scholarly journals HSPB1 Is Essential for Inducing Resistance to Proteotoxic Stress in Beta-Cells

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2178
Author(s):  
Vinícius M. Gomes ◽  
Rosangela A. M. Wailemann ◽  
Gabriel S. Arini ◽  
Talita C. Oliveira ◽  
Daria R. Q. Almeida ◽  
...  
Keyword(s):  
Beta Cell ◽  
Er Stress ◽  
Protein Degradation ◽  
Beta Cells ◽  
Degradation Pathway ◽  
Attractive Alternative ◽  
Cell Replacement ◽  
Proteotoxic Stress ◽  
Protein Ubiquitination ◽  
Beta Cell Replacement

During type 1 diabetes mellitus (T1DM) development, beta-cells undergo intense endoplasmic reticulum (ER) stress that could result in apoptosis through the failure of adaptation to the unfolded protein response (UPR). Islet transplantation is considered an attractive alternative among beta-cell replacement therapies for T1DM. To avoid the loss of beta-cells that will jeopardize the transplant’s outcome, several strategies are being studied. We have previously shown that prolactin induces protection against proinflammatory cytokines and redox imbalance-induced beta-cell death by increasing heat-shock protein B1 (HSPB1) levels. Since the role of HSPB1 in beta cells has not been deeply studied, we investigated the mechanisms involved in unbalanced protein homeostasis caused by intense ER stress and overload of the proteasomal protein degradation pathway. We tested whether HSPB1-mediated cytoprotective effects involved UPR modulation and improvement of protein degradation via the ubiquitin-proteasome system. We demonstrated that increased levels of HSPB1 attenuated levels of pro-apoptotic proteins such as CHOP and BIM, as well as increased protein ubiquitination and the speed of proteasomal protein degradation. Our data showed that HSPB1 induced resistance to proteotoxic stress and, thus, enhanced cell survival via an increase in beta-cell proteolytic capacity. These results could contribute to generate strategies aimed at the optimization of beta-cell replacement therapies.

scholarly journals Human Beta Cell Regenerative Drug Therapy for Diabetes: Past Achievements and Future Challenges

2021 ◽  
Vol 12 ◽  
Author(s):  
Peng Wang ◽  
Esra Karakose ◽  
Lauryn Choleva ◽  
Kunal Kumar ◽  
Robert J. DeVita ◽  
...  
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Normal Function ◽  
Human Stem Cells ◽  
Pancreatic Islet Transplantation ◽  
Cell Replacement ◽  
The World ◽  
Beta Cell Replacement ◽  
Human Beta Cell

A quantitative deficiency of normally functioning insulin-producing pancreatic beta cells is a major contributor to all common forms of diabetes. This is the underlying premise for attempts to replace beta cells in people with diabetes by pancreas transplantation, pancreatic islet transplantation, and transplantation of beta cells or pancreatic islets derived from human stem cells. While progress is rapid and impressive in the beta cell replacement field, these approaches are expensive, and for transplant approaches, limited by donor organ availability. For these reasons, beta cell replacement will not likely become available to the hundreds of millions of people around the world with diabetes. Since the large majority of people with diabetes have some residual beta cells in their pancreata, an alternate approach to reversing diabetes would be developing pharmacologic approaches to induce these residual beta cells to regenerate and expand in a way that also permits normal function. Unfortunately, despite the broad availability of multiple classes of diabetes drugs in the current diabetes armamentarium, none has the ability to induce regeneration or expansion of human beta cells. Development of such drugs would be transformative for diabetes care around the world. This picture has begun to change. Over the past half-decade, a novel class of beta cell regenerative small molecules has emerged: the DYRK1A inhibitors. Their emergence has tremendous potential, but many areas of uncertainty and challenge remain. In this review, we summarize the accomplishments in the world of beta cell regenerative drug development and summarize areas in which most experts would agree. We also outline and summarize areas of disagreement or lack of unanimity, of controversy in the field, of obstacles to beta cell regeneration, and of challenges that will need to be overcome in order to establish human beta cell regenerative drug therapeutics as a clinically viable class of diabetes drugs.

scholarly journals (Re)generating Human Beta Cells: Status, Pitfalls, and Perspectives

2018 ◽  
Vol 98 (3) ◽  
pp. 1143-1167 ◽  
Author(s):  
Luc Baeyens ◽  
Marie Lemper ◽  
Willem Staels ◽  
Sofie De Groef ◽  
Nico De Leu ◽  
...  
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Peptide Hormone ◽  
Insulin Injection ◽  
Current Therapy ◽  
Cell Replacement ◽  
Beta Cell Replacement

Diabetes mellitus results from disturbed glucose homeostasis due to an absolute (type 1) or relative (type 2) deficiency of insulin, a peptide hormone almost exclusively produced by the beta cells of the endocrine pancreas in a tightly regulated manner. Current therapy only delays disease progression through insulin injection and/or oral medications that increase insulin secretion or sensitivity, decrease hepatic glucose production, or promote glucosuria. These drugs have turned diabetes into a chronic disease as they do not solve the underlying beta cell defects or entirely prevent the long-term complications of hyperglycemia. Beta cell replacement through islet transplantation is a more physiological therapeutic alternative but is severely hampered by donor shortage and immune rejection. A curative strategy should combine newer approaches to immunomodulation with beta cell replacement. Success of this approach depends on the development of practical methods for generating beta cells, either in vitro or in situ through beta cell replication or beta cell differentiation. This review provides an overview of human beta cell generation.

scholarly journals Encapsulation technologies in beta cell replacement therapies for Type 1 diabetes

2016 ◽  
pp. 359-383
Author(s):  
Rahul Krishnan ◽  
David Imagawa ◽  
Clarence Foster III ◽  
Jonathan Lakey
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cell ◽  
Cell Replacement ◽  
Beta Cell Replacement
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