Abstract
BackgroundNKX6.1 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.MethodsWe 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).ResultsOur 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.ConclusionOur 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.
Highlights
NKX6.1 is a transcription factor for insulin, as well as a marker for β cell maturity
The gene regulatory network controlled by transcription factor NKX6.1 is necessary to maintain the function and identity of mature β cells [10, 11], and the overexpression of Nkx6.1 in adult mouse β cells of mice resulted in elevated glucose stimulated insulin secretion (GSIS) [10], yet the inactivation of Nkx6.1 could lead to a decrease in insulin secretion, causing diabetes [11]
The characteristics of NKX6.1 defined β-cell dedifferentiation By immunofluorescence staining with insulin and NKX 6.1 in human pancreatic tissue sections, we identified two types of dedifferentiated β cells with NKX6.1 inactivation: 1) Cells that are insulin-positive but without nucleic NKX6.1 expression are at the early stage of dedifferentiated β cells (NKX6.1Nuc-Ins+, including β cells with cytoplasmic NKX6.1 expression or no NKX6.1 expression, Fig. 1a-b); 2) Cells that are insulin-negative but with cytoplasmic expression of NKX6.1 are at the late stage of dedifferentiated β cells (NKX6.1cytIns−, Fig. 1a-b)
Summary
NKX6.1 is a transcription factor for insulin, as well as a marker for β cell maturity. The gene regulatory network controlled by transcription factor NKX6.1 is necessary to maintain the function and identity of mature β cells [10, 11], and the overexpression of Nkx6.1 in adult mouse β cells of mice resulted in elevated glucose stimulated insulin secretion (GSIS) [10], yet the inactivation of Nkx6.1 could lead to a decrease in insulin secretion, causing diabetes [11]. Nkx6.1 inactivation in adult mouse β cells could [11] induce the expression of progenitor cell markers [6, 7, 11,12,13], which exhibited a dedifferentiation stage These results are consistent with the findings that NKX6.1 expression is decreased in β cells from obese-diabetic mice and human T2DM islets compared with that in non-diabetic ones [7, 14]. NKX6.1 inactivation has been used as a protein marker for β cell dedifferentiation
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