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Page 6 of 11 Zlatkina et al. Vessel Plus 2019;3:7 I http://dx.doi.org/10.20517/2574-1209.2019.03

Glucose enters cells and progressively metabolizes, in particular, to pyruvate in a cycle of tricarboxylic acids,
subjected to oxidative phosphorylation, during which formed ATP and reactive oxygen radicals (ROS). There
are other ways in which elevated glucose concentrations can be moved to the reserve, while ROS is formed
[31]
from glucose .
In an animal with diabetes, the binding of PDX-1 to DNA in HIT-T15 cells decreases, while this effect
decreases with the use of antioxidants. Studies were conducted to clarify the place where the loss of PDX-1
[13]
occurs in the OS . These results show that the OS induces the loss of PDX-1 post-transcriptional mRNA.

In the 1990s, separate groups measured OS markers at type 2 DM using various methods (high-performance
liquid chromatography, mass spectrometry, immunocytochemistry). It has been shown that markers of OS
are increased in subjects with type 2 DM, namely: the levels of 8-OH-guanine, 8-epi-PGF2 (prostaglandin
[33]
F2), 4-OH-2-nonenal, hydroperoxides [13,32] . Yoshida et al. reported that the appointment of antidiabetic
drug at the half-year review led to a normalization of the activity of glutamylcysteine synthetase, glutathione
and thiol transport.

LIPOTOXICITY
In case of dyslipidemia and obesity, the oversupply of fat to tissues not suited for lipid storage induces
[34]
cellular dysfunction that underlies 2 type DM and coronary artery disease . Disorders of lipid metabolism
[12]
lead to the dysfunction of β-cells in patients with type 2 DM . It was shown that the influence on islets and
β-cells with high concentrations of FFAs in vitro weakens the expression of the insulin gene at the same time
with increased glucose concentration. Damaging action of FFAs on expression of insulin gene in isolated
pancreatic islets is associated with high levels of triglycerides (TG) [35,36] .

Since both palmitate and oleate inhibit insulin secretion, but only palmitate reduces the expression of
[37]
the insulin gene , it is accepted without proof that these two functional effects are based on similar
mechanisms. Scientists suggest that the inhibition of the expression of the insulin gene by palmitate may
be due to the formation of ceramides. Ceramide - an intermediate in the biosynthesis of sphingomyelin -
is formed by the interaction of sphingosine with acyl-coenzyme-A. The most important role of ceramide is
participation as a messenger in the signal path of sphingomyelin and in the regulation of cellular processes
such as differentiation, proliferation and apoptosis.

Excess quantities of ceramide inhibit the path of insulin signal transduction by inhibiting phosphorylation
of protein kinase Akt/PKB and inhibits the translocation of Akt/PKB from the cytoplasm to the plasma
membrane, which then inactivates the path of transduction of the insulin signal. Indeed, in obese people
suffering from IR, levels of ceramide in skeletal muscles are increased by 2 times. This increase is due to the
high concentrations of free fatty acids in plasma and a decrease in the intensity of phosphorylation of protein
[38]
kinase Akt .

In connection with the decrease in the binding of MafA and PDX-1 is the inhibition of transcription of the
insulin gene by palmitate [Figure 3] [13,39] . Interestingly, in contrast to glucotoxicity mechanisms that include
[39]
various types of MafA , the ways by which the formation of ceramide from palmitate dicrease PDX-1
concentration and the expression of MafA are unknown. Two main ways of signaling are modulated by
ceramides, MAPK and PI3K regulate the transcription of the insulin gene with impact on the activity of
the transcription factor. The form of C-jun N-terminal kinase (JNK) is a direct target for ceramide in many
cell systems. In β-cells, JNK inhibits transcription of insulin gene and via C-jun-dependent transcription
[41]
[40]
inhibition of E1 and C-jun-independent binding inhibition PDX-1 [Figure 3] .
To prove that increased levels of ceramide lead to glucose homeostasis disorders, experiments with animals
and pharmacological agents were carried out. Indeed, the reduction of ceramide levels (by inhibiting its