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 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 ENTPD3 Marks Mature Stem Cell Derived Beta Cells Formed by Self-Aggregation in Vitro

2021 ◽  
Author(s):  
Fiona M. Docherty ◽  
Kent A. Riemondy ◽  
Roberto Castro-Gutierrez ◽  
JaeAnn M. Dwulet ◽  
Ali H. Shilleh ◽  
...  
Keyword(s):  
Stem Cell ◽  
Replacement Therapy ◽  
Beta Cells ◽  
Nucleoside Triphosphate ◽  
Specific Marker ◽  
Detailed Knowledge ◽  
Cell Replacement Therapy ◽  
Mature Adult ◽  
Cell Replacement

Stem cell derived beta-like cells (sBC) carry the promise of providing an abundant source of insulin-producing cells for use in cell replacement therapy for patients with diabetes, potentially allowing widespread implementation of a practical cure. To achieve their clinical promise, sBC need to function comparably to mature adult beta cells, but as yet they display varying degrees of maturity. Indeed, detailed knowledge of the events resulting in human beta cell maturation remains obscure. Here we show that sBC spontaneously self-enrich into discreet islet-like cap structures within <i>in vitro</i> cultures, independent of exogenous maturation conditions. Multiple complementary assays demonstrate that this process is accompanied by functional maturation of the self-enriched sBC (seBC); however, the seBC still contain distinct subpopulations displaying different maturation levels. Interestingly, the surface protein ENTPD3 (also known as nucleoside triphosphate diphosphohydrolase-3 (NDPTase3)) is a specific marker of the most mature seBC population and can be used for mature seBC identification and sorting. Our results illuminate critical aspects of <i>in vitro</i> sBC maturation and provide important insights towards developing functionally mature sBC for diabetes cell replacement therapy.

scholarly journals Brain permeable AMPK activator R481 raises glycemia by autonomic nervous system activation and amplifies the counterregulatory response to hypoglycemia in rats

2019 ◽  
Author(s):  
Ana M. Cruz ◽  
Yasaman Malekizadeh ◽  
Julia M. Vlachaki Walker ◽  
Paul G. Weightman Potter ◽  
Katherine Pye ◽  
...  
Keyword(s):  
Nervous System ◽  
Autonomic Nervous System ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Ventromedial Hypothalamus ◽  
Whole Body ◽  
Ampk Activation ◽  
Autonomic Nervous ◽  
Glucose Levels

ABSTRACTAMP-activated protein kinase (AMPK) is a critical cellular and whole body energy sensor activated by energy stress, including hypoglycemia, which is frequently experienced by people with diabetes. Previous studies using direct delivery of an AMPK activator to the ventromedial hypothalamus (VMH) in rodents increased hepatic glucose production. Moreover, recurrent glucoprivation in the hypothalamus leads to blunted AMPK activation and defective hormonal responses to subsequent hypoglycemia. These data suggest that amplifying AMPK activation may prevent or reduce frequency hypoglycemia in diabetes. We used a novel brain-permeable AMPK activator, R481, which potently increased AMPK phosphorylation in vitro. R481 significantly increased peak glucose levels during glucose tolerance tests in rats, which were attenuated by treatment with AMPK inhibitor SBI-0206965 and completely abolished by blockade of the autonomic nervous system. This occurred without altering insulin sensitivity measured by hyperinsulinemic-euglycemic clamps. Endogenous insulin secretion was not altered by R481 treatment. During hyperinsulinemic-hypoglycemic clamp studies, R481 treatment reduced exogenous glucose requirements and amplified peak glucagon levels during hypoglycemia. These data demonstrate that peripheral administration of the brain permeable AMPK activator R481 amplifies the counterregulatory response to hypoglycemia in rats, which could have clinical relevance for prevention of hypoglycemia.

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

Regulation of glucose production in rainbow trout: role of epinephrine in vivo and in isolated hepatocytes

2000 ◽  
Vol 278 (4) ◽  
pp. R956-R963 ◽  
Author(s):  
Jean-Michel Weber ◽  
Deena S. Shanghavi
Keyword(s):  
Rainbow Trout ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Isolated Hepatocytes ◽  
Relative Increase ◽  
Dependent Manner ◽  
Rainbow Trout Oncorhynchus Mykiss

The rate of hepatic glucose production (Ra glucose) of rainbow trout ( Oncorhynchus mykiss) was measured in vivo by continuous infusion of [6-3H]glucose and in vitro on isolated hepatocytes to examine the role of epinephrine (Epi) in its regulation. By elevating Epi concentration and/or blocking β-adrenoreceptors with propranolol (Prop), our goals were to investigate the mechanism for Epi-induced hyperglycemia to determine the possible role played by basal Epi concentration in maintaining resting Ra glucose and to assess indirect effects of Epi in the intact animal. In vivo infusion of Epi caused hyperglycemia (3.75 ± 0.16 to 8.75 ± 0.54 mM) and a twofold increase in Ra glucose (6.57 ± 0.79 to 13.30 ± 1.78 μmol ⋅ kg− 1 ⋅ min− 1, n = 7), whereas Prop infusion decreased Ra from 7.65 ± 0.92 to 4.10 ± 0.56 μmol ⋅ kg− 1 ⋅ min− 1( n = 10). Isolated hepatocytes increased glucose production when treated with Epi, and this response was abolished in the presence of Prop. We conclude that Epi-induced trout hyperglycemia is entirely caused by an increase in Ra glucose, because the decrease in the rate of glucose disappearance normally seen in mammals does not occur in trout. Basal circulating levels of Epi are involved in maintaining resting Ra glucose. Epi stimulates in vitro glucose production in a dose-dependent manner, and its effects are mainly mediated by β-adrenoreceptors. Isolated trout hepatocytes produce glucose at one-half the basal rate measured in vivo, even when diet, temperature, and body size are standardized, and basal circulating Epi is responsible for part of this discrepancy. The relative increase in Ra glucose after Epi stimulation is similar in vivo and in vitro, suggesting that indirect in vivo effects of Epi, such as changes in hepatic blood flow or in other circulating hormones, do not play an important role in the regulation of glucose production in trout.

Sign in / Sign up

Export Citation Format

Share Document