Dynamic Change of β to α Ratio in Islets of Chinese People With Prediabetes and Type 2 Diabetes Mellitus

Liu, Tengli; Liang, Rui; Wang, Le; Zou, Jiaqi; Wang, Guanqiao; Liu, Na; Sun, Peng; Liu, Yaojuan; Ding, Xuejie; Lu, Chenxi; Liu, Xue; Wang, Shusen; Shen, Zhongyang

doi:10.1097/mpa.0000000000001552

Cited by 9 publications

(9 citation statements)

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“…Human Pancreatic tissue was fixed with 10% formalin, followed by dehydration, paraffin embedding, and sectioning at 3 μm. Sections were then stained according to a previously described protocol [5]. Primary antibodies are NKX6.1 (…”

Section: Immunofluorescence Analysismentioning

confidence: 99%

“…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%

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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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Section: Immunofluorescence Analysismentioning

confidence: 99%

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…There are 116 million diabetic patients in China, being the largest in the world [1,2]. β-cell de cit is one of the root causes in the development of type 2 diabetes [3,4], and our previous study showed a signi cant decrease in β-cell mass in Chinese patients with type 2 diabetes [5].…”

Section: Read Full License Abstractmentioning

confidence: 99%

“…Human Pancreatic tissue was xed with 10% formalin, followed by dehydration, para n embedding, and sectioning at 3 μm. Sections were then stained according to a previously described protocol [5]. After deparaffinization, sections were treated with EDTA antigen retrieval solution (Solarbio, Beijing, China) in a microwave oven, washed, permeabilized and blocked.…”

Section: Immuno Uorescence Analysismentioning

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

Self Cite

View full text Add to dashboard Cite

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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“…1–3 Our earlier and others’ studies have reported significant β cell mass loss in T2DM subjects. 4–9 Although apoptosis is observed in diabetic islets in human pancreatic sections, the number of apoptotic cells did not match the function degradation of diabetic islets. In the last decade, several studies have discovered β cell dedifferentiation in both diabetic animals and human beings.…”

Section: Introductionmentioning

confidence: 99%

Cytohistologic analyses of β cell dedifferentiation induced by inflammation in human islets

et al. 2021

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β cell dedifferentiation is a key mechanism for β cell dysfunction in type 2 diabetes mellitus (T2DM). Although it has been indicated in previous studies that β cell dedifferentiation could be induced by inflammation, the cytohistologic analyses of inflammation-induced β cell dedifferentiation in human islets is lacking. The present study aims to cytohistologically characterize the β cell dedifferentiation of human islets treated by proinflammatory cytokines Interleukin-1β/Tuman necrosis factor-α/Interferon-γ (IL-1β/TNF-α/IFN-γ), which is a frequently-used method to mimic the islet inflammation in previous studies. The loss of cytosolic FOXO1 expression, the loss of nucleic NKX6.1 expression, and the gain of ALDH1A3 expression in β cells are proclaimed as marking events for β cell dedifferentiation. Taking advantages of islets from organ donors and the immunofluorescence staining methods, the present study visualized the β cell dedifferentiation events marked by different markers, and quantified the frequency of each event as well. We successfully captured and described the characteristics of the differentiating/differentiated β cells. We found that dedifferentiated β cells were increased in the cytokines treated islets, evidenced by the increase of β cells with FOXO1 translocated to the nucleus (INS+FOXOnuc), β cells with NKX6.1 exported from the nucleus (INS+NKX6.1cyt), and β cells loss of NKX6.1 expression (INS+NKX6.1-), and β cells with dual expression of insulin and progenitor marker ALDH1A3. Consistently, we found that proinflammatory cytokines IL-1β/TNF-α/IFN-γ treatment reduced the mRNA expression of key β cell markers, but elevated the expression of progenitor marker genes. This study gives the most direct evidence for inflammation-induced β cell dedifferentiation in human islets, and supports the concept that anti-inflammation treatments may facilitate alleviating the β cell dedifferentiation in human T2DM islets.

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Dynamic Change of β to α Ratio in Islets of Chinese People With Prediabetes and Type 2 Diabetes Mellitus

Cited by 9 publications

References 36 publications

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

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

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

Cytohistologic analyses of β cell dedifferentiation induced by inflammation in human islets

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