muhlhausler, Pamela S-l Sim, Claire T. Roberts, Johannes D. Veldhuis, Hui Li, Rebecca L. Wilson, Chen Chen, Maria Nunez-Salces, and Harleen Kaur
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medicine.medical_specialty ,Acylation ,Placenta ,Endocrinology, Diabetes and Metabolism ,Mice ,Endocrinology ,Pregnancy ,Internal medicine ,medicine ,Animals ,RNA, Messenger ,Receptor ,Chemistry ,Stomach ,digestive, oral, and skin physiology ,Trophoblast ,medicine.disease ,Ghrelin ,Growth hormone secretion ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Gastric Mucosa ,Growth Hormone ,Dietary Supplements ,Female ,Secretagogue ,Caprylates - Abstract
Circulating growth hormone (GH) concentrations increase during pregnancy in mice and remain pituitary-derived. Whether abundance or activation of the GH secretagogue ghrelin increase during pregnancy, or in response to dietary octanoic acid supplementation, is unclear. We therefore measured circulating GH profiles in late pregnant C57BL/6J mice and in aged-matched non-pregnant females fed with standard laboratory chow supplemented with 5% octanoic or palmitic (control) acid (n = 4–13/group). Serum total and acyl-ghrelin concentrations, stomach and placenta ghrelin mRNA and protein expression, Pcsk1 (encoding prohormone convertase 1/3) and Mboat4 (membrane bound O-acyl transferase 4) mRNA were determined at zeitgeber (ZT) 13 and ZT23. Total and basal GH secretion were higher in late pregnant than non-pregnant mice (P P = 0.004), but not acyl-ghrelin, and the density of ghrelin-positive cells in the gastric antrum (P = 0.019) were higher, and gastric Mboat4 and Pcsk1 mRNA expression were lower in pregnant than non-pregnant mice at ZT23. In the placenta, ghrelin protein was localised mostly to labyrinthine trophoblast cells. Serum acyl-, but not total, ghrelin was lower at mid-pregnancy than in non-pregnant mice, but not different at early or late pregnancy. In conclusion, dietary supplementation with 5% octanoic acid did not increase activation of ghrelin in female mice. Our results further suggest that increases in maternal GH secretion throughout murine pregnancy are not due to circulating acyl-ghrelin acting at the pituitary. Nevertheless, time-dependent increased circulating total ghrelin could potentially increase ghrelin action in tissues that express the acylating enzyme and receptor.
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- 2020
38. Phytochemical and anti-neuropathic investigations of Crocus sativus via alleviating inflammation, oxidative stress and pancreatic beta-cells regeneration
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Abdalla El-Lakany, Karim Raafat, and Maha Aboul-Ela
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ved/biology.organism_classification_rank.species ,Inflammation ,Biology ,medicine.disease_cause ,030226 pharmacology & pharmacy ,01 natural sciences ,Crocin ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Crocus sativus ,medicine ,Pharmacology (medical) ,Pharmacology ,Traditional medicine ,ved/biology ,Picrocrocin ,0104 chemical sciences ,Safranal ,010404 medicinal & biomolecular chemistry ,Complementary and alternative medicine ,chemistry ,Phytochemical ,Secretagogue ,medicine.symptom ,Oxidative stress - Abstract
Objectives The aim of this study is to investigate the phytochemical and the long-term anti-neuropathic potentials of Crocus sativus cultivated in the University botanical garden, and explore its most bioactive compounds and their underlying mechanisms of action. Methods Phytochemical analysis and bio-guided isolation-procedures including RP-HPLC and 1H and 13C NMR utilizing biological models of diabetes, inflammation, and diabetic-neuropathy were used. Cultivated saffron (S-RCED) and Spanish-saffron stigma (S-SP) alone or in combination with Camellia sinus (CS) were investigated. Results The RP-HPLC analyses showed the presence of picrocrocin, crocin I, crocin II, crocin I’, crocin II’, and safranal (SAF) in both S-SP and S-RCED extracts with higher-concentrations. It had been shown that SAF was the most bioactive-compound in Crocus sativus. Both S-SP and S-RCED possessed significant (P Conclusion The oxidative stress reduction, insulin secretagogue, and pancreatic beta-cells regeneration potentials might be responsible for the mechanism underlying the anti-diabetic, anti-inflammatory and anti-diabetic neuropathy activities. Thus, the cultivated Crocus sativus might be clinically useful for protecting against many serious-disorders.
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- 2020
39. Glucose-Dependent Insulinotropic Polypeptide Is a Pancreatic Polypeptide Secretagogue in Humans
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Louise Vedtofte, Kirsa Skov-Jeppesen, Bolette Hartmann, Tina Vilsbøll, Simon Veedfald, Mikkel B. Christensen, Jens J. Holst, Filip K. Knop, and Carolyn F. Deacon
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Blood Glucose ,0301 basic medicine ,medicine.medical_specialty ,endocrine system diseases ,Swine ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,media_common.quotation_subject ,Clinical Biochemistry ,030209 endocrinology & metabolism ,Gastric Inhibitory Polypeptide ,Type 2 diabetes ,Hypoglycemia ,Pancreatic Polypeptide ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Gastrointestinal Agents ,Internal medicine ,Insulin Secretion ,medicine ,Animals ,Humans ,Insulin ,Pancreatic polypeptide ,Saline ,Retrospective Studies ,media_common ,geography ,geography.geographical_feature_category ,Chemistry ,Secretagogues ,Biochemistry (medical) ,Appetite ,Prognosis ,medicine.disease ,Islet ,030104 developmental biology ,Diabetes Mellitus, Type 2 ,Case-Control Studies ,Hyperglycemia ,Secretagogue ,Biomarkers ,Follow-Up Studies ,Hormone - Abstract
Background Glucose-dependent insulinotropic polypeptide (GIP) has been suggested to stimulate the secretion of pancreatic polypeptide (PP), an islet hormone thought to regulate gut motility, appetite, and glycemia. Objective To determine whether human GIP1-42 (hGIP) stimulates PP secretion. Method As glycemia modulates the secretion of PP, we measured plasma PP concentrations from 2 studies in healthy men (n = 10) and in patients with type 2 diabetes (T2D) (n = 12), where hGIP1-42 had been administered intravenously during fasting glycemia, hyperglycemia (12 mmol/L), and insulin-induced hypoglycemia (targets: 2.5 mmol/L [healthy]; 3.5 mmol/L [T2D]). Porcine GIP1-42 (pGIP) was also infused intra-arterially in isolated porcine pancreata (n = 4). Results Mean fasting plasma glucose concentrations were approximately 5 mmol/L (healthy) and approximately 8 mmol/L (T2D). At fasting glycemia, PP concentrations were higher during intravenous hGIP1-42 infusion compared with saline in healthy men (mean [standard error of the mean, SEM], net incremental areas under the curves (iAUCs)[0-30min], 403 [116] vs –6 [57] pmol/L × min; P = 0.004) and in patients with T2D (905 [177] vs –96 [86] pmol/L × min; P = 0.009). During hyperglycemic clamping, mean [SEM] PP concentrations were significantly higher during hGIP1-42 infusion compared with saline in patients with T2D (771 [160] vs –183 [117] pmol/L × min; P = 0.001), but not in healthy individuals (–8 [86] vs –57 [53] pmol/L × min; P = 0.69). When plasma glucose levels were declining in response to exogenous insulin, mean [SEM] PP concentrations were higher during hGIP1-42 infusion compared with saline in healthy individuals (294 [88] vs –82 [53] pmol/L × min; P = 0.0025), but not significantly higher in patients with T2D (586 [314] vs –120 [53]; P = 0.070). At target hypoglycemia, PP levels surged in both groups during both hGIP1-42 and saline infusions. In isolated pancreata, pGIP1-42 increased mean [SEM] PP output in the pancreatic venous effluent (baseline vs infusion, 24[5] vs 79 [16] pmol/min x min; P = 0.044). Conclusion GIP1-42 increases plasma PP secretion in healthy individuals, patients with T2D, and isolated porcine pancreata. Hyperglycemia blunts the stimulatory effect of hGIP1-42 in healthy individuals, but not in patients with T2D.
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- 2019
40. Pharmacologic rescue of circadian β-cell failure through P2Y1 purinergic receptor identified by small-molecule screen
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Patrick E. MacDonald, Marsha V. Newman, Akihiko Taguchi, Biliana Marcheva, Chiaki Omura, Haopeng Lin, Mark Perelis, Jocelyn E. Manning Fox, Kathryn Moynihan Ramsey, Benjamin J. Weidemann, Yumiko Kobayashi, and Joseph Bass
- Subjects
Purinergic receptor ,Circadian clock ,Secretagogue ,Circadian rhythm ,Biology ,Receptor ,Cell biology ,Hormone ,Genetic screen ,Proinsulin - Abstract
SummaryThe mammalian circadian clock drives daily oscillations in physiology and behavior through an autoregulatory transcription feedback loop present in central and peripheral cells. Ablation of the core clock within the endocrine pancreas of adult animals impairs the transcription and splicing of genes involved in hormone exocytosis and causes hypoinsulinemic diabetes. However, identification of druggable proteins and pathways to ameliorate the burden of circadian metabolic disease remains a challenge. Here, we generated β cells expressing a nano-luciferase reporter within the proinsulin polypeptide to screen 2,640 pharmacologically-active compounds and identify insulinotropic molecules that bypass the secretory defect in clock mutant β cells. We validated lead compounds in primary mouse islets and identified known modulators of ligandgated ion channels and G-protein coupled receptors, including the antihelmintic ivermectin. Single-cell electrophysiology in circadian mutant mouse and human cadaveric islets validated ivermectin as a glucose-dependent secretagogue. Genetic, genomic, and pharmacologic analyses established that the molecular clock controls the expression of the purinergic P2Y1 receptor to mediate the insulinotropic activity of ivermectin. These findings identify the P2Y1 purinergic receptor as a target to rescue circadian β-cell failure and establish a chemical genetic screen for endocrine therapeutics.
- Published
- 2021
41. Author Correction: Berberine is an insulin secretagogue targeting the KCNH6 potassium channel
- Author
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Tetsuro Izumi, Jing Lu, Miao-Miao Zhao, Jin-Kui Yang, Ting-Ting Shi, Haixia Huang, Kohichi Matsunaga, Sen Li, Hao Wang, Chen Chen, Xi Cao, and Qi Li
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Multidisciplinary ,business.industry ,Science ,Published Erratum ,Insulin ,medicine.medical_treatment ,General Physics and Astronomy ,General Chemistry ,Pharmacology ,General Biochemistry, Genetics and Molecular Biology ,Potassium channel ,chemistry.chemical_compound ,Berberine ,chemistry ,Medicine ,Secretagogue ,business ,Author name - Abstract
In this article the author name Tetsuro Izumi was incorrectly written as Testuro Izumi. The original article has been corrected.
- Published
- 2021
42. Telmisartan Potentiates Insulin Secretion via Ion Channels, Independent of the AT1 Receptor and PPARγ
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Tao Liu, Lijuan Cui, Huan Xue, Xiaohua Yang, Mengmeng Liu, Linping Zhi, Huanhuan Yang, Zhihong Liu, Min Zhang, Qing Guo, Peifeng He, Yunfeng Liu, and Yi Zhang
- Subjects
Pharmacology ,insulin secretion ,Angiotensin II receptor type 1 ,Voltage-dependent calcium channel ,Chemistry ,AT1 receptor ,Insulin ,medicine.medical_treatment ,Pancreatic islets ,RM1-950 ,telmisartan ,Kv channel ,Angiotensin II ,medicine.anatomical_structure ,Valsartan ,medicine ,Secretagogue ,Pharmacology (medical) ,Therapeutics. Pharmacology ,Telmisartan ,L-type VGCC ,medicine.drug ,Original Research - Abstract
Background and aim: Angiotensin II type 1 (AT1) receptor blockers (ARBs), as antihypertensive drugs, have drawn attention for their benefits to individuals with diabetes and prediabetes. However, the direct effects of ARBs on insulin secretion remain unclear. In this study, we aimed to investigate the insulinotropic effect of ARBs and the underlying electrophysiological mechanism. Methods: Islets isolated from Wistar rats or db/db mice were incubated with drugs under different glucose conditions for 30 minutes, then supernatant liquid was collected for insulin secretion. Intracellular Ca2+ ([Ca2+]i) levels of β-cells were measured by calcium imaging technology. Patch-clamp technology was applied to detect effects on action potential duration (APD), Voltage-dependent potassium (Kv) channels, and voltage-gated calcium channels (VGCC). In our in vivo experiment, the 8-week-old and 11-week-old db/db mice were separately administered acute oral acute oral telmisartan treatment (15 mg/kg), then the oral glucose tolerance test (OGTT) was performed to observe the insulinotropic effect of telmisartan at 2 hours following drug intake.Results: Only telmisartan among the three ARBs(telmisartan, valsartan, and irbesartan)exhibited an insulin secretagogue role in rat islets. Independent of AT1 receptor and peroxisome proliferator-activated receptor γ (PPARγ), telmisartan exerted effects on ion channels including Kv channels and L-type VGCCs to promote extracellular Ca2+ influx, thereby potentiating insulin secretion in a glucose-dependent manner. Furthermore, we identified that telmisartan directly inhibited Kv2.1 channel on a Chinese hamster ovary cell line with Kv2.1 channel overexpression. Acute exposure of db/db mice to a telmisartan dose equivalent to therapeutic doses in humans resulted in lower blood glucose and increased plasma insulin concentration in OGTT. We further observed the telmisartan-induced insulinotropic and electrophysiological effects on pathological pancreatic islets isolated from db/db mice. Conclusions: Our results establish an important insulinotropic function of telmisartan distinct from other ARBs in the treatment of diabetes.
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- 2021
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43. Liver‐Expressed Antimicrobial Peptide 2 antagonizes the insulinostatic effect of ghrelin in rat isolated pancreatic islets
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Gérard Cros, Morgane Bayle, Jérémie Neasta, Catherine Oiry, Sylvie Peraldi-Roux, Guillaume Gautheron, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), and Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
medicine.medical_specialty ,insulin secretion ,[SDV]Life Sciences [q-bio] ,Peptide ,Liver-expressed antimicrobial peptide ,Islets of Langerhans ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Insulin ,Pharmacology (medical) ,Receptors, Ghrelin ,Receptor ,LEAP2 ,islets of Langerhan ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,Pharmacology ,chemistry.chemical_classification ,0303 health sciences ,Chemistry ,Pancreatic islets ,digestive, oral, and skin physiology ,[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,Rats ,Endocrinology ,medicine.anatomical_structure ,Liver ,030220 oncology & carcinogenesis ,ghrelin ,[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,Ghrelin ,Secretagogue ,GHSR ,Endogenous agonist ,hormones, hormone substitutes, and hormone antagonists ,Antimicrobial Cationic Peptides ,Hormone - Abstract
Background The hormone ghrelin is the endogenous agonist of the G-protein coupled receptor (GPCR) termed growth-hormone secretagogue receptor (GHSR). Ghrelin inhibits glucose-stimulated insulin secretion by activating pancreatic GHSR. Recently, Liver-Expressed Antimicrobial Peptide 2 (LEAP2) was recognized as an endogenous GHSR ligand that blocks ghrelin-induced actions. Nonetheless, the effect of LEAP2 on glucose-stimulated insulin secretion from pancreatic islets is unknown. Objectives We aimed at exploring the activity of LEAP2 on glucose-stimulated insulin secretion. Methods Islets of Langerhans isolated from rat pancreas were exposed to glucose in the presence or in the absence of LEAP2 and ghrelin and then insulin secretion was assayed. Results LEAP2 did not modulate glucose-stimulated insulin secretion. However, LEAP2 blocked the insulinostatic action of ghrelin. Conclusion Our data show that LEAP2 behaves as an antagonist of pancreatic GHSR.
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- 2021
44. CRH stimulation improves 18F-FDG-PET detection of pituitary adenomas in Cushing’s disease
- Author
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Boyle, Jacqueline, Patronas, Nicholas J., Smirniotopoulos, James, Herscovitch, Peter, Dieckman, William, Millo, Corina, Maric, Dragan, Chatain, Grégoire P., Hayes, Christina Piper, Benzo, Sarah, Scott, Gretchen, Edwards, Nancy, Ray Chaudhury, Abhik, Lodish, Maya B., Sharma, Susmeeta, Nieman, Lynnette K., Stratakis, Constantine A., Lonser, Russell R., and Chittiboina, Prashant
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- 2019
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45. Naturally-occurring TGR5 agonists modulating glucagon-like peptide-1 biosynthesis and secretion.
- Author
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Jafri, Laila, Saleem, Samreen, Calderwood, Danielle, Gillespie, Anna, Mirza, Bushra, and Green, Brian D.
- Subjects
- *
GLUCAGON-like peptide 1 , *G protein-coupled receptor kinases , *PEPTIDE synthesis , *TYPE 2 diabetes treatment , *HYPOGLYCEMIC agents , *GENE expression - Abstract
Selective GLP-1 secretagogues represent a novel potential therapy for type 2 diabetes mellitus. This study examined the GLP-1 secretory activity of the ethnomedicinal plant, Fagonia cretica , which is postulated to possess anti-diabetic activity. After extraction and fractionation extracts and purified compounds were tested for GLP-1 and GIP secretory activity in pGIP/neo STC-1 cells. Intracellular levels of incretin hormones and their gene expression were also determined. Crude F . cretica extracts stimulated both GLP-1 and GIP secretion, increased cellular hormone content, and upregulated gene expression of proglucagon, GIP and prohormone convertase. However, ethyl acetate partitioning significantly enriched GLP-1 secretory activity and this fraction underwent bioactivity-guided fractionation. Three isolated compounds were potent and selective GLP-1 secretagogues: quinovic acid (QA) and two QA derivatives, QA-3β-O-β- d -glycopyranoside and QA-3β-O-β- d -glucopyranosyl-(28 → 1)-β- d -glucopyranosyl ester. All QA compounds activated the TGR5 receptor and increased intracellular incretin levels and gene expression. QA derivatives were more potent GLP-1 secretagogues than QA. This is the first time that QA and its naturally-occurring derivatives have been shown to activate TGR5 and stimulate GLP-1 secretion. These data provide a plausible mechanism for the ethnomedicinal use of F . cretica and may assist in the ongoing development of selective GLP-1 agonists. [ABSTRACT FROM AUTHOR]
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- 2016
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46. What Is the Metabolic Amplification of Insulin Secretion and Is It (Still) Relevant?
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Ingo Rustenbeck, Uwe Panten, M Morsi, Mohammed Alshafei, and Torben Schulze
- Subjects
0301 basic medicine ,insulin secretion ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Metabolic Amplification ,nutrient secretagogues ,030209 endocrinology & metabolism ,Review ,Mitochondrion ,Biochemistry ,Microbiology ,Exocytosis ,Article ,03 medical and health sciences ,0302 clinical medicine ,Adenine nucleotide ,medicine ,Secretion ,Veröffentlichung der TU Braunschweig ,glucose ,metabolic amplification ,Molecular Biology ,ddc:5 ,Cytosolic Calcium Concentration ,Chemistry ,Insulin ,cytosolic calcium concentration ,Nutrient Secretagogues ,QR1-502 ,Cell biology ,Mitochondria ,mitochondria ,ddc:57 ,030104 developmental biology ,Glucose ,Secretagogue ,Beta cell ,Publikationsfonds der TU Braunschweig ,Hormone - Abstract
The pancreatic beta-cell transduces the availability of nutrients into the secretion of insulin. While this process is extensively modified by hormones and neurotransmitters, it is the availability of nutrients, above all glucose, which sets the process of insulin synthesis and secretion in motion. The central role of the mitochondria in this process was identified decades ago, but how changes in mitochondrial activity are coupled to the exocytosis of insulin granules is still incompletely understood. The identification of ATP-sensitive K+-channels provided the link between the level of adenine nucleotides and the electrical activity of the beta cell, but the depolarization-induced Ca2+-influx into the beta cells, although necessary for stimulated secretion, is not sufficient to generate the secretion pattern as produced by glucose and other nutrient secretagogues. The metabolic amplification of insulin secretion is thus the sequence of events that enables the secretory response to a nutrient secretagogue to exceed the secretory response to a purely depolarizing stimulus and is thus of prime importance. Since the cataplerotic export of mitochondrial metabolites is involved in this signaling, an orienting overview on the topic of nutrient secretagogues beyond glucose is included. Their judicious use may help to define better the nature of the signals and their mechanism of action.
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- 2021
47. Spatial redistribution of neurosecretory vesicles upon stimulation accelerates their directed transport to the plasma membrane
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Elaine Schenk, Frederic A. Meunier, and Dietmar Oelz
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Multidisciplinary ,Chemistry ,Chromaffin Cells ,Compartment (ship) ,Vesicle ,Cell Membrane ,Cytoplasmic Vesicles ,Biological Transport ,Stimulation ,Receptor–ligand kinetics ,Vesicular transport protein ,Kinetics ,Membrane ,Biophysics ,Secretagogue ,Intracellular - Abstract
Through the integration of results from an imaging analysis of intracellular trafficking of labelled neurosecretory vesicles in chromaffin cells, we develop a Markov state model to describe their transport and binding kinetics. Our simulation results indicate that a spatial redistribution of neurosecretory vesicles occurs upon secretagogue stimulation leading vesicles to the plasma membrane where they undergo fusion thereby releasing adrenaline and noradrenaline. Furthermore, we find that this redistribution alone can explain the observed up-regulation of vesicle transport upon stimulation and its directional bias towards the plasma membrane. Parameter fitting indicates that in the deeper compartment within the cell, vesicle transport is asymmetric and characterised by a bias towards the plasma membrane. We also find that crowding of neurosecretory vesicles undergoing directed transport explains the observed accelerated recruitment of freely diffusing vesicles into directed transport upon stimulation.
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- 2021
48. Gene loci associated with insulin secretion in islets from nondiabetic mice
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Daniel M. Gatti, Rahul Das, Brian S. Yandell, Kelly A. Mitok, Ziyue Wang, Mark P. Keller, Donnie S. Stapleton, Matthew Vincent, Karl W. Broman, Kathryn L. Schueler, Shane P Simonett, Takanao Ishimura, Alan D. Attie, Mary E. Rabaglia, Gary A. Churchill, Christopher H. Emfinger, Tim Beck, and Christina Kendziorski
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0301 basic medicine ,Genetically modified mouse ,medicine.medical_specialty ,endocrine system diseases ,medicine.medical_treatment ,Mice, Inbred Strains ,Mice, Transgenic ,Type 2 diabetes ,Protein Serine-Threonine Kinases ,Biology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Diabetes mellitus ,Insulin Secretion ,Genetic variation ,medicine ,Genetic predisposition ,Animals ,Humans ,Genetic Predisposition to Disease ,Insulin ,nutritional and metabolic diseases ,General Medicine ,Protein Tyrosine Phosphatases, Non-Receptor ,medicine.disease ,DNA-Binding Proteins ,030104 developmental biology ,Endocrinology ,Diabetes Mellitus, Type 2 ,Genetic Loci ,030220 oncology & carcinogenesis ,Commentary ,Secretagogue ,Research Article ,Genome-Wide Association Study ,Transcription Factors ,Genetic screen - Abstract
Genetic susceptibility to type 2 diabetes is primarily due to β cell dysfunction. However, a genetic study to directly interrogate β cell function ex vivo has never been previously performed. We isolated 233,447 islets from 483 Diversity Outbred (DO) mice maintained on a Western-style diet, and measured insulin secretion in response to a variety of secretagogues. Insulin secretion from DO islets ranged greater than 1000-fold even though none of the mice were diabetic. The insulin secretory response to each secretagogue had a unique genetic architecture; some of the loci were specific for one condition, whereas others overlapped. Human loci that are syntenic to many of the insulin secretion quantitative trait loci (QTL) from mice are associated with diabetes-related SNPs in human genome-wide association studies. We report on 3 genes, Ptpn18, Hunk, and Zfp148, where the phenotype predictions from the genetic screen were fulfilled in our studies of transgenic mouse models. These 3 genes encode a nonreceptor type protein tyrosine phosphatase, a serine/threonine protein kinase, and a Krϋppel-type zinc-finger transcription factor, respectively. Our results demonstrate that genetic variation in insulin secretion that can lead to type 2 diabetes is discoverable in nondiabetic individuals.
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- 2019
49. Astragalin augments basal calcium influx and insulin secretion in rat pancreatic islets
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Paola Miranda Sulis, Thaís Fernandes, Fátima Regina Mena Barreto Silva, Geison M. Costa, Marisa Jádna Silva Frederico, Renata Gonçalves, Diana Rey, Luis Fernando Ospina, and Marcela Aragón
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Male ,0301 basic medicine ,medicine.medical_specialty ,SERCA ,Calcium Channels, L-Type ,Physiology ,medicine.medical_treatment ,chemistry.chemical_element ,Calcium ,Sarcoplasmic Reticulum Calcium-Transporting ATPases ,Islets of Langerhans ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,KATP Channels ,Internal medicine ,Insulin Secretion ,medicine ,Animals ,Homeostasis ,Hypoglycemic Agents ,Glucose homeostasis ,Calcium Signaling ,Kaempferols ,Rats, Wistar ,Molecular Biology ,Cells, Cultured ,Protein Kinase C ,Glucose tolerance test ,medicine.diagnostic_test ,Pancreatic islets ,Insulin ,Cell Biology ,Cyclic AMP-Dependent Protein Kinases ,Rats ,Glucose ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Dietary Supplements ,Secretagogue ,Astragalin ,030217 neurology & neurosurgery - Abstract
Astragalin is a flavonol glycoside with several biological activities, including antidiabetic properties. The objective of this study was to investigate the effects of astragalin on glycaemia and insulin secretion, in vivo, and on calcium influx and insulin secretion in isolated rat pancreatic islets, ex vivo. Astragalin (1 and 10 mg / kg) was administered by oral gavage to fasted Wistar rats and serum glucose and plasma insulin were measured. Isolated pancreatic islets were used to measure basal insulin secretion and calcium influx. Astragalin (10 mg/ kg) decreased glycaemia and increased insulin secretion significantly at 15–180 min, respectively, in the glucose tolerance test. In isolated pancreatic cells, astragalin (100 μM) stimulated calcium influx through a mechanism involving ATP-dependent potassium channels, L-type voltage-dependent calcium channels, the sarcoendoplasmic reticulum calcium transport ATPase (SERCA), PKC and PKA. These findings highlight the dietary coadjuvant, astragalin, as a potential insulin secretagogue that may contribute to glucose homeostasis.
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- 2019
50. The Structural Basis for the Binding of Repaglinide to the Pancreatic KATP Channel
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Dian Ding, Jing-Xiang Wu, Yunlu Kang, Mengmeng Wang, and Lei Chen
- Subjects
0301 basic medicine ,endocrine system ,Chemistry ,Protein subunit ,Insulin ,medicine.medical_treatment ,ATP-binding cassette transporter ,Repaglinide ,General Biochemistry, Genetics and Molecular Biology ,Potassium channel ,Cell biology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,lcsh:Biology (General) ,medicine ,Sulfonylurea receptor ,Secretagogue ,Binding site ,lcsh:QH301-705.5 ,030217 neurology & neurosurgery ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
Summary: Repaglinide (RPG) is a short-acting insulin secretagogue widely prescribed for the treatment of type 2 diabetes. It boosts insulin secretion by inhibiting the pancreatic ATP-sensitive potassium channel (KATP). However, the mechanisms by which RPG binds to the KATP channel are poorly understood. Here, we describe two cryo-EM structures: the pancreatic KATP channel in complex with inhibitory RPG and adenosine-5’-(γ-thio)-triphosphate (ATPγS) at 3.3 Å and a medium-resolution structure of a RPG-bound mini SUR1 protein in which the N terminus of the inward-rectifying potassium channel 6.1 (Kir6.1) is fused to the ABC transporter module of the sulfonylurea receptor 1 (SUR1). These structures reveal the binding site of RPG in the SUR1 subunit. Furthermore, the high-resolution structure reveals the complex architecture of the ATP binding site, which is formed by both Kir6.2 and SUR1 subunits, and the domain-domain interaction interfaces. : Ding et al. report the detailed binding site and the inhibitory mechanism of the insulin secretagogue repaglinide on the pancreatic KATP channel, revealed by a 3.3 Å cryo-EM structure and electrophysiology experiments. Keywords: diabetes, KATP channel, repaglinide, glibenclamide, sulfonylurea, glinides, Kir, SUR, ABC transporter, KNtp
- Published
- 2019
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