Increased Hormone-Negative Endocrine Cells in the Pancreas in Type 1 Diabetes

Moin, Abu Saleh Md; Dhawan, Sangeeta; Shieh, Christine; Butler, Peter C.; Cory, Megan; Butler, Alexandra E.

doi:10.1210/jc.2016-1350

Cited by 45 publications

(62 citation statements)

References 28 publications

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“…Donkey-and goat-derived secondary antibodies conjugated to FITC, Cy3, Cy5, Alexa 448, and Alexa 647 were diluted 1:200 (Jackson ImmunoResearch). MafA and NPY coimmunostaining was performed by using a protocol for using two antibodies raised in the same species (55).…”

Section: Methodsmentioning

confidence: 99%

Neuropeptide Y expression marks partially differentiated β cells in mice and humans

Rodnoi¹,

Rajkumar²,

Moin³

et al. 2017

JCI Insight

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Section: Methodsmentioning

confidence: 99%

Neuropeptide Y expression marks partially differentiated β cells in mice and humans

Rodnoi¹,

Rajkumar²,

Moin³

et al. 2017

JCI Insight

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“…The primary antibodies were detected by a cocktail of appropriate secondary antibodies (Jackson ImmunoResearch Laboratories Inc., West Grove, PA); Alexa 647 conjugated donkey anti-rabbit (1:100), Cy3 conjugated donkey anti rabbit (1:200) and FITC conjugated donkey anti-mouse (1:100). Slides were counterstained to mark the nuclei using a mounting medium containing DAPI (Vectashield, Vector Labs, Burlingame, CA), and sections were viewed and analyzed as described previously (15).…”

Section: Morphometric Analysismentioning

confidence: 99%

“…To investigate the potential endocrine cell lineage of PDG cells, we evaluated Nkx2.2 as a panendocrine transcription factor and Nkx6.1 as a beta-cell transcription factor and combined this evaluation with a cocktail of all known pancreatic hormones as described previously (15). Sections were evaluated from 4 T1D donors (6050, 6138, 6051 and 6076) and 4 age and BMI-matched nondiabetic donors (6015, 6021, 6029 and 6134).…”

Section: Morphometric Analysismentioning

confidence: 99%

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Increased Proliferation of the Pancreatic Duct Gland Compartment in Type 1 Diabetes

Moin

Butler

2016

The Journal of Clinical Endocrinology & Metabolism

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Context: Pancreatic duct glands (PDGs) have been proposed as a source of regeneration in response to exocrine pancreas injury, and thus may serve as an organ stem cell niche. There is evidence to suggest ongoing beta-cell formation in longstanding type 1 diabetes (T1D), but the source is unknown. Objective: To investigate the pancreatic duct gland (PDG) compartment of the pancreas in humans with T1D for evidence of an active regenerative signature (presence of progenitor cells and increased proliferation) and, in particular, as a potential source of beta-cells. Design, Setting and Participants: Pancreas from 46 brain dead organ donors (22 with T1D, 24 nondiabetic controls) were investigated for activation (increased proliferation) and markers of pancreatic exocrine and endocrine progenitors. Results: PDG cell replication was increased in T1D (6.3 ± 1.6 vs. 0.6 ± 0.1%, p < 0.001, T1D vs. ND), most prominently in association with pancreatic inflammation. There were increased progenitor-like cells in PDGs of T1D, but predominantly with an exocrine fate. Conclusion:The PDG compartment is activated in T1D consistent with a response to ongoing inflammation, and via resulting ductal hyperplasia may contribute to local obstructive pancreatitis and eventual pancreatic atrophy characteristic of T1D. However, there is no evidence of effective endocrine cell formation from PDGs.PRECIS: PDGs serve as a stem cell niche in the pancreas. Replication in PDGs is increased in T1D, implying ongoing inflammation, but the majority of cells in PDGs have an exocrine rather than endocrine fate. Abbreviations:ChrgA, Chromogranin A. T1D, type 1 diabetes. ND, nondiabetic. PDGs, pancreatic duct glands. INTRODUCTIONIn longstanding type 1 diabetes (T1D), there is a near complete loss of pancreatic beta-cells through autoimmune mediated cell death (1, 2). However, several lines of evidence suggest that there may be ongoing attempted beta-cell regeneration, although insufficient to be clinically meaningful. For example, even in individuals with longstanding T1D, there are still detectable insulin-expressing cells, often isolated and scattered in the exocrine pancreas or in small clusters in and around pancreatic ducts (3,4). Consistent with this, by use of sensitive assays, residual insulin secretion is often present in individuals with longstanding T1D (5-8). The Journal of Clinical Endocrinology & Metabolism; Copyright 2016 DOI: 10.1210/jc.2016 Theoretically, these observations may indicate that there are small populations of beta-cells that elude immune detection or that there is ongoing new beta-cell formation subject to continued autoimmune destruction. In favor of the latter explanation, auto-reactive T-cells targeted to pancreatic beta-cells are frequently detected many years after diabetes onset, implying sustained auto-reactivity (9). In pancreas of individuals with T1D who have sufficient residual beta-cells to evaluate, we previously reported immune cells in close proximity to insulin-expressing cells and an increased frequency of b...

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“…For example, CPHN cells are most abundant in late gestation and early infancy coincident with the most rapid period of endocrine pancreas development. They reemerge in individuals with type 1 and type 2 diabetes for whom b cell regeneration has been suggested, although this treatment has been insufficient (17)(18)(19). To date, the abundance and nature of CPHN cells in humans with CP has not been determined.…”

mentioning

confidence: 99%

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

Moin

Cory

Choi

et al. 2018

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context: Chronic pancreatitis (CP) is characterized by inflammation, fibrosis, and a loss of pancreatic acinar cells, which can result in exocrine and eventually endocrine deficiency. Pancreatitis has been reported to induce formation of new endocrine cells (neogenesis) in mice. Our recent data have implicated chromogranin A-positive hormone-negative (CPHN) cells as potential evidence of neogenesis in humans.Objective: We sought to establish if CPHN cells were more abundant in CP in humans.Design, Setting, and Participants: We investigated the frequency and distribution of CPHN cells and the expression of the chemokine C-X-C motif ligand 10 (CXCL10) and its receptor chemokine C-X-C motif receptor 3 in pancreas of nondiabetic subjects with CP.Results: CPHN cell frequency in islets was increased sevenfold in CP [2.1% 6 0.67% vs 0.35% 6 0.09% CPHN cells in islets, CP vs nonpancreatitis (NP), P , 0.01], as were the CPHN cells found as scattered cells in the exocrine areas (17.4 6 2.9 vs 4.2 6 0.6, CP vs NP, P , 0.001). Polyhormonal endocrine cells were also increased in CP (2.7 6 1.2 vs 0.1 6 0.04, CP vs NP, % of polyhormonal cells of total endocrine cells, P , 0.01), as was expression of CXCL10 in a and b cells. Conclusion:There is increased islet endogenous expression of the inflammation marker CXCL10 in islets in the setting of nondiabetic CP and an increase in polyhormonal (insulin-glucagon expressing) cells. The increase in CPHN cells in CP, often in a lobular distribution, may indicate foci of attempted endocrine cell regeneration. (J Clin Endocrinol Metab

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Increased Hormone-Negative Endocrine Cells in the Pancreas in Type 1 Diabetes

Cited by 45 publications

References 28 publications

Neuropeptide Y expression marks partially differentiated β cells in mice and humans

Neuropeptide Y expression marks partially differentiated β cells in mice and humans

Increased Proliferation of the Pancreatic Duct Gland Compartment in Type 1 Diabetes

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

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