Effect of Intra-arterial Insulin on Tissue Cholesterol and Fatty Acids in Alloxan-Diabetic Dogs

Cruz, Anatolio B.; Amatuzio, Donald S.; Grande, Francisco; Hay, Lyle J.

doi:10.1161/01.res.9.1.39

Cited by 174 publications

(35 citation statements)

References 16 publications

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“…However, none of these studies has proved that glucosamine induces insulin resistance in the absolute absence of insulin, which is always present in the blood of animals (endogenous or exogenous from insulin infusion during insulin clamp studies) or in the sera of the culture media. Besides, our observation is consistent with other earlier studies showing that hyperglycemia and hyperlipidemia do not cause as much trouble as atherosclerosis, which usually follows insulin resistance/hyperinsulinemia, in the absence of insulin (1)(2)(3)(4)(5).…”

Section: Journal Of Biological Chemistry 27097supporting

confidence: 92%

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Insulin Is a Stronger Inducer of Insulin Resistance than Hyperglycemia in Mice with Type 1 Diabetes Mellitus (T1DM)

Liu

Cao

Hong

et al. 2009

Journal of Biological Chemistry

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Subjects with type 1 diabetes mellitus (T1DM) eventually develop insulin resistance and other features of T2DM such as cardiovascular disorders. The exact mechanism has been not been completely understood. In this study, we tested the hypothesis that excessive or inappropriate exposure to insulin is a primary mediator of insulin resistance in T1DM. We found that continuous exposure of mice with non-obese diabetes to insulin detemir, which is similar to some current conventional treatment of human T1DM, induced severe insulin resistance, whereas untreated hyperglycemia for the same amount of time (2 weeks) did not cause obvious insulin resistance. Insulin resistance was accompanied by decreased mitochondrial production as evaluated by mitochondrial DNA and levels of transcripts and proteins of mitochondrion-associated genes, increased ectopic fat accumulation in liver and skeletal muscle (gastrocnemius) evaluated by measurements of triglyceride content, and elevated oxidative stress detected by the GSH/GSSG ratio. Prolonged exposure of cultured hepatocytes to insulin induced significant insulin resistance, whereas the same length of exposure to a high level of glucose (33 mM) did not cause obvious insulin resistance. Furthermore, our results showed that prolonged exposure to insulin caused oxidative stress, and blockade of mitochondrionderived oxidative stress by overexpression of manganese-superoxide dismutase prevented insulin resistance induced by the prolonged exposure to insulin. Together, our results show that excessive exposure to insulin is a primary inducer of insulin resistance in T1DM in mice.Since the beginning of the insulin era, most patients with T1DM 2 have been able to live almost normally. However, as early as the 1940s, long before the concept of insulin resistance came to light, it was noticed that the application of insulin in T1DM was associated with the development of cardiovascular disorders (1-5). Since the 1960s, it has been established that the application of insulin in T1DM always leads to insulin resistance (6 -10). Mechanisms associated with cardiovascular disorders and insulin resistance in patients with T1DM have been studied extensively but have not been completely understood.It has been shown previously that a high level of glucose and its byproducts such as glucosamine might play a critical role in the development of insulin resistance (11-21). However, it is unclear whether the effects of glucose and glucosamine on the development of insulin resistance can occur in the absolute absence of insulin. It is known that insulin can desensitize insulin signaling through activation of ERK1/2 MAPKs and/or Akt/ S6K (9, 22). It is unclear whether this scenario actually represents physiology and pathophysiology. However, it is clear that ectopic fat accumulation in liver and skeletal muscles, increased oxidative stress, and decreased mitochondrial capacity/biogenesis are clustered together with insulin resistance. It has been shown that no matter how severe the obesity is, insulin resistan...

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Section: Journal Of Biological Chemistry 27097supporting

confidence: 92%

“…However, as early as the 1940s, long before the concept of insulin resistance came to light, it was noticed that the application of insulin in T1DM was associated with the development of cardiovascular disorders (1)(2)(3)(4)(5). Since the 1960s, it has been established that the application of insulin in T1DM always leads to insulin resistance (6 -10).…”

mentioning

confidence: 99%

Insulin Is a Stronger Inducer of Insulin Resistance than Hyperglycemia in Mice with Type 1 Diabetes Mellitus (T1DM)

Liu

Cao

Hong

et al. 2009

Journal of Biological Chemistry

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“…7 It has been previously demonstrated that hyperinsulinemia induces an increase in the media-tolumen ratio of small intramyocardial arterioles of spontaneously hypertensive rats 8 (defined as "hypertrophy," although no evaluation of the media cross-sectional area was performed). Cruz et al 9 reported that long-term insulin infusion into one femoral artery in the dog caused vascular hypertrophy only in the ipsilateral side. 9 Therefore, it is possible that metabolic abnormalities characteristic of NIDDM may have an important role in the genesis of structural alterations of small resistance arteries and, consequently, in the development of the organ damage and disease frequently observed in NIDDM (ie, ischemic heart disease, renal disease, and ocular damage).…”

mentioning

confidence: 99%

“…Cruz et al 9 reported that long-term insulin infusion into one femoral artery in the dog caused vascular hypertrophy only in the ipsilateral side. 9 Therefore, it is possible that metabolic abnormalities characteristic of NIDDM may have an important role in the genesis of structural alterations of small resistance arteries and, consequently, in the development of the organ damage and disease frequently observed in NIDDM (ie, ischemic heart disease, renal disease, and ocular damage).…”

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confidence: 99%

Structural Alterations in Subcutaneous Small Arteries of Normotensive and Hypertensive Patients With Non–Insulin-Dependent Diabetes Mellitus

et al. 2001

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Background-It is not presently known whether non-insulin-dependent diabetes mellitus (NIDDM) is associated with the presence of structural alterations in small arteries or whether the combination of hypertension and NIDDM may have an additive effect on endothelial dysfunction. Therefore, we investigated subcutaneous small arteries in 12 normotensive subjects (NT group), 18 patients with essential hypertension (EH group), 13 patients with NIDDM, and 11 patients with NIDDM and EH (NIDDMϩEH group). Methods and Results-Subcutaneous small arteries were evaluated by a micromyographic technique. The internal diameter, the media-to-lumen ratio, remodeling and growth indices, and the collagen-to-elastin ratio were calculated. Concentration-response curves to acetylcholine, bradykinin, the endothelium-independent vasodilator sodium nitroprusside, and endothelin-1 were performed. The media-to-lumen ratio was higher in the EH, NIDDM, and NIDDMϩEH groups compared with the NT group. EH patients showed the presence of eutrophic remodeling, whereas NIDDM and NIDDMϩEH patients showed 40% to 46% cell growth. The collagen-to-elastin ratio was significantly increased in the EH and NIDDMϩEH groups compared with the NT group. The vasodilatation to acetylcholine and bradykinin was similarly reduced in EH, NIDDM, and NIDDMϩEH groups compared with the NT group. The contractile responses to endothelin-1 were similarly reduced in EH, NIDDM, and NIDDMϩEH patients. Conclusions-Our data suggest that the effects of NIDDM and EH on small artery morphology are quantitatively similar but qualitatively different and that the presence of hypertension in diabetic patients has little additive effect on small artery morphology and none on endothelial dysfunction.

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“…However, the manner in which insulin elevates blood pressure is unclear. Sympathetic activation, 1,2 sodium retention, 3 and vascular hypertrophy have been suggested 4 but never proven in a chronic model of hyperinsulinemia. Indeed, because of the vasodilatory effects of insulin, 2 it has been suggested the vasodilation may mask a prohypertensive effect.…”

mentioning

confidence: 99%

Subpressor Dose of L-NAME Unmasks Hypertensive Effect of Chronic Hyperinsulinemia

et al. 2000

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Abstract-We previously found that chronic exogenous hyperinsulinemia without sugar supplementation does not elevate blood pressure. This may be partially explained by the ability of insulin to release nitric oxide and cause vasodilatation.To test this hypothesis, we studied 4 groups of rats: 9 rats (body weight, 213Ϯ14 g) treated with a gradual increase of a sustained-release subcutaneous insulin pellet; 9 rats (body weight, 213Ϯ9 g) treated with N G -nitro-L-arginine methyl ester (L-NAME) in drinking water 50 mg/L; 19 rats (body weight, 217Ϯ11 g) treated with the combination of L-NAME and insulin; and 9 control rats (body weight, 218Ϯ11 g). Blood pressure was followed weekly for 6 weeks, and then rats were studied in metabolic cages. Weight gain was not different during the 6 weeks. Renal function did not differ between the 4 groups, but 24-hour urinary nitrite/nitrate excretion was lower (PϽ0.02) in L-NAME-treated and higher in insulin-treated rats. Plasma insulin doubled (PϽ0.002) in the insulin-treated rats, but there was no hypoglycemia and, by week 6, fructosamine levels were 2.1Ϯ0.2, 2.1Ϯ0.2, 2.3Ϯ0.1, and 2.3Ϯ0.2 mmol/L in control rats and rats treated with L-NAME, insulin, and L-NAME plus insulin, respectively. Systolic blood pressure, which did not differ at baseline, at week 3 was 122Ϯ17, 118Ϯ17, and 118Ϯ24 mm Hg in the control, L-NAME, and insulin groups and 136Ϯ14 mm Hg (PϽ0.03) in the combination group. At week 6, systolic blood pressure was 128Ϯ14, 127Ϯ15, and 118Ϯ13 mm Hg in the control, L-NAME, and insulin groups, respectively, and 150Ϯ14 mm Hg (PϽ0.0005) in the combination group. In a subsequent experiment, L-arginine 2 g/L abrogated the effects of L-NAME and insulin combination. In conclusion, chronic exogenous hyperinsulinemia does not affect blood pressure but may cause hypertension when endothelial function is compromised. Key Words: insulin Ⅲ nitric oxide Ⅲ sodium Ⅲ nitrites Ⅲ nitrates H yperinsulinemia was found to be common in essential hypertension even without obesity and is the foundation for the concept of the metabolic syndrome X. However, the manner in which insulin elevates blood pressure is unclear. Sympathetic activation, 1,2 sodium retention, 3 and vascular hypertrophy have been suggested 4 but never proven in a chronic model of hyperinsulinemia. Indeed, because of the vasodilatory effects of insulin, 2 it has been suggested the vasodilation may mask a prohypertensive effect. More recently it was found that, in part, insulin-induced vasodilation may be related to increase in nitric oxide synthase (NOS) activity. 5 There have been several attempts to produce hypertension in rats by way of chronic exogenous hyperinsulinemia. 6 -10 In most of these studies, increase in carbohydrate consumption (intravenous glucose or oral sucrose) was combined with insulin to prevent hypoglycemia. We previously devised a method for producing chronic exogenous hyperinsulinemia in normal rats, without sugar supplementation and without hypoglycemia, that did not affect blood pressure. 10 However, whe...

show abstract

Effect of Intra-arterial Insulin on Tissue Cholesterol and Fatty Acids in Alloxan-Diabetic Dogs

Cited by 174 publications

References 16 publications

Insulin Is a Stronger Inducer of Insulin Resistance than Hyperglycemia in Mice with Type 1 Diabetes Mellitus (T1DM)

Insulin Is a Stronger Inducer of Insulin Resistance than Hyperglycemia in Mice with Type 1 Diabetes Mellitus (T1DM)

Structural Alterations in Subcutaneous Small Arteries of Normotensive and Hypertensive Patients With Non–Insulin-Dependent Diabetes Mellitus

Subpressor Dose of L-NAME Unmasks Hypertensive Effect of Chronic Hyperinsulinemia

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