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Zlatkina et al. Vessel Plus 2019;3:7 I http://dx.doi.org/10.20517/2574-1209.2019.03 Page 5 of 11

glucose-sensitive cells that take place in the islets of Langerhans. Glucose increases the connecting of PDX-
[21]
1 with node A3 and affects the transactivating of PDX-1 ability. Furthermore, insulin gene transcription
stimulation of PDX-1 involves co-activators, like p300, which can change the structure of chromatin through
[22]
posttranslational histones modification (methylation and/or acetylation) .
At the moment, it’s been examined in detail but still controversy regarding the mechanisms by which glucose
transduction contributes to enhancing the binding of the insulin promoter and PDX-1. PDX-1 probably
[23]
experiences multiple posttranslational modifications, possibly by O-binding N-acetylglucosamine , or a
[24]
small modifier 1 . A number of kinases have been suggested for phosphorylation of intermediate PDX-1,
[25]
including mitogen-activated protein kinase (MARK) and PI3K .
Regardless of insulin, glucose regulates the expression of genes responsible for carbohydrate metabolism.
G6P, xylitol or hexosamine synthesis intermediates can be signal molecules in these processes. The study
of the role of glucose is hampered by the influence of insulin [Figure 1]. First, the entry of glucose into
the myocytes and adipocytes is carried out as a result of translocation Glut4. Secondly, GK activity is
transcriptionally regulated by glucose and insulin in the liver and pancreas.

Most of the earliest works showed paradoxical glucose ability to reduce the function of β-cells. Using the
HIT-T15 cell line and levels of glucose (0.8 or 11.1 mmol/L), long-term cell cultivation in RPMI 1640 medium
was observed to lead to low glucose concentrations, levels of insulin mRNA, which proved the fact that high
glucose concentrations cause glucotoxisity action on pancreatic β-cells. When incubation lasted for 5 or 10
[26]
weeks after the occurrence of glucotoxic effects, the function of β-cells was reversible . Hit-T15 cells have
been cultivated for a long period in an environment with a glucose concentration of 0.8 or 11.1 mmol/L with
and without somatostatin, an inhibitor of insulin secretion. Cells cultured with somatostatin had critically
low insulin levels in culture media, demonstrating the rest of β-cells. Cells exposed to high glucose and
somatostatin showed glucotoxic effect on insulin gene expression, insulin secretion content and stimulation,
depletion of β-cells.

Experiments on the line of β-cells, β-TC-6, also associated with HIT-T15 cells that are produced at high and
low glucose concentrations, have demonstrated that it is the reduction of MafA that leads to a decrease in
insulin gene expression in the presence of glucotoxicity, rather than the binding of insulin promoter factor 1
(PDX-1) and DNA.

In this case, it is important to note that these factors (PDX-1, MafA, etc.) do not work independently, but
[13]
with each other, while activating transcription of insulin . The effect of cells that secrete insulin on the
background of an elevated glucose levels for less than a month reduces the expression of the insulin gene is
[3]
associated with a decrease in MafA and PDX-1 binding activity . The decrease in PDX-1 binding activity
[21]
involves post-transcriptional control , although the exact mechanisms remain unclear. In vivo PDX-1
[27]
expression was also reduced in partially pancreatectomized hyperglycemic rats and in diabetic gerbils
[28]
Psammomysobesus and its binding activity was decreased in islets in Zucker rats with obesity and
[21]
[29]
diabetes . With glucotoxicity, the binding activity of MafA in insulin-producing cells decreases .
It is obvious that glucotoxicity may be associated with oxidative stress (OS). In the early studies it was
reported that antioxidants N-acetylcysteine and aminoguanidine protect HIT-T15 and isolated islets from
[30]
toxic action of long-term cultivation in environments with high concentrations of glucose . It is known that
β-cells, in contrast to other sources, contain a sufficiently low concentration of antioxidant enzymes. This
confirms that β-cells are at risk for oxidative stress. In diabetic rats that received antioxidants, normalization
[29]
of glucose concentrations occurs, insulin production is restored, and insulin mRNA levels are reduced .