Insulin protects against type 1 diabetes mellitus-induced aortopathy associated with the inhibition of biomarkers of vascular injury in rats (original) (raw)
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Characterization of a Rat Model of Insulin Deficiency Induced Vascular Complication
Zagazig University Medical Journal, 2013
Vascular dysfunction is one of the important diabetic complications. Here we fully characterized a rat model of streptozotocin (STZ) induced vascular complication. Diabetes was induced by single intraperitoneally injection of STZ (50 mg.kg-1 , ip).Blood pressure (BP) and isolated aorta responses phenylephrine (PE), KCl, acetylcholine (ACh), sodium nitroprusside (SNP) were recorded after 6, 8 and 10 weeks of STZ injection.In addition, serum levels of glucose, tumor necrosis factor α (TNFα), lipids, advancedglycation end products (AGEs), and arginase activity were determined. Furthermore, aortic reactive oxygen species(ROS) generation, hemeoxygenase-1 expression and collagen deposition were examined. Streptozotocin injection resulted in a significant hyperglycemia after 3 days of injection which was stable for 10 weeks. Diabetes was associated with a significant increasein BP after 6 weeks which was stable at 8 weeks. Aorta isolated from diabetic animals showed exaggerated contractility to PE and KCland impaired relaxation to ACh compared to control after 6 weeks which were clearer at 8 weeks of STZ injection. In addition, diabetic animals showed significant increases in serum levels of lipids, AGEs, TNFα and arginase enzyme activity after 8 weeks of STZ compared to control. Furthermore, aortae isolated from diabetic animals were characterized by increased ROS generation and collagen deposition. In conclusion, injecting rats with STZ at dose 50 mg.kg-1 produces a model of diabetic vascular complication after 8 weeks that are characterized by hypertension, disturbed vascular reactivity, elevated serum lipids, inflammatory cytokines and enzymes and enhanced aortic ROS generation and collagen deposition.
Insulin as a Vascular Hormone: Implications for the Pathophysiology of Cardiovascular Disease
Clinical and Experimental Pharmacology and Physiology, 1998
1. Metabolic disorders, such as obesity and non-insulindependent diabetes mellitus, and cardiovascular disorders, such as essential hypertension, congestive cardiac failure and atherosclerosis, have two features in common, namely relative resistance to insulin-mediated glucose uptake and vascular endothelial dysfunction. 2. Significant increases in limb blood flow occur in response to systemic hyperinsulinaemia, although there is marked variation in the results due to a number of confounding factors, including activation of the sympathetic nervous system. Local hyperinsulinaemia has a less marked vasodilator action despite similar plasma concentrations, but this can be augmented by coinfusing D-glucose. 3. Insulin may stimulate endothelial nitric oxide production or may act directly on vascular smooth muscle via stimulation of the Na +-H + exchanger and Na + /K +-ATPase, leading to hyperpolarization of the cell membrane and consequent closure of voltage-gated Ca 2+ channels. 4. There is evidence both for and against the existence of a functional relationship between insulin-mediated glucose uptake (insulin sensitivity) and insulin-mediated vasodilation (which can be regarded as a surrogate measure for endothelial function). 5. If substrate delivery is the rate-limiting step for insulinmediated glucose uptake (in other words, if skeletal muscle blood flow is a determinant of glucose uptake), then endothelial dysfunction, resulting in a relative inability of mediators, including insulin, to stimulate muscle blood flow, may be the underlying mechanism accounting for the association of atherosclerosis and other cardiovascular disorders with insulin resistance. 6. Glucose uptake may determine peripheral blood flow via stimulation of ATP-dependent ion pumps with consequent vasorelaxation. 7. A 'third factor' may cause both insulin resistance and endothelial dysfunction in cardiovascular disease. Candidates include skeletal muscle fibre type and capillary density, distribution of adiposity and endogenous corticosteroid production. 8. A complex interaction between endothelial dysfunction, abnormal skeletal muscle blood flow and reduced insulinmediated glucose uptake may be central to the link between insulin resistance, blood pressure, impaired glucose tolerance and the risk of cardiovascular disease. An understanding of the primary mechanisms resulting in these phenotypes may reveal new therapeutic targets in metabolic and cardiovascular disease.
Cardiovascular Actions of Insulin
Insulin has important vascular actions to stimulate production of nitric oxide from endothelium. This leads to capillary recruitment, vasodilation, increased blood flow, and subsequent augmentation of glucose disposal in classical insulin target tissues (e.g., skeletal muscle). Phosphatidylinositol 3-kinase-dependent insulin-signaling pathways regulating endothelial production of nitric oxide share striking parallels with metabolic insulin-signaling pathways. Distinct MAPK-dependent insulin-signaling pathways (largely unrelated to metabolic actions of insulin) regulate secretion of the vaso-constrictor endothelin-1 from endothelium. These and other cardiovascular actions of insulin contribute to coupling metabolic and hemodynamic homeostasis under healthy conditions. Cardiovascular diseases are the leading cause of morbidity and mortality in insulin-resistant individuals. Insulin resistance is typically defined as decreased sensitivity and/or responsiveness to metabolic actions of insulin. This cardinal feature of diabetes, obesity, and dyslipidemia is also a prominent component of hypertension, coronary heart disease, and atherosclerosis that are all characterized by endothelial dys-function. Conversely, endothelial dysfunction is often present in metabolic diseases. Insulin resistance is characterized by pathway-specific impairment in phosphatidylinositol 3-ki-nase-dependent signaling that in vascular endothelium contributes to a reciprocal relationship between insulin resistance and endothelial dysfunction. The clinical relevance of this coupling is highlighted by the findings that specific therapeutic interventions targeting insulin resistance often also ameliorate endothelial dysfunction (and vice versa). In this review, we discuss molecular mechanisms underlying cardio-vascular actions of insulin, the reciprocal relationships between insulin resistance and endothelial dysfunction, and implications for developing beneficial therapeutic strategies that simultaneously target metabolic and cardiovascular diseases. (Endocrine Reviews 28: 463– 491, 2007)
Insulin treatment enhances the myocardial angiogenic response in diabetes
The Journal of Thoracic and Cardiovascular Surgery, 2007
Objective-Growth factor and cell-based angiogenesis are attractive therapeutic options for diabetic patients with end-stage coronary disease. Reduced collateral vessel formation observed in diabetes is associated with increased expression of anti-angiogenic proteins, angiostatin and endostatin. The aim of this study was to determine the effects of insulin treatment on the diabetic angiogenic response to chronic myocardial ischemia. Methods-Yucatan miniswine were treated with alloxan (pancreatic β-cell specific toxin, 150 mg/ kg) and divided into two groups. In the diabetic group (DM, n = 8), blood glucose levels were kept greater than 250 mg/dL, and in the insulin-treated group (IDM, n = 6), intramuscular insulin was administered daily to keep blood glucose less than 150 mg/dL. A third group of age-matched swine served as nondiabetic controls (ND; n = 8). Eight weeks later, all animals underwent circumflex artery ameroid constrictor placement to induce chronic ischemia. Myocardial perfusion was assessed at 3 and 7 weeks after ameroid placement using microspheres. Microvascular function, capillary density, and myocardial expression of anti-angiogenic mediators were evaluated. Results-Diabetic animals exhibited significant impairments in endothelium-dependent microvessel relaxation to adenosine diphosphate and substance P, which were reversed in insulintreated animals. Collateral-dependent perfusion in the ischemic circumflex territory, which was profoundly reduced in diabetic animals (-0.18 ± 0.02 vs +0.23 ± 0.07 mL • min-1 • g-1 ; P < .001), improved significantly with insulin treatment (0.12 ± 0.05 mL • min-1 • g-1 ; P < .01). Myocardial expression of anti-angiogenic proteins, angiostatin and endostatin, showing a 4.3-and 3.6-fold increase in diabetic animals respectively (both P < .01 vs ND), was markedly reduced in insulintreated animals (2.3-and 1.8-fold vs ND; both P < .01). Conclusions-Insulin treatment successfully reversed diabetic coronary endothelial dysfunction and significantly improved the endogenous angiogenic response. These pro-angiogenic effects may be mediated through downregulation of anti-angiogenic mediators. Insulin therapy appears to be a promising modality to enhance the angiogenic response in diabetic patients.
The Journal of Clinical Endocrinology & Metabolism, 2000
Intercellular adhesion molecule-1 (ICAM-1) is expressed by endothelial and other cell types and participates in inflammation and atherosclerosis. It serves as a ligand for leukocyte function-associated antigen-1 on leukocytes and is partially responsible for the adhesion of lymphocytes, granulocytes, and monocytes to cytokine-stimulated endothelial cells and the subsequent transendothelial migration. Its expression on endothelial cells is increased in inflammation and atherosclerosis. As it has been suggested that insulin and hyperinsulinemia may have a role in atherogenesis, we have now investigated whether insulin has an effect on the expression of ICAM-1 on human aortic endothelial cells (HAEC). HAEC were prepared from human aortas by collagenase digestion and were grown in culture. Insulin (100 and 1000 U/mL) caused a decrease in the expression of ICAM-1 (messenger ribonucleic acid and protein) by these cells in a dose
Ultrastructural Pathology, 2018
Diabetic complications that affect vital organs such as the heart and liver represent a major public health concern. The potential protective effects of the hormone insulin against hepatocyte ultrastructural alterations induced secondary to type 1 diabetes mellitus (T1DM) in a rat model of the disease have not been investigated before. Therefore, rats were injected once with 65 mg/ kg streptozotocin (T1DM group) and the protection group (T1DM+Ins) received a daily injection of insulin 48 h post diabetic induction by streptozotocin and continued until being sacrificed at week 8. The harvested liver tissues were examined using transmission electron microscopy (TEM) and blood samples were assayed for biomarkers of liver injury enzyme, glycemia, lipidemia, inflammation, and oxidative stress. TEM images showed that T1DM induced profound hepatocyte ultrastructural alterations as demonstrated by pyknotic nucleus, condensation of chromatin, irregular nuclear membrane, swollen mitochondria, dilated rough endoplasmic reticulum, damaged intercellular space, and accumulation of few lipid droplets inside the hepatocyte cytoplasm, which were substantially protected with insulin. In addition, the blood chemistry profile complements the TEM data as demonstrated by an increase in serum levels of alanine aminotransferase (ALT), dyslipidemia, C-reactive protein (CRP), tumor necrosis factor-alpha (TNFα), interleukin-6 (IL-6), and malondialdehyde (MDA) by T1DM that were significantly (p < 0.05) reduced with insulin injections. Thus, we conclude that insulin effectively protects against T1DMinduced liver injury in rats for a period of 8 weeks, possibly due to the inhibition of inflammation, oxidative stress, and dyslipidemia.
Insulin as an anti-inflammatory and antiatherogenic modulator
Journal of the …, 2009
Data demonstrate the anti-inflammatory effects of insulin and proinflammatory effects of glucose. These data provide a mechanistic justification for the benefits of maintaining euglycemia with insulin infusions in hospitalized patients. Regimens that infuse fixed doses of insulin with high rates of glucose are usually associated with hyperglycemia, which may neutralize the beneficial effects of insulin. Therefore, we propose that such regimens should be avoided and instead replaced by insulin infusions that normalize and maintain blood glucose at a reasonably low level and ensure that plasma insulin is maintained at levels high enough to provide clinically relevant anti-inflammatory and cardioprotective effects. Trials to test this hypothesis are in progress. (
Diabetes, 2001
Blunted insulin-stimulated endothelial function may be a mechanism for the development of atherothrombotic disease in type 2 diabetes, but it is unknown whether hypoglycemic drug therapy can modulate this abnormality. We studied patients with type 2 diabetes and stable ischemic heart disease (n = 28) and lean, healthy control subjects (n = 31). Forearm blood flow was measured by venous occlusion plethysmography during dose-response studies of acetylcholine (ACh) and sodium nitroprusside (SNP) infused into the brachial artery. In the patients and 10 healthy control subjects, ACh was repeated after intrabrachial infusion of insulin. Patients were restudied after 2 months of insulin therapy with four daily subcutaneous injections (treatment group, n = 19) or without hypoglycemic drug therapy (time control group, n = 9). Insulin infusion raised venous serum insulin in the forearm to high physiological levels (133 +/- 14.6 mU/l in patients) with a minor increase in systemic venous serum insulin. This increased the ACh response by 149 +/- 47, 110 +/- 33, 100 +/- 45, and 106 +/- 44% during the four ACh doses in healthy control subjects (P < 0.0001) but had no effect in patients (P = 0.3). After 2 months, HbA(1c) in the treatment group had decreased from 10.0 +/- 0.4 to 7.5 +/- 0.2%. Although neither the ACh response (P = 0.09) nor the SNP response (P = 0.4) had changed significantly, insulin stimulation had a significant effect, as the ACh response increased by 58 +/- 25, 84 +/- 66, 120 +/- 93, and 69 +/- 36% (P = 0.0002). In the time control group, insulin stimulation remained without effect after 8 weeks (P = 0.7). In conclusion, insulin therapy partly restores insulin-stimulated endothelial function in patients with type 2 diabetes and ischemic heart disease.