In this editorial, we comment on the article by Liu et al published in the recent issue of the World Journal of Diabetes (Relationship between GCKR gene rs780094 polymorphism and type 2 diabetes with albuminuria). Type 2 diabetes mellitus (T2DM) is a chronic disorder characterized by dysregulated glucose homeostasis. The persistent elevated blood glucose level in T2DM significantly increases the risk of developing severe complications, including cardiovascular disease, re-tinopathy, neuropathy, and nephropathy. T2DM arises from a complex interplay between genetic, epigenetic, and environmental factors. Global genomic studies have identified numerous genetic variations associated with an increased risk of T2DM. Specifically, variations within the glucokinase regulatory protein (GCKR) gene have been linked to heightened susceptibility to T2DM and its associated complications. The clinical trial by Liu et al further elucidates the role of the GCKR rs780094 polymorphism in T2DM and nephropathy development. Their findings demonstrate that individuals carrying the CT or TT genotype at the GCKR rs780094 locus are at a higher risk of developing T2DM with albuminuria compared to those with the CC genotype. These findings highlight the importance of genetic testing and risk assessment in T2DM to develop effective preventive strategies and personalized treatment plans.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by impaired glucose homeostasis, essential for maintaining stable blood glucose levels[1]. This disruption arises from a combination of underlying patho-physiological mechanisms, such as insulin resistance (IR) and diminished glucose-stimulated insulin secretion (GSIS)[2]. Consequently, the interplay between IR and impaired GSIS leads to elevated fasting plasma glucose concentrations and increased hepatic glucose production, culminating in chronic hyperglycemia, a hallmark of T2DM[3]. In this editorial, we comment on the article by Liu et al[4] published in the recent issue of the World Journal of Diabetes.

Glycolysis is a fundamental metabolic pathway that converts glucose into pyruvate, which then enters the citric acid cycle for energy production[5]. Alterations in this multi-step process can dysregulate glucose homeostasis and may lead to T2DM. Glucokinase (GK) catalyzes the phosphorylation of glucose to glucose-6-phosphate which is a pivotal step in glycolysis. This irreversible reaction traps glucose within the cell and commits it to the glycolytic pathway. GK is crucial in pancreatic β-cells and the liver, where it acts as a key regulator of GSIS and glucose uptake and storage, respectively[6]. GK exhibits multi-level regulation, encompassing transcriptional and post-transcriptional mechanisms[7]. Fasting induces nuclear sequestration of GK in an inactive complex with the inhibitory protein GK regulatory protein (GCKR)[8]. Contrarywise, postprandial glucose influx promotes dissociation of the GK/GCKR complex, triggering GK to translocation to the cytoplasm for activation[8]. Thus, the GK–GCKR complex functions as a metabolic “switch”, initiating energy storage and release pathways in response to fasting/feeding status. T2DM is associated with multiple perturbations in GK regulation, including reduced gene expression, impaired compartmental shuttling mediated by GCKR, and/or dysregulation of other metabolic and hormonal pathways that normally influence GK activity[9,10], as comprehensively reviewed in a study[7].

Genome-wide association studies have identified associations between genetic variants in the GCKR gene and T2DM. These variants influence protein function through various molecular mechanisms, ultimately leading to aberrant GK activation during normoglycemia or hypoglycemia. The most extensively studied variant is rs780094, located within intron 16 of the GCKR gene. This locus disrupts binding sites for several hepatocyte-specific transcription factors, including members of the hepatic nuclear factor and Forkhead/winged-helix families, potentially regulating GCKR gene transcription. However, these regulatory interactions require further functional validation.

The rs780094 polymorphism is implicated in the risk of T2DM and dyslipidemia across various populations. In a European cohort study, researchers examined 386731 common SNPs in 2931 participants, evenly split between diabetic patients and healthy controls. They discovered a significant association between the GCKR variant rs780094 and serum triglycerides[11]. In subsequent research, the authors expanded their scope to 12 independent cohorts, totaling over 45000 individuals from diverse non-European ethnic backgrounds[11]. This more extensive study indicated that the rs780094 variant exerts opposing effects on fasting plasma triglyceride and glucose levels and correlates with CRP concentrations[12].

A cohort study of Danish subjects found that the presence of the minor A-allele in the rs780094 was linked to elevated fasting serum triacylglycerol levels, compromised insulin secretion during both fasting and OGTT, and lower HOMA-IR scores[13]. Qi et al[14] reported similar findings in a cohort of 3210 elderly Han Chinese individuals (aged between 50 and 70 years) recruited from the “Study on Nutrition and Health of Aging Population in China”. This clinical investigation revealed that the A-allele, in rs780094, exhibited a marginal association with a decreased incidence of T2DM. However, it was significantly associated with a lower risk of impaired fasting glucose, lower fasting glucose levels, and enhanced β-cell function as measured by HOMA-β[14,15]. Notably, the A-allele was also associated with elevated fasting triacylglycerol levels, but not with HOMA of insulin sensitivity[14,15]. Comparable results were reported in Chinese adults and adolescents[16] and in Japanese populations[17].

The association of the rs780094 variant is limited to the incidence of metabolic diseases and does not extend to coronary heart disease[18]. A recent study investigated the link between rs780094 and lipid accumulation, which is crucial in liver disease, particularly non-alcoholic fatty liver disease (NAFLD)[19]. Silva et al[19] conducted a metabolomics data analysis using samples from the Finnish METSIM clinical trial to comprehensively identify metabolites associated with the rs780094 variant. The findings indicated that the rs780094 minor A-allele is inversely associated with glycerophospholipids, sphingolipids, gamma-glutamylthreonine, and taurocholenate sulfates. In contrast, the same allele was positively associated with retinol, indolelactate, and N-acetyltryptophan, as well as with 12 glycerolipids and 19 glycerophospholipids[19].

The pleiotropy of the GCKR rs780094 polymorphism is significantly associated with metabolic diseases, including T2DM, its associated dyslipidemia, NAFLD, and nephropathy. Although the rs780094 variant is believed to alter GCKR gene expression, its precise mechanism of action remains elusive. Clinical evidence suggests that this variant impairs pancreatic β-cell function and disrupts hepatic triglyceride and glucose metabolism across various populations. Therefore, considering the interplay of the GCKR rs780094 polymorphism with environmental and lifestyle factors represents a promising approach to precision medicine, offering an innovative strategy for tailoring disease prevention and treatment.