scholarly journals Pax4 Expression does not Transduce Pancreatic Alpha Cells to Beta Cells

2015 ◽  
Vol 36 (5) ◽  
pp. 1735-1742 ◽  
Author(s):  
Ling Chen ◽  
Jing Zhang ◽  
Zhuo Zhang ◽  
Yaping Chu ◽  
Bing Song ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Beta Cell ◽  
Beta Cells ◽  
Cell Number ◽  
Diabetic Patients ◽  
Alpha Cells ◽  
Diabetic Mice ◽  
Glucose Response ◽  
Pancreatic Alpha Cells

Background/Aims: The lack of available beta cells greatly limits the use of beta cell transplantation as a therapy for diabetes. Thus, generation of beta cells from other sources is substantially required. Pax4 has been shown to induce reprograming of alpha cells into beta cells during embryogenesis. Nevertheless, whether expression of Pax4 in adult alpha cells could trigger this alpha-to-beta cell reprogramming is unknown. Methods: Here we generated an adeno-associated virus carrying Pax4 and GFP under a CMV promoter (AAV-Pax4). We used AAV-Pax4 to transduce a mouse alpha cell line in vitro, and to transduce primary alpha cells in diabetic mice. Reprogramming was examined by double immunostaining and by changes in beta cell number. The effects on blood glucose were evaluated by fasting blood glucose and glucose response. Results: In vitro, Pax4 overexpression neither induced insulin expression, nor suppressed glucagon expression in alpha cells. In vivo, Pax4 overexpression failed to increase beta cell number, and did not alter hyperglycemia and glucose response in diabetic mice. Conclusion: Pax4 expression is not sufficient to transduce pancreatic alpha cells into beta cells. Overexpression of Pax4 in alpha cells may not increase functional beta cell number in diabetic patients.

scholarly journals Insulin-positive ductal cells do not migrate into preexisting islets during pregnancy

2021 ◽  
Author(s):  
Qun Liu ◽  
Yinan Jiang ◽  
Lingyan Zhu ◽  
Jieqi Qian ◽  
Chaoban Wang ◽  
...  
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Gene Expression Omnibus ◽  
Glucose Response ◽  
Ductal Cells ◽  
Duct Cells ◽  
And Migration

AbstractThe adult pancreatic ductal system was suggested to harbor facultative beta-cell progenitors similar to the embryonic pancreas, and the appearance of insulin-positive duct cells has been used as evidence for natural duct-to-beta-cell reprogramming. Nevertheless, the phenotype and fate of these insulin-positive cells in ducts have not been determined. Here, we used a cell-tagging dye, CFDA-SE, to permanently label pancreatic duct cells through an intraductal infusion technique. Representing a time when significant increases in beta-cell mass occur, pregnancy was later induced in these CFDA-SE-treated mice to assess the phenotype and fate of the insulin-positive cells in ducts. We found that a small portion of CFDA-SE-labeled duct cells became insulin-positive, but they were not fully functional beta-cells based on the in vitro glucose response and the expression levels of key beta-cell genes. Moreover, these insulin-positive cells in ducts expressed significantly lower levels of genes associated with extracellular matrix degradation and cell migration, which may thus prevent their budding and migration into preexisting islets. A similar conclusion was reached through analysis of the Gene Expression Omnibus database for both mice and humans. Together, our data suggest that the contribution of duct cells to normal beta-cells in adult islets is minimal at best.

scholarly journals Alpha cell regulation of beta cell function

Diabetologia ◽  
2020 ◽  
Vol 63 (10) ◽  
pp. 2064-2075
Author(s):  
Tilo Moede ◽  
Ingo B. Leibiger ◽  
Per-Olof Berggren
Keyword(s):  
Blood Glucose ◽  
Beta Cell ◽  
Beta Cells ◽  
Endocrine Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Cell Types ◽  
Alpha Cell ◽  
Alpha Cells

Abstract The islet of Langerhans is a complex endocrine micro-organ consisting of a multitude of endocrine and non-endocrine cell types. The two most abundant and prominent endocrine cell types, the beta and the alpha cells, are essential for the maintenance of blood glucose homeostasis. While the beta cell produces insulin, the only blood glucose-lowering hormone of the body, the alpha cell releases glucagon, which elevates blood glucose. Under physiological conditions, these two cell types affect each other in a paracrine manner. While the release products of the beta cell inhibit alpha cell function, the alpha cell releases factors that are stimulatory for beta cell function and increase glucose-stimulated insulin secretion. The aim of this review is to provide a comprehensive overview of recent research into the regulation of beta cell function by alpha cells, focusing on the effect of alpha cell-secreted factors, such as glucagon and acetylcholine. The consequences of differences in islet architecture between species on the interplay between alpha and beta cells is also discussed. Finally, we give a perspective on the possibility of using an in vivo imaging approach to study the interactions between human alpha and beta cells under in vivo conditions.

scholarly journals Up-regulation of clusterin (sulfated glycoprotein-2) in pancreatic islet cells upon streptozotocin injection to rats

1999 ◽  
Vol 162 (1) ◽  
pp. 57-65 ◽  
Author(s):  
IS Park ◽  
YZ Che ◽  
M Bendayan ◽  
SW Kang ◽  
BH Min
Keyword(s):  
Cell Death ◽  
Embryonic Development ◽  
Beta Cell ◽  
Beta Cells ◽  
Endocrine Cells ◽  
Morphological Alteration ◽  
Alpha Cells ◽  
Pancreatic Alpha Cells ◽  
Tissue Reorganization ◽  
Clusterin Expression

Clusterin is a heterodimeric glycoprotein which has been shown to play important roles in programmed cell death and/or in tissue reorganization not only during embryonic development but also in damaged tissues. Recently, we reported the transient induction of clusterin in pancreatic endocrine cells during early developmental stages of islet formation. In the present study, we have investigated the expression of clusterin in pancreatic tissue of streptozotocin-treated rats which were undergoing extensive islet tissue reorganization due to degeneration of insulin beta cells. Clusterin was found in endocrine cells identified as glucagon-secreting alpha cells at the periphery of the islet. Using immunoelectron microscopy, clusterin-positive cells showed the typical ultrastructural features of pancreatic alpha cells. In addition, colocalization of clusterin and glucagon in the same secretory granules was shown by double immunogold labeling. These results imply that clusterin is a secretory molecule having endocrine and/or paracrine actions in parallel with glucagon. Further, we noted that clusterin expression was increased in pancreatic alpha cells during the process of beta cell death upon streptozotocin injection. The increase was significant as early as 1-3 h after streptozotocin treatment prior to any morphological alteration of islet beta cell and any manifestation of hyperglycemia. The expression of clusterin was steady-stately up-regulated during the process of islet reorganization caused by streptozotocin-induced cytotoxic injury. Therefore, we suggest that clusterin might be considered as a molecule induced by both embryonic development and drug-induced reorganization of the endocrine pancreas. Since clusterin expression is up-regulated in alpha cells, but not in beta cells undergoing degeneration, it may play a protective role against the cytotoxic insult.

scholarly journals Crocodile blood supplementation protects vascular function in diabetic mice

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Chui Yiu Bamboo Chook ◽  
Francis M. Chen ◽  
Gary Tse ◽  
Fung Ping Leung ◽  
Wing Tak Wong
Keyword(s):  
Endothelial Cells ◽  
Vascular Function ◽  
Quantitative Polymerase Chain Reaction ◽  
Functional Study ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Gene Expressions ◽  
Inflammatory State ◽  
Crocodile Blood

Abstract Cardiovascular disease is a major cause of mortality in diabetic patients due to the heightened oxidative stress and pro-inflammatory state in vascular tissues. Effective approaches targeting cardiovascular health for diabetic patients are urgently needed. Crocodile blood, an emerging dietary supplement, was suggested to have anti-oxidative and anti-inflammatory effects in vitro, which have yet to be proven in animal models. This study thereby aimed to evaluate whether crocodile blood can protect vascular function in diabetic mice against oxidation and inflammation. Diabetic db/db mice and their counterparts db/m+ mice were treated daily with crocodile blood soluble fraction (CBSF) or vehicle via oral gavage for 4 weeks before their aortae were harvested for endothelium-dependent relaxation (EDR) quantification using wire myograph, which is a well-established functional study for vascular function indication. Organ culture experiments culturing mouse aortae from C57BL/6 J mice with or without IL-1β and CBSF were done to evaluate the direct effect of CBSF on endothelial function. Reactive oxygen species (ROS) levels in mouse aortae were assessed by dihydroethidium (DHE) staining with inflammatory markers in endothelial cells quantified by quantitative polymerase chain reaction (qPCR). CBSF significantly improved deteriorated EDR in db/db diabetic mice through both diet supplementation and direct culture, with suppression of ROS level in mouse aortae. CBSF also maintained EDR and reduced ROS levels in mouse aortae against the presence of pro-inflammatory IL-1β. Under the pro-inflammatory state induced by IL-1β, gene expressions of inflammatory cytokines were downregulated, while the protective transcripts UCP2 and SIRT6 were upregulated in endothelial cells. Our study suggests a novel beneficial effect of crocodile blood on vascular function in diabetic mice and that supplementation of diet with crocodile blood may act as a complementary approach to protect against vascular diseases through anti-oxidation and anti-inflammation in diabetic patients. Graphical abstract

scholarly journals A small molecule HIF-1α stabilizer that accelerates diabetic wound healing

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Guodong Li ◽  
Chung-Nga Ko ◽  
Dan Li ◽  
Chao Yang ◽  
Wanhe Wang ◽  
...  
Keyword(s):  
Wound Healing ◽  
Small Molecule ◽  
Hypoxia Inducible Factor ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Impaired Wound Healing ◽  
Von Hippel Lindau ◽  
Design And Synthesis

AbstractImpaired wound healing and ulcer complications are a leading cause of death in diabetic patients. In this study, we report the design and synthesis of a cyclometalated iridium(III) metal complex 1a as a stabilizer of hypoxia-inducible factor-1α (HIF-1α). In vitro biophysical and cellular analyses demonstrate that this compound binds to Von Hippel-Lindau (VHL) and inhibits the VHL–HIF-1α interaction. Furthermore, the compound accumulates HIF-1α levels in cellulo and activates HIF-1α mediated gene expression, including VEGF, GLUT1, and EPO. In in vivo mouse models, the compound significantly accelerates wound closure in both normal and diabetic mice, with a greater effect being observed in the diabetic group. We also demonstrate that HIF-1α driven genes related to wound healing (i.e. HSP-90, VEGFR-1, SDF-1, SCF, and Tie-2) are increased in the wound tissue of 1a-treated diabetic mice (including, db/db, HFD/STZ and STZ models). Our study demonstrates a small molecule stabilizer of HIF-1α as a promising therapeutic agent for wound healing, and, more importantly, validates the feasibility of treating diabetic wounds by blocking the VHL and HIF-1α interaction.

Comparative toxicity of alloxan, N-alkylalloxans and ninhydrin to isolated pancreatic islets in vitro

1997 ◽  
Vol 155 (2) ◽  
pp. 283-293 ◽  
Author(s):  
A Jorns ◽  
R Munday ◽  
M Tiedge ◽  
S Lenzen
Keyword(s):  
Beta Cell ◽  
Pancreatic Islets ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Ultrastructural Changes ◽  
Cell Necrosis ◽  
High Concentrations ◽  
Beta Cell Necrosis

The in vitro toxicity of the diabetogenic agent alloxan as documented by the induction of beta cell necrosis was studied in isolated ob/ob mouse pancreatic islets. The effect of alloxan has been compared with that of a number of N-alkyl alloxan derivatives and with that of the structurally related compound, ninhydrin. Alloxan and its derivatives were selectively toxic to pancreatic beta cells, with other endocrine cells and exocrine parenchymal cells being well preserved, even at high concentration. In contrast, ninhydrin was selectively toxic to pancreatic beta cells only at comparatively low concentration, destroying all islet cell types at high concentrations. The ultrastructural changes induced by all the test compounds in pancreatic beta cells in vitro were very similar to those observed during the development of alloxan diabetes in vivo. The relative toxicity of the various compounds to pancreatic beta cells in vitro was not, however, related to their ability to cause diabetes in vivo. Indeed, the non-diabetogenic substances ninhydrin, N-butylalloxan and N-isobutylalloxan were very much more toxic to isolated islets than the diabetogenic compounds alloxan and N-methylalloxan. These results suggest that the differences in diabetogenicity among alloxan derivatives are not due to intrinsic differences in the susceptibility of the pancreatic beta cells to their toxicity, but may reflect differences in distribution or metabolism. High concentrations of glucose protected islets against the harmful effects of alloxan and its derivatives, but not those of ninhydrin. Low levels of glucose, and non-carbohydrate nutrients, afforded little protection, indicating that the effect of glucose is not due to the production of reducing equivalents within the cell, 3-O-Methylglucose, which protects against alloan diabetes in vivo, did not protect against alloxan toxicity in vitro. Since 3-O-methylglucose is known to prevent uptake of alloxan by pancreatic beta cells, it appears that uptake of alloxan by the cell is not a prerequisite for the induction of beta cell necrosis.

Defective stimulation of proliferation and collagen biosynthesis of human bone cells by serum from diabetic patients

1992 ◽  
Vol 127 (6) ◽  
pp. 509-514 ◽  
Author(s):  
Rolf E Brenner ◽  
Bert Riemenschneider ◽  
Werner Blum ◽  
Martin Mörike ◽  
Walter M Teller ◽  
...  
Keyword(s):  
Metabolic Control ◽  
Collagen Synthesis ◽  
Bone Cells ◽  
Cell Attachment ◽  
Cell Number ◽  
Human Bone ◽  
Diabetic Patients ◽  
Inhibitory Influence ◽  
Control Serum

We studied the influence of fasting serum from nine insulin-dependent diabetic children and adolescents under insufficient metabolic control on normal human bone cells in vitro compared with serum from eight sex- and age-matched controls. Cell number 24 h after plating was significantly less under diabetic serum, indicating impaired cell attachment, spreading and initiation of cell proliferation. Cell number after five days was reduced by 1% diabetic serum, while higher serum concentrations had diverging effects on osteoblast proliferation. Collagen synthesis of human osteoblasts was significantly reduced by 8% diabetic serum compared to 8% control serum, while synthesis of non-collagenous proteins was not affected. Duration of diabetes (several weeks up to 12 years) had no influence on these parameters. The serum from one patient, which was studied a second time under excellent metabolic control three months later, however, had lost its inhibitory influence on collagen synthesis of osteoblasts. The pattern of the interstitial collagen types I, III and V was not altered by diabetic serum. These results indicate that defective regulation of proliferation and collagen synthesis of osteoblasts by components present in human diabetic serum may be an important factor in the development of diabetic osteopenia. The negative influence might be explained in part by reduced levels of IGF-I and elevated levels of IGF binding protein-1 in the diabetic sera.

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