Page 88 - EJMO-9-1

Eurasian Journal of Medicine and
Oncology
T2D polymorphisms in Asians

transcription factor A (MAFA), glucokinase (GCK), and in the membrane of insulin granules within pancreatic
insulin (INS). In vitro studies using HMG20A-knockout β- cells. Its primary role is to facilitate zinc ion transport,
(KO) models have shown reduced expression of these thereby promoting insulin crystallization and storage.
genes. Clinical studies have also found that individuals In vitro studies have indicated that glucose stimulation
15
with T2D have lower HMG20A expression in their significantly alters the morphology of secretory granules
pancreatic islets. This observation is further supported and plasma insulin concentration in SLC30A8-KO models.
16
by the correlation between higher hemoglobin A1c levels In addition, SLC30A8 upregulation increases calcium ion
and the HMG20A rs7178572 G allele. The HMG20A (Ca²⁺) concentrations under high-glucose conditions.
17
22
rs7178572 G allele may impair HMG20A function, leading Another in vitro study involving SLC30A8-KO models
to aberrant insulin production and an increased risk of revealed typical traits, except for a marked deficiency in
T2D. zinc ion (Zn²⁺) release. Conversely, mice with SLC30A8
Insulin-like growth factor 2 mRNA-binding protein 2 overexpression demonstrated significant improvements in
(IGF2BP2) plays a crucial role in the development of β-cells. glucose tolerance. The study observed that insulin secretion
Experimental studies on IGF2BP2-knockout (KO) β-cells from islets overexpressing SLC30A8 was negatively
23
have demonstrated a reduction in insulin secretion and a impacted by glucose, whereas Zn²⁺ release was enhanced.
decline in compensatory β-cell proliferation. Interestingly, Clinical findings indicate that the presence of the SLC30A8
the transcriptional levels of the critical transcription rs13266634 C allele is associated with reduced insulin
factor pancreatic and duodenal homeobox 1 (PDX1) secretion in response to both oral and intravenous glucose
remain unchanged in both control and β-cell-specific administration. Moreover, this SNP has been linked to a
IGF2BP2-KO animals. However, PDX1 polypeptide levels decrease in the conversion of proinsulin into insulin. 24,25
are significantly reduced in IGF2BP2-KO mice, suggesting The SNPs in the SLC30A8 rs13266634 C allele contribute
that IGF2BP2 directly regulates the stability and translation to this effect and are associated with an increased risk of
of PDX1 mRNA, leading to decreased expression PDX1- T2D.
regulated genes regulated. 18 The ATP-sensitive potassium (K ATP ) channel facilitates
Overexpression of IGF2BP2 has been observed to potassium ion efflux from the cell, leading to a reduction in
enhance insulin secretion, indicating its role in promoting cellular charge and subsequent activation of calcium (Ca²⁺)
this process. IGF2BP2 supports insulin production by channels. This enables the cellular membrane to facilitate
stabilizing PDX1 polypeptides through activation of Ca²⁺ entry, a crucial step in the exocytosis of insulin
the IGF2-AKT-GSK3 signaling pathway. It has been granules. Key genetic components involved in regulating
18
proposed that the presence of the IGF2BP2 rs4402960 T this physiological process include KCNJ11, potassium
allele and rs1470579 C allele may disrupt the stability of voltage-gated channel subfamily Q member 1 (KCNQ1),
PDX1 polypeptides. This disruption is likely mediated by and transcription factor-7–like 2 (TCF7L2). The activity of
impairments in the IGF2-AKT-GSK3 signaling pathway, the K ATP channel is regulated by two key genes, KCNJ11,
which interferes with normal physiological processes, which encodes Kir6.2, and KCNQ1, which encodes Kv7.1.
particularly the augmentation of insulin secretion, thereby Previous in vitro and in vivo studies have demonstrated
increasing the risk of T2D. that SNPs in KCNJ11 and KCNQ1 genes impair insulin
secretion in response to glucose stimulation. 26
B-cell lymphoma/leukemia 11A (BCL11A) modulates
insulin secretion in pancreatic β-cells. Findings from a clinical Clinical studies have demonstrated that specific SNPs in
study indicate that patients with T2D exhibit elevated levels the KCNJ11 rs5219 A allele are associated with alterations
of BCL11A mRNA in pancreatic islets. In vitro experiments in fasting plasma glucose (FPG) and postprandial blood
27
using glucose-stimulated cells demonstrated that BCL11A glucose levels. In addition, a correlation has been identified
overexpression significantly reduced insulin synthesis, between the KCNQ1 rs2237895 C allele and decreased
19
whereas BCL11A-KO enhances insulin production. In insulin secretion. These findings suggest that SNPs in
28
addition, the BCL11A rs243021 T allele has been associated KCNJ11 and KCNQ1 genes may disrupt the functionality
with decreased insulin secretion and sensitivity, along with of the K ATP channel, impairing the depolarization of Ca²⁺
elevated glucagon levels. 20,21 These findings suggest that channels and ultimately reducing insulin secretion, thereby
individuals carrying the BCL11A rs243021 T allele may increasing the risk of T2D.
experience impaired insulin secretion and sensitivity, along The phosphatidylinositol 3-kinase (PI3K)/AKT
with disrupted glucagon regulation. signaling pathway plays a crucial role in regulating
The solute carrier family 30-member 8 (SLC30A8) gene pancreatic β-cell function. Activation of PI3K triggers the
encodes zinc transporter 8, which is prominently expressed release of Ca²⁺ from the endoplasmic reticulum. TCF7L2

Volume 9 Issue 1 (2025) 80 doi: 10.36922/ejmo.7549