Introduction
Type 2 diabetes mellitus (T2DM) poses a significant public health concern that has an impact on the quality of life of affected individuals, thereby creating a financial burden on society (1). Based on the World Health Organization (WHO) data (2019), non-communicable diseases are responsible for 74% of global deaths. Specifically, diabetes was ranked as the tenth leading cause of mortality worldwide in 2019, with fatalities accounting for 1.6 million. It is estimated that by 2035, ~592 million individuals could lose their lives due to diabetes-related complications (2). T2DM, which comprises 90% of all diabetes cases, used to be considered as a disease common in wealthy, developed countries. However, it has currently spread worldwide and is the leading cause of mortality and disability, particularly in younger individuals (3). The susceptibility to type 2 diabetes differs significantly worldwide, notably with Asian Indians, Native Americans and Pacific Islanders facing a notably elevated susceptibility to the condition. Since the 1990s, there has been a consistent increase in the worldwide occurrence of type 2 diabetes. In particular, there has been a substantial increase in the global diabetic population since the beginning of 2000(4). According to the International Diabetes Federation (IDF), 8.8% of adults globally have diabetes, with males being slightly more affected (9.6%) than females (9.0%). Presently, 463 million individuals have diabetes, and 374 million have impaired glucose tolerance (IGT), which is a precursor of the condition. Projections indicate these numbers could reach 700 million for diabetes and 548 million for IGT by the year 2045, a 51% increase from 2019(5). The global prevalence and risk factors for T2DM are presented in Fig. 1 (6,7).
T2DM is a long-term endocrine disorder marked by ‘hyperglycemia’, or the failure of the body to control blood sugar levels due to insulin resistance and a decreased insulin output. It is the most prevalent type of diabetes, affecting millions of individuals globally (8). T2DM is defined as a reduction in the responsiveness of the cells in the body to insulin, a hormone produced by the pancreas that manages blood sugar levels. To combat the resistance, the body generates more insulin; however, over time, the pancreas becomes less able to produce adequate insulin, which raises blood sugar levels (9). A variety of factors contribute to the onset of T2DM, including family background, age, socioeconomic status, ethnicity, weight issues, metabolic syndrome and specific unhealthy habits. The interaction among these risk factors in causing T2DM is a complex physiological process involving intricate genetic and environmental influences, which appear to differ across various population groups (10). Several indicators of T2DM include an increased thirst, reduced appetite, frequent urination and unexplained weight reduction. The failure to address T2DM could lead to complications, such as ulcers, heart-related issues, and harm to multiple organs such as the kidneys and nerves, as well as vision and hearing impairments (11). In addition to frequently occurring alongside other conditions, such as dyslipidemia and hypertension, T2DM poses a substantial standalone risk for developing coronary artery disease (CAD). Patients with T2DM experience elevated rates of cardiovascular disease, particularly CAD, which is associated with increased morbidity and mortality rates. While individuals without diabetes have a 25% chance of developing CAD, those with T2DM are at a 2-4-fold greater risk (12). Several research studies have established a connection between mutations in specific genes and the development of diabetes mellitus, particularly T2DM. These genes, in combination with environmental factors, contribute to the onset of T2DM through diverse pathways. The hereditary component of risk factors typically involves multiple genes interacting with each other or with environmental elements. Consequently, addressing genetic risk factors for T2DM could enhance the comprehension of these conditions and lead to improved clinical care.
Insulin-like growth factor (IGG) mRNA-2 binding protein 2 (IGF2BP2), a protein found on chromosome 3q27, plays roles in both embryonic development and the formation of the pancreas. Additionally, it governs the transcription of IGF2, a pivotal factor in the development of insulin action (13). IGF2BP2 has the potential to reduce the expression of IGF2 in both adipose tissue and the dysfunction of β-cells. This action affects a growth factor essential for regulating pancreatic development and fat cell formation. Moreover, IGF2BP2 is involved in T2DM, a condition linked to reduced insulin secretion (14). Research has demonstrated a significant association between IGF2BP2 and overweight or obesity, which are known risk factors for T2DM. Given the link between obesity and T2DM, it is hypothesized that the association between IGF2BP2 and T2DM may be influenced by obesity (15). This phenomenon is referred to as the interaction between IGF2BP2 and obesity in relation to T2DM. Moreover, IGF2BP2 is associated with decreased insulin secretion and significantly contributes to the development of T2DM across various ethnic populations.
Conversely, the sirtuin1 (SIRT1) gene, situated on chromosome 10, operates the nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase (16). It falls under the category of enzymes known as silent information regulators, contributing to ageing, longevity and the development of age-related metabolic conditions, such as T2DM (17). The protein regulates pancreatic growth by controlling pancreatic and duodenal homeobox 1 transcription, modulates hepatic metabolism and gluconeogenesis by reducing G6Pase and phosphoenolpyruvate carboxykinase transcription, and inhibits adipogenesis by binding to genes regulated by peroxisome proliferator-activated receptor-γ. Notably, SIRT1 enhances insulin secretion by downregulating uncoupling protein (Ucp2) expression in pancreatic β-cell mitochondria (18). Numerous studies have demonstrated that SIRT1 plays a crucial role in glucose-dependent insulin secretion, gluconeogenesis, regulating inflammation, lipolysis, and β-cell survival. Its association with various histones and nonhistone substrates has a significant impact on the development and advancement of diabetes, particularly T2DM (19). However, additional validation is necessary to establish definitive findings. Hence, in the present study, a meta-analysis and statistical power assessment were conducted to explore the association between gene polymorphisms of IGF2BP2 and SIRT1 and their impact on susceptibility to T2DM.
Discussion
T2DM is a complex, polygenic disorder characterized by numerous genes contributing to a higher risk of the disease. In recent times, 16 new genetic sites associated with susceptibility to T2DM have been identified by researchers (36). IGF2BP2 is a member of the mRNA-binding protein group, which is crucial for RNA localization, stability, and translation. It is prominently present in pancreatic islets and interacts with IGF2, a significant molecule involved in growth and insulin signaling (37). Based on prior research, it appears that the IGF2BP2 gene mutation is linked to reduced initial insulin secretion in response to glucose as determined by the hyperglycemic clamps and affects pancreatic β-cell function in individuals with T2DM, contributing to the development of T2DM pathogenesis (38). In in vivo research on fruit fly, Drosophila melanogaster, IGF2BP2 serves as a signaling molecule essential for insulin function, growth, and pancreas development. Elevated levels of both fasting plasma glucose and serum insulin were observed. Additionally, the gene diacylglycerol kinase gamma, similar to IGF2BP2, has been shown to be associated with regulating insulin secretion (39). Therefore, further functional investigations into the pathophysiological pathways of IGF2BP2 are required.
Ali et al (40) reported that in the Egyptian population, the homozygous (TT) genotype of IGF2BP2 (rs4402960) and the homozygous (CC) genotype of rs1470579 variants were identified as risk factors for the occurrence of T2DM. Previous meta-analyses have explored the potential link between mutations in the IGF2BP2 gene (rs4402960 and rs1470579) and the susceptibility to T2DM (41,42). The present meta-analysis encompasses articles from 2016 to 2024, representing the most recent data. However, the present study did not integrate the findings from earlier research. Conducting updated meta-analyses is crucial for maintaining the relevance and accuracy of scientific knowledge. By integrating the latest research findings, these analyses ensure that conclusions are founded on the most current and comprehensive evidence, thus advancing our understanding of gene-trait associations and guiding the effective utilization of biomarkers in diagnosis, prognosis and treatment strategies.
The SIRT1 protein functions as an epigenetic regulator in human physiology. Changes in the expression of SIRT1 are linked to various diseases, such as metabolic and cardiovascular diseases (43). SIRT1, a deacetylase-dependent NAD+, plays a crucial role in regulating insulin signaling, metabolic rate and glucose utilization. It is implicated in the pathogenesis of T2DM by regulating insulin secretion and impacting glucose metabolism in liver cells. By repressing Ucp2 and activating transcription factors, SIRT1 maintains glucose homeostasis through the modulation of downstream genes (44). The association between T2DM and SIRT1 SNP variants has been examined across diverse ethnic groups. Sadeghi et al (5 found that the SIRT1 gene variants rs12778366 and rs3758391 may be linked to susceptibility to T2DM in an Iranian population. It is essential to replicate these findings across diverse ethnicities and with larger sample sizes to improve result accuracy (45). Similarly, the study by Kaabi et al (46) found the occurrence rates of SIRT1 rs12778366 and rs3758391 SNPs within the Saudi population. Their study indicated that there is no link between these genetic variations and susceptibility to T2DM. This discovery contributes to the expanding collection of studies investigating the genetic factors associated with T2DM (46). Only a limited number of studies have been carried out on the specific SIRT1 rs7895833 gene variants. The findings across these studies are inconsistent. Therefore, the present study compiled all the available data and performed a meta-analysis. To the best of our knowledge, this is the first meta-analysis on a SIRT 1 gene polymorphism in T2DM.
Based on the findings of the present meta-analyses, a significant association was found between the IGF2BP2 rs4402960 gene and the development of T2DM in the over-dominant model. However, no substantial association was found in the allelic, recessive and dominant models. Similarly, the present study indicates that the IGF2BP2 rs1470579 gene variant is associated with an increased risk of developing T2DM in the allelic and recessive models, while no significant association was observed in the dominant and over-dominant models. Conversely, there was no notable association between the SIRT1 rs7895833 gene variant and T2DM susceptibility across all genetic models. The sensitivity analysis indicates that no single study significantly affects the overall results. The present meta-analysis confirms that both IGF2BP2 and SIRT1 gene polymorphisms adhere to the HWE principle. Egger's test and funnel plots were used to detect publication bias, revealing no evidence of bias. The reliability of the conclusions is supported by the methodological quality, which was measured using the ROB2 tool. This demonstrates a decreased risk level across different aspects of research design in each included study. Thus, statistical data firmly supports our views. Strict protocols were used to extract and analyze the data, and a power analysis verified that the sample sizes of the selected studies were sufficient.
Mohammed et al (47) concluded that the IGF2BP2 rs6777038 and rs6444082 variants may significantly contribute to the onset of T2DM in the Iraqi population. However, Liu et al (48) found that similar variants were not associated with gestational diabetes. In the study by Li et al (49), it was found that IGF2BP2 gene mutations were not significantly linked to gestational diabetes. They concluded that further research was required to validate these findings in the future. Zhu et al (50) discovered connections between miRNA polymorphisms in the insulin signaling pathways and susceptibility to T2DM, marking the first exploration of such links. Their findings indicated that variants, such as miR-133a-2 rs13040413, let-7a-1 rs13293512 and miR-27a rs895819 were associated with susceptibility to T2DM in either general or subgroup analyses within the population in China (50). Similarly, Pang et al (51) analyzed genetic variants in the SIRT1 gene promoter region in patients with T2DM and controls. The identified variants in patients with T2DM may influence the development of T2DM by affecting SIRT1 levels. Targeting these genetic variants through pharmacological aspects could offer a novel therapy for patients with T2DM (51). In addition, the study by Letonja et al (52) reported that the SIRT1 rs7069102 polymorphism exhibited a significant association with diabetic nephropathy in patients with T2DM, suggesting its potential as a marker for susceptibility to diabetic nephropathy in this population (52). Li et al (53) revealed that the SIRT1 variant rs10997866 exhibited a notable association with susceptibility to type 1 diabetes, with the G minor allele significantly increasing the risk of developing type 1 diabetes. Additional research involving larger sample sizes, diverse ethnic groups and investigations into various variants of the SIRT1 gene is essential for attaining precise conclusions.
Several proteins have been implicated in T2DM, as strongly demonstrated in the study conducted by Chahar et al (54), which revealed that the measurement of adiponectin, IGF1 and IGF2 levels in serum, combined with gene expression analysis, plays a crucial role in predicting the progression from T2DM to diabetic nephropathy. Canto-Cetina et al (55) demonstrated that fibronectin type III domain-containing protein 5 (FNDC5/irisin) was significantly linked to susceptibility to T2DM in Maya-Mestizo women under the dominant model. Their findings indicate that the FNDC5 gene modulates the production of irisin, a hormone released during exercise that aids in converting fat cells to a type that burns energy. Variations in the FNDC5 gene may affect irisin levels, thereby influencing how the body manages blood sugar and increasing the chances of developing T2DM (55). The study by Atere et al (56) revealed the association between serum amyloid A (SAA), fasting blood sugar and lipid profile markers in diabetes. Notably, SAA emerged as a superior indicator, holding the potential to improve the diagnosis and management of diabetic patients (56). Furthermore, Huang et al (57) identified HMG20A and HNF1B gene polymorphisms as being associated with an elevated risk of developing T2DM in all genetic models. Variations in these genes could affect glucose and insulin metabolism, potentially increasing the risk of developing T2DM (57).
The present study sheds light on the genetic basis of T2DM, potentially paving the way for improved diagnoses and treatment strategies. Unveiling these genetic markers could hold promise for risk assessment, early detection and personalized treatment plans. These findings highlight the crucial role of studies across diverse populations, which can enrich the understanding of the IGF2BP2 genetic variant and its contribution to the development of T2DM. Ultimately, the present study provides valuable insight into these associations, enhancing the current knowledge and emphasizing the need to unravel these complexities.
In conclusion, the present meta-analysis reveals the role of IGF2BP2 and SIRT1 gene polymorphisms in the development of T2DM. The present study found that the IGF2BP2 rs4402960 and rs1470579 variants were significant risk factors for the onset of T2DM. However, there was no significant association between the SIRT1 rs7895833 gene polymorphism and susceptibility to T2DM. Understanding the complexities of genetic predispositions can help improve risk assessment, early detection and personalized treatment strategies. The present study also emphasizes the need for ongoing investigations to validate these findings and enhance the ability to combat T2DM and mitigate its impact on public health. The present meta-analysis has certain limitations, however. The present study did not explore potential impacts from gene-environment interactions and other demographic characteristics such as age, sex and comorbidities, as the study mainly focused on gene polymorphisms. Additionally, a subgroup analysis was not conducted due to insufficient studies. The majority of the studies have focused on Asian populations. Therefore, the study necessitates a larger and more diverse sample size, encompassing various ethnicities. Further research involving diverse populations is recommended to enhance the relevance and applicability of the results.