Circulating Leptin and Adiponectin Levels in Patients with Pancreatic Cancer
Pancreatic cancer (PC) remains a malignancy with a poor prognosis, and its etiology and pathogenesis are not fully understood. Genetic susceptibility and environmental factors, including smoking, diabetes mellitus, and obesity, have been implicated as contributors to its high morbidity and mortality. Among obesity-related factors, adipokines like leptin and adiponectin (AdipoQ) have garnered attention due to their potential roles in tumor development. This meta-analysis aims to clarify conflicting findings on circulating leptin and adiponectin levels in PC patients compared to non-PC individuals, while exploring associations with clinical conditions such as cachexia, diabetes, and precancerous lesions.
Methodology and Study Design
The meta-analysis adhered to MOOSE and PRISMA guidelines, with a protocol registered on PROSPERO (CRD42020178522) and INPLASY (INPLASY202040138). A comprehensive search of PubMed, Embase, and Cochrane databases (up to April 2020) identified studies comparing circulating leptin and AdipoQ levels in PC patients versus controls. Inclusion criteria focused on observational studies with defined PC diagnoses and quantifiable adipokine measurements. Quality assessment utilized the Newcastle-Ottawa scale, and statistical analyses were conducted using Stata software (version 14.0). Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated to evaluate effect sizes. Heterogeneity was assessed using the I² statistic, and sensitivity analyses, meta-regression, and funnel plots were employed to address bias and variability.
Circulating Leptin and Adiponectin in PC vs. Non-PC Individuals
A total of 17 studies (20 subgroups) involving approximately 6,000 participants evaluated circulating leptin levels. Pooled data revealed significantly lower leptin levels in PC patients compared to non-PC individuals (SMD = −0.923, 95% CI [−1.290 to −0.556], P < 0.001). For AdipoQ, 14 studies (17 subgroups) demonstrated elevated levels in PC patients (SMD = 0.830, 95% CI [0.497–1.164], P < 0.001). Subgroup analyses stratified by ethnicity, sample size, assay methods, and body mass index (BMI) supported these findings, indicating consistent trends across diverse populations and methodologies.
Impact of Cachexia and Diabetes on Adipokine Levels
Cachexia, a common complication in advanced PC, was associated with further reductions in leptin levels. A comparison of seven studies showed significantly lower leptin levels in PC patients with cachexia versus those without (SMD = −0.440, 95% CI [−0.684 to −0.196], P < 0.001). In contrast, three studies evaluating leptin levels in PC patients with diabetes versus non-diabetic PC patients found no statistically significant difference (SMD = −0.330, 95% CI [−1.016 to 0.356], P = 0.346).
For adiponectin, no significant differences were observed between PC patients with or without cachexia (four studies, SMD = 0.135, 95% CI [−0.150 to 0.419], P = 0.353) or diabetes (three studies, SMD = 0.177, 95% CI [−0.135 to 0.490], P = 0.266). These findings suggest that cachexia specifically exacerbates leptin deficiency in PC, while AdipoQ levels remain elevated regardless of metabolic comorbidities.
Adipokine Levels in PC vs. Precancerous Lesions
Six studies compared leptin levels between PC and precancerous lesions, including intraductal papillary mucinous neoplasm (IPMN), autoimmune pancreatitis (AIP), and chronic pancreatitis (CP). PC patients exhibited significantly lower leptin levels than those with IPMN (SMD = −1.155, 95% CI [−2.132 to −0.178], P = 0.020) and AIP (SMD = −1.163, 95% CI [−1.729 to −0.597], P < 0.001). However, no significant difference was observed between PC and CP (SMD = −0.284, 95% CI [−1.000 to 0.431], P = 0.436).
AdipoQ levels were significantly higher in PC patients compared to those with CP (six studies, SMD = 0.888, 95% CI [0.431–1.345], P < 0.001). This elevation was not observed in comparisons with IPMN or AIP, highlighting a potential role for adiponectin in distinguishing PC from chronic inflammatory pancreatic conditions.
Heterogeneity and Bias Assessment
Significant heterogeneity was observed across studies (leptin: I² = 95.7%, P < 0.001; AdipoQ: I² = 94.7%, P < 0.001). Meta-regression identified the source of leptin (plasma vs. serum, P = 0.039), assay method (P = 0.034), and BMI (P = 0.029) as key contributors to heterogeneity for leptin. For AdipoQ, heterogeneity primarily stemmed from the source of controls (population-based vs. hospital-based, P < 0.001). Sensitivity analyses confirmed the robustness of the pooled estimates, with no single study significantly altering the results.
Funnel plots suggested potential publication bias for leptin, but trim-and-fill adjustment maintained the significance of the findings (adjusted SMD = −1.548, 95% CI [−2.162 to −0.933], P < 0.001). No significant bias was detected for AdipoQ.
Clinical and Mechanistic Implications
The marked reduction in leptin levels in PC patients may reflect altered energy homeostasis, particularly in cachexia, where muscle wasting and fat depletion are prevalent. Leptin, produced by adipose tissue, regulates appetite and energy expenditure; its deficiency in PC could exacerbate weight loss and metabolic dysregulation. Conversely, elevated AdipoQ levels might indicate a compensatory anti-inflammatory or insulin-sensitizing response, given adiponectin’s role in improving glucose metabolism and suppressing tumorigenic pathways.
The differential expression of adipokines between PC and precancerous lesions suggests their potential utility as diagnostic biomarkers. Lower leptin in PC compared to IPMN and AIP, coupled with higher AdipoQ in PC versus CP, could aid in differentiating malignancies from benign or inflammatory conditions.
Limitations and Future Directions
This meta-analysis has limitations, including heterogeneity across studies, variability in assay methods, and insufficient adjustment for confounders like BMI and metabolic comorbidities. Most studies were cross-sectional, limiting causal inferences. Prospective cohort studies are needed to establish temporal relationships between adipokine levels and PC development. Mechanistic research should explore how leptin deficiency and adiponectin elevation influence tumor progression, possibly through pathways involving inflammation, insulin resistance, or angiogenesis.
In conclusion, this meta-analysis provides conclusive evidence that PC is associated with decreased circulating leptin and increased adiponectin levels. These alterations are further modulated by cachexia and precancerous conditions, offering insights into the metabolic dysregulation underlying pancreatic cancer and highlighting potential avenues for biomarker development and therapeutic targeting.
doi.org/10.1097/CM9.0000000000001509
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