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1
Fakruddin, Md. "Genetics of Type 2 Diabetes: A Review." Journal of Current and Advance Medical Research 6, no. 1 (March 27, 2019): 59–63. http://dx.doi.org/10.3329/jcamr.v6i1.40787.
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Diabetes Mellitus (DM), one of the most non-communicable diseases, is increasing day by day in an alarming way. More than 140 million people are suffering from diabetes throughout the world. It is not a single disease entity, but rather a group of metabolic disorders sharing the common underlying feature of hyperglycemia. Hyperglycemia in diabetes results from defects in insulin secretion, insulin action, or, most commonly, both. The chronic hyperglycemia and attendant metabolic deregulation may be associated with secondary damage in multiple organ systems, especially the kidneys, eyes, nerves, and blood vessels. The pathophysiology of diabetes is not fully elucidated. Insulin secretory dysfunction and insulin resistance or both is main candidate for this metabolic disorder, moreover various genetic and environmental factors may also involve in this process. Racial variations play also an important role as evidenced by various studies. However, the interrelationships between the molecular and metabolic mechanisms in these parameters contributing this life threatening disease still remain a mystery to the scientists.
Journal of Current and Advance Medical Research 2019;6(1):59-63
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Raina, Sunil, and Roopali Fotra. "Association Study of Candidate Gene Uncoupling Protein 2 (UCP2) with Type 2 Diabetes Mellitus in the Different Population Groups of Jammu Region." Biosciences, Biotechnology Research Asia 16, no. 2 (June 30, 2019): 351–57. http://dx.doi.org/10.13005/bbra/2751.
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Diabetes Mellitus is a group of metabolic disorders characterized by hyperglycaemic resulting from the defects of insulin secretion, insulin action or both. The present study was conducted in order to know the molecular genetic cause of the T2DM patients belonging to the Jammu region of J&K State. Many genes have been known to be linked with the onset and progression of the T2DM therefore the present data represents the role of one of the genes Uncoupling protein 2 (UCP2) known to be strongly associated with T2DM was selected. A total of 250 confirmed cases & controls samples belonging to four population groups (Hindu, Muslim, Sikh & Christians) of Jammu region were also screened for UCP2 -866G/A promoter polymorphism (rs659366). The allelic odds ratio (OR) as observed for UCP2 -866G/A polymorphism in the four population groups showed significant association with Muslim & Sikh population groups. The study undertaken supports the findings of the previous investigations and thus is an addition to the existing literatute in support of UCP2 and T2DM.
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Vaxillaire, Martine, and Philippe Froguel. "Monogenic Diabetes in the Young, Pharmacogenetics and Relevance to Multifactorial Forms of Type 2 Diabetes." Endocrine Reviews 29, no. 3 (April 24, 2008): 254–64. http://dx.doi.org/10.1210/er.2007-0024.
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Abstract Most valuable breakthroughs in the genetics of type 2 diabetes for the past two decades have arisen from candidate gene studies and familial linkage analysis of maturity-onset diabetes of the young (MODY), an autosomal dominant form of diabetes typically occurring before 25 years of age caused by primary insulin secretion defects. Despite its low prevalence, MODY is not a single entity but presents genetic, metabolic and clinical heterogeneity. MODY can result from mutations in at least six different genes encoding the glucose sensor enzyme glucokinase and transcription factors that participate in a regulatory network essential for adult β-cell function. Additional genes have been described in other discrete phenotypes or syndromic forms of diabetes. Whereas common variants in the MODY genes contribute very modestly to type 2 diabetes susceptibility in adults, major findings emerging from the advent of genome-wide association studies will deliver an increasing number of genes and new pathways for the pathological events of the disease.
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Roe, M. W., J. F. Worley, Y. Tokuyama, L. H. Philipson, J. Sturis, J. Tang, I. D. Dukes, G. I. Bell, and K. S. Polonsky. "NIDDM is associated with loss of pancreatic beta-cell L-type Ca2+ channel activity." American Journal of Physiology-Endocrinology and Metabolism 270, no. 1 (January 1, 1996): E133—E140. http://dx.doi.org/10.1152/ajpendo.1996.270.1.e133.
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Development of non-insulin-dependent diabetes mellitus (NIDDM) is associated with defects in glucose-stimulated insulin secretion. We have investigated Zucker diabetic fatty rats (ZDF), an animal model of NIDDM, and found that, compared with control islets, the expression of mRNA encoding C- and D-isoforms of alpha 1-subunits of beta-cell L-type voltage-dependent Ca2+ channels (VDCC) was significantly reduced in islets isolated from ZDF rats. This correlated with a substantial reduction of L-type Ca2+ currents (ICa) in ZDF beta-cells. Intracellular Ca2+ concentration responses in ZDF islets after glucose, KCI, or BAY K 8644 stimulation were markedly attenuated, whereas responses evoked by carbachol were unimpaired, consistent with a specific decrease in ICa in the diabetic islets. This reduction was accompanied by loss of pulsatile insulin secretion from ZDF islets treated with oscillatory increases of external glucose concentration. Our findings suggest that the attenuation of ICa in diabetic islets may contribute to the abnormal glucose-dependent insulin secretory responses associated with NIDDM and indicate that this defect is caused by decreased expression of genes encoding beta-cell VDCC alpha 1-subunits.
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Parton, Laura E., Patrick J. McMillen, Yingnian Shen, Elizabeth Docherty, Erin Sharpe, Frédérique Diraison, Celia P. Briscoe, and Guy A. Rutter. "Limited role for SREBP-1c in defective glucose-induced insulin secretion from Zucker diabetic fatty rat islets: a functional and gene profiling analysis." American Journal of Physiology-Endocrinology and Metabolism 291, no. 5 (November 2006): E982—E994. http://dx.doi.org/10.1152/ajpendo.00067.2006.
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Accumulation of intracellular lipid may contribute to defective insulin secretion in type 2 diabetes. Although Zucker diabetic fatty (ZDF; fa/fa) rat islets are fat-laden and overexpress the lipogenic master gene, sterol regulatory element binding protein 1c (SREBP-1c), the contribution of SREBP-1c to the secretory defects observed in this model remains unclear. Here we compare the gene expression profile of lean control ( fa/+) and ZDF rat islets in the absence or presence of dominant-negative SREBP-1c (SREBP-1c DN). ZDF islets displayed elevated basal insulin secretion at 3 mmol/l glucose but a severely depressed response to 17 mmol/l glucose. While SREBP-1c DN reduced basal insulin secretion from ZDF islets, glucose-stimulated insulin secretion was not improved. Of 57 genes differentially regulated in ZDF islets and implicated in glucose metabolism, vesicle trafficking, ion fluxes, and/or exocytosis, 21 were upregulated and 5 were suppressed by SREBP-1c DN. Genes underrepresented in ZDF islets were either unaffected ( Glut-2, Kir6.2, Rab3), stimulated (voltage-dependent Ca2+ channel subunit α1D, CPT2, SUR2, rab9, syt13), or inhibited ( syntaxin 7, secretogranin-2) by SREBP-1c inhibition. Correspondingly, SREBP-1c DN largely corrected decreases in the expression of the transcription factors Pdx-1 and MafA but did not affect the abnormalities in Pax6, Arx, hepatic nuclear factor-1α (HNF1α), HNF3β/Forkhead box-a2 (Foxa2), inducible cyclic AMP early repressor (ICER), or transcription factor 7-like 2 (TCF7L2) expression observed in ZDF islets. We conclude that upregulation of SREBP-1c and mild increases in triglyceride content do not explain defective glucose-stimulated insulin secretion from ZDF rats. However, overexpression of SREBP-1c may contribute to enhanced basal insulin secretion in this model.
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Kalwat, Michael A., In Hyun Hwang, Jocelyn Macho, Magdalena G. Grzemska, Jonathan Z. Yang, Kathleen McGlynn, John B. MacMillan, and Melanie H. Cobb. "Chromomycin A2 potently inhibits glucose-stimulated insulin secretion from pancreatic β cells." Journal of General Physiology 150, no. 12 (October 23, 2018): 1747–57. http://dx.doi.org/10.1085/jgp.201812177.
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Modulators of insulin secretion could be used to treat diabetes and as tools to investigate β cell regulatory pathways in order to increase our understanding of pancreatic islet function. Toward this goal, we previously used an insulin-linked luciferase that is cosecreted with insulin in MIN6 β cells to perform a high-throughput screen of natural products for chronic effects on glucose-stimulated insulin secretion. In this study, using multiple phenotypic analyses, we found that one of the top natural product hits, chromomycin A2 (CMA2), potently inhibited insulin secretion by at least three potential mechanisms: disruption of Wnt signaling, interference of β cell gene expression, and partial suppression of Ca2+ influx. Chronic treatment with CMA2 largely ablated glucose-stimulated insulin secretion even after washout, but it did not inhibit glucose-stimulated generation of ATP or Ca2+ influx. However, by using the KATP channel opener diazoxide, we uncovered defects in depolarization-induced Ca2+ influx that may contribute to the suppressed secretory response. Glucose-responsive ERK1/2 and S6 phosphorylation were also disrupted by chronic CMA2 treatment. By querying the FUSION bioinformatic database, we revealed that the phenotypic effects of CMA2 cluster with a number of Wnt–GSK3 pathway-related genes. Furthermore, CMA2 consistently decreased GSK3β phosphorylation and suppressed activation of a β-catenin activity reporter. CMA2 and a related compound, mithramycin, are known to have DNA interaction properties, possibly abrogating transcription factor binding to critical β cell gene promoters. We observed that CMA2 but not mithramycin suppressed expression of PDX1 and UCN3. However, neither expression of INSI/II nor insulin content was affected by chronic CMA2. The mechanisms of CMA2-induced insulin secretion defects may involve components both proximal and distal to Ca2+ influx. Therefore, CMA2 is an example of a chemical that can simultaneously disrupt β cell function through both noncytotoxic and cytotoxic mechanisms. Future therapeutic applications of CMA2 and similar aureolic acid analogues should consider their potential effects on pancreatic islet function.
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Delghingaro-Augusto, Viviane, Simon Décary, Marie-Line Peyot, Martin G. Latour, Julien Lamontagne, Nicolas Paradis-Isler, Marianne Lacharité-Lemieux, et al. "Voluntary running exercise prevents β-cell failure in susceptible islets of the Zucker diabetic fatty rat." American Journal of Physiology-Endocrinology and Metabolism 302, no. 2 (January 15, 2012): E254—E264. http://dx.doi.org/10.1152/ajpendo.00360.2011.
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Physical activity improves glycemic control in type 2 diabetes (T2D), but its contribution to preserving β-cell function is uncertain. We evaluated the role of physical activity on β-cell secretory function and glycerolipid/fatty acid (GL/FA) cycling in male Zucker diabetic fatty (ZDF) rats. Six-week-old ZDF rats engaged in voluntary running for 6 wk (ZDF-A). Inactive Zucker lean and ZDF (ZDF-I) rats served as controls. ZDF-I rats displayed progressive hyperglycemia with β-cell failure evidenced by falling insulinemia and reduced insulin secretion to oral glucose. Isolated ZDF-I rat islets showed reduced glucose-stimulated insulin secretion expressed per islet and per islet protein. They were also characterized by loss of the glucose regulation of fatty acid oxidation and GL/FA cycling, reduced mRNA expression of key β-cell genes, and severe reduction of insulin stores. Physical activity prevented diabetes in ZDF rats through sustaining β-cell compensation to insulin resistance shown in vivo and in vitro. Surprisingly, ZDF-A islets had persistent defects in fatty acid oxidation, GL/FA cycling, and β-cell gene expression. ZDF-A islets, however, had preserved islet insulin mRNA and insulin stores compared with ZDF-I rats. Physical activity did not prevent hyperphagia, dyslipidemia, or obesity in ZDF rats. In conclusion, islets of ZDF rats have a susceptibility to failure that is possibly due to altered β-cell fatty acid metabolism. Depletion of pancreatic islet insulin stores is a major contributor to islet failure in this T2D model, preventable by physical activity.
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Lee, Unghwi, Chunghon Choi, Seung Hyun Ryu, Daehun Park, Sang-Eun Lee, Kitae Kim, Yujin Kim, and Sunghoe Chang. "SCAMP5 plays a critical role in axonal trafficking and synaptic localization of NHE6 to adjust quantal size at glutamatergic synapses." Proceedings of the National Academy of Sciences 118, no. 2 (December 28, 2020): e2011371118. http://dx.doi.org/10.1073/pnas.2011371118.
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Glutamate uptake into synaptic vesicles (SVs) depends on cation/H+ exchange activity, which converts the chemical gradient (ΔpH) into membrane potential (Δψ) across the SV membrane at the presynaptic terminals. Thus, the proper recruitment of cation/H+ exchanger to SVs is important in determining glutamate quantal size, yet little is known about its localization mechanism. Here, we found that secretory carrier membrane protein 5 (SCAMP5) interacted with the cation/H+ exchanger NHE6, and this interaction regulated NHE6 recruitment to glutamatergic presynaptic terminals. Protein–protein interaction analysis with truncated constructs revealed that the 2/3 loop domain of SCAMP5 is directly associated with the C-terminal region of NHE6. The use of optical imaging and electrophysiological recording showed that small hairpin RNA–mediated knockdown (KD) of SCAMP5 or perturbation of SCAMP5/NHE6 interaction markedly inhibited axonal trafficking and the presynaptic localization of NHE6, leading to hyperacidification of SVs and a reduction in the quantal size of glutamate release. Knockout of NHE6 occluded the effect of SCAMP5 KD without causing additional defects. Together, our results reveal that as a key regulator of axonal trafficking and synaptic localization of NHE6, SCAMP5 could adjust presynaptic strength by regulating quantal size at glutamatergic synapses. Since both proteins are autism candidate genes, the reduced quantal size by interrupting their interaction may underscore synaptic dysfunction observed in autism.
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Purohit, Purvi, Dipayan Roy, and Anupama Modi. "In-Silico Analysis of Key Regulatory Pathways and Hub Genes From Peripheral Blood in Type 2 Diabetes Mellitus." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A505—A506. http://dx.doi.org/10.1210/jendso/bvab048.1033.
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Abstract AbstractBackground: Type II diabetes mellitus (T2DM), characterized by fasting hyperglycemia and impaired insulin secretion and action, is a global health burden. Despite the advances in this field, the mechanism underlying T2DM is far from clear. Objective: The present study sheds light upon a systematic evaluation of the genes, pathways, and interaction networks underlying T2DM with the aid of bioinformatics. Methods: Two Gene Expression Omnibus microarray datasets: GSE148961 and GSE26168 were selected for this study. The common differentially expressed genes (DEG) were sorted by the cutoff |logFC|≥1.0 for the first dataset and |logFC|≥0.263 for the second. Gene Ontology (GO), functional enrichment, and protein-protein interaction (PPI) network were analyzed in Search Tool for the Retrieval of Interacting Genes (STRING). The MCODE and CytoHubba plugins in Cytoscape (v3.7.2) were used to identify gene clusters and top hub genes, respectively. Top 10 nodes were ranked in CytoHubba according to MCC, DMNC, MNC, Degree, and EPC methods, and genes common in at least 3 methods were selected as top nodes. Results: 88 common DEGs were identified by Venn diagram (http://bioinformatics.psb.ugent.be/cgi-bin/liste/Venn/calculate_venn.htpl). GO analysis had 91 significantly enriched biological processes, including regulated exocytosis, secretion, vesicle mediated transport, antibacterial humoral response, and neutrophil degranulation. 4 molecular functions- fibrinogen binding, fibronectin binding, lipopolysaccharide binding, and Extracellular matrix binding; and 38 cellular components, including secretory vesicle, endomembrane system, and adherens junction were significant. The PPI network was highly significant (p-value < 0.001) at medium confidence (0.400) with 88 nodes, 140 edges, and an average node degree of 3.18. The MCODE plugin revealed two clusters, the former with 14 nodes, 73 edges, and a score of 9.733, and the latter with 6 nodes, 14 edges, and a score of 4.000. 9 candidate genes: ELANE, DEFA4, BPI, MPO, LTF, CAMP, OLFM4, LCN2, and VCL were identified, amongst which ELANE, LCN2, and MPO are associated with T2DM pathogenesis, while BPI and LTF have protective effects. OLFM4 deletion has been observed to improve glucose tolerance in mice models. Conclusion: This study provides a comprehensive analysis of genes, pathways, and functions which may be pivotal in T2DM pathogenesis and may represent potential therapeutic targets.
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Gioeva, Olesya A., Anna A. Kolodkina, Evgeny V. Vasilyev, Vasiliy M. Petrov, and Anatoly N. Tiulpakov. "Hereditary variant of diabetes mellitus caused by a defect of the NEUROD1 gene (MODY6): the first description in Russia." Problems of Endocrinology 62, no. 3 (May 4, 2016): 16–20. http://dx.doi.org/10.14341/probl201662316-20.
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MODY (Maturity-Onset diabetes of the young) is a heterogeneous group of disorders characterized by autosomal dominant type of inheritance and caused by genetic defects leading to dysfunction of pancreatic b-cells. Currently 13 candidate genes of MODY, and, respectively, 13 MODY subtypes are known. The final diagnosis can be established only on the basis of molecular genetic studies, which is the «gold standard» in the diagnosis of this disease. MODY2 and MODY3 are the most prevalent subtypes and were previously described in our country. Rare MODY subtypes have not been described in Russian literature. In this article we describe the first diagnosed case of MODY6 in Russia (a defect of the NEUROD1 gene, encoding neurogenic differentiation factor 1, which plays an important role in normal differentiation of β-cells of the pancreas and the regulation of transcription of the insulin gene). Molecular genetic study was conducted using the method of next-generation sequencing, has recently been widely used for genetic verification of monogenic diseases and, in particular, MODY. Technology of next-generation sequencing for diagnosing inherited disorders of carbohydrate metabolism in domestic practice used for the first time.
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Taron, Christopher H., Jill M. Wiedman, Stephen J. Grimme, and Peter Orlean. "Glycosylphosphatidylinositol Biosynthesis Defects in Gpi11p- and Gpi13p-deficient Yeast Suggest a Branched Pathway and Implicate Gpi13p in Phosphoethanolamine Transfer to the Third Mannose." Molecular Biology of the Cell 11, no. 5 (May 2000): 1611–30. http://dx.doi.org/10.1091/mbc.11.5.1611.
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Glycosylphosphatidylinositols (GPIs) are critical for membrane anchoring and intracellular transport of certain secretory proteins. GPIs have a conserved trimannosyl core bearing a phosphoethanolamine (EthN-P) moiety on the third mannose (Man-3) through which the glycolipid is linked to protein, but diverse GPI precursors with EthN-Ps on Man-1 and Man-2 have also been described. We report on two essential yeast genes whose products are required late in GPI assembly. GPI11 (YDR302w) encodes a homologue of human Pig-Fp, a protein implicated in the addition of EthN-P to Man-3. PIG-F complements thegpi11 deletion, but the rescued haploids are temperature sensitive. Abolition of Gpi11p or Pig-Fp function inGPI11 disruptants blocks GPI anchoring and formation of complete GPI precursors and leads to accumulation of two GPIs whose glycan head groups contain four mannoses but differ in the positioning and number of side chains, probably EthN-Ps. The less polar GPI bears EthN-P on Man-2, whereas the more polar lipid has EthN-P on Man-3. The latter finding indicates that Gpi11p is not required for adding EthN-P to Man-3. Gpi13p (YLL031cp), a member of a family of phosphoryltransferases, is a candidate for the enzyme responsible for adding EthN-P to Man-3. Depletion of Gpi13p in a Gpi11p-defective strain prevents formation of the GPI bearing EthN-P on Man-3, and Gpi13p-deficient strains accumulate a Man4-GPI isoform that bears EthN-P on Man-1. We further show that the lipid accumulation phenotype of Gpi11p-deficient cells resembles that of cells lacking Gpi7p, a sequence homologue of Gpi13p known to add EthN-P to Man-2 of a late-stage GPI precursor. This result suggests that in yeast a Gpi11p-deficiency can affect EthN-P addition to Man-2 by Gpi7p, in contrast to the Pig-Fp defect in mammalian cells, which prevents EthN-P addition to Man-3. Because Gpi11p and Pig-Fp affect EthN-P transfer to Man-2 and Man-3, respectively, these proteins may act in partnership with the GPI-EthN-P transferases, although their involvement in a given EthN-P transfer reaction varies between species. Possible roles for Gpi11p in the supply of the EthN-P donor are discussed. Because Gpi11p- and Gpi13p-deficient cells accumulate isoforms of Man4-GPIs with EthN-P on Man-2 and on Man-1, respectively, and because the GPIs that accumulate in Gpi11p-defective strains are likely to have been generated independently of one another, we propose that the yeast GPI assembly pathway is branched.
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Skokowa, Julia. "Aberrant G-CSFR Signaling in Congenital Neutropenia." Blood 122, no. 21 (November 15, 2013): SCI—45—SCI—45. http://dx.doi.org/10.1182/blood.v122.21.sci-45.sci-45.
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Abstract Clinical observations revealed that congenital neutropenia (CN) patients harboring either ELANE or HAX mutations have similar bone marrow morphology, responses to G-CSF therapy, requirements of G-CSF dosages, and the risk of developing leukemia. Therefore, we suggested a common pathomechanism of defective G-CSFR-triggered granulopoiesis downstream of both mutated genes in these patients. We identified severely diminished expression and functions of the transcription factors lymphoid enhancer binding factor-1 (LEF-1) and C/EBPa in myeloid cells of CN patients, in comparison to healthy individuals and patients with cyclic neutropenia (CyN). LEF-1 expression was abrogated in patients harboring either ELANE or HAX1 mutations, which suggested LEF-1 as a possible common candidate factor for defective G-CSFR signaling. We further identified a mechanism of the diminished LEF-1 expression downstream of HAX1 or ELANE mutations. HAX1 is HCLS1-Associated protein X1. HCLS1 is Hematopoietic Cell-Specific Lyn Substrate 1. We found that HCLS1 protein is expressed at high levels in human myeloid cells and is phosphorylated upon stimulation with G-CSF. HCLS1 interacted with LEF-1 protein, inducing nuclear translocation of LEF-1, LEF-1 autoregulation, C/EBPa activation, and granulocytic differentiation. In CN patients with HAX1 mutations, we found profound defects in the G-CSF-triggered phosphorylation of HCLS1, subsequently leading to abrogated nuclear transport and autoregulation of LEF-1. In CN patients with ELANE mutations we detected severely reduced levels of the natural inhibitor of neutrophil elastase (NE), and secretory leukocyte protease inhibitor (SLPI). We demonstrated the important role of SLPI in myeloid differentiation by activation of Erk1/2 phosphorylation and subsequent phErk1/2-triggered tyrosine phosphorylation and activation of the LEF-1 protein. Therefore, the direct link between ELANE mutations and diminished LEF-1 expression was established: in these patients LEF-1 protein expression is diminished due to the reduced levels of SLPI. We further evaluated how G-CSF treatment overcomes maturation arrest of granulopoiesis in CN patients despite the absence of LEF-1 and C/EBPa in myeloid cells. We identified nicotinamide phosphoribosyltransferase (NAMPT) as an essential enzyme mediating G-CSF-triggered granulopoiesis in healthy individuals and in CN patients. Treatment of healthy individuals with G-CSF resulted in upregulation of NAMPT levels in myeloid cells and in plasma. NAMPT and NAD+ amounts were even more dramatically elevated by G-CSF treatment of CN individuals. The molecular events triggered by NAMPT included elevation of NAD+, NAD+-dependent activation of protein deacetylase sirtuin-1 (SIRT1), binding of SIRT1 to the myeloid specific transcription factors C/EBPα and C/EBPβ, and activation of these transcription factors. In CN patients, C/EBPα expression is severely diminished; therefore “steady-state” granulopoiesis could not be activated. G-CSF treatment induces expression of C/EBPβ in these patients via NAMPT and SIRT1 and operated via the “emergency” pathway. We also investigated the patterns of acquisition of leukemia-associated-mutations in 31 CN patients developing leukemia using next-generation DNA deep sequencing. Intriguingly, 20 of the 31 patients (64.5%) demonstrated mutations within RUNX1. The majority of patients with RUNX1 mutations (85%) had acquired CSF3R mutations. Other leukemia-associated mutations in the patients with RUNX1 mutations were found infrequently. Cytogenetics of the leukemic cells revealed that 10 patients with RUNX1 mutations developed monosomy 7, and six patients had trisomy 21. Single cell analysis in two patients revealed that RUNX1 and CSF3R mutations were segregated in the same malignant clone. Functional studies demonstrated proliferative advantage of CD34+ cells transduced with mutated RUNX1 and CSF3R. By analysis of the leukemogenic role of the defective G-CSFR signaling in CN patients we identified a significant and sustained elevation in the levels of phospho-STAT5 in hematopoietic CD34+ cells of CN patients which were even higher in CN/ acute myeloid leukemia patients. The other possible reason for the leukemogenic transformation could be elevated NAMPT/SIRT-triggered deacetylation of tumor supressor protein p53, proto-oncogene FOXO3a and Akt proteins. Disclosures: No relevant conflicts of interest to declare.
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Malczewska-Malec, Malgorzata, Iwona Wybranska, Iwona Leszczynska-Golabek, Lukasz Partyka, Jadwiga Hartwich, Agata Jabrocka, Beata Kiec-Wilk, Malgorzata Kwasniak, Marcin Motyka, and Aldona Dembinska-Kiec. "Analysis of candidate genes in Polish families with obesity." Clinical Chemistry and Laboratory Medicine (CCLM) 42, no. 5 (January 10, 2004). http://dx.doi.org/10.1515/cclm.2004.083.
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AbstractThis study analyzes the relationship between risk factors related to overweight/obesity, insulin resistance, lipid tolerance, hypertension, endothelial function and genetic polymorphisms associated with: i) appetite regulation (leptin, melanocortin-3-receptor (MCR-3), dopamine receptor 2 (D2R)); ii) adipocyte differentiation and insulin sensitivity (peroxisome proliferator-activated receptor-γThe 122 members of 40 obese Caucasian families from southern Poland participated in the study. The genotypes were analyzed by restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) or by direct sequencing. Phenotypes related to obesity (body mass index (BMI), fat/lean body mass composition, waist-to-hip ratio (WHR)), fasting lipids, glucose, leptin and insulin, as well as insulin during oral glucose tolerance test (OGTT) (4 points within 2 hours) and during oral lipid tolerance test (OLTT) (5 points within 8 hours) were assessed. The insulin sensitivity indexes: homeostasis model assessment of insulin resistance, whole body insulin sensitivity index, hepatic insulin sensitivity and early secretory response to an oral glucose load (HOMA-IR, ISI-COMP, ISI-HOMA and DELTA) were calculated.The single gene mutations such as CWe conclude that the polymorphisms we investigated were weakly correlated with obesity but significantly modified the risk factors of the metabolic syndrome.
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Velho, G., and P. Froguel. "Genetic, metabolic and clinical characteristics of maturity onset diabetes of the young." European Journal of Endocrinology, March 1, 1998, 233–39. http://dx.doi.org/10.1530/eje.0.1380233.
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Maturity onset diabetes of the young (MODY) is a genetically and clinically heterogeneous subtype of non-insulin-dependent diabetes mellitus (NIDDM) characterised by early onset, autosomal dominant inheritance and a primary defect in insulin secretion. To date, three MODY genes have been identified on chromosomes 20q (MODY1/hepatic nuclear factor (HNF)-4alpha), 7p (MODY2/glucokinase) and 12q (MODY3/HNF-1alpha). Mutations in MODY2/glucokinase result in mild chronic hyperglycaemia as a result of reduced pancreatic beta-cell responsiveness to glucose, and decreased net accumulation of hepatic glycogen and increased hepatic gluconeogenesis after meals. In contrast, MODY1 and MODY3 are characterised by severe insulin secretory defects, and by major hyperglycaemia associated with microvascular complications. The role of the three known MODY genes in susceptibility to the more common late-onset NIDDM remain uncertain. Genetic studies seem to exclude a role as major susceptibility genes, but leave unresolved whether they may have a minor role in a polygenic context or an important role in particular populations.
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Low, Blaise Su Jun, Chang Siang Lim, Shirley Suet Lee Ding, Yaw Sing Tan, Natasha Hui Jin Ng, Vidhya Gomathi Krishnan, Su Fen Ang, et al. "Decreased GLUT2 and glucose uptake contribute to insulin secretion defects in MODY3/HNF1A hiPSC-derived mutant β cells." Nature Communications 12, no. 1 (May 25, 2021). http://dx.doi.org/10.1038/s41467-021-22843-4.
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AbstractHeterozygous HNF1A gene mutations can cause maturity onset diabetes of the young 3 (MODY3), characterized by insulin secretion defects. However, specific mechanisms of MODY3 in humans remain unclear due to lack of access to diseased human pancreatic cells. Here, we utilize MODY3 patient-derived human induced pluripotent stem cells (hiPSCs) to study the effect(s) of a causal HNF1A+/H126D mutation on pancreatic function. Molecular dynamics simulations predict that the H126D mutation could compromise DNA binding and gene target transcription. Genome-wide RNA-Seq and ChIP-Seq analyses on MODY3 hiPSC-derived endocrine progenitors reveal numerous HNF1A gene targets affected by the mutation. We find decreased glucose transporter GLUT2 expression, which is associated with reduced glucose uptake and ATP production in the MODY3 hiPSC-derived β-like cells. Overall, our findings reveal the importance of HNF1A in regulating GLUT2 and several genes involved in insulin secretion that can account for the insulin secretory defect clinically observed in MODY3 patients.
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Lake, Juniper A., Jack C. M. Dekkers, and Behnam Abasht. "Genetic basis and identification of candidate genes for wooden breast and white striping in commercial broiler chickens." Scientific Reports 11, no. 1 (March 24, 2021). http://dx.doi.org/10.1038/s41598-021-86176-4.
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AbstractWooden breast (WB) and white striping (WS) are highly prevalent and economically damaging muscle disorders of modern commercial broiler chickens characterized respectively by palpable firmness and fatty white striations running parallel to the muscle fiber. High feed efficiency and rapid growth, especially of the breast muscle, are believed to contribute to development of such muscle defects; however, their etiology remains poorly understood. To gain insight into the genetic basis of these myopathies, a genome-wide association study was conducted using a commercial crossbred broiler population (n = 1193). Heritability was estimated at 0.5 for WB and WS with high genetic correlation between them (0.88). GWAS revealed 28 quantitative trait loci (QTL) on five chromosomes for WB and 6 QTL on one chromosome for WS, with the majority of QTL for both myopathies located in a ~ 8 Mb region of chromosome 5. This region has highly conserved synteny with a portion of human chromosome 11 containing a cluster of imprinted genes associated with growth and metabolic disorders such as type 2 diabetes and Beckwith-Wiedemann syndrome. Candidate genes include potassium voltage-gated channel subfamily Q member 1 (KCNQ1), involved in insulin secretion and cardiac electrical activity, lymphocyte-specific protein 1 (LSP1), involved in inflammation and immune response.
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Khambata, Kushaan, Sanketa Raut, Sharvari Deshpande, Sweta Mohan, Shobha Sonawane, Reshma Gaonkar, Zakiya Ansari, et al. "DNA methylation defects in spermatozoa of male partners from couples experiencing recurrent pregnancy loss." Human Reproduction, December 15, 2020. http://dx.doi.org/10.1093/humrep/deaa278.
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Abstract STUDY QUESTION What is the sperm DNA methylation status of imprinted genes in male partners from couples experiencing recurrent pregnancy loss (RPL)? SUMMARY ANSWER Aberrations in sperm DNA methylation status of several imprinted genes, such as insulin like growth factor-2-H19 differentially methylated region (IGF2-H19 DMR), intergenic differentially methylated region (IG-DMR), mesoderm specific transcript (MEST), zinc finger protein which regulates apoptosis and cell cycle arrest (ZAC), DMR in intron 10 of KCNQ1 gene (KvDMR), paternally expressed gene 3 (PEG3) and paternally expressed gene 10 (PEG10), as well as decreased sperm global 5-methylcytosine (5mC) levels, are associated with RPL. WHAT IS KNOWN ALREADY RPL is defined as loss of two or more pregnancies, affecting 1–2% of couples of reproductive age. Although there are several maternal and paternal aetiological factors contributing to RPL, nearly 50% of the cases remain idiopathic. Thus, there is a need to identify putative paternal factors that could be contributing towards pregnancy loss in cases of idiopathic RPL. STUDY DESIGN, SIZE, DURATION In this case–control study, 112 couples undergoing RPL with no identifiable cause were recruited from September 2015 to May 2018. The control group comprised of 106 healthy proven fertile couples with no history of infertility or miscarriage. PARTICIPANTS/MATERIALS, SETTING, METHODS In this study, we investigated the paternal genetic and epigenetic factors that could be associated with RPL. We studied DNA methylation, by pyrosequencing, of selected imprinted genes implicated in embryo development, such as IGF2-H19 DMR, IG-DMR, MEST, ZAC, KvDMR, PEG3, PEG10 and small nuclear ribonucleoprotein polypeptide N (SNRPN) in sperm of men whose partners present RPL. Global DNA methylation in sperm was evaluated by studying 5mC content and long interspersed nuclear element 1 (LINE1) promoter methylation. We also studied polymorphisms by pyrosequencing in the IGF2-H19 DMR as well in the IGF2 promoter in both groups. MAIN RESULTS AND THE ROLE OF CHANCE In the RPL group, we found a significant decrease in the global sperm 5mC levels and significant decrease in DNA methylation at three CpG sites in LINE1 promoter. For IGF2-H19 DMR and IG-DMR, a significant decrease in sperm DNA methylation at specific CpG sites was observed in RPL group. For maternally imprinted genes like MEST, ZAC, KvDMR, PEG3 and PEG10 hypermethylation was noted. Polymorphism studies for IGF2-H19 DMR and IGF2 revealed significant differences in the genotypic frequencies in males. LIMITATIONS, REASONS FOR CAUTION In this study, we analysed the methylation levels of selected candidate imprinted genes implicated in embryo development. Detection of methylation changes occurring at the genome-wide level may reveal further candidate genes having a better distinction between the control and study groups. WIDER IMPLICATIONS OF THE FINDINGS Our study demonstrates that certain polymorphisms and aberrant sperm methylation status in imprinted genes are associated with RPL and could contribute to the aetiology of RPL. This study suggests that investigation of paternal genetic and epigenetic factors could be useful in identification of possible causes of idiopathic RPL. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by Department of Science and Technology-Science and Engineering Research Board (EMR/2014/000145) and National Institute for Research in Reproductive Health intramural funds (RA/872/01-2020). All authors declare no conflict of interest. TRIAL REGISTRATION NUMBER N/A.
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Kolic, Jelena, Leanne Beet, Peter Overby, Haoning Howard Cen, Evgeniy Panzhinskiy, Daren R. Ure, Jennifer L. Cross, Robert B. Huizinga, and James D. Johnson. "Differential Effects of Voclosporin and Tacrolimus on Insulin Secretion From Human Islets." Endocrinology 161, no. 11 (September 7, 2020). http://dx.doi.org/10.1210/endocr/bqaa162.
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Abstract The incidence of new onset diabetes after transplant (NODAT) has increased over the past decade, likely due to calcineurin inhibitor–based immunosuppressants, including tacrolimus (TAC) and cyclosporin. Voclosporin (VCS), a next-generation calcineurin inhibitor, is reported to cause fewer incidences of NODAT but the reason is unclear. While calcineurin signaling plays important roles in pancreatic β-cell survival, proliferation, and function, its effects on human β-cells remain understudied. In particular, we do not understand why some calcineurin inhibitors have more profound effects on the incidence of NODAT. We compared the effects of TAC and VCS on the dynamics of insulin secretory function, programmed cell death rate, and the transcriptomic profile of human islets. We studied 2 clinically relevant doses of TAC (10 ng/mL, 30 ng/mL) and VCS (20 ng/mL, 60 ng/mL), meant to approximate the clinical trough and peak concentrations. TAC, but not VCS, caused a significant impairment of 15 mM glucose-stimulated and 30 mM KCl-stimulated insulin secretion. This points to molecular defects in the distal stages of exocytosis after voltage-gated Ca2+ entry. No significant effects on islet cell survival or total insulin content were identified. RNA sequencing showed that TAC significantly decreased the expression of 17 genes, including direct and indirect regulators of exocytosis (SYT16, TBC1D30, PCK1, SMOC1, SYT5, PDK4, and CREM), whereas VCS has less broad, and milder, effects on gene expression. Clinically relevant doses of TAC, but not VCS, directly inhibit insulin secretion from human islets, likely via transcriptional control of exocytosis machinery.
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Deng, Shuzhen, Wenda Sun, Lihong Dong, Guobing Cui, and Yi Zhen Deng. "MoGT2 Is Essential for Morphogenesis and Pathogenicity of Magnaporthe oryzae." mSphere 4, no. 5 (September 4, 2019). http://dx.doi.org/10.1128/msphere.00309-19.
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ABSTRACT Magnaporthe oryzae causes the rice blast disease, which is one of the most serious diseases of cultivated rice worldwide. Glycosylation is an important posttranslational modification of secretory and membrane proteins in all eukaryotes, catalyzed by glycosyltransferases (GTs). In this study, we identified and characterized a type 2 glycosyltransferase, MoGt2, in M. oryzae. Targeted gene deletion mutants of MoGT2 (mogt2Δ strains) were nonpathogenic and were impaired in vegetative growth, conidiation, and appressorium formation at hyphal tips. Moreover, MoGT2 plays an important role in stress tolerance and hydrophobin function of M. oryzae. Site-directed mutagenesis analysis showed that conserved glycosyltransferase domains (DxD and QxxRW) are critical for biological functions of MoGt2. MoGT2 deletion led to altered glycoproteins during M. oryzae conidiation. By liquid chromatography-tandem mass spectrometry (LC-MS/MS), we identified several candidate proteins as potential substrates of MoGt2, including several heat shock proteins, two coiled-coil domain-containing proteins, aminopeptidase 2, and nuclease domain-containing protein 1. On the other hand, we found that a conidiation-related gene, genes involved in various metabolism pathways, and genes involved in cell wall integrity and/or osmotic response were differentially regulated in the mogt2Δ mutant, which may potentially contribute to its condiation defects. Taken together, our results show that MoGt2 is important for infection-related morphogenesis and pathogenesis in M. oryzae. IMPORTANCE The ascomycete fungus Magnapothe oryzae is the causal agent of rice blast disease, leading to severe loss in cultivated rice production worldwide. In this study, we identified a conserved type 2 glycosyltransferase named MoGt2 in M. oryzae. The mogt2Δ targeted gene deletion mutants exhibited pleiotropic defects in vegetative growth, conidiation, stress response, hyphal appressorium-mediated penetration, and pathogenicity. Furthermore, conserved glycosyltransferase domains are critical for MoGt2 function. The comparative transcriptome analysis revealed potential target genes under MoGt2 regulation in M. oryzae conidiation. Identification of potential glycoproteins modified by MoGt2 provided information on its regulatory mechanism of gene expression and biological functions. Overall, our study represents the first report of type 2 glycosyltransferase function in M. oryzae infection-related morphogenesis and pathogenesis.
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Mae, Junnosuke, Kazuki Nagaya, Yuko Okamatsu-Ogura, Ayumi Tsubota, Shinya Matsuoka, Junko Nio-Kobayashi, and Kazuhiro Kimura. "Adipocytes and Stromal Cells Regulate Brown Adipogenesis Through Secretory Factors During the Postnatal White-to-Brown Conversion of Adipose Tissue in Syrian Hamsters." Frontiers in Cell and Developmental Biology 9 (July 5, 2021). http://dx.doi.org/10.3389/fcell.2021.698692.
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Brown adipose tissue (BAT) is a specialized tissue that regulates non-shivering thermogenesis. In Syrian hamsters, interscapular adipose tissue is composed primarily of white adipocytes at birth, which is converted to BAT through the proliferation and differentiation of brown adipocyte progenitors and the simultaneous disappearance of white adipocytes. In this study, we investigated the regulatory mechanism of brown adipogenesis during postnatal BAT formation in hamsters. Interscapular adipose tissue of a 10-day-old hamster, which primarily consists of brown adipocyte progenitors and white adipocytes, was digested with collagenase and fractioned into stromal–vascular (SV) cells and white adipocytes. SV cells spontaneously differentiated into brown adipocytes that contained multilocular lipid droplets and expressed uncoupling protein 1 (Ucp1), a marker of brown adipocytes, without treatment of adipogenic cocktail such as dexamethasone and insulin. The spontaneous differentiation of SV cells was suppressed by co-culture with adipocytes or by the addition of white adipocyte-conditioned medium. Conversely, the addition of SV cell-conditioned medium increased the expression of Ucp1. These results indicate that adipocytes secrete factors that suppress brown adipogenesis, whereas SV cells secrete factors that promote brown adipogenesis. Transcriptome analysis was conducted; however, no candidate suppressing factors secreted from adipocytes were identified. In contrast, 19 genes that encode secretory factors, including bone morphogenetic protein (BMP) family members, BMP3B, BMP5, and BMP7, were highly expressed in SV cells compared with adipocytes. Furthermore, the SMAD and MAPK signaling pathways, which represent the major BMP signaling pathways, were activated in SV cells, suggesting that BMPs secreted from SV cells induce brown adipogenesis in an autocrine manner through the SMAD/MAPK signaling pathways. Treatment of 5-day-old hamsters with type I BMP receptor inhibitor, LDN-193189, for 5 days reduced p38 MAPK phosphorylation and drastically suppressed BAT formation of interscapular adipose tissue. In conclusion, adipocytes and stromal cells regulate brown adipogenesis through secretory factors during the postnatal white-to-brown conversion of adipose tissue in Syrian hamsters.
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Bloyd, Michelle, Steven Coon, James Iben, Ninet Sinaii, Fabio Rueda Faucz, Nicola Santoro, Sonia Caprio, Constantine A. Stratakis, and Edra London. "OR22-07 Novel Variants in Protein Kinase a Signaling-Related Genes Identified in Obese Children with and Without NAFLD." Journal of the Endocrine Society 4, Supplement_1 (April 2020). http://dx.doi.org/10.1210/jendso/bvaa046.1880.
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Abstract Context: Nonalcoholic fatty liver disease (NAFLD) is estimated to affect nearly 10% of Americans age 2-19 and about 38% of those affected are obesei. NAFLD is characterized by triglyceride accumulation in hepatocytes and can progress to nonalcoholic steatohepatitis, end stage liver disease and hepatocellular carcinoma. The underlying causes of NAFLD in youth are unclear although obesity, insulin resistance, type 2 diabetes mellitus and metabolic syndrome are risk factors. Genome-wide association studies and candidate gene studies have found several single nucleotide polymorphisms that affect susceptibility to and progression of NAFLD, but clinical translation for some of these genetics is lackingii. Study design: Because mouse models of dysregulated PKA signaling demonstrate the centrality of this pathway in hepatic lipid metabolism and glucose homeostasis, we hypothesized that defects in hepatic PKA signaling genes could affect susceptibility to or severity of NAFLD in children. We asked whether identified variants might be associated with differences in clinical markers in a cohort of obese pediatric patients (non-NAFLD, n=295; NAFLD, n=165) followed at Yale Medical School, where clinical data and genomic DNA were collected. Exon sequencing of 54 PKA-related candidate genes included those coding for PKA subunits, PDEs and other proteins integral to the hepatic PKA system. Variants were ranked by allele frequency and potential pathogenicity. Ongoing analyses aim to identify associations between single variants and potential additive effects with clinical parameters (anthropometric, liver function, glucose metabolism, plasma lipids). Results: Gene variants were identified in ABCA1, ADCY4, ADCY5, AKAP7, CREB3L1, CREB3L4, CREM, CYP27A1, DHCR7, ERN1, GYS2, IL6, IL10RB, MC2R, PDE1B, PDE2A, PDE3B, PDE4A, PDE7B, PDE10A, PDE11A, PPARGC1B, PRKAR2A, and PRKAR1B. Reported variants met criteria of high to moderate impact based on 9 in silico scores that predict pathogenicity. Allele frequency ranged from 2.5 to over 50 times higher in our cohort than the general population. One or more variant was identified in 34.9% of non-NAFLD and 19.4% of NAFLD patients (p=.0004). Conclusion: We report PKA-related gene variants among a cohort of pediatric obese patients that might serve as useful predictors of risk of NAFLD or obesity. Further analyses will help determine whether any of these variants may play a functional role in NAFLD. Endnotes i Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C. Pediatrics. 2006;118(4):1388. ii Vespasiani-Gentilucci U, Gallo P, Dell’Unto C et al. World J Gastroenterol. 2018;24(43):4835-4845.
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Fan, Liyan, David R. Sweet, Domenick A. Prosdocimo, Komal S. Keerthy, and Mukesh K. Jain. "SUN-653 Bypassing Skeletal Muscle Lipid Handling Deficiencies as a Therapy for Metabolic Disease." Journal of the Endocrine Society 4, Supplement_1 (April 2020). http://dx.doi.org/10.1210/jendso/bvaa046.1878.
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Abstract Metabolic diseases and their serious sequelae such as non-alcoholic fatty liver disease (NAFLD) pose a substantial clinical burden. It is now well recognized that skeletal muscle is a major site for the metabolism of all major macronutrients, and derangements in these muscle processes significantly contribute to metabolic disease. Studies over the last 15 years have identified the transcription factor Krüppel-like factor 15 (KLF15) as an important regulator and effector of metabolic processes across various tissues, and furthermore, genome-wide studies have identified human KLF15 variants with increased body mass index and diabetes. Given the importance of skeletal muscle in maintaining metabolic homeostasis, we generated a skeletal muscle specific KLF15 knockout (K15-SKO) mouse to study the role of skeletal muscle KLF15 in regulating systemic metabolism. We found that this animal is prone to developing obesity and insulin resistance at baseline, a phenotype that is greatly exacerbated in response to high fat diet (HFD). Strikingly, K15-SKO mice show a propensity toward developing NAFLD, as demonstrated by increased micro- and macrovesicular steatosis, hepatocellular ballooning, increased hepatic fatty acid and triglyceride deposition, and elevated Cd36 expression. A potential cause of NAFLD is the accumulation of excess lipids and lipid intermediates due to defects in the lipid flux pathway in extrahepatic tissues. Indeed, we see defects in the expression of genes involved in the carnitine shuttle and a paucity of long-chain acylcarnitines in K15-SKO skeletal muscle. Furthermore, RNA sequencing of skeletal muscle from K15-SKO mice shows downregulation in a number of pathways involved in lipid handling. This indicates that KLF15 serves as a novel extrahepatic molecular regulator of hepatic health. It has been previously shown that a diet rich in short-chain fatty acids (SCFA) can bypass defects in lipid handling and ultimately improve metabolic health. To explore this therapeutic avenue, we gave K15-SKO mice either normal chow (NC) or a SCFA-rich diet for 7 weeks. We observed decreased weight gain and improved glucose homeostasis in SCFA-rich diet fed mice. In addition to being a preventative strategy, SCFA-rich diets may also serve as a potential therapy to rescue from metabolic disease. To this end, we gave K15-SKO mice HFD for 5 weeks followed by 7 weeks of either NC or SCFA-rich diet. We observed that providing SCFAs can improve metabolic health and ameliorate the phenotype seen due to defects in skeletal muscle lipid handling: mice given SCFA-rich diet following HFD had significantly decreased weight gain and improved insulin sensitivity. These studies demonstrate that skeletal muscle KLF15 serves as an important regulator of lipid flux and hepatic health, and that SCFA-rich diets are a promising candidate for metabolic disease resultant of impaired lipid handling.
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Najib, Ahmad. "ACORUS CALAMUS L ON TYPE 2 DIABETES MELLITUS MEDICATION." Universal Journal of Pharmaceutical Research, May 15, 2020. http://dx.doi.org/10.22270/ujpr.v5i2.391.
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Diabetes is one of the metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Type 2 diabetes, which accounts for ~90–95% of those with diabetes, the cause is a combination of resistance to insulin action and an inadequate compensatory insulin secretory response. Adequate glycemic control is thus one of the key factors to treat and/or reduce the diabetes and many plants have been used to reduce the glucose level by inhibiting the α-glucosidase that breaks down starch and disaccharides to glucose. Acorus calamus L (AC), a folk medicine to treat type 2 diabetes. In vitro α-glucosidase assay were carried out by measuring the release of p-nitrophenol, the insulin sensitizing activity, AC significantly decreased fasting serum glucose, and suppressed the increase of blood glucose levels after 2g/kg glucose loading in normal mice, in silico study showed that chemical compound on AC can inhibit α-glucosidase and the present study is designed to investigate the effects and molecular mechanisms of AC on glucagon-like peptide-1 (GLP-1) expression and secretion related to its hypoglycemic effects.
Peer Review History:
Received 8 January 2020; Revised 9 February; Accepted 1 March, Available online 15 March 2020
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Received file
Average Peer review marks at initial stage: 5.5/10
Average Peer review marks at publication stage: 7.5/10
Reviewer(s) detail:
Name: Dr. Mohamed Said Fathy Al-Refaey
Affiliation: University of Sadat City, Menofia, Egypt
E-mail: mido_ph212@yahoo.com
Name: Dr. Gehan Fawzy Abdel Raoof Kandeel
Affiliation: Pharmacognosy Department, National Research Centre, Dokki, 12622, Giza, Egypt
E-mail: gehankandeel9@yahoo.com
Comments of reviewer(s):
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