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Sobenin et al. Is insulin atherogenic?

Table 3: The effect of exogenous insulin addition on atherogenic properties of diabetic patients’ serum
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Intracellular cholesterol content, µg/mg cell protein [ H]-thymidine incorporation, dpm/mg cell protein at
at insulinconcentration (mU/mL) insulinconcentration (mU/mL)
0 1 10 100 1,000 0 1 10 100 1,000
Control 43 ± 1 45 ± 1 42 ± 2 45 ± 1 44 ± 2 16 ± 3 19 ± 2 17 ± 1 19 ± 2 20 ± 2
Patient 4 43 ± 3 45 ± 2 46 ± 2 44 ± 2 47 ± 3 16 ± 3 12 ± 4 16 ± 5 19 ± 6 20 ± 2
Patient 5 44 ± 3 45 ± 2 47 ± 2 47 ± 2 46 ± 3 18 ± 3 15 ± 2 16 ± 1 13 ± 3 14 ± 3
Patient 6 69 ± 3* 69 ± 5* 71 ± 4* 74 ± 3* 74 ± 4* 12 ± 2 15 ± 2 15 ± 4 17 ± 2 18 ± 5
Patient 7 82 ± 4* 81 ± 2* 86 ± 3* 86 ± 3* 81 ± 5* 27 ± 3 # 28 ± 3 # 35 ± 4 # 34 ± 4 # 30 ± 3 #
Subendothelial intimal cells were incubated with 40% patient’s serum with or without exogenous insulin addition, as described in Methods
section.*: significant intracellular cholesterol accumulation, P < 0.05; #: significant increase in [ H]-thymidine incorporation, P < 0.05
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due to exogenous insulin administration, but the role effects of insulin were intensively discussed for a long
of insulin in atherogenesis in this category of patients time, but then left aside for decades, without reaching
remains unknown. consensus.

Theoretically, there are many reasons why insulin All further studies focused on clinical effectiveness of
might affect the vessel wall in diabetic patients. Insulin insulin therapy, with a partial respect to cardiovascular
is a widely recognized and important growth factor. outcomes, which could serve as the indirect markers
Initially, the hypothesis on insulin atherogenicity derived of proatherogenic or, vice versa, beneficial effects
from old studies in non-diabetic animals given large of insulin on atherosclerosis progression. Large
doses of insulin, which showed enhanced cholesterol observational studies performed in diabetic patients
synthesis in the aorta [32-34] . Later studies showed did not solve the controversy on the effects of
that atherosclerosis-like biochemical and histological insulin treatment on atherosclerosis progression and
changes in aortas of Wistar rats could be induced by cardiovascular risk, although they have demonstrated
long-term insulin treatment and hyperinsulinemia [35,36] . some reduction in cardiovascular events under
However, these findings were not supported in improved glycemic control during the long-term follow-
other studies in hyperinsulinemic or insulin-treated up [46] . The Epidemiology of Diabetes Interventions and
animals [37,38] . Insulin did not produce any effect on Complications (EDIC) Study, which was designed as
the transfer of cholesterol from circulation into arterial the follow-up long-term study of the Diabetes Control
wall [39] . It was also demonstrated that insulin did not and Complications Trial (DCCT), was aimed to estimate
modify lipogenesis by the rat intima-media even at the effects of glycemic control on major cardiovascular
very high concentrations [40] . endpoints (all fatal and nonfatal cardiovascular events,
angina, revascularization, and also fatal and nonfatal
It is suggested that insulin may cause an increased myocardial infarction, and stroke as secondary
cellular proliferation in tissue culture [13,41] . However, to endpoints) in type 1 diabetes mellitus patients [47,48] . The
demonstrate such an effect of insulin, the cells needed EDIC study participants were followed annually, and
to be starved in serum-deficient medium for several after a mean of 18 years from the start of the DCCT,
days, the conditions being far from physiological, and a 42% reduction in cardiovascular disease outcomes
then only at high insulin concentrations [42] . However, was observed along with a 57% reduction in fatal and
Ledet had not been able to demonstrate the growth- nonfatal myocardial infarction, and stroke [48] . Thus,
stimulating effect of insulin; moreover, there was a prospective studies have provided indirect evidence
growth-promoting effect of serum from recent-onset supporting the absence of harmful effects of intensive
type 1 diabetic patients, although serum insulin levels insulin therapy on atherosclerosis progression in type
were extremely low [43] . Also, against the “insulin 1 diabetic patients. Moreover, intensive insulin therapy
hypothesis” stand the observations of beneficial was shown to be beneficial with respect to instrumental
effects of insulin treatment on the development of measures of atherosclerosis, namely, coronary artery
atherosclerosis-like lesions in streptozotocin-diabetic calcification and carotid intima media thickness [49,50] .
rats. In well-controlled rats, tunica media of coronary
arteries contained the normal relative amount of In contrast, studies in type 2 diabetic patients who
connective tissue and number of cells, as compared to were appointed to intensive insulin therapy provided
the poorly controlled diabetic animals [44] . Additionally, rather controversial results. The United Kingdom
hyperinsulinemia did not stimulate the early stages of Prospective Diabetes Study (UKPDS) demonstrated
arterial smooth muscle cells proliferation in the rat after a non-significant 16% decrease in fatal and nonfatal
aortic injury [45] . So, the speculated pro-atherogenic myocardial infarction along with a non-significant 6%

178 Vessel Plus ¦ Volume 1 ¦ December 28, 2017