Decreased Expression of Cilia Genes in Pancreatic Islets as a Risk Factor for Type 2 Diabetes in Mice and Humans

Kluth, Oliver; Stadion, Mandy; Gottmann, Pascal; Aga, Heja; Jähnert, Markus; Scherneck, Stephan; Vogel, Heike; Krus, Ulrika; Seelig, Anett; Ling, Charlotte; Gerdes, Jantje M.; Schürmann, Annette

doi:10.1016/j.celrep.2019.02.056

Cited by 36 publications

(57 citation statements)

References 41 publications

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“…Recent work has explored the link between ciliary dysfunction and diabetes (10,11,15,51). Here we show that primary cilia are required for multiple aspects of β-cell function, and we globally survey the cilia-dependent signaling network in islets.…”

Section: Discussionmentioning

confidence: 86%

Primary cilia control glucose homeostasis via islet paracrine interactions

Hughes

Cho

Conway

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Pancreatic islets regulate glucose homeostasis through coordinated actions of hormone-secreting cells. What underlies the function of the islet as a unit is the close approximation and communication among heterogeneous cell populations, but the structural mediators of islet cellular cross talk remain incompletely characterized. We generated mice specifically lacking β-cell primary cilia, a cellular organelle that has been implicated in regulating insulin secretion, and found that the β-cell cilia are required for glucose sensing, calcium influx, insulin secretion, and cross regulation of α- and δ-cells. Protein expression profiling in islets confirms perturbation in these cellular processes and reveals additional targets of cilia-dependent signaling. At the organism level, the deletion of β-cell cilia disrupts circulating hormone levels, impairs glucose homeostasis and fuel usage, and leads to the development of diabetes. Together, these findings demonstrate that primary cilia not only orchestrate β-cell–intrinsic activity but also mediate cross talk both within the islet and from islets to other metabolic tissues, thus providing a unique role of cilia in nutrient metabolism and insight into the pathophysiology of diabetes.

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Section: Discussionmentioning

confidence: 86%

Primary cilia control glucose homeostasis via islet paracrine interactions

Hughes

Cho

Conway

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…NZO mice are a polygenic model for obesity and type 2 diabetes, developing metabolic stress-induced beta-cell failure under a specific high-caloric dietary regimen. This is composed of an initial carbohydrate-free, high-fat diet (-CH), triggering insulin resistance and obesity, followed by a carbohydrate-rich diet (+CH) that finally leads to hyperglycemia, beta-cell dysfunction and apoptosis [ [31] , [32] , [33] , [34] ]. By extending the metabolic challenge, the impact of an advanced age on pancreatic beta-cells under metabolic stress conditions was examined (study design illustrated in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Mouse models prone to postprandial metabolic stress, such as NZO mice, mimic the human obesity-associated type 2 diabetes and were used in the present study. As previously described, young NZO mice exhibited obesity and insulin resistance when kept on a diet without carbohydrates, followed by depletion of insulin stores and a progressive loss of functional beta-cells in response to a carbohydrate intervention [ 27 , 31 , 32 , 34 , 42 ]. These mice showed distinct body weight gain due to ad libitum availability to the high-caloric carbohydrate-free diet.…”

Section: Discussionmentioning

confidence: 99%

Redox homeostasis and cell cycle activation mediate beta-cell mass expansion in aged, diabetes-prone mice under metabolic stress conditions: Role of thioredoxin-interacting protein (TXNIP)

et al. 2020

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Overnutrition contributes to insulin resistance, obesity and metabolic stress, initiating a loss of functional beta-cells and diabetes development. Whether these damaging effects are amplified in advanced age is barely investigated. Therefore, New Zealand Obese (NZO) mice, a well-established model for the investigation of human obesity-associated type 2 diabetes, were fed a metabolically challenging diet with a high-fat, carbohydrate restricted period followed by a carbohydrate intervention in young as well as advanced age. Interestingly, while young NZO mice developed massive hyperglycemia in response to carbohydrate feeding, leading to beta-cell dysfunction and cell death, aged counterparts compensated the increased insulin demand by persistent beta-cell function and beta-cell mass expansion. Beta-cell loss in young NZO islets was linked to increased expression of thioredoxin-interacting protein (TXNIP), presumably initiating an apoptosis-signaling cascade via caspase-3 activation. In contrast, islets of aged NZOs exhibited a sustained redox balance without changes in TXNIP expression, associated with higher proliferative potential by cell cycle activation. These findings support the relevance of a maintained proliferative potential and redox homeostasis for preserving islet functionality under metabolic stress, with the peculiarity that this adaptive response emerged with advanced age in diabetes-prone NZO mice.

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“…Cilia are present, e.g., in endocrine β-cells, and it has been reported that cilia play a role in insulin signaling, insulin secretion, and β-cell function ( Gerdes et al, 2014 ). We recently reported that cilia-gene regulation has a strong impact on the presence and dynamics of cilia in islets which, in turn, determines diabetes susceptibility ( Kluth et al, 2019 ). However, as there are multiple transcript variants described for Ttc39a , which encode distinct isoforms, the specific role of the differently expressed isoform in the pathogenesis of diabetes in mice has to be clarified.…”

Section: Discussionmentioning

confidence: 99%

“…Glucose-stimulated insulin secretion (GSIS) was performed, as described ( Kluth et al, 2019 ). Briefly, 30 isolated and 24 h recovered islets were equilibrated in Krebs-Ringer buffer for 30 min under low glucose (2.8 mM) conditions and transferred into perifusion chambers (PERI5-115, Biorep Technologies Inc., Miami Lakes, FL, United States) with a continuous flow of 100 μl/min.…”

Section: Methodsmentioning

confidence: 99%

Identification of Novel Potential Type 2 Diabetes Genes Mediating β-Cell Loss and Hyperglycemia Using Positional Cloning

et al. 2020

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Type 2 diabetes (T2D) is a complex metabolic disease regulated by an interaction of genetic predisposition and environmental factors. To understand the genetic contribution in the development of diabetes, mice varying in their disease susceptibility were crossed with the obese and diabetes-prone New Zealand obese (NZO) mouse. Subsequent whole-genome sequence scans revealed one major quantitative trait loci (QTL), Nidd/DBA on chromosome 4, linked to elevated blood glucose and reduced plasma insulin and low levels of pancreatic insulin. Phenotypical characterization of congenic mice carrying 13.6 Mbp of the critical fragment of DBA mice displayed severe hyperglycemia and impaired glucose clearance at week 10, decreased glucose response in week 13, and loss of β-cells and pancreatic insulin in week 16. To identify the responsible gene variant(s), further congenic mice were generated and phenotyped, which resulted in a fragment of 3.3 Mbp that was sufficient to induce hyperglycemia. By combining transcriptome analysis and haplotype mapping, the number of putative responsible variant(s) was narrowed from initial 284 to 18 genes, including gene models and non-coding RNAs. Consideration of haplotype blocks reduced the number of candidate genes to four ( Kti12 , Osbpl9 , Ttc39a , and Calr4 ) as potential T2D candidates as they display a differential expression in pancreatic islets and/or sequence variation. In conclusion, the integration of comparative analysis of multiple inbred populations such as haplotype mapping, transcriptomics, and sequence data substantially improved the mapping resolution of the diabetes QTL Nidd/DBA . Future studies are necessary to understand the exact role of the different candidates in β-cell function and their contribution in maintaining glycemic control.

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Decreased Expression of Cilia Genes in Pancreatic Islets as a Risk Factor for Type 2 Diabetes in Mice and Humans

Cited by 36 publications

References 41 publications

Primary cilia control glucose homeostasis via islet paracrine interactions

Primary cilia control glucose homeostasis via islet paracrine interactions

Redox homeostasis and cell cycle activation mediate beta-cell mass expansion in aged, diabetes-prone mice under metabolic stress conditions: Role of thioredoxin-interacting protein (TXNIP)

Identification of Novel Potential Type 2 Diabetes Genes Mediating β-Cell Loss and Hyperglycemia Using Positional Cloning

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