Anti-Atherogenic Effect of Insulin in vivo

Abstract

Metabolic syndrome is a risk factor for atherosclerosis and restenosis. In metabolic syndrome, insulin resistance coexists with hyperinsulinemia and hyperlipidemia. Hyperlipidemia has growth-promoting effects, whereas insulin has both growth-promoting and growth-inhibitory effects on vascular smooth muscle cells in vitro. The objective of this study was to investigate the effects of hyperlipidemia and hyperinsulinemia on vascular cell growth in vivo after arterial injury. Rats fed a low-fat diet were treated with either subcutaneous blank (LFC) or insulin (LFI) implants. Rats fed a high-fat diet also received blank (HFC) or insulin (HFI) implants. After 3 days, rats received balloon carotid injury, and 14 days later they were sacrificed to measure neointimal area and proliferation. Hyperinsulinemia was present in LFI and HFI and hyperlipidemia was present in HFC and HFI. Neointimal area was higher in HFC (0.153 ± 0.009 mm², p < 0.05) but lower in LFI (0.098 ± 0.005, p < 0.01) than LFC (0.127 ± 0.005). In HFI (0.142 ± 0.008, p < 0.05) neointimal area was not different from HFC or LFC. In conclusion, insulin reduced neointimal growth, but the effect of insulin was diminished by the high-fat diet. Thus, our results demonstrate an anti-atherogenic effect of insulin in vivo and suggest that in metabolic syndrome insulin resistance rather than hyperinsulinemia is the atherogenic risk factor.

Insulin Increases Reendothelialization and Inhibits Cell Migration and Neointimal Growth After Arterial Injury

“…6,7 At higher plasma concentrations (Ϸ2000 pmol/L) we previously found that insulin does increase intimal cell proliferation despite decreasing neointimal growth. 36 Taken together, these data suggest that the effect of insulin is dose-, time-, and cell-type dependent. IGF-1, which shares similar signaling with that of insulin but preferentially stimulates MAPK versus PI3K, increased intimal thickness.…”

Insulin Inhibits and Oral Sucrose Increases Neointimal Growth after Arterial Injury in Rats

“…The rats were divided into 6 groups: (1) rats with blank implants and access to tap water (control = C); (2) rats with insulin implant (5 U/day) and access to glucose in their drinking water as a 40% (w/v) solution [insulin (5 U/day) + 40% oral glucose = I5G] as in Kim et al [9] but with i.p. glucose infusion (25%) to avoid any glucose lowering; (3) rats with insulin implant (4 U/day, which is similar to ∼3.9 U/day used in Foster et al [16]) and access to glucose in their drinking water as a 40% (w/v) solution [insulin (4 U/day) + 40% oral glucose = I4G]; (4) rats with insulin implant (4 U/day) and access to sucrose in their drinking water as a 10% (w/v) solution as in Foster et al [16] [insulin (4 U/day) + 10% oral sucrose = I4S]; (5) rats with blank implants and access to glucose in their drinking water as a 40% (w/v) solution (control glucose = CG), and (6) rats with blank implants and access to sucrose in their drinking water as 10% (w/v) solution (control sucrose = CS).…”

“…glucose infusion (25%) to avoid any glucose lowering; (3) rats with insulin implant (4 U/day, which is similar to ∼3.9 U/day used in Foster et al [16]) and access to glucose in their drinking water as a 40% (w/v) solution [insulin (4 U/day) + 40% oral glucose = I4G]; (4) rats with insulin implant (4 U/day) and access to sucrose in their drinking water as a 10% (w/v) solution as in Foster et al [16] [insulin (4 U/day) + 10% oral sucrose = I4S]; (5) rats with blank implants and access to glucose in their drinking water as a 40% (w/v) solution (control glucose = CG), and (6) rats with blank implants and access to sucrose in their drinking water as 10% (w/v) solution (control sucrose = CS). The rats were fed a normal-fat diet, consisting of 12% fat in calories as used in Kim et al [9]. This diet, despite having the same fat content of the standard chow used in another study where we found insulin to decrease neointimal growth [11], was defined as low-fat in Kim et al [9] to contrast it to the high-fat diet also used in that paper.…”

“…In our previous study, we investigated the effect of hyperinsulinemia on neointimal hyperplasia after balloon catheter injury, a model of restenosis. Normal rats on insulin treatment (5 U/day) and given a control diet had significantly reduced neointimal growth at 14 days after arterial injury [9]. However, the beneficial effect of insulin was diminished after a high-fat diet, which induces insulin resistance similar to the metabolic syndrome.…”

“…However, the beneficial effect of insulin was diminished after a high-fat diet, which induces insulin resistance similar to the metabolic syndrome. The decrease in neointimal area induced after insulin treatment in rats fed the control diet occurred despite an increase in smooth muscle cell (SMC) proliferation [9]. However, one limitation of the study was that the plasma glucose levels in the insulin-treated rats were lower than normal, and it has been shown in previous studies that hypoglycemia induced by insulin can decrease DNA synthesis in the rat aorta up to 4 days after arterial injury [10].…”