Salsalate Prevents β-Cell Dedifferentiation in OLETF Rats with Type 2 Diabetes through Notch1 Pathway

Diabetes is a metabolic disease characterized by hyperglycemia. Over 90% of patients with diabetes have type 2 diabetes. Pancreatic β-cells are endocrine cells that produce and secrete insulin, an essential endocrine hormone that regulates blood glucose levels. Deficits in β-cell function and mass play key roles in the onset and progression of type 2 diabetes. Apoptosis has been considered as the main contributor of β-cell dysfunction and decrease in β-cell mass for a long time. However, recent studies suggest that β-cell failure occurs mainly due to increased β-cell dedifferentiation rather than limited β-cell proliferation or increased β-cell death. In this review, we summarize the current advances in the understanding of the pancreatic β-cell dedifferentiation process including potential mechanisms. A better understanding of β-cell dedifferentiation process will help to identify novel therapeutic targets to prevent and/or reverse β-cell loss in type 2 diabetes.

Download Full-text

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

10.21203/rs.3.rs-45910/v2 ◽

2020 ◽

Author(s):

Tengli Liu ◽

Peng Sun ◽

Jiaqi Zou ◽

Le Wang ◽

Guanqiao Wang ◽

...

Keyword(s):

Type 2 Diabetes ◽

Glycated Hemoglobin ◽

Absolute Number ◽

Organ Donors ◽

Β Cells ◽

Β Cell ◽

Cell Dedifferentiation ◽

Insulin Expression ◽

Type 2 Diabetic

Abstract 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 (NKX6.1Nuc-Ins+), and cells with cytoplasmic NKX6.1 expression but no insulin expression (NKX6.1cytIns-) 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 NKX6.1Nuc-Ins+ and NKX6.1cytIns- 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.

Download Full-text

The Anna Karenina model of β cell maturation in development and their dedifferentiation in type 1 and type 2 diabetes

10.1101/2021.02.16.431507 ◽

2021 ◽

Author(s):

Sutichot D. Nimkulrat ◽

Zijian Ni ◽

Jared Brown ◽

Christina Kendziorski ◽

Barak Blum

Keyword(s):

Type 2 Diabetes ◽

Cell Function ◽

Lineage Tracing ◽

Β Cells ◽

Β Cell ◽

Cell Dedifferentiation ◽

Anna Karenina ◽

Β Cell Function

AbstractLoss of mature β cell function and identity, or β cell dedifferentiation, is seen in all types of diabetes mellitus. Two competing models explain β cell dedifferentiation in diabetes. In the first model, β cells dedifferentiate in the reverse order of their developmental ontogeny. This model predicts that dedifferentiated β cells resemble β cell progenitors. In the second model, β cell dedifferentiation depends on the type of diabetogenic stress. This model, which we call the “Anna Karenina” model, predicts that in each type of diabetes, β cells dedifferentiate in their own way, depending on how their mature identity is disrupted by any particular diabetogenic stress. We directly tested the two models using a β cell-specific lineage-tracing system coupled with RNA-sequencing in mice. We constructed a multidimensional map of β cell transcriptional trajectories during the normal course of β cell postnatal development and during their dedifferentiation in models of both type 1 diabetes (NOD) and type 2 diabetes (BTBR-Lepob/ob). Using this unbiased approach, we show here that despite some similarities between immature and dedifferentiated β cells, β cells dedifferentiation in the two mouse models is not a reversal of developmental ontogeny and is different between different types of diabetes.

Download Full-text

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

10.21203/rs.3.rs-45910/v1 ◽

2020 ◽

Author(s):

Tengli Liu ◽

Peng Sun ◽

Jiaqi Zou ◽

Le Wang ◽

Guanqiao Wang ◽

...

Keyword(s):

Type 2 Diabetes ◽

Glycated Hemoglobin ◽

Absolute Number ◽

Organ Donors ◽

Β Cells ◽

Β Cell ◽

Cell Dedifferentiation ◽

Insulin Expression ◽

Type 2 Diabetic

Abstract 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.

Download Full-text

The Anna Karenina Model of β Cell Maturation in Development and their Dedifferentiation in Type 1 and Type 2 Diabetes

10.2337/figshare.14770101 ◽

2021 ◽

Author(s):

Sutichot D. Nimkulrat ◽

Matthew N. Bernstein ◽

Zijian Ni ◽

Jared Brown ◽

Christina Kendziorski ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cell Function ◽

Lineage Tracing ◽

Β Cells ◽

Β Cell ◽

Cell Dedifferentiation ◽

Anna Karenina ◽

Β Cell Function

Loss of mature β cell function and identity, or β cell dedifferentiation, is seen in both type 1 and type 2 diabetes. Two competing models explain β cell dedifferentiation in diabetes. In the first model, β cells dedifferentiate in the reverse order of their developmental ontogeny. This model predicts that dedifferentiated β cells resemble β cell progenitors. In the second model, β cell dedifferentiation depends on the type of diabetogenic stress. This model, which we call the “Anna Karenina” model, predicts that in each type of diabetes, β cells dedifferentiate in their own way, depending on how their mature identity is disrupted by any particular diabetogenic stress. We directly tested the two models using a β cell-specific lineage-tracing system coupled with RNA-sequencing in mice. We constructed a multidimensional map of β cell transcriptional trajectories during the normal course of β cell postnatal development and during their dedifferentiation in models of both type 1 diabetes (NOD) and type 2 diabetes (BTBR-Lepob/ob). Using this unbiased approach, we show here that despite some similarities between immature and dedifferentiated β cells, <a>β cells dedifferentiation in the two mouse models is not a reversal of developmental ontogeny and is different between </a>different types of diabetes.

Download Full-text

Diazoxide Prevents Diabetes through Inhibiting Pancreatic β-Cells from Apoptosis via Bcl-2/Bax Rate and p38-β Mitogen-Activated Protein Kinase

Endocrinology ◽

10.1210/en.2006-0738 ◽

2007 ◽

Vol 148 (1) ◽

pp. 81-91 ◽

Cited By ~ 40

Author(s):

Qin Huang ◽

Shizhong Bu ◽

Yongwei Yu ◽

Zhiyong Guo ◽

Gautam Ghatnekar ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cell Apoptosis ◽

Critical Role ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells ◽

Oletf Rats ◽

Insulin Secretory Capacity ◽

Secretory Capacity

Increased apoptosis of pancreatic β-cells plays an important role in the occurrence and development of type 2 diabetes. We examined the effect of diazoxide on pancreatic β-cell apoptosis and its potential mechanism in Otsuka Long Evans Tokushima Fatty (OLETF) rats, an established animal model of human type 2 diabetes, at the prediabetic and diabetic stages. We found a significant increase with age in the frequency of apoptosis, the sequential enlargement of islets, and the proliferation of the connective tissue surrounding islets, accompanied with defective insulin secretory capacity and increased blood glucose in untreated OLETF rats. In contrast, diazoxide treatment (25 mg·kg−1·d−1, administered ip) inhibited β-cell apoptosis, ameliorated changes of islet morphology and insulin secretory function, and increased insulin stores significantly in islet β-cells whether diazoxide was used at the prediabetic or diabetic stage. Linear regression showed the close correlation between the frequency of apoptosis and hyperglycemia (r = 0.913; P < 0.0001). Further study demonstrated that diazoxide up-regulated Bcl-2 expression and p38β MAPK, which expressed at very low levels due to the high glucose, but not c-jun N-terminal kinase and ERK. Hence, diazoxide may play a critical role in protection from apoptosis. In this study, we demonstrate that diazoxide prevents the onset and development of diabetes in OLETF rats by inhibiting β-cell apoptosis via increasing p38β MAPK, elevating Bcl-2/Bax ratio, and ameliorating insulin secretory capacity and action.

Download Full-text

The Anna Karenina Model of β Cell Maturation in Development and their Dedifferentiation in Type 1 and Type 2 Diabetes

10.2337/figshare.14770101.v1 ◽

2021 ◽

Author(s):

Sutichot D. Nimkulrat ◽

Matthew N. Bernstein ◽

Zijian Ni ◽

Jared Brown ◽

Christina Kendziorski ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cell Function ◽

Lineage Tracing ◽

Β Cells ◽

Β Cell ◽

Cell Dedifferentiation ◽

Anna Karenina ◽

Β Cell Function

Loss of mature β cell function and identity, or β cell dedifferentiation, is seen in both type 1 and type 2 diabetes. Two competing models explain β cell dedifferentiation in diabetes. In the first model, β cells dedifferentiate in the reverse order of their developmental ontogeny. This model predicts that dedifferentiated β cells resemble β cell progenitors. In the second model, β cell dedifferentiation depends on the type of diabetogenic stress. This model, which we call the “Anna Karenina” model, predicts that in each type of diabetes, β cells dedifferentiate in their own way, depending on how their mature identity is disrupted by any particular diabetogenic stress. We directly tested the two models using a β cell-specific lineage-tracing system coupled with RNA-sequencing in mice. We constructed a multidimensional map of β cell transcriptional trajectories during the normal course of β cell postnatal development and during their dedifferentiation in models of both type 1 diabetes (NOD) and type 2 diabetes (BTBR-Lepob/ob). Using this unbiased approach, we show here that despite some similarities between immature and dedifferentiated β cells, <a>β cells dedifferentiation in the two mouse models is not a reversal of developmental ontogeny and is different between </a>different types of diabetes.

Download Full-text

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

10.21203/rs.3.rs-45910/v3 ◽

2020 ◽

Author(s):

Tengli Liu ◽

Peng Sun ◽

Jiaqi Zou ◽

Le Wang ◽

Guanqiao Wang ◽

...

Keyword(s):

Type 2 Diabetes ◽

Glycated Hemoglobin ◽

Absolute Number ◽

Organ Donors ◽

Β Cells ◽

Β Cell ◽

Cell Dedifferentiation ◽

Insulin Expression ◽

Type 2 Diabetic

Abstract 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: We obtained pancreatic sections from organ donors and immunofluorescence staining with NKX6.1 and insulin was performed to characterize NKX6.1 expression in subjects with or without type 2 diabetes mellitus (T2DM).Results: Our results showed that cells with insulin expression but no nucleic NKX6.1 expression (NKX6.1Nuc-Ins+), and cells with cytoplasmic NKX6.1 expression but no insulin expression (NKX6.1cytIns-) 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 might mainly occur after T2DM was diagnosed.Conclusion: Our results suggested that NKX6.1 expression in β cells was changed in type 2 diabetic subjects, evidenced by significantly increased NKX6.1Nuc-Ins+ and NKX6.1cytIns- cells. This abnormality did 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.

Download Full-text