Displaying all 9 publications

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  1. Tan SY, Mei Wong JL, Sim YJ, Wong SS, Mohamed Elhassan SA, Tan SH, et al.
    Diabetes Metab Syndr, 2018 10 10;13(1):364-372.
    PMID: 30641727 DOI: 10.1016/j.dsx.2018.10.008
    Type 1 and type 2 diabetes mellitus is a serious and lifelong condition commonly characterised by abnormally elevated blood glucose levels due to a failure in insulin production or a decrease in insulin sensitivity and function. Over the years, prevalence of diabetes has increased globally and it is classified as one of the leading cause of high mortality and morbidity rate. Furthermore, diabetes confers a huge economic burden due to its management costs as well as its complications are skyrocketing. The conventional medications in diabetes treatment focusing on insulin secretion and insulin sensitisation cause unwanted side effects to patients and lead to incompliance as well as treatment failure. Besides insulin and oral hypoglycaemic agents, other treatments such as gene therapy and induced β-cells regeneration have not been widely introduced to manage diabetes. Therefore, this review aims to deliver an overview of the current conventional medications in diabetes, discovery of newer pharmacological drugs and gene therapy as a potential intervention of diabetes in the future.
    Matched MeSH terms: Diabetes Mellitus, Type 1/genetics
  2. Chellappan DK, Sivam NS, Teoh KX, Leong WP, Fui TZ, Chooi K, et al.
    Biomed Pharmacother, 2018 Dec;108:1188-1200.
    PMID: 30372820 DOI: 10.1016/j.biopha.2018.09.138
    BACKGROUND: Type 1 diabetes mellitus (T1DM) is an autoimmune disorder characterized by T cell-mediated self-destruction of insulin-secreting islet β cells. Management of T1DM is challenging and complicated especially with conventional medications. Gene therapy has emerged as one of the potential therapeutic alternatives to treat T1DM. This review primarily focuses on the current status and the future perspectives of gene therapy in the management of T1DM. A vast number of the studies which are reported on gene therapy for the management of T1DM are done in animal models and in preclinical studies. In addition, the safety of such therapies is yet to be established in humans. Currently, there are several gene level interventions that are being investigated, notably, overexpression of genes and proteins needed against T1DM, transplantation of cells that express the genes against T1DM, stem-cells mediated gene therapy, genetic vaccination, immunological precursor cell-mediated gene therapy and vectors.

    METHODS: We searched the current literature through searchable online databases, journals and other library sources using relevant keywords and search parameters. Only relevant publications in English, between the years 2000 and 2018, with evidences and proper citations, were considered. The publications were then analyzed and segregated into several subtopics based on common words and content. A total of 126 studies were found suitable for this review.

    FINDINGS: Generally, the pros and cons of each of the gene-based therapies have been discussed based on the results collected from the literature. However, there are certain interventions that require further detailed studies to ensure their effectiveness. We have also highlighted the future direction and perspectives in gene therapy, which, researchers could benefit from.

    Matched MeSH terms: Diabetes Mellitus, Type 1/genetics*
  3. Rohana AG, Loh KC, Tin SK, Soh CH, Nazaimoon WM, Fong KY, et al.
    Med J Malaysia, 2011 Jun;66(2):133-7.
    PMID: 22106694
    HLA-DQA1, -DQB1, and -DRB1 gene polymorphism were analyzed to study type 1 DM susceptibility in Malay patients from Southeast Asia (Malaysia and Singapore). Patients showed significant increases in the occurrence of DQA1*0501 (50.7% vs. 20.4%; RR = 3.97; Pc < 0.01), DQB1*0201 (48% vs. 19.1%; RR = 3.86; Pc < 0.05), and DRB1*0301 (38.7 vs. 6.8%; RR = 8.36; 95% Pc < 0.05). Conversely, significant decreases were noted in the occurrence of DQA1*0601 (14.7% vs. 35.2%; RR = 0.33; Pc = 0.008) and DQB1*0601 (4% vs. 23.5%; RR = 0.16; Pc < 0.05) in type 1 DM patients. Using a logistic regression model, we derived a risk prediction model for type 1 DM in our indigenous Malay population based on the identified HLA genotypes. The RR for type 1 DM increases by a factor of 5.68 for every unit increase in the number of DRB1*0301 allele (P < 0.001), and decreases by a factor of 0.18 per unit increase in the number of DQB1*0601 allele (P < 0.001). After adjusting for these two HLA genotypes, DQA1*0501, DQB1*0201 and DQA1*0601 were not statistically significant as risk predictors. The lower incidence of type 1 DM in the Malay population may be contributed by the genotypic combinations of DR and DQ genes as well as the linkage disequilibria between susceptible and protective alleles.
    Matched MeSH terms: Diabetes Mellitus, Type 1/genetics*
  4. Yaacob NS, Goh KS, Norazmi MN
    Exp. Toxicol. Pathol., 2012 Jan;64(1-2):127-31.
    PMID: 20674317 DOI: 10.1016/j.etp.2010.07.005
    The peroxisome proliferator-activated receptors (PPARs) have been implicated in regulating the immune response. We determined the relative changes in the transcriptional expression of PPAR isoforms (α, γ1 and γ2) and cytokines involved in the pathogenesis of type 1 diabetes (T1D) in the immune cells of 5 weeks, 10 weeks and diabetic male non-obese diabetic (NOD) mice compared to those of female NOD mice from our previous studies, "normalized" against their respective non-obese diabetic resistant (NOR) mice controls. Overall PPARα was significantly more elevated in the macrophages of female NOD mice of all age groups whereas PPARγ, particularly the PPARγ2 isoform was more depressed in the macrophages and CD4(+) lymphocytes of female NOD mice compared to their male counterparts. The pro-inflammatory cytokines, IL-1 and TNFα, as well as the Th1 cytokines, IL-2 and IFNγ were more elevated in female NOD mice whereas the Th2 cytokine, IL-4, was more depressed in these mice compared to their male counterparts. These findings suggest that the preponderance of T1D in female NOD mice may be influenced by the more pronounced changes in the expression of PPAR isoforms and pathogenic cytokines compared to those in male NOD mice.
    Matched MeSH terms: Diabetes Mellitus, Type 1/genetics
  5. Hussain S, Mohd Ali J, Jalaludin MY, Harun F
    Pediatr Diabetes, 2013 Jun;14(4):299-303.
    PMID: 23350652 DOI: 10.1111/pedi.12011
    We report a rare case of permanent neonatal diabetes (PND) due to insulin (INS) gene mutation in a 51-month-old girl who presented with hyperglycemia in the neonatal period. Mutational analysis of KCNJ11 and INS was performed and this detected a novel heterozygous c.38T>G (p.Leu13Arg) INS de novo mutation. The non-conservative change substitutes the highly conserved L(13) residue within the hydrophobic core region of the preproinsulin signal peptide. Given the frequent tendency of heterozygous INS mutations to exhibit dominant negative disease pathogenesis, it is likely that the mutant preproinsulin perturbed the non-mutant counterpart progression and processing within the β-cells, and this resulted to a permanent form of congenital diabetes.
    Matched MeSH terms: Diabetes Mellitus, Type 1/genetics
  6. Wong HB
    Ann Acad Med Singap, 1985 Apr;14(2):334-42.
    PMID: 4037695
    Insulin-dependent diabetes mellitus (IDDM) is inherited in a multifactorial manner with polygenes and environmental factors contributing to its emergence in a particular individual. The evidence for such a mode of inheritance is reviewed. One of the most important genetic roles is that played by the HLA genes on chromosome 6 and the different alleles which increase or decrease susceptibility in Caucasians, Japanese, Singapore Chinese and Shanghai Chinese are described. It is inferred that these alleles are different in different ethnic groups. The other genes which are important are unknown. The environmental influences are less well known although viral infections may act as triggers. Because the morbidity and mortality are still extremely serious in IDDM patients in spite of insulin therapy, it is proposed that preventive measures should be instituted in families prone to IDDM. The role of prenatal diagnosis is discussed especially in those families with multiple HLA susceptibility genes present. Great care paid to management of hyperglycemia from onset of the disease may reduce future morbidity and mortality.
    Matched MeSH terms: Diabetes Mellitus, Type 1/genetics
  7. Yaacob NS, Kaderi MA, Norazmi MN
    J Clin Immunol, 2004 Mar;24(2):177-84.
    PMID: 15024185 DOI: 10.1023/B:JOCI.0000019783.61674.1d
    Type 1 diabetes is an autoimmune disease that results from the destruction of the insulin-producing pancreatic beta islet cells, probably via the influence of cytokines. However, direct correlation between the expression of selected cytokines by various immune cells at different time points during the progression of the disease has not yet been clearly demonstrated. In this study, we showed that the mRNA expression of the pro-inflammatory cytokines, TNF-alpha, IL-1 beta, IL-6, and GM-CSF, were increased while the anti-inflammatory cytokine, TGF-beta, decreased in the peritoneal macrophages of nonobese diabetic (NOD) mice. IL-6 expression however decreased when the mice became diabetic. Surprisingly the expression of IFN-gamma and IL-2 by splenic CD4+ cells were lower in 5-week-old NOD mice as compared to the nonobese diabetic resistant (NOR) control mice, but their expression was higher in older NOD mice. The expression of IL-4 and IL-10 decreased in splenic CD4-positive lymphocytes. Splenic CD8-positive lymphocytes expressed increased levels of IFN-gamma and IL-10 but the latter decreased sharply when diabetes occurred. The relevance of these findings to the pathogenesis of type 1 diabetes is discussed.
    Matched MeSH terms: Diabetes Mellitus, Type 1/genetics
  8. Lee WW, Ooi BC, Thai AC, Loke KY, Tan YT, Rajan U, et al.
    Singapore Med J, 1998 Aug;39(8):359-62.
    PMID: 9844497
    To determine the incidence of insulin dependent diabetes mellitus (IDDM) in children 0-12 years of age in Singapore, which has a population of 2.9 million.
    Matched MeSH terms: Diabetes Mellitus, Type 1/genetics
  9. Yaacob NS, Kaderi MA, Norazmi MN
    J Clin Immunol, 2009 Sep;29(5):595-602.
    PMID: 19472040 DOI: 10.1007/s10875-009-9300-1
    BACKGROUND: The peroxisome proliferator-activated receptors (PPARs) have been implicated in immune regulation. We determined the transcriptional expression of the three isoforms, PPARalpha, PPARgamma1, and PPARgamma2 in the peritoneal macrophages, CD4- and CD8-positive lymphocytes in non-obese diabetic (NOD) mice at 5 and 10 weeks of age as well as at diabetic stage.

    RESULTS: Compared to the non-obese diabetic resistant (NOR) mice, the peritoneal macrophages of NOD mice expressed increased levels of PPARalpha but reduced levels of PPARgamma2, while PPARgamma1 expression was unchanged in all age groups. CD4-positive lymphocytes expressed low levels of PPARalpha in diabetic NOD mice and greatly reduced expression of PPARgamma2 in all age groups. Unlike peritoneal macrophages and CD4-positive cells, the CD8-positive cells expressed low levels of PPARgamma1 in diabetic NOD mice but no difference in PPARalpha and PPARgamma2 expression was observed compared to NOR mice.

    CONCLUSION: The current findings may suggest an important regulatory role of PPARs in the pathogenesis of autoimmune diabetes.

    Matched MeSH terms: Diabetes Mellitus, Type 1/genetics
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