PAX4 gene variations predispose to ketosis-prone diabetes

Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Human Molecular Genetics (Impact Factor: 6.39). 01/2005; 13(24):3151-9. DOI: 10.1093/hmg/ddh341
Source: PubMed


Ketosis-prone diabetes (KPD) is a rare form of type 2 diabetes, mostly observed in subjects of west African origin (west Africans and African-Americans), characterized by fulminant and phasic insulin dependence, but lacking markers of autoimmunity observed in type 1 diabetes. PAX4 is a transcription factor essential for the development of insulin-producing pancreatic beta-cells. Recently, a missense mutation (Arg121Trp) of PAX4 has been implicated in early and insulin deficient type 2 diabetes in Japanese subjects. The phenotype similarities between KPD and Japanese carriers of Arg121Trp have prompted us to investigate the role of PAX4 in KPD. We have screened 101 KPD subjects and we have found a new variant in the PAX4 gene (Arg133Trp), specific to the population of west African ancestry, and which predisposes to KPD under a recessive model. Homozygous Arg133Trp PAX4 carriers were found in 4% of subjects with KPD but not in 355 controls or 147 subjects with common type 2 or type 1 diabetes. In vitro, the Arg133Trp variant showed a decreased transcriptional repression of target gene promoters in an alpha-TC1.6 cell line. In addition, one KPD patient was heterozygous for a rare PAX4 variant (Arg37Trp) that was not found in controls and that showed a more severe biochemical phenotype than Arg133Trp. Clinical investigation of the homozygous Arg133Trp carriers and of the Arg37Trp carrier demonstrated a more severe alteration in insulin secretory reserve, during a glucagon-stimulation test, compared to other KPD subjects. Together these data provide the first evidence that ethnic-specific gene variants may contribute to the predisposition to this particular form of diabetes and suggest that KPD, like maturity onset diabetes of the young, is a rare, phenotypically defined but genetically heterogeneous form of type 2 diabetes.

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Available from: Franck Mauvais-Jarvis
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    • "MIN6 cells were transfected with 1 μg pFOX-RIPI-Luc (35,36) or pFOX-Luc (promoterless) and 100 ng Npas4-pcDNA3.1 or pcDNA3.1 and 50 ng pCMV-Renilla using Lipofectamine 2000 (LifeTech). After 48 h, cells were lysed with passive lysis buffer (PLB), and luciferase activity was quantified with the Dual Luciferase Reporter assay (Promega) on a SpectraMaxL luminometer (Molecular Devices). "
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    ABSTRACT: Cellular homeostasis requires intrinsic sensing mechanisms to temper function in the face of prolonged activity. In the pancreatic β-cell, glucose is likely a physiological trigger that activates an adaptive response to stimulation, thereby maintaining cellular homeostasis. Immediate early genes (IEGs) are activated as a first line of defense in cellular homeostasis and are largely responsible for transmitting an environmental cue to a cellular response. Here we examine the regulation and function of the novel β-cell IEG, neuronal PAS domain protein 4 (Npas4). Using MIN6 cells, mouse and human islets, as well as in vivo infusions, we demonstrate that Npas4 is expressed within pancreatic islets and is upregulated by β-cell depolarizing agents. Npas4 tempers β-cell function through a direct inhibitory interaction with the insulin promoter and by blocking the potentiating effects of GLP-1 without significantly reducing glucose-stimulated secretion. Finally, Npas4 expression is induced by classical endoplasmic reticulum (ER) stressors and can prevent thapsigargin- and palmitate-induced dysfunction and cell death. These results suggest that Npas4 is a key activity-dependent regulator that improves β-cell efficiency in the face of stress. We posit that Npas4 could be a novel therapeutic target in type 2 diabetes that could both reduce ER stress and cell death and maintain basal cell function.
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    • "HLA markers seem to be not useful to distinguish patients in this heterogeneous group since there was no association between these markers and insulin requirement at six months (6/7 of A−β+HLA− patients remained on insulin treatment, and 5/11 patients from A−β+HLA+ patients were under oral agents). Other genetic markers were associated with propensity to KPD [32]. Nevertheless such markers are not suitable for routine diagnosis. "
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    ABSTRACT: We aimed to characterize the different subgroups of ketosis-prone diabetes (KPD) in a sample of Tunisian patients using the Aβ scheme based on the presence or absence of β-cell autoantibodies (A+ or A-) and β-cell functional reserve (β+ or β-) and we investigated whether HLA class II alleles could contribute to distinct KPD phenotypes. We enrolled 43 adult patients with a first episode of ketosis. For all patients we evaluated clinical parameters, β-cell autoimmunity, β-cell function and HLA class II alleles. Frequency distribution of the 4 subgroups was 23.3% A+β-, 23.3% A-β-, 11.6% A+β+ and 41.9% A-β+. Patients from the group A+β- were significantly younger than those from the group A-β- (P = .002). HLA susceptibility markers were significantly more frequent in patients with autoantibodies (P = .003). These patients also had resistance alleles but they were more frequent in A+β+ than A+β- patients (P = .04). Insulin requirement was not associated to the presence or the absence of HLA susceptibility markers. HLA class II alleles associated with susceptibility to autoimmune diabetes have not allowed us to further define Tunisian KPD groups. However, high prevalence of HLA resistance alleles in our patients may reflect a particular genetic background of Tunisian KPD population.
    Full-text · Article · Mar 2011 · Experimental Diabetes Research
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    • "Analyses of relative frequencies of HLA alleles in these patients have produced conflicting results. Some investigators have failed to find an association with HLA susceptibility alleles (Mauvais-Jarvis et al., 2004). In contrast, others have found an increased frequency of HLA-DR3 and HLA-DR4 compared with non-diabetic populations (Banerji et al., 1994). "
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    ABSTRACT: Ketosis prone type 2 diabetes mellitus which was once described as "atypical diabetes" is being recognized increasingly worldwide; being originally described in African population has been seen in multiple ethnic groups, especially in urban areas. These patients are typically obese, middle-aged men with a strong family history of type 2 diabetes. The pathophysiologic mechanisms involved in its cause are unknown, but preliminary evidence suggests that patients with ketosis-prone type 2 diabetes have a unique propensity to glucose desensitization. These individuals have negative autoantibodies associated with type 1 diabetes but frequently HLA class II DRB1*03 and/or DRB1*04 are detected. Severe impairment of both insulin secretion and insulin action are found at presentation. Aggressive diabetes management results in marked improvement in beta cell function and insulin sensitivity sufficient to allow discontinuation of insulin therapy within a few months of treatment. In the long run, insulin can be substituted with oral hypoglycemic agents in most of these patients under careful supervision and close follow up. Molecular investigations into KPD syndromes utilizing multiple approaches (genomic, metabolic, proteomic) to generate etiological hypotheses can help us understand the underlying defects of insulin secretion and sensitivity in these and other types of diabetic patients.
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