Dysfunction of Persisting β Cells Is a Key Feature of Early Type 2 Diabetes Pathogenesis

Cohrs, Christian M.; Panzer, Julia K.; Drotar, Denise M.; Enos, Stephen J.; Kipke, Nicole; Chen, Chunguang; Bozsak, Robert; Schöniger, Eyke; Ehehalt, Florian; Distler, Marius; Brennand, Ana; Bornstein, Stefan R.; Weitz, Jürgen; Solimena, Michele; Speier, Stephan

doi:10.1016/j.celrep.2020.03.033

Cited by 109 publications

(95 citation statements)

References 58 publications

(75 reference statements)

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“…The living pancreas slice technique has allowed us and others to assess numerous parameters of islet cell function from tissues containing the intact endocrine and exocrine compartments (23,(25)(26)(27)(28)(29)(30)(31)(32)(33). We posited that this technological approach would facilitate investigation of structurally altered, infiltrated, or damaged islets during T1D disease pathogenesis, which are thought to be lost during classical islet isolation procedures.…”

Section: Resultsmentioning

confidence: 99%

“…The tissue slice technique was developed in the rodent model (23) and optimized for fresh human pancreatic tissue from surgical resections (24,25). In rodents, tissue slices have been shown to be of major value for the study of not only endocrine cell types (e.g., α, β, and δ cells), but also immune, acinar, and vascular cells of the pancreas (24-28, 30, 37).…”

Section: Discussionmentioning

confidence: 99%

“…Here, we implemented a platform that we believe to be novel for the study of pancreas tissue slices obtained from human organ donors. This approach, which was originally developed for mouse pancreas (23), was recently adapted for the study of human pancreas tissue obtained from surgical biopsy or resection (24,25) and, in these settings, has been successfully used to study various aspects of rodent and human islet biology (23,(25)(26)(27)(28)(29)(30)(31)(32)(33). In this potentially novel study, we report that slices (a) can be readily prepared from pancreata from nondiabetic (ND) donors and donors with T1D; (b) have preserved endocrine, exocrine, and immune tissue compartments; and (c) allow correlation of anatomical, physiological, and clinical data.…”

Section: Introductionmentioning

confidence: 99%

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Pancreas tissue slices from organ donors enable in situ analysis of type 1 diabetes pathogenesis

et al. 2020

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pancreas tissue slices from organ donors enable in situ analysis of type 1 diabetes pathogenesis

et al. 2020

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“…Although many patient samples (>100) have been assessed for molecular profiling using lasercaptured islets from fixed pancreas samples, it remains to be determined how efficiently this can be adapted to the in vitro assessment of live islets. Importantly, a very recent study [41] has now successfully demonstrated the in vitro islet dysfunction within live pancreas slices from individuals with impaired glucose tolerance or type 2 diabetes.…”

Section: Increasing Scale: Connecting Molecular and Functional Phenotmentioning

confidence: 99%

Molecular and functional profiling of human islets: from heterogeneity to human phenotypes

2020

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Efforts to phenotype pancreatic islets have contributed tremendously to our present understanding of endocrine function and diabetes. A continued evolution in approaches to study islet physiology is important given the need to establish reference points for mature islet functionality, understanding biological variation amongst individuals and cells, and the ongoing appreciation of the role for islets in diabetes susceptibility. Recent efforts in islet biology have focused on technological improvements in imaging, molecular profiling and data analysis, along with a push for enhanced transparency and reporting. The integration of these approaches within a classical islet physiology framework, and approaches to link these data with in vivo human phenotypes, will be critical as we move towards a better understanding of islet function in health and disease. Here we discuss what we feel are important issues and useful approaches to consider as we move forward as a field in islet and beta cell phenotyping.

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“…There are 116 million diabetic patients in China, being the largest in the world [1,2]. β-cell deficit is one of the root causes in the development of type 2 diabetes [3,4], and our previous study showed a significant decrease in β-cell mass in Chinese patients with type 2 diabetes [5]. One of the main causes of β-cell deficit in type 2 diabetes is the loss of key transcription factors in mature β cells, which makes β cells back to a "dedifferentiated" state, including NKX6.1 [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Increased Frequency of β Cells with Abnormal NKX6.1 Expression in Type 2 Diabetes but not in Subjects with Higher Risk for Type 2 Diabetes

Liu

Sun

Zou

et al. 2020

Preprint

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Background: NKX6.1 is a transcription factor for insulin, as well as a marker for β cell maturity. Abnormal NKX6.1 expression in β cells, such as translocation from the nucleus to cytoplasm or lost expression, has been shown as a marker for β cell dedifferentiation.Methods: Here, we obtained pancreata sections from organ donors, and aim to characterize NKX6.1 expression in subjects with or without type 2 diabetes mellitus (T2DM), and NKX6.1 and insulin immunofluorescence staining was performed.Results: Our results showed that cells with insulin expression but no nucleic NKX6.1 expression (NKX6.1 Nuc- Ins + ), and cells with cytoplasmic NKX6.1 expression but no insulin expression (NKX6.1 cyt Ins - ) were significantly increased in T2DM subjects and positively correlated with glycated hemoglobin (HbA1c), indicating the elevated β cell dedifferentiation with NKX6.1 inactivation in T2DM. To investigate whether β cell dedifferentiation has initiated in subjects with higher risks for T2DM, we next analyzed the association between β-cell dedifferentiation level in ND subjects with different ages, body mass index, and HbA1c. The results showed the absolute number and percentage of dedifferentiated β cells with NKX6.1 inactivation did not significantly change in subjects with advanced aging, obesity, or modest hyperglycemia, indicating that the β cell dedifferentiation may mainly occur after T2DM was diagnosed.Conclusion: In sum, our results suggested that NKX6.1 expression in β cells is changed in type 2 diabetic subjects, evidenced by significantly increased NKX6.1 Nuc- Ins + and NKX6.1 cyt Ins - cells. This abnormality does not occur more frequently in subjects with a higher risk for T2DM, suggesting that β cell dedifferentiation might be secondary to the pathological changes in T2DM.

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Dysfunction of Persisting β Cells Is a Key Feature of Early Type 2 Diabetes Pathogenesis

Cited by 109 publications

References 58 publications

Pancreas tissue slices from organ donors enable in situ analysis of type 1 diabetes pathogenesis

Pancreas tissue slices from organ donors enable in situ analysis of type 1 diabetes pathogenesis

Molecular and functional profiling of human islets: from heterogeneity to human phenotypes

Increased Frequency of β Cells with Abnormal NKX6.1 Expression in Type 2 Diabetes but not in Subjects with Higher Risk for Type 2 Diabetes

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