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Page 2 of 11 Zlatkina et al. Vessel Plus 2019;3:7 I http://dx.doi.org/10.20517/2574-1209.2019.03

INTRODUCTION
Our narrative review summarizes the results of studies of trigger mechanisms (in particularly, glucotoxicity)
in insulin resistance (IR) and type 2 diabetes mellitus (DM) development. When searching PubMed for
the next keyword combination “insulin resistance and type 2 diabetes and mechanisms”, we received 4,307
results (2,976 of them in the last 10 years). When narrowing the search with the keyword combination
“insulin resistance and type 2 diabetes and glucotoxicity”, we received 104 results (55 of them in the last 10
years). Mostly, the article presented literary sources limited to the search for the last 10 years (until now).
Nevertheless, we included older publications (preferring high-ranking journals) in case of seminal studies or
when few studies were available for a specific topic. Of the articles retained, we included 57 that were most
specific to trigger mechanisms in IR and DM development.

Type 2 DM is a progressive chronic disease characterized by chronic hyperglycemia caused by IR and β-cell
[1]
dysfunction . Pancreatic β-cells play a fundamental role in the maintenance of glucose homeostasis in
[2]
mammalians . It is proved that by the time of type 2 DM development, sensitivity of peripheral tissues to
[3]
insulin is reduced by 70%, and insulin secretion - by 50% . The loss of insulin sensitivity in muscle, fat and
liver tissues has the greatest clinical significance. Understanding of IR development mechanisms, search for
genes responsible for its development is extremely important for the working out of new approaches to the
treatment of type 2 DM. A study in the field of molecular biology has shown that patients with type 2 DM have
genetic defects that are responsible for transmission of the signal after joining of insulin with the receptor
[4]
(post-receptor defects) .

Insulin realizes the metabolic effect through the activation of phosphatidylinositol-3-kinase (PI3K) and
protein kinase B (PKB, Akt). Serine/threonine kinase Akt phosphorylates GSK3β and FOXOs transcription
factors that directly or indirectly mediate the effect of insulin on transcription of genes involved in
carbohydrate metabolism. The deletion or deactivation of the genes Akt1 and Akt2 blocks the effect of
[5,6]
insulin on glucose metabolism .
[7]
Through PI3K and phosphorylation of proto-oncogene Cbl, activates glucose transporter 4 (Glut4) . Thus,
the biological effect of insulin is associated with the activation of glucose uptake by adipocytes and myocytes
(Glut4), activation of glycogen synthesis (glycogen synthase) and protein (S6-kinase). Insulin regulates
transcription of more than 150 genes. There are 7 groups of insulin-regulated sequences or elements (IRS/
[8]
IRE) , including sterol-regulated element-binding protein 1c (SREBP-1c). SREBPs are transcription factors
of the helix-loop-helix (bHLH) family in the liver. Forms SREBP-1a, SREBP-1c and SREBP-2 affect the
homeostasis of cholesterol and lipids. Srebp-1c expression is regulated by insulin regardless of glucose level
[9]
[Figure 1] .
Hyperexpression of dominant negative forms of SREBP-1c prevents induction of hepatic pyruvate kinase,
[10]
spot 14 and fatty acid synthase mediated by insulin . The expression of glucokinase (GK) in the liver is
regulated by insulin, regardless of the level of glycemia.

Insulin also causes repression through removal from the core and acceleration of the degradation of a FOXO
transcription positive regulator. In β-cells, the FOXO1 nuclear factor is a repressor of the positive activity of
the nuclear transcription factor Hnf3β (FOXO2) in the PDX1 promoter, while insulin increases repression
through deletion of FOXO1 from the nucleus.

The highly conservative area, located 340 bp upstream of the start of transcription initiation, subsequently
renamed as a promoter of insulin, controls the production of insulin by tissues and the regulation of the
insulin gene itself. Most factors act here, which determine high transcription, these include cis-regulatory