Elevated β-cell stress levels promote severe diabetes development in mice with MODY4

Trojanowski, Bernadette M.; Salem, Heba; Neubauer, Heike; Simon, Eric J.; Wagner, Martin; Dorajoo, Rajkumar; Boehm, Bernhard O.; Labriola, Letícia; Wirth, Thomas; Baumann, Bernd

doi:10.1530/joe-19-0208

Cited by 5 publications

(6 citation statements)

References 52 publications

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“…Additional environmental or genetic factors are clearly acting alongside PDX1 mutations in the etiology of MODY. In support of this idea, the selective, inducible inhibition of IKK/NF-κB signaling in pancreatic β-cells could induce bona fide diabetes in pre-diabetic adult Pdx1 +/ − mice 12 .…”

Section: Introductionmentioning

confidence: 86%

A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes

Hildebrand

Tomei

et al. 2021

Cell Death Dis

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Maturity-onset diabetes of the young, MODY, is an autosomal dominant disease with incomplete penetrance. In a family with multiple generations of diabetes and several early onset diabetic siblings, we found the previously reported P33T PDX1 damaging mutation. Interestingly, this substitution was also present in a healthy sibling. In contrast, a second very rare heterozygous damaging mutation in the necroptosis terminal effector, MLKL, was found exclusively in the diabetic family members. Aberrant cell death by necroptosis is a cause of inflammatory diseases and has been widely implicated in human pathologies, but has not yet been attributed functions in diabetes. Here, we report that the MLKL substitution observed in diabetic patients, G316D, results in diminished phosphorylation by its upstream activator, the RIPK3 kinase, and no capacity to reconstitute necroptosis in two distinct MLKL−/− human cell lines. This MLKL mutation may act as a modifier to the P33T PDX1 mutation, and points to a potential role of impairment of necroptosis in diabetes. Our findings highlight the importance of family studies in unraveling MODY’s incomplete penetrance, and provide further support for the involvement of dysregulated necroptosis in human disease.

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Section: Introductionmentioning

confidence: 86%

A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes

Hildebrand

Tomei

et al. 2021

Cell Death Dis

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“…However, the additional deterioration of β-cell function by I kappa B kinase (IKK) / Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inhibition enhanced transformation to rapidly progressing diabetes, characterized by hyperglycemia, low insulinemia, and decreased β-cell mass. 20 Our study demonstrated that the PDX-1 high-risk polymorphism in T2DM patients resulted in lower early phase insulin secretion levels. A human study reported that there was a decreased PDX-1 expression in human islets of patients with T2DM compared with that in non-diabetic subjects, which was a result of DNA methylation due to hyperglycemia.…”

Section: Discussionmentioning

confidence: 55%

Significance of pancreatic duodenal homeobox-1 (PDX-1) genetic polymorphism in insulin secretion in Japanese patients with type 2 diabetes

Okura

Nakamura

Ito

et al. 2022

BMJ Open Diab Res Care

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IntroductionPancreatic and duodenal homeobox factor-1 (PDX-1) is an imperative gene for insulin secretion in maturity-onset diabetes of the young 4. PDX-1 gene polymorphism was associated with lower first-phase insulin secretion in a genome-wide association study of intravenous glucose tolerance test. It was not associated with type 2 diabetes risk and insulin secretion in a genome-wide oral glucose tolerance test study. However, there have been no reports of overt type 2 diabetes and insulin resistance evaluation using a glucose clamp. We investigated PDX-1 polymorphism, insulin secretion, and insulin resistance in overt type 2 diabetes.Research design and methodsWe performed a meal tolerance test (MTT) and hyperinsulinemic–euglycemic clamping on 63 Japanese subjects, 30 with type 2 diabetes and 33 non-diabetic. We analyzed the rs1124607 PDX-1 gene polymorphism and defined A/C and C/C as the high-risk group and A/A as the low-risk group.ResultsHOMA-beta (homeostatic model assessment beta-cell function) was significantly lower in the high-risk group than in the low-risk group for all subjects (72.9±54.2% vs 107.0±63.5%, p<0.05). Glucose levels and glucose area under the curve (AUC) were not significantly different between both the risk groups. The insulin levels at 60 and 120 min and the insulin AUC after MTT were remarkably lower in the high-risk group than those in the low-risk group for all subjects (AUC 75.7±36.7 vs 112.7±59.5, p<0.05). High-risk subjects with type 2 diabetes had significantly lower insulin levels at 30 and 60 min and insulin AUC than low-risk subjects. Non-diabetic high-risk subjects depicted significantly lower insulin levels at 120 and 180 min. There were negligible differences in insulin resistance between the risk groups.ConclusionsThese results suggest that the PDX-1 genetic polymorphism is crucial for insulin secretion in Japanese patients with type 2 diabetes.

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“…Transgenics presented rapid onset of diabetes characterized by hyperglycemia, hyperinsulinemia, and loss of β-cell mass. 114 Although this is a model of diabetes, it could be potentially combined with high fat or other dietary intervention to introduce hyperlipidemia and/or obesity.…”

Section: Genetic Manipulationsmentioning

confidence: 99%

Cardiometabolic Syndrome: An Update on Available Mouse Models

et al. 2020

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Cardiometabolic syndrome (CMS), a disease entity characterized by abdominal obesity, insulin resistance (IR), hypertension, and hyperlipidemia, is a global epidemic with approximately 25% prevalence in adults globally. CMS is associated with increased risk for cardiovascular disease (CVD) and development of diabetes. Due to its multifactorial etiology, the development of several animal models to simulate CMS has contributed significantly to the elucidation of the disease pathophysiology and the design of therapies. In this review we aimed to present the most common mouse models used in the research of CMS. We found that CMS can be induced either by genetic manipulation, leading to dyslipidemia, lipodystrophy, obesity and IR, or obesity and hypertension, or by administration of specific diets and drugs. In the last decade, the ob/ob and db/db mice were the most common obesity and IR models, whereas Ldlr−/− and Apoe−/− were widely used to induce hyperlipidemia. These mice have been used either as a single transgenic or combined with a different background with or without diet treatment. High-fat diet with modifications is the preferred protocol, generally leading to increased body weight, hyperlipidemia, and IR. A plethora of genetically engineered mouse models, diets, drugs, or synthetic compounds that are available have advanced the understanding of CMS. However, each researcher should carefully select the most appropriate model and validate its consistency. It is important to consider the differences between strains of the same animal species, different animals, and most importantly differences to human when translating results.

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Elevated β-cell stress levels promote severe diabetes development in mice with MODY4

Cited by 5 publications

References 52 publications

A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes

A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes

Significance of pancreatic duodenal homeobox-1 (PDX-1) genetic polymorphism in insulin secretion in Japanese patients with type 2 diabetes

Cardiometabolic Syndrome: An Update on Available Mouse Models

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