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Sobenin et al. Is insulin atherogenic?

INTRODUCTION Center, Moscow, Russia. All participants gave their
written informed consent prior to their inclusion in the
Insulin-dependent (type 1) diabetes mellitus is known to study.
favor an accelerated development of atherosclerosis,
although the reasons for premature atherogenesis in The group of study participants consisted of 33
diabetic patients remain obscure. Several hypotheses type 1 diabetic patients aged 20 to 44 (17 men, 16
exist, which try to describe the molecular, cellular and women) with diabetes duration ranging from 0 to 16
biochemical mechanisms of premature atherogenesis years. They were characterized by rather low level of
in diabetic patients, but all have failed to sufficiently antibodies to insulin (less than 50 nU/mL), therefore,
explain this phenomenon. Proposed mechanisms the possibility of insulin resistance attributable to
include the harmful effects of advanced glycosylation antibodies was excluded [18] . The type of diabetes
end products, modification of low density lipoproteins was verified according to recommendations from
by non-enzymatic glycosylation, lipoprotein retention the American Diabetes Association [19] . None of the
in the arterial wall, enhanced oxidative stress, patients had clinical manifestations of coronary
inflammation, endothelial dysfunction, and alterations heart disease. All patients received intensive insulin
in metabolism of vitamins and minerals [1-5] . In addition therapy with glargine (“Lantus”, Sanofi-Aventis
to these potential factors, it is necessary to consider the Deutschland GmbH, Germany) as basal insulin, and
possible role of insulin in the process of atherosclerosis glulisine (“Apidra”, Sanofi-Aventis Deutschland GmbH,
development. Since hyperinsulinemia is associated Germany) as prandial insulin. None of the patients had
with increased cardiovascular risk, hyperinsulinemia coronary heart disease or other clinical manifestations
and hepatic portal hypoinsulinemia due to injection of atherosclerosis, arterial hypertension or kidney
of insulin preparations widely used in the treatment disease. The selection and recruitment of study
of type 1 diabetic patients could be responsible, at participants was designed to avoid any significant
least in part, for cardiovascular consequences of the comorbidity or drug administration, which could
disease. The results of epidemiological studies and potentially affect the results of experiments. Venous
experimental studies in animal models supported blood (5 mL) was drawn once in the morning before
systemic hyperinsulinemia as a major plausible meals at the first day at the hospital. Fasting blood
factor in the development of atherosclerosis in glucose was 8.2 ± 0.4 mmol/L, HbA1c was 9.2 ± 0.3%,
diabetic patients [6-10] . Insulin resistance is strongly serum cholesterol level was 5.2 ± 0.2 mmol/L, and
associated with hyperinsulinemia, and is considered triglyceride level was 1.4 ± 0.2 mmol/L.
as the major pathologic mechanism for susceptibility
to premature atherosclerosis and cardiovascular Additionally, the second group of study participants
disease [11,12] . However, the effects of exogenous consisted of 3 patients with newly diagnosed type 1
insulin on atherosclerosis progression have not been diabetes mellitus (1 man and 2 women aged 18, 19 and
sufficiently studied. Experimental studies demonstrate 23, respectively), who were characterized by low levels
direct in vitro effects of insulin on angiogenesis, as of immunoreactive insulin (IRI) and residual C-peptide
well as on endothelial and arterial smooth muscle secretion (1.6 ± 0.5 mU/L and 0.8 ± 0.2 ng/mL,
cell proliferation [13,14] . Nevertheless, this contention respectively), and significantly elevated blood glucose
remains controversial, and there is no definitive levels (20.0 ± 0.2 mmol/L) without severe ketoacidosis
settlement on the role of insulin in atherogenesis [15-17] . on admission to hospital. Intensive therapy with insulin
To elucidate this matter, the present study tested the glulisine and insulin glargine was started immediately.
influence of insulin on cellular proliferation and total For monitoring of glucose level, IRI level and blood
cholesterol content in cultured subendothelial cells serum atherogenicity, venous blood was taken several
derived from human aorta and mouse peritoneal times throughout the duration of hospitalization
macrophages. Additionally, the effect of exogenous immediately before the start of intensive insulin therapy,
insulin on atherogenicity of serum from diabetic then at 30 min, 2 h, 6 h, 12 h, 24 h and 7 days after
patients was investigated. the first insulin injection. On the 10th day, the patients
were discharged from the hospital and were examined
METHODS at outpatient clinics 21 days after the start of intensive
insulin therapy.
Patients
This study was conducted in accordance with the Blood collected from patients was incubated for 1 h
Helsinki Declaration of 1975 as revised in 1983. It was at 37 ºC and centrifuged for 30 min at 1,000 g. The
approved by the local ethics committee of the Institute resultant serum samples were stored frozen (-20 ºC)
for Atherosclerosis Research, Skolkovo Innovation for 4-7 days before examination.

Vessel Plus ¦ Volume 1 ¦ December 28, 2017 175