Page 89 - EJMO-9-1

Eurasian Journal of Medicine and
Oncology
T2D polymorphisms in Asians

is pivotal in regulating this signaling pathway. Through activated receptor gamma coactivator 1-alpha (PGC1A),
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direct regulation by insulin gene enhancer protein 1 and diacylglycerol kinase delta (DGKD), play a role in
(ISL1) and insulin-1 (INS1), as well as indirect regulation insulin regulation. Inflammatory cytokines, such as dual
through MAFA, presenilin-1 (PS1), and presenilin-2 specificity phosphatase 9 (DUSP9), further contribute to
(PS2), TCF7L2 influences proinsulin expression, thereby this regulation (Table 1). While these genes are highlighted
affecting insulin maturation and Ca²⁺ ion release. The risk due to their SNPs being associated with T2D, they are not
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alleles rs7903146 and rs12255372 are linked to increased exclusively responsible for the observed effects.
TCF7L2 mRNA expression. Interestingly, the HOMA-B The role of adiponectin, regulated by ADIPOQ, as an
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index for the T allele of rs7903146 show a decline. These insulin sensitizer in target organs through the activation
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findings suggest that the rs12255372 T allele and rs7903146 of adenosine monophosphate-activated protein kinase
T allele in the TCF7L2 initially enhance insulin secretion (AMPK) signaling is well-documented in academic literature.
by promoting Ca²⁺ ion release. However, over time, these A clinical study on the ADIPOQ rs1501299 T allele, which has
SNPs may impair pancreatic β-cell function, increasing the been found to be dominant among individuals of Caucasian
risk of T2D. descent, showed elevated insulin levels and increased total
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3.2. Insulin catabolism adiponectin levels. Similarly, another SNPs, the ADIPOQ
rs266729 G allele, exhibited comparable results. A potential
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The clearance of insulin primarily occurs in the liver mechanism underlying these observation is that the ADIPOQ
and kidney, with approximately 80% of secreted insulin rs16861194 G allele may affect adiponectin gene expression
being cleared during its initial transit through the liver. in adipose tissue, leading to decreased insulin sensitivity in
Insulin-degrading enzyme (IDE) plays a central role in peripheral tissue effectors.
insulin catabolism (Table 1). This process occurs through
IDE’s recognition of the substrate’s three-dimensional A clinical study showed that individuals with T2D
configuration. 33,34 demonstrated a significant decrease in plasma GAS6
levels. 39,40 In vitro studies further showed that GAS6
Previous study has indicated that individuals with T2D expression decreased with increased deposition of adipose
exhibit elevated IDE levels. An in vivo study involving tissue. Moreover, the absence of GAS6 led to a reduced
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IDE-KO models demonstrated that the absence of IDE adiponectin expression. Similarly, in an insulin resistance
exacerbates hyperinsulinemia and insulin resistance, while model, both adiponectin and GAS6 expression levels were
not causing any notable alterations in insulin clearance. found to be decreased. Another clinical study on the
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This effect is accompanied by an increase in pancreatic GAS6 rs8191974 T allele found that individuals with the
β-cell functionality. Conversely, increased IDE expression A allele exhibited higher GAS6 levels and lower glucose
through adenoviral delivery has been shown to enhance levels. The presence of the GAS6 rs8191974 T allele in
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glucose tolerance and increase insulin sensitivity. This the Asian population has been suggested to potentially
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indicates that IDE regulates insulin levels in accordance decrease susceptibility to T2D. This phenomenon may be
with the body’s metabolic needs and requirements. The explained by the elevated GAS6 levels, which amplifies
IDE rs10509645 C allele has the potential to increase IDE the impact of adiponectin on AMPK activation, thereby
levels, thereby enhancing the catabolic activity of insulin improving insulin sensitivity.
and potentially raising the risk of T2D (Figure 2).
Thiazolidinediones, a class of PPARγ agonists that
3.3. Peripheral insulin sensitivity regulator enhance adiponectin levels, are widely used in the treatment
Insulin is synthesized by pancreatic β-cells and of T2D. The PPARG rs1801282 G allele has been linked to
subsequently secreted into the circulatory system, where protective effects against T2D within the Asian population.
it acts on various peripheral tissues, including skeletal Nevertheless, the precise mechanism accountable for this
muscle and adipose tissue. Peripheral insulin sensitivity protective effect remains a topic of debate. Multiple clinical
is modulated by adipose tissue through adipokines, studies have documented that the PPARG rs1801282
which are influenced by genes such as adiponectin, C1Q G allele is associated with decreased insulin sensitivity,
and collagen domain containing (ADIPOQ), growth elevated cholesterol levels, and increased body mass
43-45
arrest-specific 6 (GAS6), and peroxisome proliferator- index (BMI). Interestingly, an additional clinical study
activated receptor gamma (PPARG). In addition, genes reported conflicting findings, suggesting that this allele
that directly impact peripheral organs like skeletal muscle, may instead enhance insulin sensitivity, lower cholesterol
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including ADAM metallopeptidase with thrombospondin levels, and decrease BMI.
type 1 motif 9 (ADAMTS9), Krüppel-Like family of The impact of the PPARG rs1801282 G allele is evident
transcription factor-14 (KLF14), peroxisome proliferator- in its modulation of transcription factor interactions,

Volume 9 Issue 1 (2025) 81 doi: 10.36922/ejmo.7549