Mapping global new-onset, worsening, and resolution of diabetes following partial pancreatectomy: a systematic review and meta-analysis

Background and aims: Partial pancreatectomy, commonly used for chronic pancreatitis, or pancreatic lesions, has diverse impacts on endocrine and metabolism system. The study aims to determine the global prevalence of new-onset, worsening, and resolution of diabetes following partial pancreatectomy. Methods: The authors searched PubMed, Embase, Web of Science, and Cochrane Library from inception to October, 2023. DerSimonian-Laird random-effects model with Logit transformation was used. Sensitivity analysis, meta-regression, and subgroup analysis were employed to investigate determinants of the prevalence of new-onset diabetes. Results: A total of 82 studies involving 13 257 patients were included. The overall prevalence of new-onset diabetes after partial pancreatectomy was 17.1%. Univariate meta-regression indicated that study size was the cause of heterogeneity. Multivariable analysis suggested that income of country or area had the highest predictor importance (49.7%). For subgroup analysis, the prevalence of new-onset diabetes varied from 7.6% (France, 95% CI: 4.3–13.0) to 38.0% (UK, 95% CI: 28.2–48.8, P<0.01) across different countries. Patients with surgical indications for chronic pancreatitis exhibited a higher prevalence (30.7%, 95% CI: 21.8–41.3) than those with pancreatic lesions (16.4%, 95% CI: 14.3–18.7, P<0.01). The type of surgical procedure also influenced the prevalence, with distal pancreatectomy having the highest prevalence (23.7%, 95% CI: 22.2–25.3, P<0.01). Moreover, the prevalence of worsening and resolution of preoperative diabetes was 41.1 and 25.8%, respectively. Conclusions: Postoperative diabetes has a relatively high prevalence in patients undergoing partial pancreatectomy, which calls for attention and dedicated action from primary care physicians, specialists, and health policy makers alike.


Introduction
Pancreatoduodenectomy (PD) and distal pancreatectomy (DP) are well-established treatment procedures used worldwide for chronic pancreatitis, benign or (potentially) malignant pancreatic lesions [1][2][3] .However, the implementation of PD and DP is associated with the loss of upper gastrointestinal and pancreato-biliary parenchyma, leading to impaired upper gastrointestinal functions [4,5] .To mitigate the substantial decrease in functional capacity of the upper gastrointestinal tract, some organ-preserving pancreatectomy procedures have been developed, including duodenum-preserving pancreatic head resection (DPPHR), pancreatic head resection with segmental duodenectomy (PHRSD), central pancreatectomy (CP), and tumor enucleation (TEU) [6][7][8] .These procedures aim to preserve pancreatic tissue, gastric antrum, duodenum, and common bile duct for maintaining the functionality of the residual pancreatic parenchyma and the upper gastrointestinal tract [9] .
It is widely acknowledged that partial pancreatectomy carries the potential of developing new-onset diabetes (referred to as type 3c diabetes) as well as exacerbating or resolving preexisting diabetes [10] .However, the real-world dynamics of diabetes development, progression, and changes following partial pancreatic resection still require further investigation.Certain macro factors that may contribute to the emergence of new-onset diabetes such as regional variation, socioeconomic class, and medical level have not been taken into account in previous studies [11,12] .Additionally, with regard to significant heterogeneity between different clinical studies, a comprehensive analysis of the preoperative, perioperative, and postoperative factors beyond indication and procedure of surgery is required to undertake.Moreover, the assessment of the worsening and resolution of diabetes following partial pancreatectomy has not been conducted in current systematic reviews [9,13] .
In this study, we aim to map the global new-onset, worsening, and resolution of diabetes following partial pancreatectomy.We performed a systematic review and meta-analysis through mining the existing data on postoperative diabetes after pancreatic resection.The study will broaden our knowledge of surgeryrelated postoperative changes of pancreatic endocrine function and provide evidence for clinical decision-making.
We included studies for meta-analysis as follows: (1) a cohort study or case-control study fully published in English; (2) identified patients undergoing partial pancreatectomy; (3) reported number of preoperative and postoperative diabetes.We excluded studies for meta-analysis as follows: (1) individuals less than 18 years; (2) no sufficient information for data extraction.

Selection criteria
The studies were meticulously evaluated following predetermined criteria.The preliminary screening of titles and abstracts was performed by two reviewers independently.To ensure accuracy, an additional investigator critically reviewed a randomly selected 10% subset of the studies.Subsequently, the full texts of potentially relevant articles were thoroughly examined by any two of the authors, and any disparities were resolved through group discussion or, if necessary, by a fifth reviewer.Consensus was successfully attained in all cases, establishing a high level of agreement among the reviewers.

Data extraction
We extracted data at all levels reported in the study, including first author of the study, time of publication, study period, country or area, geographic region, income of country or area assessed by World Bank, the level of country development, study size, study population, indication of surgery, procedure and process of surgery, length of hospital stay, postoperative complications, duration of follow-up, diabetes diagnosis and the prevalence of new-onset, worsening and resolution of diabetes.Two authors independently reviewed and extracted data from the included studies by utilizing a custom-designed data extraction form tailored to the requirements of this investigation.Data were then cross-validated to guarantee accuracy by any of two authors.In cases where duplicate data were identified, the entry with the smaller sample size or shorter followup duration was excluded to prevent redundancy.

Quality assessment and statistical analysis
The quality assessment of the 82 included studies was conducted using the Newcastle-Ottawa Scale (NOS) (Supplementary Table 1, Supplemental Digital Content 4, http://links.lww.com/JS9/B617).No studies were excluded based on their quality scores to ensure transparency and encompass all available evidence in this domain.Consistency checks were conducted and the Metaprop module within the R-4.2.2 statistical software package was employed for meta-analysis.A 95% CI was estimated using the Wilson score method, and the pooled prevalence was calculated using the DerSimonian-Laird random-effects model with Logit transformation.The heterogeneity among the included studies was evaluated through the Cochran Q statistics and I 2 statistics.Estimates with a P-value less than .05for the Q-statistic and an I 2 value of 50% or higher were considered to indicate moderate heterogeneity.Given the anticipated heterogeneity in global data, a random-effects model was employed to pool the

HIGHLIGHTS
• Partial pancreatectomy carries the potential of triggering new-onset diabetes (referred to as type 3c diabetes).• The global prevalence of new-onset diabetes after partial pancreatectomy was found to be 17.1% with significant heterogeneity influenced by macro factors such as regional variation, development, and income levels as well as micro factors including indication and procedure of surgery.
• Postoperative diabetes has a relatively high prevalence in patients undergoing partial pancreatectomy, which calls for attention and dedicated action.
prevalence of new-onset, worsening and resolution of diabetes.Focusing on the significant heterogeneity associated with newonset diabetes, we employed a meticulous sensitivity analysis approach by conducting a comprehensive series of leave-one-out diagnostic tests.Furthermore, the results were validated using a dedicated function within the metafor package to enhance the reliability and validity of our findings.As no outliers were identified through the sensitivity analysis, meta-regression was then conducted using a mixed-effects model.The considered covariates included country or area, geographic region, income of country or area, development level of country, study size, and study quality score.Subsequently, multivariable meta-regression (multimodel inference) was carried out using the 'dmetar' package to determine the best-fitting predictor combinations and identify the most significant overall predictors.Subgroup analyses were performed to assess potential confounding effects of heterogeneity.The difference between groups was assessed using a P-value, with a threshold of P < 0.05 indicating a statistical significance.

Literature search and study characteristics
A total of 8736 records were identified.After eliminating duplicates, 5259 records remained.We screened the titles and abstracts and excluded 5116 ineligible records.The full texts of the remaining 143 records were evaluated for eligibility, with 61 being excluded.Ultimately, the analysis comprised 82 eligible studies involving 13 257 patients undergoing partial pancreatectomy, with 11 064 allocated to examine new-onset diabetes, 607 for worsening diabetes, and 1233 for resolution of diabetes (Fig. 1, Supplementary Table 1, Supplemental Digital Content 4, http:// links.lww.com/JS9/B617)  . The quaity assessment scores for the included studies were presented in Supplementary Table 1 (Supplemental Digital Content 4, http://links.lww.com/JS9/B617).

Discussion
Partial pancreatectomy for chronic pancreatitis, benign or (potentially) malignant pancreatic lesions is associated with the development, exacerbation, and resolution of diabetes.The global prevalence of new-onset diabetes was found to be 17.1% with significant difference between different countries.Univariate meta-regression indicated that study size was the causes of heterogeneity and multivariable analysis suggested that income of country or area has the highest predictor importance.Furthermore, a notable disparity of postoperative diabetes prevalence was identified with statistical significance due to the indication and type of surgery.Once developing diabetes, more than 50% of individuals required insulin therapy to effectively manage their blood glucose levels.It is noteworthy that pancreatic resection not only carried the potential to trigger newonset or worsening diabetes but also held promise for ameliorating preexisting diabetes.
Recent systematic reviews have aimed to estimate the prevalence of new-onset diabetes following partial pancreatectomy [9,[11][12][13] .However, to our knowledge, this study represents the most comprehensive review to date, incorporating the largest number of studies on postoperative diabetes worldwide.Our investigation involved a series of rigorous and extensive analysis, first considering certain macro-level factors such as country and regional disparities, as well as economic development level, to examine their potential impact on the occurrence of postoperative diabetes.In addition, we conducted a comprehensive examination of preoperative, perioperative, and postoperative variables, while also scrutinizing the global prevalence of worsening and resolution of diabetes following partial pancreatectomy.Our study has several limitations.First, despite its comprehensive nature, there is a notable scarcity of research studies from developing countries with lower-middle or low-income.This lack of representation hampers the generalizability of our findings.Second, the metabolic information in some studies were self-reported, and the diagnosis of diabetes did not strictly adhere to WHO-criteria.This potential reporting bias may introduce uncertainties and affect the accuracy of the results.Third, it is reported that the proportion of pancreas removal was associated with postoperative diabetes [38,67] .However, due to the limited availability of studies, we failed to further analyze these data.Lastly, because there was insufficient data from the included studies, our meta-analysis did not thoroughly examine the impact of preoperative diabetes types, surgical indications, and specific surgical procedures on the exacerbation and resolution of diabetes.
Our findings indicated that some western countries, including UK, Germany, and USA, exhibited higher prevalence of postoperative diabetes compared to some eastern countries, such as China, Korea, and Japan.This observed disparity can be attributed to variations in dietary habits in different countries.
Western countries often embrace a diet characterized by a greater consumption of processed foods, which are typically abundant in unhealthy fats, added sugars, and refined carbohydrates.
These dietary patterns may lead to an increased risk of developing diabetes [98,99] .In contrast, eastern countries, particularly China, Korea, and Japan, traditionally prioritize diets rich in whole grains, vegetables, and seafood, which are generally regarded as healthier choices.These dietary preferences may contribute to a lower prevalence of postoperative diabetes in these regions [100,101] .Notably, countries such as Italy and France, renowned for their adherence to internationally acclaimed health-conscious dietary pattern known as the Mediterranean diet, showed the lowest prevalence of postoperative diabetes [102] .
Furthermore, our analysis revealed that higher prevalence of new-onset diabetes in developed and high-income countries compared to developing countries with upper-middle income.Indeed, it is acknowledged that significant strides have been achieved in healthcare infrastructure in developing countries with an upper-middle income level over the past decade [103] .In the realm of pancreatectomy, these countries have made noteworthy advancements in critical aspects, encompassing preoperative assessments, surgical techniques, and postoperative management, thereby bringing them into greater conformity with global standards [104,105] .It is interesting that a considerable proportion of patients undergoing pancreatic resection in these countries often engage in physically demanding occupations due to their relatively underdeveloped economies.This specific employment setting could potentially operate as a mitigating factor, reducing the prevalence of postoperative diabetes [106] .Although the lack of relevant data and the restricted rigor of research design prevented us from including data from developing with lower-middle or low incomes in our meta-analysis, we are able to present a general picture of the state of pancreatectomy in these areas.In comparison to high-income countries that possess cutting-edge medical infrastructure, such as state-of-the-art operating rooms, CT scanners, MRI machines, and robotic surgical systems, lowermiddle and low-income countries often grapple with substantial challenges related to basic healthcare infrastructure [107] .In addition, high-income countries benefit from a well-established cadre of highly proficient surgeons who specialize in the complexities of pancreatic surgery [107] .Conversely, lower-middle and low-income countries frequently encounter the formidable obstacle of inadequate specialized training programs and a shortage of experienced surgeons possessing the necessary expertise to undertake intricate pancreatic resections [107] .The insufficiency of healthcare infrastructure and the scarcity of specialized medical professionals have markedly increased the incidence of postoperative complications among patients undergoing pancreatic resection in these nations [108,109] .It is possible that these factors have contributed to a dearth of research on the longterm outcomes of pancreatic resections within these nations, such as exocrine and endocrine insufficiency.A potential explanation for the elevated occurrence of newonset diabetes in patients undergoing partial pancreatectomy for chronic pancreatitis is likely attributed to the progressive destruction of pancreatic parenchyma [110] .Conversely, in patients with benign or (potentially) malignant pancreatic lesions, the remaining pancreatic parenchyma is relatively healthy [13] .Notably, following tumor resection, the impaired pancreatic βcell function caused by tumor cells shows a remarkable improvement, as well as the degree of peripheral insulin resistance [111][112][113][114] .Consequently, these patients have a lower risk of developing new-onset diabetes.In terms of different surgical procedures, it is widely acknowledged that the extent and location of pancreas removal are significantly associated with the development of diabetes [10] .Our study, based on empirical data, demonstrated that specific pancreas-preserving techniques, such as CP and TEU, effectively reduced the risk of postoperative diabetes.Previous research has indicated that islet density and distribution are approximately two times higher in the tail region compared to that in the head and body regions, which may account for the highest risk of new-onset diabetes in patients undergoing the DP procedure [115] .The impact of duodenal preservation on the emergence of postoperative diabetes remains a matter of controversy.The resection of the duodenum may induce alterations in incretin secretion, including a decrease in gastric inhibitory polypeptide secretion and an increase in glucagon-like peptide 1 (GLP-1) secretion, which regulate β-cell function and insulin sensitivity in peripheral tissues [10,116,117] .
Another interesting finding was that there was no statistically significant disparity in postoperative diabetes prevalence between two BMI groups (BMI <25 and BMI ≥ 25).Although previous studies have suggested that overweight and obese individuals may exhibit a relatively compromised pancreatic parenchyma, commonly referred to as soft pancreatic tissue, we posit that the impairment in pancreatic β-cell function resulting from fatty infiltration is much less severe compared to the pancreatic diseases that necessitate surgical intervention [118] .In fact, it appears that the degree of damage to the pancreatic parenchyma is nearly indistinguishable between both groups.Within these two groups, we still believed that the primary determinant for postoperative diabetes may be the insufficient insulin secretion resulting from the resection of pancreatic parenchyma.Furthermore, the relatively limited number of studies included in the subgroup analysis may contribute to the absence of statistically significant difference.Additional research efforts may be merited to conduct a more comprehensive exploration of this matter.
The concern is not groundless.First, diabetes exerts a profound impact on one's quality of life.Belyaev et al. [42] provided evidence of patients enduring postoperative endocrine or exocrine insufficiency, or both, reporting significant declines in their physical well-being.In a comparative study examining the quality of life after partial pancreatic resection, postoperative diabetes exhibited the most detrimental effects on leisure activities and physical functioning [85] .Second, a remarkable 52.9% of patients developing new-onset diabetes required insulin therapy to effectively manage their blood glucose levels, and 41.1% of individuals with preoperative diabetes experienced a deterioration in metabolic control.Furthermore, despite certain similarities between type 3c diabetes and type 2 diabetes, type 3c diabetes presents greater challenges in blood glucose management due to notable fluctuations associated with the deficiency of pancreatic polypeptide and exogenous insulin treatment [119,120] .However, it is important to recognize that pancreatic resection does not solely yield negative outcomes.Notably, 25.8% of patients experienced a restoration from previously diagnosed diabetes, although the underlying mechanism needs further investigation.
In conclusion, postoperative diabetes has a relatively high prevalence in patients undergoing partial pancreatectomy and poses negative effects on their life.This calls for attention and dedicated action from primary care physicians, specialists, and health policy makers alike.

Figure 2 .
Figure 2. Global prevalence of new-onset diabetes following partial pancreatectomy.

Table 1
Subgroup analysis for new-onset diabetes following partial pancreatectomy.

Table 2
Pooled estimates of risk factors for new-onset diabetes following partial pancreatectomy.