Hotspots and prospects of stem cell therapy for type 2 diabetes:bibliometric and visual analysis based on publications,clinical registries,drug approval information,and patent information in China and the United States

Editorial Office of ,Shenyang,Liaoning Province,China

Abstract

Key words:bibliometrics; cell transplantation; clinical registration; drug; patent; stem cells; type 2 diabetes; visualization

INTRODUCTION

The incidence of type 2 diabetes mellitus,a degenerative disease that severely impacts the health of patients,is increasing annually worldwide.Patients with type 2 diabetes often exhibit a decreased number of islet β cells and functional decline with age,which in turn reduces insulin secretion,leading to abnormal glucose metabolism and related metabolic disorders.1Currently,insulin,insulin intervention,and exercise plus diet are the main clinical methods to treat type 2 diabetes.2,3However,blood glucose levels still tend to gradually increase with disease progression.4Thus,new treatment measures are necessary to improve therapeutic effects.

Stem cell therapy involves the use of transplanted stem cells to repair or replace damaged cells or tissues.5Previous studies have attempted to transplant embryonic stem cells,pluripotent stem cells,and adult stem cells to treat type 2 diabetes.6,7These stem cells may differentiate into islet β cells in the right microenvironment; secrete a variety of pro-angiogenic factors to promote islet angiogenesis,increase local oxygen supply and nutritional components,and promote β cell proliferation; or secrete multiple nutritional factors to reduce β-cell apoptosis.8

To this end,we conducted a search of multiple global databases to summarize and visualize the current status and frontiers of research into stem cell therapies for type 2 diabetes,both in China and globally.Additionally,we evaluated the distribution of different types of stem cells for treatment of type 2 diabetes in the literature.Our findings provide informatics that may facilitate the clinical treatment of type 2 diabetes with stem cell therapies.

DATA AND METHODS

Data collection Literature databases

WanFang (China) and Web of Science (United States) databases were searched for relevant literature published from inception until December 2019,using the keywords “stem cell transplantation” and “type 2 diabetes” in Chinese and English,respectively.

Clinical registries

The Chinese Clinical Trials Registry (www.chictr.org.cn) and ClinicalTrials.gov were searched for clinical research registrations regarding stem cell therapy for type 2 diabetes.

Drugs and patents

A search of the China National Medical Products Administration,US Food and Drug Administration (FDA),China National Intellectual Property Administration,and US Patent and Trademark Office was conducted to screen for drugs and patents related to stem cell therapy for type 2 diabetes.

Data analysis

For articles related to stem cell therapy for type 2 diabetes,assessments of publication date,authors,institutional affiliations,journals,funding source,citation frequency,and download frequency were conducted using software provided by WanFang and Web of Science.CiteSpace5.6.R1 was used to analyze the annual distribution of keywords and burst terms extracted from Web of Science.We also manually retrieved information for drugs included in the Chinese Clinical Trial Registry,ClinicalTrials.gov,China National Medical Products Administration,and US FDA database,as well as patents included in the China National Intellectual Property Administration,and US Patent and Trademark Office.Information classification was implemented using Excel 2010 (Microsoft,Redmond,WA,USA).

RESULTS

Annual distribution of publications regarding stem cell therapy for type 2 diabetes

The world’s earliest article regarding stem cell therapy for type 2 diabetes was published in 1998.Subsequently,the number of relevant articles increased at a slow rate but began to sharply increase in 2012.In China,the first study of stem cell therapy for type 2 diabetes was reported in 2000; prior to 2008,the number of articles published was less than 15 per year,which has since slightly increased to 30-40 articles per year (Figure1).

Comparison of publications on different types of stem cells for the treatment of type 2 diabetes

In China,the main types of stem cells used for treatment of type 2 diabetes were bone marrow mesenchymal stem cells and pancreatic stem cells,as reported in 65 and 62 articles,respectively.The dates of publication were mainly distributed from 2009 to 2016 for bone marrow mesenchymal stem cells,and in 2009,2011,and 2015 for pancreatic stem cells (Figure2).

Distribution of countries/territories with publications regarding stem cell therapy for type 2 diabetes

According to retrieval results from the Web of Science database,publications on stem cell therapy for type 2 diabetes were from 67 countries and regions.Countries with over 40 relevant articles included the United States,China,Italy,Japan,United Kingdom,Canada,South Korea,Germany,and Spain (Figure3).Over 50% of publications were from the United States and China.

Figure1:Annual distribution of publications related to stem cell therapy for type 2 diabetes in China and worldwide.Note:Chinese data are from WanFang database,while global data are from the Web of Science database.

Figure2:Annual distribution of publications regarding different types of stem cells for type 2 diabetes in China.

Figure3:Major countries/territories with publications on stem cell therapy for type 2 diabetes based on the Web of Science database.

Distribution of institutions with publications pertinent to stem cell therapy for type 2 diabetes China and global institutions with published articles regarding stem cell therapy for type 2 diabetes

According to results retrieved from the WanFang database,institutions with over five relevant publications were relatively scattered geographically,including Shanghai Jiao Tong University,Peking Union Medical College,Chinese Academy of Medical Sciences,and Affiliated Hospital of Qingdao University School of Medicine (Figure4A).According to results retrieved from the Web of Science database,relevant publications were mainly from the University of California and Harvard University,which have both published more than 35 research articles in this field.In addition,PLA General Hospital and Shanghai Jiao Tong University published many relevant publications in global journals (Figure4B).

Comparison of institutions with publications related to different types of stem cell research articles

Differences in the distribution of research institutions were observed regarding focus on different types of stem cells.In China,institutions with many publications on bone marrow mesenchymal stem cells for type 2 diabetes included the Third Affiliated Hospital of Sun Yat-sen University,Lanzhou General Hospital of Lanzhou Military Region,Shenzhen People’s Hospital,and Affiliated Hospital of Qingdao University School of Medicine.There were three institutions with more than two publications on adipose stem cells for type 2 diabetes,including Yantai Yuhuangding Hospital,PLA Navy Yantai Hospital,and Qingdao University School of Medicine.Institutions with more than two publications on embryonic stem cell therapy included Peking University Third Hospital,Yantai Yuhuangding Hospital,PLA Navy Yantai Hospital,and Qingdao University School of Medicine.Pancreatic stem cell therapy for diabetes was mainly reported by Northwest A & F University.Outside China,Shahid Beheshti University Medical Sciences and Ciber Centro De Investigacion Biomedica En Red had the highest number of publications on bone marrow mesenchymal stem cells and adipose stem cells for type 2 diabetes,respectively.Harvard University had the highest number of publications on embryonic stem cells and pancreatic stem cells (Figure5).Institutions with more than two publications on embryonic stem cell therapy included Peking University Third Hospital,Yantai Yuhuangding Hospital,PLA Navy Yantai Hospital,and Qingdao University School of Medicine.

Distribution of authors with publications on stem cell therapy for type 2 diabetes

Whether inside or outside China,authors engaged in stem cell therapy for type 2 diabetes published relatively low numbers of articles on the subject.Indeed,only three authors published more than 10 relevant articles (Figure6).We also found that numbers of publications on different types of stem cells were similar between the top ten authors (Figure7).

Distribution of journals with publications on stem cell therapy for type 2 diabetes

In China,there were 155 journals with publications on stem cell therapy for type 2 diabetes,most of which were core journals issued by the Institute of Scientific and Technical Information of China and/or Peking University.The Chinese journal that published the highest number of relevant articles wasChinese Journal of Tissue Engineering Research,which published 44 relevant articles,followed byChinese Journal of Diabetes Mellitus,with 11 relevant articles (Figure8).Globally,PLoS One,Diabetes,Diabetologia,andStem Cell Research Therapypublished the highest numbers of relevant articles in this field (Figure8).

Comparison of journals with publications on different types of stem cells for treating type 2 diabetes

Chinese Journal of Tissue Engineering Researchwas the first journal in China to publish articles describing multiple types of stem cells for the treatment of type 2 diabetes (Figure9A-D).Globally,publications regarding different types of stem cells have been published in various journals.Stem Cell Research Therapyfocused on the use of adipose stem cells for type 2 diabetes,whereasDiabetologiahad the largest number of publications on embryonic stem cells for type 2 diabetes.PloS Onetended to publish articles describing use of pancreatic stem cells for type 2 diabetes (Figure9E-H).

Distribution of funding agencies related to stem cell therapy for type 2 diabetes

Fifty-three of the 290 relevant articles published in China were funded by the Guangdong Natural Science Foundation of China,Guangdong Science and Technology Plan Project,General Project of Lanzhou Military Region,National Natural Science Foundation of China,and/or Tianjin Science and Technology Plan of China.The main institutions funding studies on stem cell therapy for type 2 diabetes worldwide included the National Institutes Of Health (NIH) and US Department of Health and Human Services,followed by the National Natural Science Foundation of China (Figure10).

Figure5:Distribution of institutions with studies on different types of stem cells for the treatment of type 2 diabetes.

Figure6:Distribution of authors with the most publications on stem cell therapy for type 2 diabetes.

Figure7:Distribution of authors with publications on different types of stem cells for treating type 2 diabetes.

Figure8:Distribution of major journals with publications on stem cell therapy for type 2 diabetes.

Keyword distribution of publications on stem cell therapy for type 2 diabetes

The top ten Chinese keywords for searches in WanFang related to stem cell therapy for type 2 diabetes were “diabetes,” “transplantation,” “stem cells,” “bone marrow mesenchymal stem cells,” “stem cell transplantation,” “type 2 diabetes,” “islet transplantation,” “diabetic foot,” “type 1 diabetes,” and “rats.” The first six keywords appeared more than 30 times (Figure11A).The top ten keywords for searches in Web of Science were “diabetes mellitus,” “stem cell,” “mesenchymal stem cell,” “differentiation,” “bone marrow,” “expression,” “transplantation,” “diabetes,” “in vitro,” and “insulin resistance.” The first eight of these keywords appeared over 100 times (Figure11B).

Figure9:Distribution of journals with publications on different types of stem cells for type 2 diabetes.

Figure10:Distribution of funding agencies related to stem cell therapy for type 2 diabetes.

To evaluate research hotspots,CiteSpace was used to calculate the burst terms of Web of Science results (Figure11C).Previous studies mainly focused on the differentiation of stem cells.However,since 2010,increasing concern has been paid to the secretory function of stem cells,i.e.,possible effects of growth factors secreted from stem cells or factors that promote the secretion of growth factors from stem cells.

Figure11:Top keywords related to stem cell therapy for type 2 diabetes.

Highly-cited and highly-downloaded publications regarding stem cell therapy for type 2 diabetes in China

In China,the most frequently cited article regarding stem cell therapy for type 2 diabetes was cited 14 times,while another 8 articles were cited more than 10 times (Table1).

There were ten Chinese articles related to stem cell therapy for type 2 diabetes downloaded over 300 times,and two articles were downloaded over 500 times (Table2).

Clinical registration information for stem cell therapies for type 2 diabetes

There were four clinical registries regarding stem cell therapy for type 2 diabetes registered by Chinese institutional authors in the China Clinical Trial Registry (Table3).One trial was registered in 2010,2012,2018,and 2019.Types of stem cells involved included adipose stem cells,dental pulp mesenchymal stem cells,and umbilical cord mesenchymal stem cells.Two trials were conducted at the General Hospital of the Chinese Armed Police Force,one at the Renmin Hospital of Hubei University of Medicine,and one at Shanghai Changhai Hospital.

There were 17 funded clinical registries regarding stem cell therapy for type 2 diabetes on ClinicalTrials.gov (Table4).Registration year,country,and stem cell type of the included registries are shown in Figure12.

China had the largest number of relevant clinical registries in ClincialTrials.gov (eight registries),followed by India (five registries),Vietnam (two registries),the United States (one registry),and the Philippines (one registry),as shown in Figure12B.

Figure12:Registration year,country,and type of stem cells used for relevant clinical registries in ClinicalTrials.gov.

Drug information and patent information related to stem cell therapies for type 2 diabetes

China has not yet approved the use of stem cells as drugs,although 14 cell or gene products have been permitted by the US FDA.29However,none of the US FDA-approved products are for the treatment of diabetes.

Table1:Highly-cited publications on stem cell therapy for type 2 diabetes in China

China had a remarkable increase in the number of patents for stem cell treatments for diabetes in 2017 and 2018.The main type of stem cells cited in patents was mesenchymal stem cells (Table5).In the United States,patents related to stem cell treatment of diabetes are relatively rare (Table6).

DISCUSSION

To visually show the overall development of stem cell therapies for type 2 diabetes,we analyzed relevant publications,clinical registries,and patents based on research data and information from WanFang,Web of Science,Chinese Clinical Trial Registry,ClinicalTrials.gov,China National Medical Products Administration,US FDA,China National Intellectual Property Administration,and the US Patent and Trademark Office.Although the number of relevant publications,patent applications,and drug approvals is slowly rising in China,research on stem cell therapy for type 2 diabetes is rapidly developing.PLoS One,Diabetes,Diabetologia,andStem Cell Research Therapyhave all published articles related to stem cell therapy for type 2 diabetes from Chinese authors.In terms of institutional support,the University of California and Harvard University are core institutions with many publications devoted to stem cell therapies for type 2 diabetes.Regarding funding,the NIH,US Department of Health and Human Services,and National Natural Science Foundation of China have supported many studies on stem cell therapy for type 2 diabetes.

Types of stem cells that have been used for type 2 diabetes include bone marrow mesenchymal stem cells,adipose stem cells,embryonic stem cells,and pancreatic stem cells.Transplantation of bone marrow mesenchymal stem cells and pancreatic stem cells are more frequently reported as potential treatments for type 2 diabetes.Although globally no stem cell therapy for type 2 diabetes has been approved,there are many patents related to such treatments.Transplantation of adult stem cells and immune rejection of exogenous stem cell transplantation remain the focus of attention for future research on stem cell therapies for type 2 diabetes.The use of stem cell transplantation for type 2 diabetes is an innovative method with many unknown factors,and further improvements in clinical efficacy and safety are warranted.

Table2:Highly-downloaded publications on stem cell therapy for type 2 diabetes in China

Table3:Clinical registries regarding stem cell therapy for type 2 diabetes by Chinese institutions and authors in the China Clinical Trial Registry

Table4:Clinical registries regarding stem cell therapy for type 2 diabetes in ClinicalTrials.gov

Table4:Continued

Table5:Patents related to stem cell therapy for diabetes in China

Table6:Patents related to stem cell therapy for diabetes in the United States

Data sharing statement

No data is reported in the article.

Plagiarism check

Checked twice by iThenticate.

Peer review

Externally peer reviewed.

Open access statement

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