scholarly journals Towards the Development of a Female Animal Model of T1DM Using Hyaluronic Acid Nanocoated Cell Transplantation: Refinements and Considerations for Future Protocols

Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1925
Author(s):  
Fernanda Zamboni ◽  
Ibrahim F. Cengiz ◽  
Ana M. Barbosa ◽  
Antonio G. Castro ◽  
Rui L. Reis ◽  
...  
Keyword(s):  
Hyaluronic Acid ◽  
Low Dose ◽  
Developmental Stages ◽  
Single Cells ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Encapsulated Cells ◽  
Female Mice ◽  
Glucose Levels ◽  
Elevated Glucose

Female mice (Black 6 strain) (C57BL/6) aged 6 weeks were subject to low dose streptozotocin (STZ) treatment for five consecutive days to mimic type 1 diabetes mellitus (T1DM) with insulitis. At two weeks after STZ injections, evaluation of the elevated glucose levels was used to confirm diabetes. The diabetic mice were then subject to the transplantation of pancreatic β-cells (MIN-6 line). Four groups of mice were studied. The first group was injected with saline-only acting as the placebo surgery control, also known as SHAM group, the second and third groups were injected with MIN-6 single cells and polyethylene glycol-modified dipalmitoyl-glycerol-phosphatidyl ethanolamine (PEG-DPPE) modified MIN-6 single cells (500 µg per 1.106 cells), respectively, while the fourth group was injected with hyaluronic acid (HA)-coated MIN-6 single cells (5 bilayers). At seven- and fourteen-days following transplantation, the mice were euthanised. The renal and pancreatic tissues were then collected and histologically analysed. The induction of diabetes in female mice, through five-consecutive daily STZ injections resulted in inconsistent glycaemic levels. Interestingly, this shows an incomplete diabetes induction in female mice, of which we attribute to sex dimorphism and hormonal interferences. Transplantation failure of free-floating encapsulated cells was unable to decrease blood glucose hyperglycaemia to physiological ranges. The result is attributed to deprived cell–cell interactions, leading to decreased β-cells functionality. Overall, we highlight the necessity of refining T1DM disease models in female subjects when using multiple low-dose STZ injections together with transplantation protocols. Considerations need to be made regarding the different developmental stages of female mice and oestrogen load interfering with pancreatic β-cells susceptibility to STZ. The use of pseudo islets, cell aggregates and spheroids are sought to improve transplantation outcome in comparison to free-floating single cells.

Cell-wide analysis of secretory granule dynamics in three dimensions in living pancreatic β-cells: evidence against a role for AMPK-dependent phosphorylation of KLC1 at Ser517/Ser520 in glucose-stimulated insulin granule movement

2010 ◽  
Vol 38 (1) ◽  
pp. 205-208 ◽  
Author(s):  
Angela McDonald ◽  
Sarah Fogarty ◽  
Isabelle Leclerc ◽  
Elaine V. Hill ◽  
D. Grahame Hardie ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glutathione Transferase ◽  
Three Dimensions ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Glucose Levels ◽  
Insulin Granules ◽  
Elevated Glucose ◽  
Glucose Stimulated Insulin Secretion

Glucose-stimulated insulin secretion from pancreatic β-cells requires the kinesin-1/Kif5B-mediated transport of insulin granules along microtubules. 5′-AMPK (5′-AMP-activated protein kinase) is a heterotrimeric serine/threonine kinase which is activated in β-cells at low glucose concentrations, but inhibited as glucose levels increase. Active AMPK blocks glucose-stimulated insulin secretion and the recruitment of insulin granules to the cell surface, suggesting motor proteins may be targets for this kinase. While both kinesin-1/Kif5B and KLC1 (kinesin light chain-1) contain consensus AMPK phosphorylation sites (Thr693 and Ser520, respectively) only recombinant GST (glutathione transferase)–KLC1 was phosphorylated by purified AMPK in vitro. To test the hypothesis that phosphorylation at this site may modulate kinesin-1-mediated granule movement, we developed an approach to study the dynamics of all the resolvable granules within a cell in three dimensions. This cell-wide approach revealed that the number of longer excursions (>10 μm) increased significantly in response to elevated glucose concentration (30 versus 3 mM) in control MIN6 β-cells. However, similar changes were seen in cells overexpressing wild-type KLC1, phosphomimetic (S517D/S520D) or non-phosphorylatable (S517A/S520A) mutants of KLC1. Thus, changes in the phosphorylation state of KLC1 at Ser517/Ser520 seem unlikely to affect motor function.

scholarly journals Teucrium polium: Potential Drug Source for Type 2 Diabetes Mellitus

Biology ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 128
Author(s):  
Yaser Albadr ◽  
Andrew Crowe ◽  
Rima Caccetta
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Secretion ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Glucose Levels ◽  
Teucrium Polium

The prevalence of type 2 diabetes mellitus is rising globally and this disease is proposed to be the next pandemic after COVID-19. Although the cause of type 2 diabetes mellitus is unknown, it is believed to involve a complex array of genetic defects that affect metabolic pathways which eventually lead to hyperglycaemia. This hyperglycaemia arises from an inability of the insulin-sensitive cells to sufficiently respond to the secreted insulin, which eventually results in the inadequate secretion of insulin from pancreatic β-cells. Several treatments, utilising a variety of mechanisms, are available for type 2 diabetes mellitus. However, more medications are needed to assist with the optimal management of the different stages of the disease in patients of varying ages with the diverse combinations of other medications co-administered. Throughout modern history, some lead constituents from ancient medicinal plants have been investigated extensively and helped in developing synthetic antidiabetic drugs, such as metformin. Teucrium polium L. (Tp) is a herb that has a folk reputation for its antidiabetic potential. Previous studies indicate that Tp extracts significantly decrease blood glucose levels r and induce insulin secretion from pancreatic β-cells in vitro. Nonetheless, the constituent/s responsible for this action have not yet been elucidated. The effects appear to be, at least in part, attributable to the presence of selected flavonoids (apigenin, quercetin, and rutin). This review aims to examine the reported glucose-lowering effect of the herb, with a keen focus on insulin secretion, specifically related to type 2 diabetes mellitus. An analysis of the contribution of the key constituent flavonoids of Tp extracts will also be discussed.

scholarly journals Androgen excess in pancreatic β cells and neurons predisposes female mice to type 2 diabetes

JCI Insight ◽  
2018 ◽  
Vol 3 (12) ◽  
Author(s):  
Guadalupe Navarro ◽  
Camille Allard ◽  
Jamie J. Morford ◽  
Weiwei Xu ◽  
Suhuan Liu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Androgen Excess ◽  
Female Mice

scholarly journals Mitochondrial–Endoplasmic Reticulum Interplay: A Lifelong On–Off Relationship?

Contact ◽  
2019 ◽  
Vol 2 ◽  
pp. 251525641986122 ◽  
Author(s):  
Corina T. Madreiter-Sokolowski ◽  
Roland M. Malli ◽  
Wolfgang F. Graier
Keyword(s):  
Endoplasmic Reticulum ◽  
Adenosine Triphosphate ◽  
Therapeutic Strategies ◽  
Mitochondrial Activity ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Potential Target ◽  
Pathological Conditions ◽  
Elevated Glucose ◽  
Stimulation Of

This article comments recent publications that highlight an intriguing importance of specific settings in the interaction between the mitochondria and the endoplasmic reticulum to ensure cell-specific functions like the responsiveness to elevated glucose in pancreatic β-cells. Hence, alterations of the mitochondria–endoplasmic reticulum communications under various pathological conditions like aging or cancer often come with enhanced Ca2+ transfer that, in turn, yields stimulation of basal mitochondrial activity to meet the increasing adenosine triphosphate demand of the very cell. Such observations identify mitochondria-associated membranes as potential target for new therapeutic strategies against aging or cancer.

scholarly journals Role of Hck in the Pathogenesis of Encephalomyocarditis Virus-Induced Diabetes in Mice

2001 ◽  
Vol 75 (4) ◽  
pp. 1949-1957 ◽  
Author(s):  
K. S. Choi ◽  
H. S. Jun ◽  
H. N. Kim ◽  
H. J. Park ◽  
Y. W. Eom ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Low Dose ◽  
Kinase Inhibitor ◽  
Src Kinase ◽  
Encephalomyocarditis Virus ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Necrosis Factor Alpha ◽  
Diabetes In Mice ◽  
Tnf Α

ABSTRACT Soluble mediators such as interleukin-1β, tumor necrosis factor alpha (TNF-α), and inducible nitric oxide synthase (iNOS) produced from activated macrophages play an important role in the destruction of pancreatic β cells in mice infected with a low dose of the D variant of encephalomyocarditis (EMC-D) virus. The tyrosine kinase signaling pathway was shown to be involved in EMC-D virus-induced activation of macrophages. This investigation was initiated to determine whether the Src family of kinases plays a role in the activation of macrophages, subsequently resulting in the destruction of β cells, in mice infected with a low dose of EMC-D virus. We examined the activation of p59/p56Hck, p55Fgr, and p56/p53Lynin macrophages from DBA/2 mice infected with the virus. We found that p59/p56Hck showed a marked increase in both autophosphorylation and kinase activity at 48 h after infection, whereas p55Fgr and p56/p53Lyn did not. The p59/p56Hck activity was closely correlated with the tyrosine phosphorylation level of Vav. Treatment of EMC-D virus-infected mice with the Src kinase inhibitor, PP2, resulted in the inhibition of p59/p56Hck activity and almost complete inhibition of the production of TNF-α and iNOS in macrophages and the subsequent prevention of diabetes in mice. On the basis of these observations, we conclude that the Src kinase, p59/p56Hck, plays an important role in the activation of macrophages and the subsequent production of TNF-α and nitric oxide, leading to the destruction of pancreatic β cells, which results in the development of diabetes in mice infected with a low dose of EMC-D virus.

Protective effect of 4,6-O-ethylidene glucose against the cytotoxicity of streptozotocin in pancreatic β cells in vivo: indirect evidence for the presence of a glucose transporter in β cells

1987 ◽  
Vol 112 (3) ◽  
pp. 375-378 ◽  
Author(s):  
J. Kawada ◽  
M. Okita ◽  
M. Nishida ◽  
Y. Yoshimura ◽  
K. Toyooka ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Glucose Transporter ◽  
Indirect Evidence ◽  
Tolerance Test ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Glucose Levels ◽  
In Vivo Experiments ◽  
Glucose Transport System

ABSTRACT Ethylidene glucose (4,6-O-ethylidene glucose; EG) is known to bind the outer surface of the glucose transporter in the membranes of human erythrocytes and other mammalian cells. If a glucose transport system is present on pancreatic β cells and recognizes the glucose moiety of streptozotocin (STZ), EG should protect β cells from the cytotoxicity of STZ when it is administered with STZ. This possibility was examined in in-vivo experiments in rats. When EG and STZ were injected into rats together the animals did not become diabetic, as judged by (1) their blood glucose levels, (2) response in a glucose-tolerance test, and (3) insulin secretion in response to feeding. These results suggest that there is a glucose transporter present in β cells and also the transport of streptozotocin into β cells through this system. J. Endocr. (1987) 112, 375–378

The Ins and Outs of Secretion from Pancreatic β-Cells: Control of Single-Vesicle Exo- and Endocytosis

Physiology ◽  
2007 ◽  
Vol 22 (2) ◽  
pp. 113-121 ◽  
Author(s):  
Patrick E. MacDonald ◽  
Patrik Rorsman
Keyword(s):  
Plasma Membrane ◽  
Plasma Glucose ◽  
Secretory Vesicles ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Glucose Levels ◽  
Single Vesicle

Exocytosis of insulin-containing secretory vesicles in pancreatic β-cells is crucial to maintenance of plasma glucose levels. They fuse with the plasma membrane in a regulated manner to release their contents and are subsequently recaptured either intact or through conventional clathrin-mediated endocytosis. Here, we discuss these mechanisms in β-cells at the single-vesicle level.

Hypoglycemic effects of wheat bran alkyresorcinols in high-fat/high-sucrose diet and low-dose streptozotocin-induced type 2 diabetic male mice and protection of pancreatic β cells

2019 ◽  
Vol 10 (6) ◽  
pp. 3282-3290 ◽  
Author(s):  
Jie Tu ◽  
Guanhui Liu ◽  
Xitao Cao ◽  
Shuyun Zhu ◽  
Qiang Li ◽  
...  
Keyword(s):  
Wheat Bran ◽  
Low Dose ◽  
High Fat ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Sucrose Diet ◽  
High Sucrose Diet ◽  
High Sucrose ◽  
Type 2 Diabetic

In the present study, the hypoglycemic effects of wheat bran alkyresorcinols were investigated in type 2 diabetes mellitus mice induced by a high-fat/high-sucrose diet combined with low dose streptozotocin.

Emerging roles for the ubiquitin-proteasome system and autophagy in pancreatic β-cells

2009 ◽  
Vol 296 (1) ◽  
pp. E1-E10 ◽  
Author(s):  
Taila Hartley ◽  
John Brumell ◽  
Allen Volchuk
Keyword(s):  
Cell Function ◽  
Ubiquitin Proteasome System ◽  
Contributory Factor ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Glucose Levels ◽  
Pathological Conditions ◽  
Ubiquitin Proteasome

Protein degradation in eukaryotic cells is mediated primarily by the ubiquitin-proteasome system and autophagy. Turnover of protein aggregates and other cytoplasmic components, including organelles, is another function attributed to autophagy. The ubiquitin-proteasome system and autophagy are essential for normal cell function but under certain pathological conditions can be overwhelmed, which can lead to adverse effects in cells. In this review we will focus primarily on the insulin-producing pancreatic β-cell. Pancreatic β-cells respond to glucose levels by both producing and secreting insulin. The inability of β-cells to secrete sufficient insulin is a major contributory factor in the development of type 2 diabetes. The aim of this review is to examine some of the crucial roles of the ubiquitin-proteasome system and autophagy in normal pancreatic β-cell function and how these pathways may become dysfunctional under pathological conditions associated with metabolic syndromes.

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