scholarly journals Activin A, exendin-4, and glucose stimulate differentiation of human pancreatic ductal cells

2013 ◽  
Vol 217 (3) ◽  
pp. 241-252 ◽  
Author(s):  
Hyo-Sup Kim ◽  
Seung-Hyun Hong ◽  
Seung-Hoon Oh ◽  
Jae-Hyeon Kim ◽  
Myung-Shik Lee ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Pancreatic Islets ◽  
Nude Mice ◽  
High Glucose ◽  
Activin A ◽  
Alternative Source ◽  
Ductal Cells ◽  
Pancreatic Ductal Cells ◽  
Insulin Producing Cells

Islet transplantation is one treatment option for diabetes mellitus. However, novel sources of pancreatic islets or insulin-producing cells are required because the amount of donor tissue available is severely limited. Pancreatic ductal cells are an alternative source of β-cells because they have the potential to differentiate into insulin-producing cells. We investigated whether treatment of human pancreatic ductal cells with activin A (ActA) and exendin-4 (EX-4) stimulated transdifferentiation of the cells, bothin vitroandin vivo. We treated human pancreatic ductal cells with ActA and EX-4 in high-glucose media to induce differentiation into insulin-producing cells and transplanted the cells into streptozotocin-induced diabetic nude mice. Co-treatment of mice with ActA and EX-4 promoted cell proliferation, induced expression of pancreatic β-cell-specific markers, and caused glucose-induced insulin secretion compared with the ActA or EX-4 mono-treatment groups respectively. When pancreatic ductal cells treated with ActA and EX-4 in high-glucose media were transplanted into diabetic nude mice, their blood glucose levels normalized and insulin was detected in the graft. These findings suggest that pancreatic ductal cells have a potential to replace pancreatic islets for the treatment of diabetes mellitus when the ductal cells are co-treated with ActA, EX-4, and glucose to promote their differentiation into functional insulin-producing cells.

Activin A and Glucose Derived Human Pancreatic Ductal Cells into Insulin-producing Cells

2007 ◽  
Vol 31 (1) ◽  
pp. 44
Author(s):  
Seung Hyun Hong ◽  
Chul Han ◽  
Hyo Sup Kim ◽  
Mi Kyung Park ◽  
Young Jin Lee ◽  
...  
Keyword(s):  
Activin A ◽  
Ductal Cells ◽  
Pancreatic Ductal Cells ◽  
Insulin Producing Cells

Ductal Cell Reprogramming to Insulin-Producing Beta-Like Cells as a Potential Beta Cell Replacement Source for Chronic Pancreatitis

2019 ◽  
Vol 14 (1) ◽  
pp. 65-74 ◽  
Author(s):  
Aravinth P. Jawahar ◽  
Siddharth Narayanan ◽  
Gopalakrishnan Loganathan ◽  
Jithu Pradeep ◽  
Gary C. Vitale ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Beta Cell ◽  
Lineage Tracing ◽  
Clinical Tool ◽  
Glucose Levels ◽  
Ductal Cells ◽  
Pancreatic Ductal Cells ◽  
Insulin Producing Cells ◽  
Ductal Cell ◽  
Recent Advances

Islet cell auto-transplantation is a novel strategy for maintaining blood glucose levels and improving the quality of life in patients with chronic pancreatitis (CP). Despite the many recent advances associated with this therapy, obtaining a good yield of islet infusate still remains a pressing challenge. Reprogramming technology, by making use of the pancreatic exocrine compartment, can open the possibility of generating novel insulin-producing cells. Several lineage-tracing studies present evidence that exocrine cells undergo dedifferentiation into a progenitor-like state from which they can be manipulated to form insulin-producing cells. This review will present an overview of recent reports that demonstrate the potential of utilizing pancreatic ductal cells (PDCs) for reprogramming into insulin- producing cells, focusing on the recent advances and the conflicting views. A large pool of ductal cells is released along with islets during the human islet isolation process, but these cells are separated from the pure islets during the purification process. By identifying and improving existing ductal cell culture methods and developing a better understanding of mechanisms by which these cells can be manipulated to form hormone-producing islet-like cells, PDCs could prove to be a strong clinical tool in providing an alternative beta cell source, thus helping CP patients maintain their long-term glucose levels.

scholarly journals High-glucose-induced miR-214-3p inhibits BMSCs osteogenic differentiation in type 1 diabetes mellitus

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Rongze Wang ◽  
Yuanxu Zhang ◽  
Fujun Jin ◽  
Gongchen Li ◽  
Yao Sun ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Type 1 Diabetes Mellitus ◽  
Osteogenic Differentiation ◽  
High Glucose ◽  
Bone Homeostasis ◽  
Marrow Mesenchymal Stem Cells

Abstract Type 1 diabetes mellitus (T1DM) is an autoimmune insulin-dependent disease associated with destructive bone homeostasis. Accumulating evidence has proven that miRNAs are widely involved in the regulation of bone homeostasis. However, whether miRNAs also regulate osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) in T1DM mice is under exploration. In this study, miRNA microarray was utilized to screen the differentially expressed miRNAs, which uncovered that miR-214-3p potentially inhibited BMSCs osteogenic differentiation in T1DM mice. We found that high glucose suppressed BMSCs osteogenic differentiation with significant elevation of the miR-214-3p expression. Further study found that the osteogenic differentiation of BMSCs was inhibited by AgomiR-214-3p while enhanced by AntagomiR-214-3p in BMSCs supplemented with high glucose. Moreover, we found that miR-214-3p knockout T1DM mice were resistant to high-glucose-induced bone loss. These results provide a novel insight into an inhibitory role of high-glucose-induced miR-214-3p in BMSCs osteogenic differentiation both in vitro and in vivo. Molecular studies revealed that miR-214-3p inhibits BMSCs osteogenic differentiation by targeting the 3′-UTR of β-catenin, which was further corroborated in human bone specimens and BMSCs of T1DM patients. Taken together, our study discovered that miR-214-3p is a pivotal regulator of BMSCs osteogenic differentiation in T1DM mice. Our findings also suggest that miR-214-3p could be a potential target in the treatment of bone disorders in patients with T1DM.

scholarly journals Glucose stimulates and insulin inhibits release of pancreatic TRH in vitro

2000 ◽  
pp. 60-65 ◽  
Author(s):  
J Benicky ◽  
V Strbak
Keyword(s):  
B Cells ◽  
Pancreatic Islets ◽  
High Glucose ◽  
Adenosine Monophosphate ◽  
Isolated Pancreatic Islets ◽  
Glucose Addition ◽  
Adult Rat ◽  
Camp Stimulation ◽  
Stimulation Of

OBJECTIVE: Pancreatic TRH is present in insulin-producing B-cells of the islets of Langerhans. There is fragmentary evidence that it may be involved in glucoregulation. The aim of our present study was to analyze how glucose and insulin affect TRH secretion by the pancreatic islets. DESIGN: Isolated pancreatic islets were incubated with different concentrations of glucose, insulin and glucagon, and TRH release was measured. RESULTS: In the present study, 6 and 12mmol/l d-glucose caused significant TRH release from isolated adult rat pancreatic islets when compared with that in the presence of the same concentrations of biologically ineffective l-glucose. Thirtymmol/l d-glucose was also ineffective, but this was not due to depression of secretion by hyperosmolarity since isosmotic compensation for the high glucose addition did not restore its stimulatory effect. Five micromol/l dibutyryl cyclic 3',5'-adenosine monophosphate (db-cAMP) increased both basal and glucose-stimulated TRH release, but this effect was not seen with 50micromol/l db-cAMP. Stimulation of phosphodiesterase by imidazole resulted in decreased basal but not glucose-stimulated release of TRH. Glucagon (10(-7)mol/l) did not affect either basal or glucose-stimulated release of TRH, while insulin (10(-7) and 10(-6)mol/l) inhibited both. CONCLUSION: Our present data showing that glucose stimulates and insulin inhibits pancreatic TRH release are compatible with the possibility that this substance may play a role in glucoregulation.

In Vivo Cell Transformation: Neogenesis of Beta Cells from Pancreatic Ductal Cells

1995 ◽  
Vol 4 (4) ◽  
pp. 371-383 ◽  
Author(s):  
Lawrence Rosenberg
Keyword(s):  
Endocrine Cell ◽  
Islet Cell ◽  
Cell Transformation ◽  
Islet Cells ◽  
Cell Mass ◽  
Postnatal Period ◽  
Islet Neogenesis ◽  
Ductal Cells ◽  
Pancreatic Ductal Cells

During embryogenesis, islet cells differentiate from primitive duct-like cells. This process leads to the formation of islets in the mesenchyme adjacent to the ducts. In the postnatal period, any further expansion of the pancreatic endocrine cell mass will manifest itself either by a limited proliferation of the existing islet cells, or by a reiteration of ontogenetic development. It is the latter, cell transformation by a process of differentiation from a multipotential cell, that will be referred to in this review as islet neogenesis. To better appreciate the mechanisms underlying islet cell neogenesis, some of the basic concepts of developmental biology will be reviewed. Considerable discussion is devoted to the subject of transdifferentiation, a change in a cell or in its progeny from one differentiated phenotype to another, where the change includes both morphological and functional phenotypic markers. While in vitro studies with fetal and neonatal pancreata strongly suggest that new islet tissue is derived from ductal epithelium, what is not established is whether the primary cell is a committed endocrine cell or duct-like cell capable of transdifferentiation. Next, research in the field of β-cell neogenesis is surveyed, in preparation for the examination of whether there is a physiological means of inducing islet cell regeneration, and whether the new islet mass will function in a regulated manner to reverse or stabilize a diabetic state? Our belief is that the pancreas retains the ability to regenerate a functioning islet cell mass in the postnatal period, and that the process of cell transformation leading to islet neogenesis is mediated by growth factors that are intrinsic to the gland. Furthermore, it is our contention that these factors act directly or indirectly on a multipotential cell, probably associated with the ductular epithelium, to induce endocrine cell differentiation. In other words, new islet formation in the postnatal period reiterates the normal ontogeny of islet cell development. These ideas will be fully developed in a discussion of the Partial Duct Obstruction (PDO) Model.

scholarly journals Reprogramming of Mice Primary Hepatocytes into Insulin-Producing Cells by Transfection with Multicistronic Vectors

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Haizhao Luo ◽  
Rongping Chen ◽  
Rui Yang ◽  
Yan Liu ◽  
Youping Chen ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Transcription Factor ◽  
Ectopic Expression ◽  
Potential Method ◽  
Diabetic Mice ◽  
Primary Hepatocytes ◽  
Neurogenin 3 ◽  
Transfected Cells ◽  
Insulin Producing Cells

The neogenesis of insulin-producing cells (IPCs) from non-beta-cells has emerged as a potential method for treating diabetes mellitus (DM). Many groups have documented that activation of pancreatic transcription factor(s) in hepatocytes can improve the hyperglycemia in diabetic mice. In the present study, we explored a novel protocol that reprogrammed primary hepatocytes into functional IPCs by using multicistronic vectors carrying pancreatic and duodenal homeobox-1 (Pdx1), neurogenin 3 (Ngn3), and v-musculoaponeurotic fibrosarcoma oncogene homolog A (MafA). These triple-transfected cells activated multiple beta-cell genes, synthesized and stored considerable amounts of insulin, and released the hormone in a glucose-regulated manner in vitro. Furthermore, when transplanted into streptozotocin-induced diabetic mice, the cells markedly ameliorated glucose tolerance. Our results indicated that ectopic expression of Pdx1, Ngn3, and MafA facilitated hepatocytes-to-IPCs reprogramming. This approach may offer opportunities for treatment of DM.

An in Vitro Study of Pancreatic Ductal Cells

1978 ◽  
Vol 157 (1) ◽  
pp. 23-28 ◽  
Author(s):  
M. Singh ◽  
N. M. Parks ◽  
P. D. Webster
Keyword(s):  
In Vitro Study ◽  
Vitro Study ◽  
Ductal Cells ◽  
Pancreatic Ductal Cells

scholarly journals Pancreatic islets of bank vole show signs of dysfunction after prolonged exposure to high glucose concentrations in vitro

2010 ◽  
Vol 206 (1) ◽  
pp. 47-54 ◽  
Author(s):  
Martin Blixt ◽  
Bo Niklasson ◽  
Stellan Sandler
Keyword(s):  
Gender Difference ◽  
Pancreatic Islets ◽  
High Glucose ◽  
Prolonged Exposure ◽  
Cell Function ◽  
Insulin Biosynthesis ◽  
Bank Voles ◽  
Glucose Tolerant ◽  
Β Cell Function

Bank voles develop glucose intolerance/diabetes mellitus when kept in captivity. We have characterized β-cell function of glucose intolerant/diabetic animals, and found that this animal model has features of both human type 1 and type 2 diabetes. The aim of this study was to study the functional alterations of islets isolated from glucose tolerant bank voles after a prolonged exposure to various glucose concentrations in vitro. For this purpose, pancreatic islets from normal (glucose tolerant) male and female bank voles were cultured at different glucose concentrations (5.6, 11.1 (control), or 28 mM) whereupon islet functions were examined. Overall, islet insulin output was lowered at 5.6 mM glucose, and similar to control, or enhanced after culture in 28 mM glucose. High glucose culture led to decreased insulin contents, but there was no change in islet DNA content and in morphological assessments of cell death, with the latter findings suggesting that the so-called glucotoxicity had not evolved. A slight gender difference was observed in that islets isolated from females exhibited a glucose-regulated (pro)insulin biosynthesis rate and insulin gene expression. In conclusion, we have found that islets isolated from female and male bank voles are affected by glucose concentrations in vitro in that some signs of dysfunction were observed upon high glucose exposure. A minor gender difference was observed suggesting that the islets of the females may more readily adapt to the elevated glucose concentration than islets of the male bank voles. It could be that these in vitro gender differences observed may represent a mechanism underlying the gender difference in diabetes development observed among bank voles.

scholarly journals Expansion and conversion of human pancreatic ductal cells into insulin-secreting endocrine cells

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Jonghyeob Lee ◽  
Takuya Sugiyama ◽  
Yinghua Liu ◽  
Jing Wang ◽  
Xueying Gu ◽  
...  
Keyword(s):  
Endocrine Cells ◽  
General Strategy ◽  
In Vitro Production ◽  
Β Cell ◽  
Ductal Cells ◽  
Adult Human ◽  
Pancreatic Ductal Cells ◽  
Pancreatic Cells ◽  
Vitro Production

Pancreatic islet β-cell insufficiency underlies pathogenesis of diabetes mellitus; thus, functional β-cell replacement from renewable sources is the focus of intensive worldwide effort. However, in vitro production of progeny that secrete insulin in response to physiological cues from primary human cells has proven elusive. Here we describe fractionation, expansion and conversion of primary adult human pancreatic ductal cells into progeny resembling native β-cells. FACS-sorted adult human ductal cells clonally expanded as spheres in culture, while retaining ductal characteristics. Expression of the cardinal islet developmental regulators Neurog3, MafA, Pdx1 and Pax6 converted exocrine duct cells into endocrine progeny with hallmark β-cell properties, including the ability to synthesize, process and store insulin, and secrete it in response to glucose or other depolarizing stimuli. These studies provide evidence that genetic reprogramming of expandable human pancreatic cells with defined factors may serve as a general strategy for islet replacement in diabetes.

Sustained exposure of toxically damaged mouse pancreatic islets to high glucose does not increase β-cell dysfunction

1989 ◽  
Vol 123 (1) ◽  
pp. 47-51 ◽  
Author(s):  
D. L. Eizirik ◽  
S. Sandler
Keyword(s):  
Pancreatic Islets ◽  
Insulin Release ◽  
High Glucose ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Stimulation ◽  
Cell Dysfunction ◽  
Mouse Pancreatic Islets ◽  
Insulin Secretory Response

ABSTRACT The aim of this study was to clarify whether prolonged in-vitro exposure of either normal or damaged β cells to a high glucose environment can be toxic to these cells. For this purpose NMRI mice were injected intravenously with a diabetogenic dose of streptozotocin (SZ; 160 mg/kg) or vehicle alone (controls). Their islets were isolated 15 min after the injection and subsequently maintained in culture for 21 days in the presence of 11·1 or 28 mmol glucose/l. After this period, during acute glucose stimulation, the control islets showed a marked increase in their insulin release in response to a high glucose stimulus. In the SZ-exposed islets there was a decrease in DNA and insulin contents, and a deficient insulin secretory response to glucose. However, in the SZ-damaged islets as well as in the control islets, culture with 28 mmol glucose/l compared with 11·1 mmol glucose/l did not impair islet retrieval after culture, islet DNA content or glucose-induced insulin release. Thus, the degree of damage was similar in the SZ-treated islets cultured at the two concentrations of glucose. These results suggest that glucose is not toxic to normal or damaged mouse pancreatic islets over a prolonged period in tissue culture. Journal of Endocrinology (1989) 123, 47–51

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