Academic literature on the topic 'Candidate genes; Insulin secretory defects'

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

The distinctions between what has previously been termed cell therapy and gene therapy have become blurred. Cell therapy traditionally implied the in vitro expansion of cells that could subsequently be engrafted into patients to elicit a therapeutic effect, while gene therapy was a term applied to the genetic manipulation of tissues or cells in vivo or ex vivo. With the amazing advances that have been achieved using transcription factors to reprogramme cells, this distinction, at least for regenerative medicine applications, no longer exists. In this chapter, following the statement of the unmet clinical need, we review potential sources of new β‎ cells and approaches to β‎ cell replacement therapy; discuss how recent advances in safety and efficacy of gene transfer technology can augment cellular therapeutic approaches, and summarize pure gene therapy approaches dependent on expression of genes encoding insulin and other glucose-lowering hormones in the recipient’s own cells. Since both type 1 and type 2 diabetes are associated with a decline in β‎ cell mass, cell and gene therapy targeted at the β‎ cell and insulin replacement have potential applications for both forms of the disease. In type 1 diabetes, uninterrupted compliance with insulin injection therapy is necessary to prevent potentially fatal ketoacidosis. The landmark Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications follow-up study have confirmed that chronic hyperglycaemic microvascular and macrovascular complications can be prevented by tight glycaemic control, but this was at the expense of a threefold increase in severe hypoglycaemia—one of the greatest fears of those living with daily insulin injections. Overall, the health implications and economic costs of type 1 diabetes are massive, and increasing annually. There is, therefore, an unquestionable clinical need for new therapeutic options. While transplantation of whole pancreas together with its blood supply can entirely normalize blood glucose levels, the major surgery required is associated with 5% mortality in the first year, even in the most experienced centres. Isolation and transplantation of purified insulin-secreting islets of Langerhans from a donor pancreas requires only minimally invasive cannulation of the portal vein transhepatically under X-ray guidance. This offers the promise of more widespread implementation restoring excellent control, preventing both long-term complications and severe hypoglycaemia. Capacity will, however, be severely limited by the scarcity of deceased donor organs: currently sufficient for fewer than 1% of those who might benefit from this form of treatment. This has provided impetus to efforts to produce a replenishable supply of glucose-responsive insulin-secreting cells that could be used in transplantation. One potential source might involve the in vitro differentiation of stem cells derived from embryonic and adult tissue. Type 2 diabetes is marked by both a resistance of target tissue to the effects of insulin and impaired function of the β‎ cell. The major β‎-cell defects relate to an impaired secretory response to glucose, altered kinetics of secretion including pulsatility, accumulation of islet amyloid polypeptide, an increase in glucagon-secreting α‎ cells, and a decline in β‎-cell mass. Current therapy for type 2 diabetes involves a combination of drugs directed at improvements in both insulin sensitivity and β‎-cell function, together with management of associated cardiovascular risk factors. Conventional treatment modalities have not been able to prevent the inexorable progressive loss of β‎-cell function necessitating insulin replacement in the majority over time, but this is often insufficient to sustainably achieve target glucose levels outwith intensive clinical trials. It is envisaged that novel cell therapy approaches will enable restoration of β‎-cell mass.