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Sobenin et al. Is insulin atherogenic?

decrease in all-cause mortality in newly diagnosed in good agreement with the data on the absence of
type 2 diabetic patients followed-up for 10 years [51] . atherogenicity of insulin from studies performed on
Post-trial follow-up for another 10 years demonstrated experimental models different from ours [37-40,44,45] .
15% reduction in myocardial infarction, and 13%
reduction in all-cause mortality [52] . However, it is It must be noted that this study has certain limitations.
difficult to interpret the UKPDS results, since intensive First, the power of the study may be limited because
glycemic control was achieved by sulfonylurea of the small sample size. Second, the second group
derivatives and/or insulin. Later studies mainly aimed of patients with newly diagnosed type 1 diabetes
to assess cardiovascular disease risk in intensively mellitus consisted only of 3 patients, that is too low for
controlled type 2 diabetic patients [Action to Control complex disease; therefore, the obtained results may
Cardiovascular Risk in Diabetes (ACCORD); Action be discussed only as a case report. Third, only 2 major
in Diabetes and Vascular Disease: Preterax and traits of atherosclerotic cellular phenotype (namely,
Diamicron Modified-Release Controlled Evaluation cholesterol accumulation and proliferative activity)
(ADVANCE); Veterans Affairs Diabetes Trial (VADT)] were examined, and others were not studied, like
failed to reproduce the beneficial effects observed enhanced synthesis of protein and matrix components,
in UKPDS [53-55] . It should be noted that insulin use and proinflammatory response. Finally, insulin action in
ranged from 41-90% among intensively controlled cell culture studies was not controlled in experiments
subjects in these trials. Within 3.5-5.6 years of follow- using insulin receptor knockout/knockdown cells.
up, no significant reductions in cardiovascular disease
were demonstrated. Moreover, the ACCORD trial Biologically, from a functional point of view, insulin
was prematurely stopped after a median follow-up of overlaps with various much more potent growth
3.4 years due to a statistically significant 22% higher factors, e.g. somatomedins, platelet-derived growth
all-cause mortality just in a subgroup with intensive factor and epidermal growth factor, which may disguise
glucose control [56] . Thus, it could be proposed that the action of insulin, especially in epidemiological
intensive glucose lowering in treatment of type 2 surveys. So, one may speculate that hyperinsulinemia
diabetic patients is associated with a higher incidence in diabetic patients might play an atherogenic role but
of mortality, although the role of insulin treatment was in indirect manner or be tightly accompanied by other
never elucidated. However, the most recent meta- atherogenic factors, which are responsible for the
analysis of the benefits and harms of intensive glucose initiation of atherogenesis and further development of
lowering therapy performed on the data from 58,160 atherosclerotic lesions.
type 2 diabetic patients in 13 randomized controlled
trials has provided the evidence that intensive glucose DECLARATIONS
lowering therapy compared to conventional glucose
control therapy is associated with a reduced risk of Authors’ contributions
major cardiovascular events and myocardial infarction. Concept and experimental studies, data analysis
At the same time, intensive glucose lowering therapy and statistical analysis, and manuscript editing: I.A.
does not affect significantly the risks of cardiac death, Sobenin
stroke, congestive heart failure, and total mortality [57] . Literature search and patients’ recruitment: V.A.
Orekhova
The results of our study show that insulin does not Clinical examination and clinical data acquisition: A.V.
exert direct atherogenic actions, at least on such Grechko
phenotypic characteristics as intracellular cholesterol General coordination and supervision of the research
accumulation and cell proliferation. An effect on project, and manuscript editing: A.N. Orekhov
cholesterol content or proliferative activity was not
observed in cultured cells, a result that could possibly Financial support and sponsorship
be attributed to the high concentration of serum used. The study was supported by the Ministry of Education
Certainly, these results do not indicate that insulin and Sciences of the Russian Federation (Grant #
has no proatherogenic effect at all, and numerous 14.W02.16.6995-Scientific_School).
possibilities of atherogenic action remain, which
could be detected by other parameters. On the other Conflict of interests
hand, blood serum atherogenicity in type 1 diabetic There are no conflicts of interests.
patients did not correlate with insulin level in serum
samples. The addition of exogenous insulin to the Patient consent
cultural medium did not modify atherogenic effects All participants gave their written informed consent
of diabetic patients’ sera. The obtained results are prior to their inclusion in the study.

Vessel Plus ¦ Volume 1 ¦ December 28, 2017 179