Insulin as a mitogenic factor: Role in the pathogenesis of cardiovascular disease

doi:10.1016/0002-9343(91)90041-U

The American Journal of Medicine

Volume 90, Issue 2, Supplement 1, 21 February 1991, Pages S62-S65

https://doi.org/10.1016/0002-9343(91)90041-U Get rights and content

Abstract

Evidence has been accumulating that insulin has actions that may promote the development of atherosclerosis. Research has involved three broad areas: actions of insulin on cultured arterial cells, the effect of insulin on isolated artery preparations, and the development of lipid-containing lesions in the arteries of experimental animals. Insulin, in concentrations similar to those found in physiologic conditions, stimulates proliferation of cultured arterial smooth muscle cells from a number of species, including humans. Insulin also stimulates migration of smooth muscle cells. Cholesterol synthesis and low-density lipoprotein interaction with its receptor in smooth muscle cells are stimulated by insulin. Insulin's mitogenic action appears to be mediated by the insulin-like growth factor receptor. Endothelial cells cultured from large vessels are resistant to the actions of insulin, but hyperglycemia inhibits their proliferation. Insulin deficiency protects animals from experimental atherosclerosis; this protection is lost with insulin treatment. Insulin administration results in lipid-containing lesions in chickens and rats fed a normal diet, and in increased lipid synthesis in the arteries of pigs and dogs. Isolated artery preparations from insulin-deficient or insulin-treated animals undergo lipid metabolism at a rate that correlates with the insulin concentrations in the donor animals. The biological actions of insulin (and glucose) on arterial tissue suggest that hyperglycemia and hyperinsulinemia may promote the development of atherosclerosis.

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Citation Excerpt :
A high ABI is attributed to arterial calcification, and the pathogenesis differs from atherosclerosis in that it is related to changes in the medial layer of the arterial wall.15 Patients with DM may have accelerated arterial stiffening due to the effects of hyperglycemia and insulin on connective tissue proteins and cellular proliferation, respectively.16,17 In a study of 16,493 individuals referred for outpatient, noninvasive lower extremity arterial testing, 17% had poorly compressible lower extremity arteries, defined as an ABI ≥1.4 and/or an ankle systolic blood pressure >255 mm Hg.
Peripheral arterial disease increases cardiovascular risk in many patient populations. The risks associated with an abnormal ankle-brachial index (ABI) in patients with type 2 diabetes and stable coronary artery disease have not been well described with respect to thresholds and types of cardiovascular events.
We examined 2,368 patients in the BARI 2D trial who underwent ABI assessment at baseline. Death and major cardiovascular events (death, myocardial infarction and stroke) during follow-up (average 4.3 years) were assessed across the ABI spectrum and by categorized ABI: low (≤0.90), normal (0.91-1.3), high (>1.3), or noncompressible.
A total of 12,568 person-years were available for mortality analysis. During follow-up, 316 patients died, and 549 had major cardiovascular events. After adjustment for potential confounders, with normal ABI as the referent group, a low ABI conferred an increased risk of death (relative risk [RR] 1.6, CI 1.2-2.2, P = .0005) and major cardiovascular events (RR 1.4, CI 1.1-1.7, P = .004). Patients with a high ABI had similar outcomes as patients with a normal ABI, but risk again increased in patients with a noncompressible ABI with a risk of death (RR 1.9, CI 1.3-2.8, P = .001) and major cardiovascular event (RR 1.5, CI 1.1-2.1, P = .01).
In patients with coronary artery disease and type 2 diabetes, ABI screening and identification of ABI abnormalities including a low ABI (<1.0) or noncompressible artery provide incremental prognostic information.
Usefulness of baseline obesity to predict development of a high ankle brachial index (from the multi-ethnic study of atherosclerosis)
2011, American Journal of Cardiology
Citation Excerpt :
Accordingly, when a small sample of patients with type 2 diabetes was started on insulin therapy, which is thought to increase insulin sensitivity, a decrease in a marker for arterial stiffness was observed.25 Insulin resistance also induces smooth muscle cell proliferation and the nonenzymatic glycosylation of proteins such as collagen.26,27 The aggregate effect of these insulin-related changes may directly increase ABI, particularly if they are shown to preferentially affect lower extremity arteries.
An abnormally high ankle-brachial index (ABI) is associated with increased all-cause and cardiovascular mortality. The relation of obesity to incident high ABI has not been characterized. The aim of this study was to investigate the hypothesis that increased obesity—quantified by body weight, body mass index, waist circumference, and waist-to-hip-ratio—is positively associated with a high ABI (≥1.3) and with mean ABI increases over a 4-year follow-up. Prevalence and incidence ratios for a high ABI were obtained for 6,540 and 5,045 participants, respectively, in the Multi-Ethnic Study of Atherosclerosis (MESA), using log-binomial regression models adjusted for demographic, cardiovascular, and inflammatory and novel risk factors. Linear regression was used to analyze mean ABI change. The prevalence and incidence of a high ABI were significantly higher for the highest compared to the lowest quartile of every baseline measure of obesity, with weight and body mass index demonstrating the highest incidence ratios (2.7 and 2.4, respectively). All prevalence and incidence ratios were positive and graded across obesity quartiles and were persistent in the subpopulation without diabetes. In those with normal baseline ABI values, 1 MESA standard deviation increase in every baseline measure of obesity was associated with significant increases in mean ABI values. In conclusion, independent, positive, and graded associations of increasing obesity with prevalent and incident high ABI and with mean increases in ABI values over time were found. Weight and body mass index seemed to be at least as strongly, if not more strongly, associated with a high ABI than were measures of abdominal obesity.
The association between elevated ankle systolic pressures and peripheral occlusive arterial disease in diabetic and nondiabetic subjects
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Citation Excerpt :
Several pathways are proposed to explain arterial stiffening in DM patients. Insulin triggers cultured smooth muscle cell proliferation.28 Hyperglycemia is responsible of nonenzymatic glycosylation of several proteins, including collagen and elastin.29
The presence of a high ankle-brachial index (ABI) is related to stiff ankle arteries due to medial calcification. Recently, this condition has attracted new interest after reports of a worse cardiovascular prognosis, similar to a low ABI. We sought to compare risk factors contributing to a low (≤0.90) and high (≥1.40) ABI. Additionally, we hypothesized that in instances of high ABI, occlusive PAD may coexist.
This cross-sectional study was conducted at vascular laboratories in a university medical center. The subjects were 510 ambulatory patients (37% had diabetes) previously examined at our vascular laboratories and who responded positively to our invitation. We collected data on smoking, diabetes, hypertension, dyslipidemia, and cardiovascular disease history. The noninvasive assessment of lower limb arteries consisted of the measurement of ABI, toe-brachial index (TBI), and posterior tibial artery peak flow velocity (Pk-PT). A TBI >0.7 and a Pk-PT >10 cm/s were considered normal.
High- and low-ABI were detected, respectively, in 2.1% and 57.8% of limbs. For a low ABI, age (odds ratio [OR], 1.29/10 y), pack-years (OR, 1.08/10 units), and hypertension (OR, 1.90) were independent significant (P < .001) factors. A strong association was found between diabetes and high ABI (OR, 16.0; P < .001). When ABI ranges were compared with TBI and Pk-PT results, those with ABI ≤0.90 and ABI ≥1.40 presented similar patterns of abnormalities. Pk-PT or TBI, or both, was abnormal in more than 80% of cases in both ABI ≤0.90 and ≥1.40 groups. The ABI vs TBI relationship appeared linear in nondiabetic patients, but had an inverted J-shape in diabetic patients, suggesting high ABI masked leg ischemia.
Diabetes is the dominant risk factor for a high (≥1.40) ABI. Occlusive PAD is highly prevalent in subjects with high ABI, and these subjects should be considered as PAD-equivalent.
Insulin, diabetes, and recurrent stenosis: Not so sweet
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The roles of insulin resistance, hyperinsulinemia, and thiazolidinediones in cardiovascular disease
2003, American Journal of Medicine
Citation Excerpt :
Data from human and animal studies offer a plausible basis for the association between insulin excess and CVD. However, most of these studies have been conducted in small populations in highly controlled settings.15,16,50–55 It has been suggested that insulin is a vasoactive peptide capable of inducing pressor effects, including increased sympathetic activity, renal sodium retention, and vascular smooth muscle cell proliferation.30,56
Although it is difficult to distinguish between the relative effects of insulin resistance and hyperinsulinemia, insulin resistance is clearly associated with significantly increased cardiovascular and cerebrovascular risk. This effect is consistent across the spectrum of worsening glycemic control, from the onset of impaired glucose tolerance to the development of clinical diabetes. It is more difficult to discriminate between the roles of elevated circulating insulin and proinsulin levels; the association between insulin levels and cardiovascular risk is weak. The thiazolidinediones (TZDs) significantly improve insulin sensitivity and exert numerous effects on the vascular bed, including improved endothelial function, decreased vascular inflammation, decreased plasma free fatty acid levels, improved dyslipidemic profiles, and inhibition of vascular smooth muscle proliferation. These findings provide increasing evidence to suggest that the TZDs may have a beneficial effect on atherosclerosis and may reduce the incidence and severity of adverse cardiovascular outcomes. These effects remain to be substantiated by the results of large outcomes studies to evaluate the impact of glycemic control and reversal of insulin resistance on cardiovascular events.
The Negative Impact of Insulin Resistance/Hyperinsulinemia on Chronic Heart Failure and the Potential Benefits of Its Screening and Treatment
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View full text

Insulin as a mitogenic factor: Role in the pathogenesis of cardiovascular disease

Abstract

Atherosclerosis

Atherosclerosis

Lancet

Lancet

Metabolism

Metabolism

Atherosclerosis

J Lipid Res

Atherosclerosis

Lancet

The pathogenesis of atherosclerosis—an update

N Engl J Med

Insulin receptors in human endothelial cells: Identification and characterization

J Clin Endocrinol Metab

Effect of insulin on the proliferation of cultured primate arterial smooth muscle cells

Circ Res

Insulin as a cellular growth regulator of rat arterial smooth muscle cells in vitro

Horm Metab Res

Hormonal requirements for growth of arterial smooth muscle cells in vitro: an endocrine approach to atherosclerosis

Science

Differential responsiveness to insulin of endothelial and support cells from micro- and macrovessels

J Clin Invest

Effect of insulin on growth of cultured human arterial smooth muscle cells

Diabetologia

Two separate receptors for insulin and insulinlike growth factors on arterial smooth muscle cells

Exp Clin Endocrinol

Direct demonstration of separate receptors for growth and metabolic activities of insulin and multiplication-stimulating activity (an insulinlike growth factor) using antibodies to the insulin receptor

J Clin Invest

Effects of insulin and glucose on the cells of the arterial wall: Interaction of insulin with dibutyryl cyclic AMP and low-density lipoprotein in arterial cells

Diabetes Metab

Binding and biological actions of insulin-like growth factors on human arterial smooth muscle cells

Horm Metab Res

Receptors and growth-promoting effects of insulin and insulinlike growth factors on cells from bovine retinal capillaries and aorta

J Clin Invest