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Page 8 of 11 Zlatkina et al. Vessel Plus 2019;3:7 I http://dx.doi.org/10.20517/2574-1209.2019.03
[50]
is increased in islets after high-calorie feeding in rodents or after exposure with fatty acids in vitro .
Fourthly, oleic acid activates UCP-2 promoter in INS-1 cells, the effect mediating directly SREBP1c [51]
[52]
and indirectly by peroxisome proliferation activator receptor . These observations confirm that the FFA
stimulates the UCP-2 expressions in β-cells, possibly causing by dissociation of mitochondria.

Thus, the expression of UCP-2 levels in return to FFA can be a cellular ways of protection from
overabundance of energy-containing components and OS. Harmful FFA action on the function of β-cells
[17]
occurs if only glucose levels are increased. Prentki et al. assumed that glucose was the main determinant
of FFA in β-cells. When the glucose concentration is not elevated, the FFA are transported via carnitine-
palmityl-transferase-1 (CPT-1) to the mitochondria. When the concentrations of both glucose and FFA
increase, the cycle of tricarboxylic acids generates signals that promote the formation of malonyl-CoA in
the cytosol. Its role is to inhibit CPT-1, thus blocking the oxidation of fatty acids and, as a consequence, the
accumulation of acetyl-CoA in the cytosol [11,17] . In addition, the accumulation of long-chain acyl-CoA in the
cytosol, possibly directly, or by generating lipid-stimulating signals, either directly or through the generation
[11]
of lipid-forming signals, can affect pancreatic β-cells . Among the metabolic effects that guide the splitting
[53]
of FFA to formation, glucose stimulates the gene expression which is taken partly in lipogenesis . There
is an enzyme - AMP-activated protein kinase (AMPK), which works as a metabolic sensor, and during an
[54]
over-nutrition feeds signal to the β-cells to go into the “storage state” . AMPK activity inversely correlates
[55]
with levels of glucose and is expressed with the help of palmitate in pancreatic β-cells. The SREBP1c
transcription factor acts as an stimulator, transmitting the signal received by AMPK about changes in
the expression of gene, which leads to an increase of lipids formation. It is known that glucose is able to
stimulate the production of the X liver receptor, which is able to stimulate the production of SREBP1c and
[5]
hyperlipidemia .
The release of excessive amounts of FFA leads to lipotoxicity, as lipids and their metabolites produce OS in
the endoplasmic network and mitochondria. This affects both adipose and non-fat tissue, making up its
[12]
pathophysiology in such organs like liver and pancreas . FFA released from excessive triglycerides deposits
also inhibit lipogenesis, breaking a sufficient clearance triglyceride levels. The release of FFA under the
action of endothelial lipoprotein lipase from increased serological triglycerides within the limits of increased
β-lipoproteins causes lipotoxicity, which leads to insulin receptor dysfunction. Long-term insulin-resistant
state creates hyperglycemia with compensated hepatic gluconeogenesis. The latter increases hepatic glucose
production, further exacerbating hyperglycemia caused by insulin resistance. FFA also reduce the utilization
of insulin-stimulated glucose in the muscles. Lipotoxicity from excessive amounts of FFA also reduces
[56]
insulin secretion by pancreatic β-cells, which ultimately leads to the depletion of these cells .

Therefore, the constant high glucose directs the fatty acids to cellular lipid synthesis. More recently, studies
have shown that the metabolism of lipids and their transport are also involved in the mechanism of
glucolipotoxicity.

In in vitro studies, important information regarding the molecular and cellular bases of glucolipotoxicity
has been provided. Various functional results of chronically elevated levels of FFA are mediated by clear
mechanisms and some of in vitro observations have been reproduced in vivo on rodent models.

CONCLUSION
Thus, the insulin gene is expressed in pancreatic β-cells. The main physiological regulator of the expression
of insulin gene is glucose. It controls the effect of transcription factors, insulin mRNA stability, and
transcription rate. Deterioration of the function of β-cells causes increased levels of glucose and lipids
(glucolipotoxicity) at type 2 DM. Glucolipotoxicity mechanisms affect the transcription factors MafA
and PDX-1. The OS and the synthesis of ceramides have important damages to the value of the β-cells.
Reducing glucose levels is a key factor in the treatment of type 2 DM, preventing macro- and microvascular