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Page 4 of 11 Zlatkina et al. Vessel Plus 2019;3:7 I http://dx.doi.org/10.20517/2574-1209.2019.03
[12]
(bHLH), binded with box E1 . Activator E1 is a dimer consisting of two polypeptide chains. The interaction
between the dimerization transcription factors (bHLH) and the insulin promoter factor (PDX-1), includes
[13]
other coactivators and DNA-binding proteins, for example, MafA, co-promoter C1 . MafA controls
the expression of β-cells, a specific expression of the insulin gene through a cis-regulatory element called
RIPE3b1, and function as a powerful transactivator of the insulin gene [13,14] . While PDX-1 and NeuroD are
expressed in different types of islet cells, MafA is a specific transactivator of the insulin gene only in β-cells.
Therefore, the power of MafA as an activator of the insulin gene, together with the unique expression in
[15]
β-cells, increases the probability that MafA is the main factor in the formation and function of these cells .

The deterioration of β-cells may result from a combination of genetic and environmental factors.
Hyperglycemia, even moderate, observed before the development of diabetes, can lead to damage to β-cells
through a process known as “glucotoxicity”. The second phenomenon, lipotoxicity, also leads to β-cell
[12]
damage . Both of these processes can be considered as abnormal, because glucose and lipid levels are not
toxic, but very important for normal functioning of β-cells. Therefore, there is a range of variances from the
normoglycemic and normolipidemia conditions to disturbed hyperglycemic and hyperlipidemia conditions.
[16]
Unger and colleagues were the first to introduce the concept of “glucotoxicity” and “lipotoxicity” . In their
first article, glucose toxicity means continuous super-stimulation of β-cell glucose, which ultimately leads
to insulin stores exhaustion, aggravation of hyperglycemia and to final worsening of β-cells functioning.
The hypothesis about the cause of β-cell functioning aggravation was based on the exposure of β-cells in
conditions of excessive lipid levels. The recognition of glucolipotoxicity presence is based on changes in
intracellular lipids, which form the basis of lipotoxicity mechanism and depend on elevated glucose levels.
[17]
Thus, glucotoxicity and lipotoxicity are correlated and have the same mechanisms .

GLUCOTOXICITY
Glycogen accumulation, due to impaired metabolism, contributes to this “glucotoxicity” via dysregulated
[18]
biochemical pathways promoting β-cell dysfunction .
In general, some studies in vitro, tried to find glucolipotoxicity mechanisms formation, using isolated
Langerhans islets and β-cells in pancreatic tissue. Long-term exposition of insulin-secreted cells or isolated
islets together with increased free fatty acids (FFA) levels and glucose can cause insulin-induced glucose
[11]
secretion depression, damage to insulin gene expression and apoptotic death of cells .

The increase of IR and defeat of β-cells are the basis of type 2 DM progression and these two factors have
different values and degrees of change. IR provokes changes that occur before the onset of hyperglycemia,
and reaches its maximum values at relatively early stages of disease progression. Data extrapolated from
UKPDS and Belfast Diet Study suggests that β-cell dysfunction precedes the development of diabetes for
up to 15 years. In addition, the UKPDS showed a correlation between long-term, gradual deterioration of
glycemic control and progressive dysfunction of β-cells, confirming the view that the defeat of these cells
may be the leading factor in the disease [19,20] .

Studies, which are currently being conducted, show that disorders on the part of β-cells are not only in an
insulin secretion depression. They are multi-factorial and involve a lot of defects, in particular: alternation in
the ability of β-cells to respond the stimulation of glucose (change I phase of insulin secretion), violation of
insulin formation (proinsulin/insulin ratio), changes in β-cell mass.

The main regulator of pancreatic β-cells functioning and regulator of insulin gene expression, synthesis and
secretion of insulin is glucose. Due to glucose action, all the stages of insulin release (transcription, slicing
of pre-RNA, stability of mRNA) are made. In this case, the main elements that regulate the transcription
of the insulin gene are C1, E1, A3 [Figure 2]. In addition, the peripheral glucose sensitive element binds