scholarly journals β-Cell Deficit in Obese Type 2 Diabetes, a Minor Role of β-Cell Dedifferentiation and Degranulation

2016 ◽  
Vol 101 (2) ◽  
pp. 523-532 ◽  
Author(s):  
Alexandra E. Butler ◽  
Sangeeta Dhawan ◽  
Jonathan Hoang ◽  
Megan Cory ◽  
Kylie Zeng ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endocrine Cell ◽  
Endocrine Cells ◽  
Cell Types ◽  
Minor Role ◽  
Β Cells ◽  
Β Cell ◽  
Cell Dedifferentiation ◽  
The Impact

Abstract Context: Type 2 diabetes is characterized by a β-cell deficit and a progressive defect in β-cell function. It has been proposed that the deficit in β-cells may be due to β-cell degranulation and transdifferentiation to other endocrine cell types. Objective: The objective of the study was to establish the potential impact of β-cell dedifferentiation and transdifferentiation on β-cell deficit in type 2 diabetes and to consider the alternative that cells with an incomplete identity may be newly forming rather than dedifferentiated. Design, Setting, and Participants: Pancreata obtained at autopsy were evaluated from 14 nondiabetic and 13 type 2 diabetic individuals, from four fetal cases, and from 10 neonatal cases. Results: Whereas there was a slight increase in islet endocrine cells expressing no hormone in type 2 diabetes (0.11 ± 0.03 cells/islet vs 0.03 ± 0.01 cells/islet, P < .01), the impact on the β-cell deficit would be minimal. Furthermore, we established that the deficit in β-cells per islet cannot be accounted for by an increase in other endocrine cell types. The distribution of hormone negative endocrine cells in type 2 diabetes (most abundant in cells scattered in the exocrine pancreas) mirrors that in developing (embryo and neonatal) pancreas, implying that these may represent newly forming cells. Conclusions: Therefore, although we concur that in type 2 diabetes there are endocrine cells with altered cell identity, this process does not account for the deficit in β-cells in type 2 diabetes but may reflect, in part, attempted β-cell regeneration.

scholarly journals Increased vimentin in human α- and β-cells in type 2 diabetes

2017 ◽  
Vol 233 (3) ◽  
pp. 217-227 ◽  
Author(s):  
Maaike M Roefs ◽  
Françoise Carlotti ◽  
Katherine Jones ◽  
Hannah Wills ◽  
Alexander Hamilton ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Epithelial To Mesenchymal Transition ◽  
Islet Cells ◽  
Cell Types ◽  
Β Cells ◽  
Β Cell ◽  
Mesenchymal Transition ◽  
Cell Expression

Type 2 diabetes (T2DM) is associated with pancreatic islet dysfunction. Loss of β-cell identity has been implicated via dedifferentiation or conversion to other pancreatic endocrine cell types. How these transitions contribute to the onset and progression of T2DM in vivo is unknown. The aims of this study were to determine the degree of epithelial-to-mesenchymal transition occurring in α and β cells in vivo and to relate this to diabetes-associated (patho)physiological conditions. The proportion of islet cells expressing the mesenchymal marker vimentin was determined by immunohistochemistry and quantitative morphometry in specimens of pancreas from human donors with T2DM (n = 28) and without diabetes (ND, n = 38) and in non-human primates at different stages of the diabetic syndrome: normoglycaemic (ND, n = 4), obese, hyperinsulinaemic (HI, n = 4) and hyperglycaemic (DM, n = 8). Vimentin co-localised more frequently with glucagon (α-cells) than with insulin (β-cells) in the human ND group (1.43% total α-cells, 0.98% total β-cells, median; P < 0.05); these proportions were higher in T2DM than ND (median 4.53% α-, 2.53% β-cells; P < 0.05). Vimentin-positive β-cells were not apoptotic, had reduced expression of Nkx6.1 and Pdx1, and were not associated with islet amyloidosis or with bihormonal expression (insulin + glucagon). In non-human primates, vimentin-positive β-cell proportion was larger in the diabetic than the ND group (6.85 vs 0.50%, medians respectively, P < 0.05), but was similar in ND and HI groups. In conclusion, islet cell expression of vimentin indicates a degree of plasticity and dedifferentiation with potential loss of cellular identity in diabetes. This could contribute to α- and β-cell dysfunction in T2DM.

scholarly journals 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

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.

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

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.

scholarly journals 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

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.

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

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-<i>Lep<sup>ob/ob</sup></i>). 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.

Exploring the role of the HNF-1αG319S polymorphism in β cell failure and youth-onset type 2 diabetes: Lessons from MODY and Hnf-1α-deficient animal models

2015 ◽  
Vol 93 (5) ◽  
pp. 487-494 ◽  
Author(s):  
Michael E. Jonasson ◽  
Brandy A. Wicklow ◽  
Elizabeth A.C. Sellers ◽  
Vernon W. Dolinsky ◽  
Christine A. Doucette
Keyword(s):  
Type 2 Diabetes ◽  
Cell Function ◽  
Glucose Sensing ◽  
Future Research ◽  
Cell Phenotype ◽  
Β Cells ◽  
Β Cell ◽  
Onset Type ◽  
The Impact

The prevalence of youth-onset type 2 diabetes (T2D) is rapidly increasing worldwide, disproportionately affecting Indigenous youth with Oji-Cree heritage from central Canada. Candidate gene screening has uncovered a novel and private polymorphism in the Oji-Cree population in the hepatocyte nuclear factor-1 alpha (HNF-1α) gene, where a highly conserved glycine residue at position 319 is changed to a serine (termed HNF-1αG319S or simply G319S). Oji-Cree youth who carry one or two copies of the “S-allele” present at diagnosis with less obesity, reduced indicators of insulin resistance, and lower plasma insulin levels at diagnosis, suggestive of a primary defect in the insulin-secreting β cells. Few studies on the impact of the HNF-1αG319S variant on β cell function have been performed to date; however, much can be learned from other clinical phenotypes of HNF-1α-deficiency, including HNF-1α mutations that cause maturity-onset diabetes of the young 3 (MODY3). In addition, evaluation of Hnf-1α-deficient murine models reveals that HNF-1α plays a central role in the regulation of insulin secretion by regulating the expression of key genes involved in β cell glucose-sensing, mitochondrial function, and the maintenance of the β cell phenotype in differentiated β cells. The overall goal of this minireview is to explore the impact of HNF-1α-deficiency on the β cell to better inform future research into the mechanisms of β cell dysfunction in Oji-Cree youth with T2D.

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

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-<i>Lep<sup>ob/ob</sup></i>). 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.

scholarly journals 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

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.

scholarly journals 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

2021 ◽  
Vol 21 (1) ◽  
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.

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