Olfactory marker protein regulation of glucagon secretion in hyperglycemia

Oh, Ju Hun; Han, Ye Eon; Bao, Ya Ru; Kang, Chan Woo; Koo, Jae Hyung; Ku, Cheol Ryong; Cho, Yoon Hee; Lee, Mi Kyung

doi:10.1038/s12276-022-00843-8

Cited by 3 publications

(2 citation statements)

References 36 publications

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“…Along these lines, new α-cell targets are continuing to be identified which have potential for small molecule interventions. Recent work showed the olfactory marker protein ( Omp ) regulates cAMP in α-cells and affects AMP kinase activity ( 34 ). α-cell-specific Omp knockout mice have reduced baseline AMPK phosphorylation and knockdown of Omp in an α-cell line caused a loss of glucose-induced reduction in cAMP levels.…”

Section: Discussionmentioning

confidence: 99%

Small molecule glucagon release inhibitors with activity in human islets

et al. 2023

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PurposeType 1 diabetes (T1D) accounts for an estimated 5% of all diabetes in the United States, afflicting over 1.25 million individuals. Maintaining long-term blood glucose control is the major goal for individuals with T1D. In T1D, insulin-secreting pancreatic islet β-cells are destroyed by the immune system, but glucagon-secreting islet α-cells survive. These remaining α-cells no longer respond properly to fluctuating blood glucose concentrations. Dysregulated α-cell function contributes to hyper- and hypoglycemia which can lead to macrovascular and microvascular complications. To this end, we sought to discover small molecules that suppress α-cell function for their potential as preclinical candidate compounds. Prior high-throughput screening identified a set of glucagon-suppressing compounds using a rodent α-cell line model, but these compounds were not validated in human systems. ResultsHere, we dissociated and replated primary human islet cells and exposed them to 24 h treatment with this set of candidate glucagon-suppressing compounds. Glucagon accumulation in the medium was measured and we determined that compounds SW049164 and SW088799 exhibited significant activity. Candidate compounds were also counter-screened in our InsGLuc-MIN6 β-cell insulin secretion reporter assay. SW049164 and SW088799 had minimal impact on insulin release after a 24 h exposure. To further validate these hits, we treated intact human islets with a selection of the top candidates for 24 h. SW049164 and SW088799 significantly inhibited glucagon release into the medium without significantly altering whole islet glucagon or insulin content. In concentration-response curves SW088799 exhibited significant inhibition of glucagon release with an IC50 of 1.26 µM. ConclusionGiven the set of tested candidates were all top hits from the primary screen in rodent α-cells, this suggests some conservation of mechanism of action between human and rodents, at least for SW088799. Future structure-activity relationship studies of SW088799 may aid in elucidating its protein target(s) or enable its use as a tool compound to suppress α-cell activity in vitro.

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Section: Discussionmentioning

confidence: 99%

Small molecule glucagon release inhibitors with activity in human islets

et al. 2023

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“…For example, it was demonstrated that ectopic odorant receptors (ORs) in pancreatic islets regulate insulin and glucagon secretion, fatty acid oxidation, lipogenesis, thermogenesis, and other processes. At least 47 ORs have been proven to be expressed in human pancreatic islets and the pancreatic β-cell line MIN6 [162], where these receptors regulate insulin secretion and inflammation [163][164][165][166][167]. The olfactory marker protein (OMP) is also expressed in pancreatic islets, especially in α-cells, in which it participates in glucagon secretion regulation.…”

Section: Taar1 Co-expression Cluster Changes In Metabolic Diseasesmentioning

confidence: 99%

Trace Amine-Associated Receptors and Monoamine-Mediated Regulation of Insulin Secretion in Pancreatic Islets

Vaganova,

Shemyakova,

Lenskaia

et al. 2023

Biomolecules

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Currently, metabolic syndrome treatment includes predominantly pharmacological symptom relief and complex lifestyle changes. Trace amines and their receptor systems modulate signaling pathways of dopamine, norepinephrine, and serotonin, which are involved in the pathogenesis of this disorder. Trace amine-associated receptor 1 (TAAR1) is expressed in endocrine organs, and it was revealed that TAAR1 may regulate insulin secretion in pancreatic islet β-cells. For instance, accumulating data demonstrate the positive effect of TAAR1 agonists on the dynamics of metabolic syndrome progression and MetS-associated disease development. The role of other TAARs (TAAR2, TAAR5, TAAR6, TAAR8, and TAAR9) in the islet’s function is much less studied. In this review, we summarize the evidence of TAARs’ contribution to the metabolic syndrome pathogenesis and regulation of insulin secretion in pancreatic islets. Additionally, by the analysis of public transcriptomic data, we demonstrate that TAAR1 and other TAAR receptors are expressed in the pancreatic islets. We also explore associations between the expression of TAARs mRNA and other genes in studied samples and demonstrate the deregulation of TAARs’ functional associations in patients with metabolic diseases compared to healthy donors.

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Association between urinary mixture metal levels and olfactory function in coal miners

Li,

Jiao,

et al. 2024

Front. Public Health

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BackgroundExposure to occupational metallic mixtures has a potential impact on olfactory function. However, research evidence is limited on the potential impact of exposure to metallic mixtures and olfactory dysfunction. Furthermore, the coal dust generated contains multiple various metals during coal mining, and no study yet has focus on the olfactory dysfunction of coal miners.ObjectivesIn this study, we evaluate the association between urinary metallic mixtures and olfactory function in coal miners, while also exploring the potential applicability of plasma olfactory marker protein (OMP) as a biomarker for assessing olfaction.MethodsFrom July to October 2023, coal workers from seven different coal mining enterprises were recruited for the survey when they come for the employee health checkup. Ultimately, 376 participants were met the inclusion criteria and, respectively, determined with the concentrations of urine (16 metals) and plasma (OMP). Meanwhile, applying UPSIT to access their olfactory function. Binary logistic regression and restricted cubic spline (RCS) model were used to estimate the association of individual metals with olfactory function. Bayesian kernel machine regression (BKMR) and Quantile g-computation (QG-C) regression were employed to assess the overall association between metal mixtures and olfactory function and identify the major contributing elements.ResultsIn a single-metal model, two metals in urine were found to be significantly associated with olfactory function. RCS analysis further revealed that the association between Iron (Fe) and olfactory function was linear, while Lead (Pb) exhibited a non-linear. The BKMR model demonstrated a significant positive association between metal mixture concentration and olfactory function. Combined QG-C regression analysis suggested that metals Cr, Fe, Se, Sb, and Pb could impact the performance of the olfactory test (UPSIT), with Pb being identified as the most influential contributor. The correlation between plasma OMP protein levels and urinary metal concentrations was weak.ConclusionMultiple metals are associated with olfactory function in the coal miners. A significant positive association was observed between metal mixture concentrations and olfactory function, with Pb being the most important contributor. In this study, plasma OMP has not been demonstrated to serve as a biomarker for olfactory function.

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Olfactory marker protein regulation of glucagon secretion in hyperglycemia

Cited by 3 publications

References 36 publications

Small molecule glucagon release inhibitors with activity in human islets

Small molecule glucagon release inhibitors with activity in human islets

Trace Amine-Associated Receptors and Monoamine-Mediated Regulation of Insulin Secretion in Pancreatic Islets

Association between urinary mixture metal levels and olfactory function in coal miners

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