Page 91 - EJMO-9-1

Eurasian Journal of Medicine and
Oncology
T2D polymorphisms in Asians

which has been associated with a protective effect against of Fas cell surface death receptor (FAS) was observed
T2D, may contribute to enhanced insulin sensitivity by to undergo a 60% reduction as a result of the inhibitory
improving the functional activity of KLF14. effects induced by tumor necrosis factor-alpha (TNF-α).
PGC-1α is primarily known for its role in fatty Furthermore, the presence of TNF-α impeded the capacity
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acid oxidation but also significantly influences insulin of insulin to enhance the expression of FAS. On the other
activity. In vivo studies have demonstrated that increased hand, it was observed that in cells with an overexpression
expression of PGC-1α leads to the upregulation of of DUSP9 exhibited a mitigating effect on the ability of
insulin signaling molecules. Elevated PGC-1α levels TNF-α to decrease FAS expression. Furthermore, the
have been shown to enhance the expression of key inhibitory effects were observed on the phosphorylation
metabolic genes, including insulin receptor (INSR), of extracellular signal-regulated kinase (ERK) and c-Jun
insulin receptor substrate 2 (IRS2), mammalian target of N-terminal kinase (JNK), with a comparatively lesser
rapamycin (MTOR), rapamycin-insensitive companion inhibition observed on the phosphorylation of p38
of mammalian target of rapamycin, regulatory associated mitogen-activated protein kinase (p38MAPK). As a
protein with MTOR, and Ras homolog enriched in brain, result, the phosphorylation of serine 307 on IRS1, induced
while decreasing the expression of genes such as insulin by anisomycin, was abolished, leading to an increased
receptor substrate 1 (IRS1), phosphoinositide-3-kinase sensitivity of the insulin signaling pathway.
regulatory subunit 1, and DEP domain-containing mTOR- The upregulation of DUSP9 in the hepatic tissue
interacting protein. Mechanistically, PGC-1α modulates of mice led to a decrease in characteristics associated
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insulin signaling rather than directly metabolizing lipids. with insulin resistance. The findings of a clinical study
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This effect is particularly evident in cases where insulin indicated that DUSP9 rs5945326 A allele demonstrated
resistance coexists with elevated lipid levels. According a moderate influence on the rise of HOMA of insulin
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to a meta-analysis, the PGC1A rs3736265 A allele has resistance and HOMA-B values. In addition, another
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been associated with lower FPG levels and reduced total study demonstrated that these SNPs were associated with
cholesterol levels. However, the PGC1A rs8192678 A an increase in resistin levels. The cumulative evidence
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allele may impair the regulatory function of PGC-1α in indicates that the DUSP9 rs5945326 A allele may alter
fatty acid oxidation, leading to reduced insulin signaling. the protective effect of DUSP9, potentially increasing the
Individuals diagnosed with T2D have been found susceptibility to insulin resistance.
to exhibit a decrease in the expression of DGKD. A 3.4. The circadian rhythm regulation of insulin
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study combining in vitro and in vivo approaches has
demonstrated that the administration of a DGKD inhibitor Circadian mechanisms play a crucial role in regulating
leads to a significant reduction in glucose transport. physiological processes at both the cellular and tissue
This effect is attributed to a signaling cascade involving levels. In pancreatic islets, the autonomous transcriptional
diacylglycerol and protein kinase C (PKC). As a result, regulation of β-cells may influence their function
there is a notable decline in the tyrosine phosphorylation throughout the diurnal cycle, which is governed by
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of the insulin receptor triggered by insulin. In addition, melatonin. The effects of the melatonin hormone on
there is a decrease in the serine/threonine phosphorylation peripheral tissues are mediated through the activation of
of AKT and AKT substrate of 160 kDa. Beyond AKT, two distinct transmembrane receptors, namely melatonin
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DGKD also influences AMPK activity. An in vivo study receptor 1A (MT1) and melatonin receptor 1B (MT2).
involving DGKD-KO mice revealed a reduction in AMPK These receptors are encoded by melatonin receptor 1A
activation and signaling, accompanied by decreased (MTNR1A) gene and MTNR1B gene, respectively (Table 1).
lipid oxidation and an increased conversion of free fatty Both isoforms are found within the islet of Langerhans,
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acids into triglycerides. This suggests that the DGKD where they regulate insulin secretion from β-cells and
rs838720 G allele may potentially reduce insulin sensitivity glucagon secretion from α-cells. 66
by influencing the phosphorylation of AKT and AMPK An in vivo study demonstrated that the administration
through PKC, which in turn promotes the colocalization of melatonin resulted in a decrease in the initial release
of insulin receptor substrate. of insulin and an increase in blood glucose levels across
Peripheral insulin sensitivity is also influenced by all participants. This suggests that melatonin plays
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inflammatory genes, which are regulated by DUSP9. In a homeostatic role by modulating insulin secretion
vitro studies have shown an increase in the expression of during nocturnal periods or sleep, thereby preventing
DUSP9 during adipocyte differentiation, specifically in cell hyperglycemia or hypoglycemia (Figure 3). Previous studies
lines that exhibit responsiveness to insulin. The expression have demonstrated a significant correlation between the

Volume 9 Issue 1 (2025) 83 doi: 10.36922/ejmo.7549