Publications by authors named "Honey Modi"

8 Publications

  • Page 1 of 1

Folding mutations suppress early beta-cell proliferation.

Elife 2018 12 14;7. Epub 2018 Dec 14.

Diabetes Research Group, Life Sciences Institute, Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, Canada.

Exploring how proliferation and maturation of beta-cells can be impaired after birth will shed light on the origins of various forms of diabetes.
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http://dx.doi.org/10.7554/eLife.43475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294546PMC
December 2018

High-content screening identifies a role for Na(+) channels in insulin production.

R Soc Open Sci 2015 Dec 2;2(12):150306. Epub 2015 Dec 2.

Department of Cellular and Physiological Sciences University of British Columbia Life Sciences Centre, 2350 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3.

Insulin production is the central feature of functionally mature and differentiated pancreatic β-cells. Reduced insulin transcription and dedifferentiation have been implicated in type 2 diabetes, making drugs that could reverse these processes potentially useful. We have previously established ratiometric live-cell imaging tools to identify factors that increase insulin promoter activity and promote β-cell differentiation. Here, we present a single vector imaging tool with eGFP and mRFP, driven by the Pdx1 and Ins1 promoters, respectively, targeted to the nucleus to enhance identification of individual cells in a high-throughput manner. Using this new approach, we screened 1120 off-patent drugs for factors that regulate Ins1 and Pdx1 promoter activity in MIN6 β-cells. We identified a number of compounds that positively modulate Ins1 promoter activity, including several drugs known to modulate ion channels. Carbamazepine was selected for extended follow-up, as our previous screen also identified this use-dependent sodium channel inhibitor as a positive modulator of β-cell survival. Indeed, carbamazepine increased Ins1 and Ins2 mRNA in primary mouse islets at lower doses than were required to protect β-cells. We validated the role of sodium channels in insulin production by examining Nav1.7 (Scn9a) knockout mice and remarkably islets from these animals had dramatically elevated insulin content relative to wild-type controls. Collectively, our experiments provide a starting point for additional studies aimed to identify drugs and molecular pathways that control insulin production and β-cell differentiation status. In particular, our unbiased screen identified a novel role for a β-cell sodium channel gene in insulin production.
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http://dx.doi.org/10.1098/rsos.150306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4807443PMC
December 2015

Autocrine Action of IGF2 Regulates Adult β-Cell Mass and Function.

Diabetes 2015 Dec 17;64(12):4148-57. Epub 2015 Sep 17.

Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland

Insulin-like growth factor 2 (IGF2), produced and secreted by adult β-cells, functions as an autocrine activator of the β-cell insulin-like growth factor 1 receptor signaling pathway. Whether this autocrine activity of IGF2 plays a physiological role in β-cell and whole-body physiology is not known. Here, we studied mice with β-cell-specific inactivation of Igf2 (βIGF2KO mice) and assessed β-cell mass and function in aging, pregnancy, and acute induction of insulin resistance. We showed that glucose-stimulated insulin secretion (GSIS) was markedly reduced in old female βIGF2KO mice; glucose tolerance was, however, normal because of increased insulin sensitivity. While on a high-fat diet, both male and female βIGF2KO mice displayed lower GSIS compared with control mice, but reduced β-cell mass was observed only in female βIGF2KO mice. During pregnancy, there was no increase in β-cell proliferation and mass in βIGF2KO mice. Finally, β-cell mass expansion in response to acute induction of insulin resistance was lower in βIGF2KO mice than in control mice. Thus, the autocrine action of IGF2 regulates adult β-cell mass and function to preserve in vivo GSIS in aging and to adapt β-cell mass in response to metabolic stress, pregnancy hormones, and acute induction of insulin resistance.
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http://dx.doi.org/10.2337/db14-1735DOI Listing
December 2015

Glutamine stimulates biosynthesis and secretion of insulin-like growth factor 2 (IGF2), an autocrine regulator of beta cell mass and function.

J Biol Chem 2014 Nov 30;289(46):31972-31982. Epub 2014 Sep 30.

Center for Integrative Genomics, University of Lausanne, CH-1015 Lausanne, Switzerland. Electronic address:

IGF2 is an autocrine ligand for the beta cell IGF1R receptor and GLP-1 increases the activity of this autocrine loop by enhancing IGF1R expression, a mechanism that mediates the trophic effects of GLP-1 on beta cell mass and function. Here, we investigated the regulation of IGF2 biosynthesis and secretion. We showed that glutamine rapidly and strongly induced IGF2 mRNA translation using reporter constructs transduced in MIN6 cells and primary islet cells. This was followed by rapid secretion of IGF2 via the regulated pathway, as revealed by the presence of mature IGF2 in insulin granule fractions and by inhibition of secretion by nimodipine and diazoxide. When maximally stimulated by glutamine, the amount of secreted IGF2 rapidly exceeded its initial intracellular pool and tolbutamide, and high K(+) increased IGF2 secretion only marginally. This indicates that the intracellular pool of IGF2 is small and that sustained secretion requires de novo synthesis. The stimulatory effect of glutamine necessitates its metabolism but not mTOR activation. Finally, exposure of insulinomas or beta cells to glutamine induced Akt phosphorylation, an effect that was dependent on IGF2 secretion, and reduced cytokine-induced apoptosis. Thus, glutamine controls the activity of the beta cell IGF2/IGF1R autocrine loop by increasing the biosynthesis and secretion of IGF2. This autocrine loop can thus integrate changes in feeding and metabolic state to adapt beta cell mass and function.
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http://dx.doi.org/10.1074/jbc.M114.587733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231675PMC
November 2014

Glucagon-like peptide-1 increases beta-cell glucose competence and proliferation by translational induction of insulin-like growth factor-1 receptor expression.

J Biol Chem 2010 Apr 9;285(14):10538-45. Epub 2010 Feb 9.

Department of Physiology and Center for Integrative Genomics, University of Lausanne, CH-1015 Lausanne, Switzerland.

Glucagon-like peptide-1 (GLP-1) protects beta-cells against apoptosis, increases their glucose competence, and induces their proliferation. We previously demonstrated that the anti-apoptotic effect was mediated by an increase in insulin-like growth factor-1 receptor (IGF-1R) expression and signaling, which was dependent on autocrine secretion of insulin-like growth factor 2 (IGF-2). Here, we further investigated how GLP-1 induces IGF-1R expression and whether the IGF-2/IGF-1R autocrine loop is also involved in mediating GLP-1-increase in glucose competence and proliferation. We show that GLP-1 up-regulated IGF-1R expression by a protein kinase A-dependent translational control mechanism, whereas isobutylmethylxanthine, which led to higher intracellular accumulation of cAMP than GLP-1, increased both IGF-1R transcription and translation. We then demonstrated, using MIN6 cells and primary islets, that the glucose competence of these cells was dependent on the level of IGF-1R expression and on IGF-2 secretion. We showed that GLP-1-induced primary beta-cell proliferation was suppressed by Igf-1r gene inactivation and by IGF-2 immunoneutralization or knockdown. Together our data show that regulation of beta-cell number and function by GLP-1 depends on the cAMP/protein kinase A mediated-induction of IGF-1R expression and the increased activity of an IGF-2/IGF-1R autocrine loop.
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http://dx.doi.org/10.1074/jbc.M109.091116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2856261PMC
April 2010

Design and synthesis of novel 3-hydroxy-cyclobut-3-ene-1,2-dione derivatives as thyroid hormone receptor beta (TR-beta) selective ligands.

Bioorg Med Chem Lett 2008 Jul 14;18(14):3919-24. Epub 2008 Jun 14.

Zydus Research Centre, Medicinal Chemistry, Sarkhej-Bavla N. H.8A, Moraiya, Ahmedabad, Gujarat 382210, India.

Design and synthesis of a novel 3-hydroxy-cyclobut-3-ene-1,2-dione derivatives are reported and their in vitro thyroid hormone receptor selectivity has been evaluated in the thyroid luciferase receptor assay. The 3-[3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy)-phenylamino]-4-hydroxy-cyclobut-3-ene-1,2-dione 21 has shown selectivity towards thyroid hormone receptor beta.
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http://dx.doi.org/10.1016/j.bmcl.2008.06.038DOI Listing
July 2008

Synthesis and antidiabetic activity of 2,5-disubstituted-3-imidazol-2-yl-pyrrolo[2,3-b]pyridines and thieno[2,3-b]pyridines.

Bioorg Med Chem 2007 Nov 10;15(21):6782-95. Epub 2007 Aug 10.

Zydus Research Centre, Cadila Healthcare Ltd, Sarkhej-Bavala N H 8A, Moraiya, Ahmedabad, India.

In the present investigation, two series of 2,5-disubstituted-3-imidazol-2-yl-pyrrolo[2,3-b]pyridines (2a-l) and thieno[2,3-b]pyridines (3a-l) were designed as analogs of BL 11282 (1). The in vitro glucose dependent insulinotropic activity of all the test compounds was evaluated using RIN5F cell based assay and all the test compounds showed glucose and concentration dependent insulin secretion. The in vivo antidiabetic activities of most potent compounds from each series (2c and 3c) were assessed in C57BL/6J mice. Compounds 2c and 3c showed dose dependent insulin secretion and significant glucose reduction in vivo. In general, compounds 2c and 3c were found to be equipotent at all the three different doses selected and with respect to BL 11282, both the test compounds were found to be more potent, at all the time points.
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http://dx.doi.org/10.1016/j.bmc.2007.08.005DOI Listing
November 2007

Synthesis of 3,8,9-trisubstituted-1,7,9-triaza-fluorene-6-carboxylic acid derivatives as a new class of insulin secretagogues.

Bioorg Med Chem 2007 Sep 8;15(17):5950-64. Epub 2007 Jun 8.

Zydus Research Center, Cadila Healthcare Ltd, Sarkhej-Bavala NH 8A, Moraiya, Ahmedabad, India.

beta-Carbolines stimulate insulin secretion in a glucose-dependent manner, probably by acting on I(3)-binding site. Knowing the in vitro glucose-dependent insulinotropic potential of beta-carbolines, in this project, three series of substituted-triaza-fluorene-6-carboxylic acids (5a-v, 6a-t, and 7a-t) were designed (analogs of beta-carboline) as a new class of insulinotropic agents. The in vitro glucose-dependent insulinotropic activities of test compounds were evaluated using RIN5F assay. Interestingly, with respect to the control, test compounds showed concentration-dependent insulin release, only in presence of glucose load (16.7 mmol). Some of the test compounds from each series were found to be equipotent to standard compound (Harmane), indicating that the pyridine ring systems of substituted-triaza-fluorenes act as bioisosteres of benzene ring in beta-carbolines.
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http://dx.doi.org/10.1016/j.bmc.2007.05.075DOI Listing
September 2007