Increased Chromogranin A–Positive Hormone-Negative Cells in Chronic Pancreatitis

Moin, Abu Saleh Md; Cory, Megan; Choi, Jung-In; Ong, A.; Dhawan, Sangeeta; Dry, Sarah M.; Butler, Peter C.; Rizza, Robert A.; Butler, Alexandra E.

doi:10.1210/jc.2017-01562

Cited by 21 publications

(21 citation statements)

References 30 publications

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“…In support to our findings, CXCL10 expression in alpha-cells was previously reported by Tanaka et al in Japanese fulminant diabetes cases (26) and, more recently, by Moin et al (44) in pancreatic islets of multiorgan donors with chronic pancreatitis, thus confirming and extending the observation of CXCL10 expression in alpha-cells in autoimmune diabetes.…”

Section: Discussionsupporting

confidence: 93%

Pancreatic Alpha-Cells Contribute Together With Beta-Cells to CXCL10 Expression in Type 1 Diabetes

et al. 2020

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C-X-C Motif Chemokine Ligand 10 (CXCL10) is a pro-inflammatory chemokine specifically recognized by the ligand receptor CXCR3 which is mostly expressed in T-lymphocytes. Although CXCL10 expression and secretion have been widely associated to pancreatic islets both in non-obese diabetic (NOD) mice and in human type 1 diabetic (T1D) donors, the specific expression pattern among pancreatic endocrine cell subtypes has not been clarified yet. Therefore, the purpose of this study was to shed light on the pancreatic islet expression of CXCL10 in NOD, in C57Bl/6J and in NOD-SCID mice as well as in human T1D pancreata from new-onset T1D patients (DiViD study) compared to non-diabetic multiorgan donors from the INNODIA European Network for Pancreatic Organ Donors with Diabetes (EUnPOD). CXCL10 was expressed in pancreatic islets of normoglycaemic and new-onset diabetic NOD mice but not in C57Bl/6J and NOD-SCID mice. CXCL10 expression was increased in pancreatic islets of new-onset diabetic NOD mice compared to normoglycaemic NOD mice. In NOD mice, CXCL10 colocalized both with insulin and glucagon. Interestingly, CXCL10-glucagon colocalization rate was significantly increased in diabetic vs. normoglycaemic NOD mouse islets, indicating an increased expression of CXCL10 also in alpha-cells. CXCL10 was expressed in pancreatic islets of T1D patients but not in non-diabetic donors. The analysis of the expression pattern of CXCL10 in human T1D pancreata from DiViD study, revealed an increased colocalization rate with glucagon compared to insulin. Of note, CXCL10 was also expressed in alpha-cells residing in insulin-deficient islets (IDI), suggesting that CXCL10 expression in alpha cells is not driven by residual beta-cells and therefore may represent an independent phenomenon. In conclusion, we show that in T1D CXCL10 is expressed by alpha-cells both in NOD mice and in T1D patients, thus pointing to an additional novel role for alpha-cells in T1D pathogenesis and progression.

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Section: Discussionsupporting

confidence: 93%

Pancreatic Alpha-Cells Contribute Together With Beta-Cells to CXCL10 Expression in Type 1 Diabetes

et al. 2020

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“…Here CgA cleavage products lead to proangiogenic activity, as cleavage of the N- and C-terminal regions of CgA can activate antiangiogenic (vasostatin) and proangiogenic sites (CST), respectively ( 1 ). Further supporting the notion that CgA and its cleavage products can be diagnostic markers for various diseases, is that elevated levels of CgA have been detected in the plasma of patients with neuroendocrine tumors ( 25 ), hypertension ( 99 , 100 ) and various inflammatory diseases, such as RA ( 6 , 101 , 102 ), SLE ( 6 ), IBD ( 53 , 54 , 103 – 105 ) as well as T1DM and T2DM ( 62 , 106 – 109 ). However, not all assays used in the aforementioned studies allow to discern full-length from proteolytically processed CgA ( 125 ) and it would be very interesting to compare this to levels of unprocessed CgA and its cleavage products.…”

Section: Clinical Implications Of Cstmentioning

confidence: 85%

“…In line with this, alternated plasma levels of CST or its prohormone CgA have been observed in the context of various diseases. Plasma levels of CST are reduced in patients suffering from T2DM and hypertension ( 75 , 95 , 98 ), whereas elevated levels of the pro-hormone CgA have been detected in the plasma of patients with neuroendocrine tumors ( 25 ), hypertension ( 99 , 100 ) and various inflammatory diseases, such as RA ( 6 , 101 , 102 ), SLE ( 6 ), inflammatory bowel disease (IBD) ( 53 , 54 , 103 – 105 ) as well as T1DM and T2DM ( 62 , 106 – 109 ). This suggests that the lower levels of CST are caused by a dysregulation of proteolytic processing of CgA ( 98 ).…”

Section: Cleavage Products Of the Pro-hormone Chromogranin Amentioning

confidence: 99%

Catestatin as a Target for Treatment of Inflammatory Diseases

et al. 2018

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It is increasingly clear that inflammatory diseases and cancers are influenced by cleavage products of the pro-hormone chromogranin A (CgA), such as the 21-amino acids long catestatin (CST). The goal of this review is to provide an overview of the anti-inflammatory effects of CST and its mechanism of action. We discuss evidence proving that CST and its precursor CgA are crucial for maintaining metabolic and immune homeostasis. CST could reduce inflammation in various mouse models for diabetes, colitis and atherosclerosis. In these mouse models, CST treatment resulted in less infiltration of immune cells in affected tissues, although in vitro monocyte migration was increased by CST. Both in vivo and in vitro, CST can shift macrophage differentiation from a pro- to an anti-inflammatory phenotype. Thus, the concept is emerging that CST plays a role in tissue homeostasis by regulating immune cell infiltration and macrophage differentiation. These findings warrant studying the effects of CST in humans and make it an interesting therapeutic target for treatment and/or diagnosis of various metabolic and immune diseases.

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“…In addition, a high inflammatory environment in the islets leads to an increase in β-cell dedifferentiation level [14,15]. These results suggest that hyperglycemia, hyperlipidemia, and proinflammatory cytokine as pathological factors are the driving forces for β-cell dedifferentiation [16,17].…”

Section: Obesity Did Not Affect Nkx61 Expression In β Cellsmentioning

confidence: 97%

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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Increased Chromogranin A–Positive Hormone-Negative Cells in Chronic Pancreatitis

Cited by 21 publications

References 30 publications

Pancreatic Alpha-Cells Contribute Together With Beta-Cells to CXCL10 Expression in Type 1 Diabetes

Pancreatic Alpha-Cells Contribute Together With Beta-Cells to CXCL10 Expression in Type 1 Diabetes

Catestatin as a Target for Treatment of Inflammatory Diseases

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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