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

ABSTRACT: Maturity-onset diabetes of the young (MODY) is a group of monogenetic forms of diabetes mellitus caused by mutations in genes regulating ?-cell development and function. MODY represents a heterogeneous group of non-insulin dependent diabetes arising in childhood or adult life. Interestingly, clinical heterogeneity in MODY patients like variable disease onset and severity is observed even among individual family members sharing the same mutation, an issue that is not well understood. As high blood glucose levels are a well-known factor promoting ?-cell stress and ultimately leading to cell death, we asked whether additional ?-cell stress might account for the occurrence of disease heterogeneity in mice carrying a MODY4 mutation. In order to challenge ?-cells, we established a MODY4 animal model based on Pdx1 (pancreatic and duodenal homeobox 1) haploinsufficiency, which allows conditional modulation of cell stress by genetic inhibition of the stress-responsive IKK/NF-?B signalling pathway. While Pdx1+/- mice were found glucose intolerant without progressing to diabetes, additional challenge of ?-cell function by IKK/NF-?B inhibition promoted rapid diabetes development showing hyperglycaemia, hypoinsulinemia and loss of ?-cell mass. Disease pathogenesis was characterized by deregulation of genes controlling ?-cell homeostasis and function. Importantly, restoration of normal IKK/NF-?B signalling reverted the diabetic phenotype including normalization of glycaemia and ?-cell mass. Our findings implicate that the avoidance of additional ?-cell stress can delay a detrimental disease progression in MODY4 diabetes. Remarkably, an already present diabetic phenotype can be reversed when ?-cell stress is normalized.

SUBMITTER: Trojanowski B

PROVIDER: S-EPMC6933809 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Trojanowski Bernadette M BM Salem Heba H HH Neubauer Heike H Simon Eric E Wagner Martin M Dorajoo Rajkumar R Boehm Bernhard O BO Labriola Leticia L Wirth Thomas T Baumann Bernd B

The Journal of endocrinology 20200201 2

Maturity-onset diabetes of the young (MODY) is a group of monogenetic forms of diabetes mellitus caused by mutations in genes regulating β-cell development and function. MODY represents a heterogeneous group of non-insulin-dependent diabetes arising in childhood or adult life. Interestingly, clinical heterogeneity in MODY patients like variable disease onset and severity is observed even among individual family members sharing the same mutation, an issue that is not well understood. As high bloo ...[more]

PMID: 31682591

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Project description:BackgroundThe endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) is a known modulator of inflammation and ligand to both, pro-inflammatory cannabinoid receptor 1 (CB1) and anti-inflammatory CB2. While the role of both receptors in atherogenesis has been studied extensively, the significance of 2-AG for atherogenesis is less well characterized.MethodsThe impact of 2-AG on atherogenesis was studied in two treatment groups of ApoE-/- mice. One group received the monoacylglycerol lipase (MAGL)-inhibitor JZL184 [5 mg/kg i.p.], which impairs 2-AG degradation and thus causes elevated 2-AG levels, the other group received vehicle for four weeks. Simultaneously, both groups were fed a high-cholesterol diet. The atherosclerotic plaque burden was assessed in frozen sections through the aortic sinus following oil red O staining and infiltrating macrophages were detected by immunofluorescence targeting CD68. In vitro, the effect of 2-AG on B6MCL macrophage migration was assessed by Boyden chamber experiments. Transcription of adhesion molecules and chemokine receptors in macrophages was assessed by qPCR.ResultsAs expected, application of the MAGL-inhibitor JZL184 resulted in a significant increase in 2-AG levels in vascular tissue (98.2 ± 16.1 nmol/g vs. 27.3 ± 4.5 nmol/g; n = 14-16; p < 0.001). ApoE-/- mice with elevated 2-AG levels displayed a significantly increased plaque burden compared to vehicle treated controls (0.44 ± 0.03 vs. 0.31 ± 0.04; n = 14; p = 0.0117). This was accompanied by a significant increase in infiltrating macrophages within the atherosclerotic vessel wall (0.33 ± 0.02 vs. 0.27 ± 0.01; n = 13-14; p = 0.0076). While there was no alteration to the white blood counts of JZL184-treated animals, 2-AG enhanced macrophage migration in vitro by 1.8 ± 0.2 -fold (n = 4-6; p = 0.0393) compared to vehicle, which was completely abolished by co-administration of either CB1- or CB2-receptor-antagonists. qPCR analyses of 2-AG-stimulated macrophages showed an enhanced transcription of the chemokine CCL5 (1.59 ± 0.23 -fold; n = 5-6; p = 0.0589) and its corresponding receptors CCR1 (2.04 ± 0.46 -fold; n = 10-11; p = 0.0472) and CCR5 (2.45 ± 0.62 -fold; n = 5-6; p = 0.0554).ConclusionTaken together, elevated 2-AG levels appear to promote atherogenesis in vivo. Our data suggest that 2-AG promotes macrophage migration, possibly by the CCL5-CCR5/CCR1 axis, and thereby contributes to vascular inflammation. Thus, decreasing vascular 2-AG levels might represent a promising therapeutic strategy in patients suffering from atherosclerosis and coronary heart disease.

Dataset Information

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

Publications

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

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