Type 1 diabetes mellitus: much progress, many opportunities

Powers, Alvin C.

doi:10.1172/jci142242

Cited by 76 publications

(54 citation statements)

References 154 publications

(178 reference statements)

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Section: Discussionmentioning

confidence: 99%

“…Reduced pancreatic β-cell mass is the ultimate cause of impaired insulin synthesis and secretion in DM [ 31 , 32 ]. Apoptosis of β-cells explains in part the insufficient insulin production and secretion in DM [ 32 , 33 , 34 ]. Autoimmune-isletitis-associated cell damage in type 1 DM and hyperglycemia-associated oxidative stress and endoplasmic reticulum stress in type 2 DM are involved in pancreatic β-cell apoptosis [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Islet inflammation or isletitis is a common pathological finding in type 1 and type 2 DM [ 32 , 33 ]. Inflammation in type 1 DM results from an autoimmune response to islet β-cells characterized by a predominant infiltration of CD8+ T-cells and less-abundant CD4+ T cells, B cells, and macrophages [ 32 , 35 ]. In type 2 DM, initial compensatory islet hyperplasia occurs in response to insulin resistance followed by a progressive β-cell dysfunction leading to hyperglycemia, increased oxidative stress, and infiltration of pancreatic islets by macrophages and T-cells [ 31 , 33 , 41 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

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Protective Role of Recombinant Human Thrombomodulin in Diabetes Mellitus

Okano

Takeshita

Yasuma

et al. 2021

Cells

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Diabetes mellitus is a global threat to human health. The ultimate cause of diabetes mellitus is insufficient insulin production and secretion associated with reduced pancreatic β-cell mass. Apoptosis is an important and well-recognized mechanism of the progressive loss of functional β-cells. However, there are currently no available antiapoptotic drugs for diabetes mellitus. This study evaluated whether recombinant human thrombomodulin can inhibit β-cell apoptosis and improve glucose intolerance in a diabetes mouse model. A streptozotocin-induced diabetes mouse model was prepared and treated with thrombomodulin or saline three times per week for eight weeks. The glucose tolerance and apoptosis of β-cells were evaluated. Diabetic mice treated with recombinant human thrombomodulin showed significantly improved glucose tolerance, increased insulin secretion, decreased pancreatic islet areas of apoptotic β-cells, and enhanced proportion of regulatory T cells and tolerogenic dendritic cells in the spleen compared to counterpart diseased mice treated with saline. Non-diabetic mice showed no changes. This study shows that recombinant human thrombomodulin, a drug currently used to treat patients with coagulopathy in Japan, ameliorates glucose intolerance by protecting pancreatic islet β-cells from apoptosis and modulating the immune response in diabetic mice. This observation points to recombinant human thrombomodulin as a promising antiapoptotic drug for diabetes mellitus.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Protective Role of Recombinant Human Thrombomodulin in Diabetes Mellitus

Okano

Takeshita

Yasuma

et al. 2021

Cells

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“…Diabetes mellitus is characterized by chronic hyperglycemia due to partial or absolute insulin deficiency (type 1 diabetes, T1D) or pancreatic beta cell dysfunction and/or insulin inaction (type 2 diabetes, T2D) ( 1 – 3 ). In T1D, autoimmune cells infiltrate pancreatic islets (insulitis) and target pancreatic beta cells for destruction, leading to loss of the beta cell mass necessary for maintenance of euglycemia.…”

Section: Introductionmentioning

confidence: 99%

Role of Exosomes in Islet Transplantation

et al. 2021

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Exosomes are known for their ability to transport nucleic acid, lipid, and protein molecules, which allows for communication between cells and tissues. The cargo of the exosomes can have a variety of effects on a wide range of targets to mediate biological function. Pancreatic islet transplantation is a minimally invasive cell replacement therapy to prevent or reverse diabetes mellitus and is currently performed in patients with uncontrolled type 1 diabetes or chronic pancreatitis. Exosomes have become a focus in the field of islet transplantation for the study of diagnostic markers of islet cell viability and function. A growing list of miRNAs identified from exosomes collected during the process of isolating islets can be used as diagnostic biomarkers of islet stress and damage, leading to a better understanding of critical steps of the isolation procedure that can be improved to increase islet yield and quality. Exosomes have also been implicated as a possible contributor to islet graft rejection following transplantation, as they carry donor major histocompatibility complex molecules, which are then processed by recipient antigen-presenting cells and sensed by the recipient immune cells. Exosomes may find their way into the therapeutic realm of islet transplantation, as exosomes isolated from mesenchymal stem cells have shown promising results in early studies that have seen increased viability and functionality of isolated and grafted islets in vitro as well as in vivo. With the study of exosomes still in its infancy, continued research on the role of exosomes in islet transplantation will be paramount to understanding beta cell regeneration and improving long-term graft function.

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The Application of High‐Throughput Approaches in Identifying Novel Therapeutic Targets and Agents to Treat Diabetes

Lim

2022

Advanced Biology

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An early example of HTS in drug development came from the identification of new antibiotics using 96-well microtiter plates, whereby fermentations of an established actinomycetes library were incubated with a panel of microorganisms, and after optimization, a screening capacity of 10 000 fermentation broths per week was achieved. [1] In the following decades, the rapid development of molecular biology techniques and advances in automated equipment have changed how new drugs are identified, and a variety of HTS-identified drugs have been approved to treat different diseases. [2] For a comprehensive list of HTS-identified drugs, please refer to the excellent review by Macarron et al. [2] High-throughput applications can also be combined with other unbiased "Omics" technologies used to study genomics, epigenomics, transcriptomics, proteomics, and metabolomics. [3] Diabetes is an incurable disease characterized by the inability of the body to maintain normoglycemia due to decreased sensitivity of various tissues to insulin and insufficient amounts of circulating insulin, a hormone produced by pancreatic β-cells. [4] Diabetes is associated with chronic complications, like macrovascular diseases (e.g., cardiovascular diseases) and microvascular diseases (e.g., damages in nerve, kidney, eye, and foot). [5,6] More than 537 million adults are currently living with diabetes, and this number is expected to increase to 693 million by 2045. In 2021, 6.7 million deaths worldwide were attributed to diabetes, [7] which made it the ninth leading cause of death. [8] Globally, the prevalence of diabetes also brings a heavy burden to healthcare systems, with an estimated expenditure of over 966 billion U.S. dollars per year. [7] Diabetes is generally categorized into two groups: Type I diabetes mellitus (T1DM) and Type II diabetes mellitus (T2DM), but there are still some cases that have different etiologies, such as gestational diabetes mellitus and monogenic diabetes. [9] Since the discovery of insulin in 1921, [10] significant progress has been made in diabetes pharmacotherapy and therapeutic technology; [11][12][13] however, since a permanent cure is unavailable, the discovery and development of anti-diabetic drugs is still at the forefront of diabetes research. With the rapid advancement in high-throughput omics technologies, combined with accumulated genome-wide association study (GWAS) data, a better understanding of diabetes pathophysiology may one day lead to the discovery of novel therapeutic targets. [14,15] This review will During the past decades, unprecedented progress in technologies has revolutionized traditional research methodologies. Among these, advances in highthroughput drug screening approaches have permitted the rapid identification of potential therapeutic agents from drug libraries that contain thousands or millions of molecules. Moreover, high-throughput-based therapeutic target discovery strategies can comprehensively interrogate relationships between biomolecules (e.g., gene, RNA, and protein) and diseas...

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Type 1 diabetes mellitus: much progress, many opportunities

Cited by 76 publications

References 154 publications

Protective Role of Recombinant Human Thrombomodulin in Diabetes Mellitus

Protective Role of Recombinant Human Thrombomodulin in Diabetes Mellitus

Role of Exosomes in Islet Transplantation

The Application of High‐Throughput Approaches in Identifying Novel Therapeutic Targets and Agents to Treat Diabetes

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