On April 16, 2023, the two authors (ZH and QC) independently undertook searches and accrued articles from the Web of Science database, probing for articles bearing the title “diabetes remission” or “diabetes mellitus remission” or “type 2 diabetes remission” or “type 2 diabetes mellitus remission” or “T2DM remission” or “remission of diabetes” or “remission of diabetes mellitus” or “remission of type 2 diabetes” or “remission of type 2 diabetes mellitus” or “reversal of diabetes” or “reversal of diabetes mellitus” or “reversal of type 2 diabetes” or “reversal of type 2 diabetes mellitus” or “reversal of T2DM” or “reverse diabetes” or “reverse diabetes mellitus” or “reverse type 2 diabetes” or “ reverse type 2 diabetes mellitus” or “ reverse T2DM” or “diabetes be reversed” or “diabetes mellitus be reversed” or “type 2 diabetes be reversed” or “type 2 diabetes mellitus be reversed” or “T2DM be reversed” spanning from January 1, 2000, to April 16, 2023, in the English language. Post exclusion of news reports, conference abstracts, health science dissemination, and articles that were incongruous to the theme, salient data (titles, keywords, author metadata, abstracts, citations, etc.) was retrieved and archived in TXT format for subsequent utilization. Thereafter, two authors (GC and CL) omitted articles that were inapposite to the central theme, culminating in a total of 970 references.

Initially, we fabricated cooperation network maps of nations, institutions, and contributors utilizing CiteSpace (6.1.R6 Advanced). Within these maps, each node signifies a distinct nation, institution, or contributor, and the connectors imply that the associated nodes have collaborative affiliations. The more pronounced the connectors, the more robust the collaborative affiliations. Subsequently, we incepted keyword co-occurrence and keyword emergence maps. We then executed a keyword clustering exploration: a clustering map, a chronology map, and a temporal sector map. The magnitude of the circle within the map corresponds to the recurrence: the more expansive the circle’s diameter, the more elevated the recurrence of the node. The breadth of the circle depicts the recurrence of the associated content manifested across distinct years, and the links between nodes denote co-presence. The collaborative network maps generated by CiteSpace lack the capability to delineate the dimensions of the nodes; hence, they are unable to delineate variances in magnitude. Additionally, a multitude of labels, such as nations, institutions, and authors, often induce overlap, diminishing the visual clarity. The collaborative network map fashioned by VOSviewer possesses the merit of succinctness and lucidity (31). As such, we harnessed VOSviewer (1.6.18) to conduct a concurrent analysis of nations, institutions, authorship, and collaborations in articles, and to instigate a co-presence examination of co-citations and article sources. The circles on the map represent distinct nations, institutions, authors, and journals, and the size of the circle delineates quantity. The more expansive the circle’s diameter, the greater the node count. The connector extending between the circles indicates a co-presence association amongst nodes.

Through the analysis of article sources, one gains insights into the contemporary professional and preeminent teams and scholars in the realm of diabetes remission research. This elucidation offers directional guidance and foundational underpinning for associated investigators. Future trajectories of specialized domains can be inferred by an integrative assessment of publication tendencies amongst authors, institutions, nations, and journals.

This investigation revealed that, from an authorial standpoint, Taylor R boasts the highest quantity of both authored and cited manuscripts. Furthermore, his affiliated institution, the University of Newcastle, predominates in terms of manuscript publications. In the institutional collaboration network diagram ( Figure 3A ), the University of Newcastle predominantly liaised with the University of Glasgow in England. Within the authorial collaboration schematic ( Figure 4 ), Taylor R emerged as the most dynamic, forging alliances with an array of teams and individuals, suggesting that he has rendered seminal contributions to the discipline of diabetes remission. Professor Roy Taylor stands as a luminary in the T2DM landscape, dedicating decades to the exploration of efficacious strategies for diabetes remission. He postulated that obesity is intricately intertwined with the genesis, evolution, and remission of diabetes. Through efficacious weight reduction, remission can be achieved, leading him to advocate the mechanism of diabetes progression and remission as the “twin vicious cycle theory” (42). His consortium executed a plethora of investigations into the attainment of diabetes remission via dietary curtailment, encompassing the “COUNTERPOINT study, COUNTERBALANCE study, and DiRECT study” (16). The quintessential exploration within Taylor’s oeuvre is the DiRECT study (43), which discerned that relying solely on dietary curtailment, the remission rates for T2DM patients at the 1- and 2-year marks stand at 45.6% and 35.6% respectively. Moreover, when these patients experienced a weight reduction exceeding 15 kg, the remission rates for T2DM at 1 and 2 years escalated to 86.1% and 70.0% respectively. Through the aforementioned series of investigations, Taylor also validated the “double vicious circle theory”. By shedding excess weight, patients can diminish superfluous fat burdens, curtail bodily fat proportions below the “personal fat threshold,” ameliorate liver and pancreatic fat accumulations, thereby enhancing insulin sensitivity. This facilitates the transformation of de-differentiated islet cells back into insulin-secreting β cells, culminating in T2DM remission. The findings from Professor Taylor’s team serve as a watershed in diabetes remission research, offering both a referential framework and directional compass for scholars in analogous domains.

America boasts the predominant count of published articles ( Table 1 ). Numerous institutions within America maintain profound interactions, and among the top ten institutions in terms of article publication volume, five hail from America, collectively representing half of the overall article count published by these leading institutions ( Table 2 ). Fifty percent of the preeminent ten journals that disseminate the majority of articles on diabetes remission are American entities ( Table 5 ). In summation, academic establishments and researchers in America exhibit pronounced zeal for diabetes remission investigations, and intranational affiliations manifest both frequent and intimate collaborations. Publishing bodies in America also confer substantial emphasis on the advancement of diabetes remission. Consequently, America is poised to proffer augmented contributions to the diabetes remission domain in forthcoming years. A multitude of American scholars harbor an inclination towards metabolic surgery research to actualize diabetes remission, exemplified by teams such as Laferrère B’s ensemble at Columbia University (44), Schauer PR’s collective at the Cleveland Clinic (45), and Cummings DE’s contingent at Washington University (46), with evident interdisciplinary collaborations among these groups ( Figure 4 ) (44). There also exist teams oriented towards dietary therapy for diabetes remission, such as the Look AHEAD Research Group (47). China ranks as the runner-up in terms of overall article publication ( Table 1 ). A significant proportion of Chinese teams are engrossed in metabolic surgery research pertinent to diabetes remission, with exemplars like Zhu S’s faction from the Third Xiangya Hospital, Central South University (48), Jia W’s group from the Shanghai Jiao Tong University Affiliated Sixth People’s Hospital (49), and Zhang P’s assembly from the Shanghai Pudong Hospital of Fudan University (50). These teams also engage in intra-national collaborations (51). The most salient study on diabetes remission in England emanates from the series of investigations on dietary curtailment by Taylor R’s team, as elucidated previously. Moreover, certain English teams frequently establish collaborations with other European nations, notably Italy and Germany, with a predominant focus on metabolic surgery (52, 53). In Canada, certain teams, such as Lipscombe LL’s consortium from the University of Chicago (54) and the Carpentier AC’s coalition from the Centre de recherche du Centre hospitalier universitaire de Sherbrooke (55), delve into metabolic surgery, while others, such as Gerstein HC’s team, explore alternative remission strategies, encompassing hypoglycemic drugs and lifestyle interventions (56). Canada often forges collaborations with its southern neighbor, America (57). In Japan, metabolic surgery remains a paramount research area (58, 59). Spain hosts teams engrossed in metabolic surgery (60) and others probing the impact of dietary regimens on diabetes remission, exemplified by the CORDIOPREV study (61). In India, the majority of teams are engrossed in metabolic surgery (62, 63). Danish research related to diabetes remission is likewise dominated by metabolic surgery (64, 65).

International collaboration on diabetes remission is somewhat scant, primarily confined to geographically proximate nations. Broadly speaking, endeavors in diabetes remission necessitate an enhancement in collaborative synergies; however, there are understandable rationales behind the current state of affairs. One impeding factor is that prior to 2021, the definition of diabetes remission remained nebulous, and its criteria were discordant for an extended duration. Such ambiguities rendered the design and outcomes of pertinent studies variably heterogeneous, potentially curtailing intergroup collaborations. In August 2021, an assemblage of international multidisciplinary specialists, orchestrated by the American Diabetes Association, advocated for the term “remission” as the most apt descriptor. Furthermore, they posited that HbA1c <6.5%, ascertained a minimum of three months post the discontinuation of hypoglycemic therapeutic agents, should serve as the benchmark for remission (17). Given this resolution of terminological and criteria disputes concerning T2DM remission, it is anticipatory that ensuing research in diabetes remission will exhibit enhanced cohesion, fostering more streamlined alliances amongst research collectives and nations. Numerous modalities exist for diabetes remission, inclusive of bariatric surgery (14, 15), lifestyle interventions (16), short-term intensive insulin therapy (14), non-insulin hypoglycemic agents (66), immune modulation (67, 68), and transplantation (13, 69). Distinct research paradigms adhered to by various teams might circumscribe collaborative endeavors. Notwithstanding the inherent discrepancies in research foci and their consequent findings, there exists mutual edification and facilitation. Such interplay can be bolstered by the instigation of scholarly symposia and the fostering of scholarly exchanges. Additionally, the pandemic milieu of recent years has invariably impacted the momentum of pertinent clinical research and team interactions. Yet, during this health crisis, the publication trajectory concerning diabetes remission has persisted in its growth. With the ongoing stabilization of the epidemic, it is optimistically projected that investigations germane to diabetes remission will witness continued vigor, yielding more profound insights in the foreseeable future, and ultimately bestowing greater therapeutic dividends upon diabetic patients.

In illuminating research focal points, we rendered various network diagrams predicated on keywords from the articles, presenting a comprehensive panorama of the specific content and temporal evolution of these focal points. The keyword with the preeminent frequency was “bariatric surgery”. Moreover, terms such as “weight loss”, “beta cell function”, and “insulin resistance”/”resistance” were prominent among high-frequency and high-centrality keywords. These terms, alongside their related keywords, made recurrent appearances in the maps elucidating keyword co-occurrence ( Figure 8 ) and keyword clustering ( Figure 10 ) in subsequent sections. This suggests a rich repository of studies centered on weight loss, particularly focusing on the remission of diabetes (primarily T2DM) via bariatric surgery. Investigations into remission mechanisms predominantly hinge on two cardinal pathogenic mechanisms: beta cell functionality and insulin resistance. Overweight/obesity-induced fatty liver and pancreas, which result from energy surfeit, are intricately linked to the pathogenesis and progression of T2DM (70, 71). Taylor’s proposition of the “twin cycle hypothesis” posits that excessive caloric intake culminates in significant adipose accumulation in the body, engendering insulin resistance and perturbations in beta cell functionality, eventually manifesting as T2DM. If the aforementioned sequela is attenuated via weight reduction, the natural corollary is the remission of diabetes (34, 42). An escalating corpus of literature underscores weight reduction as a pivotal factor in the remission of diabetes (33, 72–74). Currently, the two preeminent modalities for weight loss in the therapeutic regimen for T2DM encompass bariatric surgery and lifestyle modifications. These strategies have garnered significant attention in recent diabetes remission research, a trend corroborated in our subsequent keyword emergence ( Figure 9 ) and keyword time-zone map ( Figure 11 ) analysis.

Emergent terms, being high-frequency words discerned via fluctuations in keyword frequency within a delineated timeframe, encapsulate the zeitgeist of research during that epoch. The research was trifurcated based on the commencement and culmination of keyword emergence ( Figure 9 ). The inaugural stage spanned 2000 to 2005, with research keywords predominantly revolving around “beta cells”, “differentiation”, “translation”, “in vivo”, “expression”, and “t-cell”. During this phase, a majority of studies embarked on exploratory endeavors into the feasibility and underlying mechanisms of remission [mainly Type 1 Diabetes Mellitus (T1DM)] in the context of transplantation-related or in vivo studies. They emphasized the pivotal role of transformations in beta cell functionality during the remission trajectory.

During this time frame, the primary emphasis of research in transplantation therapy was directed towards pancreas transplantation and islet transplantation. The pancreas could be transplanted either independently or in conjunction with the kidneys. In December 1966, a significant milestone was achieved when four surgeons, namely Kelly, Lillehei, Merkel, and Idezuk, hailing from the University of Minnesota Hospital in America, successfully conducted the inaugural pancreas kidney transplantation procedure for two individuals with diabetes and renal failure (75). This groundbreaking achievement marked the commencement of a novel epoch in the realm of clinical pancreas transplantation, offering hope to individuals afflicted with diabetes and renal failure, who were facing imminent mortality. Subsequently, a substantial volume of pancreas transplantation procedures has been conducted globally, resulting in a notable rise in the post-transplantation insulin detachment rate from 40% to exceeding 70% within the preceding decade (76).

Islet transplantation, which had its genesis in the mid-1970s, resurged in prominence due to the successful execution of the Edmonton protocol in 2000 (77). Edmond administered pancreatic islet transplantation to 7 T1DM patients presenting with pronounced hypoglycemia and metabolic instabilities, culminating in all the patients ceasing insulin administration. The mean HbA1c values normalized, blood sugar variability markedly diminished, and no instances of severe hypoglycemia were reported subsequently. Absence of noteworthy contraindications or adverse reactions, and the obviation of hormonal therapy were also notable. In 2022, the Edmonton protocol team published findings from a cohort study conducted at a single center, examining the outcomes of islet transplantation up to 20 years post-transmission (78). The study encompassed a median follow-up period of 7.4 years and included 255 patients who underwent allogeneic islet transplantation. Of these patients, 78 (70%) experienced sustained graft survival, while 77 (30%) experienced non-sustained graft survival. Among the total patient population, 201 individuals (79%) achieved insulin independence. Notably, the rate of insulin independence was higher among transplant survivors compared to non-transplant survivors. The prevalence and stability of HbA1c levels and fasting blood glucose levels, along with a notable improvement in hypoglycemia, were observed over the course of the follow-up period. These findings provide evidence for the safety and efficacy of islet transplantation as a treatment modality for T1DM. Furthermore, the continued advancement and implementation of relevant technologies in the field of islet transplantation hold promise for achieving a definitive cure for T1DM in the future.

Simultaneously, the Edmonton protocol team conducted a comparative analysis of the follow-up data pertaining to patients who underwent pancreatic islet transplantation (n=266) and pancreas transplantation pancreas transplantation (n=146) at the research center within the same time frame (79). The findings revealed that while the pancreas transplantation group exhibited elevated mortality rates, surgery-related complications, and readmission rates, it demonstrated superior outcomes in terms of insulin independence, graft survival rate, and blood glucose control. These results suggest that pancreas transplantation holds greater potential than islet transplantation in diabetes remission.

Since the year 2000, numerous investigations have been conducted in the domains of islet transplantation and pancreas transplantation. Both approaches to transplantation offer potential benefits such as reducing patients’ dependence on insulin, mitigating the occurrence of severe hypoglycemic events, and enhancing the management of blood sugar levels. In the wake of Edmonton protocol, a plethora of clinical and animal studies were conducted, yielding favorable experimental outcomes (80, 81). Such pioneering results further galvanized preliminary investigations into immunosuppressive modalities, stem cell transplantation, and genetic therapeutic interventions (37, 82–84), and catalyzed a myriad of studies on beta cell function (85, 86). This era was marked by a profusion of studies investigating potential strategies for the reversal/remission of T1DM. In 2005, the American Diabetes Association (ADA) promulgated an article titled “Thirty years of investigating the autoimmune basis for type 1 diabetes: why can’t we prevent or reverse this disease?” (87). This manuscript offered a retrospective examination of the knowledge amassed during this time, and in tandem with the analysis of these research endeavors, proffered guidance for forthcoming inquiries with aspirations to translate these findings into efficacious modalities for the prevention or reversal of T1DM.

From 2005 to 2010, keywords such as “in vitro”, “mouse”, “nod mice”, “receptor”, and “regulatory T cells” manifested in succession, signifying that in vitro and mouse experiments transitioned into primary research foci. A significant portion of investigations during this timeframe endeavored to elucidate the phenomena and underlying mechanisms of diabetes remission via foundational experiments. This epoch, representing the second stage, extended until 2015. Concurrently, there was an intensified quest to identify modalities for diabetes reversal beyond mere transplantation. This pursuit was underscored in 2006 when D’Amour et al. disseminated a seminal article detailing the synthesis of endocrine pancreatic cells (88). These cells exhibit a secretion profile comprising insulin, glucagon, somatostatin, pancreatic polypeptides, and auxin-releasing peptides. This pioneering investigation marked the inaugural documentation of the derivation of hormone-expressing endocrine pancreatic cells from human embryonic stem cells subjected to in vitro differentiation. The research posits that the transplantation of insulin-producing pancreatic beta cells, with the intent to augment the depleting reserve of such cells in T1DM patients, could potentially herald a therapeutic paradigm or even a definitive resolution for the condition, thereby rejuvenating optimism for diabetes remission.

Subsequent to 2010, terms such as “medical therapy”, “glucose”, “hypertension”, and other clinical pertinent keywords emerged, denoting a transition in the research trajectory on diabetes remission from a foundational to a clinical orientation. Spanning 2010 to 2015, a plethora of clinical evaluations substantiated the premise that short-term intensive insulin therapy possesses the efficacy to facilitate T2DM remission (89, 90). This evolution in research emphasis signified a shift from foundational experiments towards clinical trials, with the primary research axis transitioning from T1DM to T2DM.

In 2016, coinciding with the promulgation of guidelines for metabolic surgery as an intervention for diabetes (91), the research interest in employing this modality for achieving T2DM remission experienced a notable upsurge. A considerable body of literature attested that metabolic surgery emerged as the technique boasting the superior remission rate amongst all extant remission strategies (14, 15). Consequently, the research vigor persisted, yielding substantive findings. Investigations concerning its remission mechanisms, prognostic indicators, and predictive models attained a high degree of sophistication (92, 93). The triumphant outcomes of metabolic surgery in facilitating T2DM remission illuminated the potential of weight reduction as a realistic avenue towards T2DM remission. This spurred researchers to delve deeper into alternative methodologies for weight reduction conducive to T2DM remission. Subsequent investigations corroborated that a substantial proportion of patients, nearing half, could attain a drug-free remission state for T2DM solely via dietary and lifestyle alterations aimed at weight loss (15, 16, 94). In the wake of these revelations, lifestyle intervention swiftly ascended as a pivotal research domain within the wider landscape of diabetes remission, succeeding metabolic surgery. Specifically, dietary regimens underscored by caloric restriction emerged as focal points. The 2021 remission guideline for T2DM accentuated the paramountcy of lifestyle interventions in ameliorating diabetes (17). In 2020 (95) and 2022 (96), ADA unveiled two distinct guidelines emphasizing dietary therapy for T2DM remission. This trajectory underscores the indispensable role of diet therapy in mitigating diabetes, heralding it as an epicenter of research endeavors both presently and in foreseeable future epochs. Post-2019, a preponderance of investigations has gravitated towards clinical research, characterized by keywords such as “low-calorie diet”, “long-term remission”, “roux‐en‐y gastric bypass”, “management”, and “lifestyle intervention”. This inclination elucidates that within the clinical domain of diabetes remission, bariatric surgery and lifestyle interventions underscored by a low-calorie diet remain the predominant foci. The triad of “low-calorie diet”, “management”, and “lifestyle intervention” are poised to maintain their prominence through 2023, signifying that contemporary and imminent research nuclei in diabetes remission revolve around lifestyle interventions fortified by dietary regimens. The manifestation of these keywords attests to the prevailing trend that research on diabetes remission through bariatric surgery and lifestyle interventions targeting weight reduction has gained momentum in recent years, and prognostications suggest an inclination towards lifestyle intervention-centric research in the near future. This trend is corroborated by observations from the keyword time zone map ( Figure 11 ) and the keyword clustering timeline map ( Figure 12 ).

Various strategies have been proposed to realize diabetes remission, encompassing metabolic surgery, lifestyle intervention, insulin intensive therapy, and non-insulin hypoglycemic drugs (14). Metabolic surgery is the most efficacious, with a maximum remission rate of approximately 70%–80% at 1–2 years after surgery (97, 98), followed by lifestyle interventions with caloric restriction, with a 40%–80% average remission rate at 1 year after intervention (95), and intensive insulin therapy, which can also provide remission in 30%–70% of patients with T2DM (66, 99). However, the efficacy of oral hypoglycemic drugs as an intervention for diabetes remission understudied, with limited research indicating remission rates predominantly below 30% (14, 100).

Lifestyle interventions commonly prioritize interventions involving low calorie or even very low calorie diet. However, patients often encounter difficulties in maintaining adherence due to intense and persistent hunger. In cases where patients are unable to sustain dietary control after restricting their intake, weight regain may occur, thereby impacting the attainment and sustenance of remission. Metabolic surgery is specifically designed for individuals with severe obesity, particularly those experiencing complications. Nevertheless, its application is limited in scope and it is an invasive treatment option that is often met with low patient acceptance. Nevertheless, there is a scarcity of research examining the efficacy of antidiabetic medications in remission of T2DM, despite their relatively high acceptance and compliance rates. Current research findings indicate that these drugs exhibit inferior remission outcomes compared to lifestyle intervention and metabolic surgery. However, in recent times, novel hypoglycemic drugs, such as glucagon-like peptide-1 receptor agonists (GLP-1RA), Sodium-glucose cotransporter-2 inhibitors (SGLT-2i), and dipeptidyl peptidase-4 inhibitors, have been introduced both domestically and internationally (101–103). These medications, which operate through diverse mechanisms, demonstrate favorable hypoglycemic effects and offer potential benefits in preserving or even safeguarding pancreas function. Among these, SGLT-2i, GLP-1RA, dual glucose-dependent diabetes peptides (GIP), and the GLP-1RA tirzepatide exhibit a range of additional advantages beyond glucose reduction, including potential mechanisms for remission of T2DM, such as weight loss (71, 103–105). Hence, there exist numerous unexplored and enhanced areas within the domain of diabetes remission research that warrant future investigation. These areas encompass evaluating the efficacy of recently introduced hypoglycemic medications, examining the potential benefits of combining diverse mitigation strategies to enhance compliance and response rates, and exploring the impact of improved care and management on increasing remission rates, among others.

Given that China has the highest number of diabetes patients globally, the imperative to discover effective approaches for treating and remission of diabetes is even more pronounced. Chinese traditional medicine possesses distinct advantages in the treatment of various diseases. While certain medications, such as Tianqi capsule, Jin qi jiang tang tablet, and Jin li da granule, have demonstrated efficacy in remission/reversal of prediabetes (106), limited research exists on their effectiveness in remission of clinical diabetes. Consequently, further investigation is warranted to explore mitigation strategies tailored to the Chinese population, with particular emphasis on harnessing the unique attributes of traditional Chinese medicine for the treatment and remission of diabetes.