Islet inflammation and ductal proliferation may be linked to increased pancreatitis risk in type 2 diabetes

Schludi, Belinda; Moin, Abu Saleh Md; Montemurro, Chiara; Gurlo, Tatyana; Matveyenko, Aleksey V.; Kirakossian, David; Dawson, David W.; Dry, Sarah M.; Butler, Peter C.; Butler, Alexandra E.

doi:10.1172/jci.insight.92282

Cited by 19 publications

(18 citation statements)

References 49 publications

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“…One consequence may be the activation of regenerative programs, perhaps resulting in an increase in newly forming endocrine cells. These findings are in keeping with our recently published work in the human islet amyloid polypeptide rat model of type 2 diabetes (HIP rat) where we demonstrated a twofold increase in replication in the pancreatic duct gland (PDG) compartment in the prediabetic state (28). The fact that this increased PDG replication was present in the HIP rat before the deranged metabolism accompanying diabetes implies that islet inflammation is a sufficient stimulus to induce ductal replication, and we reported that this is also the case in pancreas from human brain-dead organ donors in whom there was increased PDG and ductal replication in both type 1 (29) and type 2 diabetes (28).…”

Section: Frequency Of Polyhormonal Cells In Cpsupporting

confidence: 92%

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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Section: Frequency Of Polyhormonal Cells In Cpsupporting

confidence: 92%

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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“…We confirmed previously that similar to humans and mice, PDGs in rat pancreatic tissue sections appear as coiled structures embedded in the mesenchyme surrounding the main duct, and are readily stained with Alcian blue and p-aminosalicylic acid, and also characterized by the increased proliferation rate relative to normal ductal cells (12). For current study we set out to collect only PDGs in the substantial layer of mesenchyme where, based on 7 extensive experience (6,12,17,19), they are readily and rapidly identified, ensuring specificity and quality of collected RNA.…”

Section: Ratssupporting

confidence: 66%

“…While the existence of blind pouches from main pancreatic ducts bearing stem cell markers has been appreciated for many years, only recently has this anatomical compartment been named the pancreatic duct gland (PDG) compartment and been proposed as a stem cell niche responsible for repair of pancreas following acute injury (20). (17,19). 13 The turnover of pancreatic duct epithelial cells is much less frequent than that of the cells that form intestinal villi.…”

Section: Discussionmentioning

confidence: 99%

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In the setting of β-cell stress, the pancreatic duct gland transcriptome shows characteristics of an activated regenerative response

Butler

Kirakossian

Gurlo

et al. 2018

American Journal of Physiology-Gastrointestinal and Liver Physi

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The pancreatic duct gland (PDG) compartment has been proposed as a potential stem cell niche based on its coiled tubular structure embedded in mesenchyme, its proliferation and expansion in response to pancreatic injury, and the fact that it contains endocrine and exocrine epithelial cells. Little is known of the molecular signature of the PDG compartment in either a quiescent state or the potentially activated state during beta cell stress characteristic of diabetes. To address this, we performed RNA sequencing on RNA obtained from PDGs of wild type versus pre-diabetic HIP rats, a model of type 2 diabetes. The transcriptome of the PDG compartment, compared to a library of 84 tissue types, placed PDGs midpoint between the exocrine and endocrine pancreas and closely related to seminiferous tubules, consistent with a role as a stem cell niche for the exocrine and endocrine pancreas. Standard differential expression analysis (permissive threshold p<0.005) identified 245 genes differentially expressed in PDGs from HIP rats versus WT rats, with overrepresentation of transcripts involved in acute inflammatory responses, regulation of cell proliferation, and tissue development, while pathway analysis pointed to enrichment of cell movement-related pathways. In conclusion the transcriptome of the PDG compartment is consistent with a pancreatic stem cell niche that is activated by ongoing beta cell stress signals. The documented PDG transcriptome provides potential candidates to be exploited for lineage tracing studies of this as yet little investigated compartment.

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“…T2D is associated with b cell stress and chronic inflammation as well as subclinical pancreatitis, which increases CXCL1 and triggers proliferation in the human pancreatic ductal epithelium [136]. Interleukin 17 (IL-17) induces the expression of regenerating islet-derived protein 3-beta (REG3b), which is a mediator of pancreatitis during acinar-to-ductal metaplasia and in early pancreatic intraepithelial neoplasia (PanIN) lesions.…”

Section: Morbid Obesitymentioning

confidence: 99%

Microbiome and morbid obesity increase pathogenic stimulus diversity

Brücher

Jamall

2019

4open

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The microbiome, the relationship between environmental factors, a high-fat diet, morbid obesity, and host response have been associated with cancer, only a small fraction of which (<10%) are genetically triggered. This nongenetic association is underpinned by a worldwide increase in morbid obesity, which is associated with both insulin resistance and chronic inflammation. The connection of the microbiome and morbid obesity is reinforced by an approximate shift of about 47% in the estimated total number of bacteria and an increase from 38,000,000,000,000 in a reference man to 56,000,000,000,000 in morbid obesity leading to a disruption of the microbial ecology within the gut. Humans contain 6,000,000,000 microbes and more than 90% of the cells of the human body are microorganisms. Changes in the microflora of the gut are associated with the polarization of ion channels by butyrate, thereby influencing cell growth. The decrease in the relative proportion of Bacteroidetes together with a change in the fermentation of carbohydrates by bacteria is observed in morbid obesity. The disruption of homeostasis of the microflora in the obese changes signaling and crosstalk of several pathways, resulting in inflammation while suppressing apoptosis. The interactions between the microbiome and morbid obesity are important to understand signaling and crosstalk in the context of the progression of the six-step sequence of carcinogenesis. This disruption of homeostasis increases remodeling of the extracellular matrix and fibrosis followed by the none-resolvable precancerous niche as the internal pathogenic stimuli continue. The chronic stress explains why under such circumstances there is a greater proclivity for normal cells to undergo the transition to cancer cells.

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Islet inflammation and ductal proliferation may be linked to increased pancreatitis risk in type 2 diabetes

Cited by 19 publications

References 49 publications

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

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

In the setting of β-cell stress, the pancreatic duct gland transcriptome shows characteristics of an activated regenerative response

Microbiome and morbid obesity increase pathogenic stimulus diversity

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