adrenomedullin and Insulin-Resistance

Topics: Adrenomedullin; Angiotensin II; Cardiovascular Diseases; Humans; Hypertension; Insulin Resistance; Metabolic Syndrome; Renin-Angiotensin System; Sodium Chloride

The balance between reactive oxigen species (ROS) production and degradation is important in defining oxidative stress. In aging process, ROS production increases and degradation is impaired and thus oxidative stress is accumulated. Oxidative stress damages organs both directly and indirectly. Protein, lipid, as well as DNA are directly react with ROS, more over, ROS interact with intracellular signaling system. It is reported that several transcription factors such as NF-kappaB, AP-1 and ASK-1 and also it interferes MAPK activity. Besides these signaling, we recently showed that insulin resistance is induced by accumulated oxidative stress in aged mice. Adrenomedullin deficient mice accumulate higher oxidative stress and insulin resistance developed in aging. Oxidative stress in aging relates not only direct organ damage but also induce risk factors for vascular damage such as metabolic syndrome.

Topics: Adrenomedullin; Aging; Animals; Gene Expression Regulation; Humans; Insulin Resistance; Metabolic Syndrome; Mitogen-Activated Protein Kinases; Oxidative Stress; Peptides; Reactive Oxygen Species; Risk Factors; Signal Transduction; Transcription Factors

A novel vasodilator, adrenomedullin (AM), which acts as an autocrine/paracrine factor in cardiovascular system, has antiproliferative and antimigrative effects. AM gene transfer prevents the development of cuff-induced vascular injury. Moreover, AM knockout mice exhibited an increase in angiotensin (Ang) II/salt loading-induced coronary arterial lesion, hypoxia-induced pulmonary vascular damage, and cuff-induced vascular injury associated with enhancement in reactive oxygen species (ROS) generation. In addition, AM expression was stimulated by ROS, and AM directly inhibits oxidative stress so that AM might be a negative feedback substance against ROS-induced organ damages. In addition, AM increases nitric oxide and ameliorates insulin resistance, leading to oxidative stress. Consequently, endogenous AM might compensatively inhibit the development of vascular diseases at least partly through an antioxidative effect.

Topics: Adrenomedullin; Animals; Cardiovascular Diseases; Humans; Insulin Resistance; Nitric Oxide; Peptides; Reactive Oxygen Species; Receptors, Adrenomedullin; Receptors, Peptide; Vascular Diseases; Vasodilation

Topics: Adrenomedullin; Animals; Antioxidants; Cardiovascular Diseases; Disease Models, Animal; Homozygote; Humans; Insulin Resistance; Kidney Diseases; Mice; Mice, Knockout; Oxidative Stress; Peptides

Topics: Adrenomedullin; Angiotensin II; Animals; Antioxidants; Cardiovascular Diseases; Cyclic N-Oxides; Humans; Insulin Resistance; Life Style; Lipoproteins, LDL; Nitric Oxide; Oxidative Stress; Peptides; Reactive Oxygen Species; Receptors, LDL; Receptors, Oxidized LDL; Scavenger Receptors, Class E; Spin Labels

To evaluate adrenomedullin levels in patients with polycystic ovary syndrome (PCOS).. Prospective study.. Department of obstetrics and gynecology in a university hospital.. Thirty-eight women with PCOS and 29 healthy control subjects were enrolled in the study.. Plasma adrenomedullin, serum androstenedione, free T, T, DHEAS, SHBG, thyrotropin, PRL, FSH, LH, and E2 were measured in each subject. Insulin resistance was estimated by fasting insulin level, fasting glucose:insulin ratio and 75-g glucose tolerance test for 2 hours.. Plasma adrenomedullin levels and correlations among adrenomedullin and gonadotropins, female sex steroids, androgens, and insulin resistance.. There was no significant difference concerning plasma adrenomedullin concentrations between the groups. In patients with PCOS, fasting glucose, fasting insulin, body mass index, and free T were inversely correlated with the plasma adrenomedullin. Plasma adrenomedullin was significantly correlated with glucose:insulin ratio. After controlling for body mass index, there were no significant correlations between the above-mentioned parameters.. Adrenomedullin may play a role in regulating the insulin metabolism in patients with PCOS.

Topics: Adolescent; Adrenomedullin; Adult; Female; Humans; Hyperinsulinism; Insulin Resistance; Peptides; Polycystic Ovary Syndrome; Statistics as Topic

White adipose tissue (WAT) dysfunction has been associated with adipose tissue low-grade inflammation and oxidative stress leading to insulin resistance (IR). Adrenomedullin (ADM), an endogenous active peptide considered as an adipokine, is associated with adipocytes function.. We evaluated the protective effects of ADM against IR in 3T3-L1 adipocytes treated by palmitic acid (PA) and in visceral white adipose tissue (vWAT) of obese rats fed with high-fat diet.. We found that endogenous protein expressions of ADM and its receptor in PA-treated adipocytes were markedly increased. PA significantly induced impaired insulin signaling by affecting phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) axis and glucose transporter-4 (GLUT-4) levels, whereas ADM pretreatment enhanced insulin signaling PI3K/Akt and GLUT-4 membrane protein levels, decreased pro-inflammatory cytokines tumor necrosis factor α (TNFα), interleukin-1β (IL-1β) and IL-6 levels, and improved oxidative stress accompanied with reduced reactive oxygen species (ROS) levels and increased anti-oxidant enzymes manganese superoxide dismutase 2 (SOD2), glutathione peroxidase (GPx1) and catalase (CAT) protein expressions. Furthermore, ADM treatment not only improved IR in obese rats, but also effectively restored insulin signaling, and reduced inflammation and oxidative stress in vWAT of obese rats.. This study demonstrates a prevention potential of ADM against obesity-related metabolic disorders, due to its protective effects against IR, inflammation and oxidative stress in adipocytes.

Topics: Adipocytes; Adrenomedullin; Animals; Inflammation; Insulin; Insulin Resistance; Obesity; Palmitic Acid; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats

High N-terminal pro-brain-type natriuretic peptide levels have been associated with a lower risk of type 2 diabetes mellitus (T2D). However, less is known about other cardiac stress biomarkers in this context. Here we evaluated the association of mid-regional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-arginine vasopressin (copeptin), C-terminal pro-endothelin-1 (CT-proET-1) and mid-regional pro-adrenomedullin (MR-proADM) with incident T2D and changes in glucose metabolism.. We performed a prospective cohort study using data from the population-based KORA F4/FF4 study. 1773 participants (52.3% women) with MR-proANP measurements and 960 (52.7% women) with copeptin, CT-proET-1 and MR-proADM measurements were included. We examined associations of circulating plasma levels of MR-proANP, copeptin, CT-proET-1 and MR-proADM with incident T2D, the combined endpoint of incident prediabetes/T2D and with fasting and 2 h-glucose, fasting insulin, HOMA-IR, HOMA-B and HbA1c at follow-up. Logistic and linear regression models adjusted for age, sex, waist circumference, height, hypertension, total/HDL cholesterol ratio, triglycerides, smoking, physical activity and parental history of diabetes were used to compute effect estimates.. During a median follow-up time of 6.4 years (25th and 75th percentiles: 6.0 and 6.6, respectively), 119 out of the 1773 participants and 72 out of the 960 participants developed T2D. MR-proANP was inversely associated with incident T2D (odds ratio [95% confidence interval]: 0.75 [0.58; 0.96] per 1-SD increase of log MR-proANP). Copeptin was positively associated with incident prediabetes/T2D (1.29 [1.02; 1.63] per 1-SD increase of log copeptin). Elevated levels of CT-proET-1 were associated with increased HOMA-B at follow-up, while elevated MR-proADM levels were associated with increased fasting insulin, HOMA-IR and HOMA-B at follow-up. These associations were independent of previously described diabetes risk factors.. High plasma concentrations of MR-proANP contributed to a lower risk of incident T2D, whereas high plasma concentrations of copeptin were associated with an increased risk of incident prediabetes/T2D. Furthermore, high plasma concentrations of CT-proET-1 and MR-proADM were associated with increased insulin resistance. Our study provides evidence that biomarkers implicated in cardiac stress are associated with incident T2D and changes in glucose metabolism.

Topics: Adrenomedullin; Adult; Aged; Aged, 80 and over; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Female; Germany; Glycopeptides; Heart Diseases; Humans; Incidence; Insulin Resistance; Male; Middle Aged; Peptide Fragments; Prediabetic State; Prognosis; Prospective Studies; Protein Precursors; Risk Assessment; Risk Factors; Time Factors

Obese children are at increased risk for abnormal cardiac structure and function. Little is known about adrenomedullin (AM), a cytokine produced in various organs and tissues, as a biomarker of cardiac hypertrophy in obese children. This study aimed to assess the plasma AM levels in a cohort of obese children and its relationship to left ventricular (LV) functions.. The study included 60 obese children and 60 non-obese children matched for age and gender as control group. Blood pressure, serum lipid profile, fasting glucose, insulin and plasma AM and the homeostatic model assessment of insulin resistance (HOMA-IR) were measured. Cardiac dimensions and LV functions were assessed using conventional echocardiography.. Compared to control subjects, obese children had higher blood pressure (P = 0.01), insulin (P = 0.001), HOMA-IR (P = 0.001), and AM (P = 0.001). Moreover, obese children had higher LV mass index (LVMI) (P = 0.001), indicating LV hypertrophy; prolonged isovolumic relaxation times (P = 0.01), prolonged mitral deceleration time (DcT) (P = 0.01) and reduced ratio of mitral E-to-mitral A-wave peak velocity (P = 0.01), indicating LV diastolic dysfunction. Laboratory abnormalities were only present in children with LV hypertrophy. In multivariate analysis in obese children with LV hypertrophy, AM levels were positively correlated with LVMI [odds ratio (OR) 1.14, 95% confidence interval (Cl) 1.08-1.13, P = 0.0001] and mitral DcT (OR 2.25, 95% CI 1.15-2.05, P = 0.01) in the presence of higher blood pressure and HOMA-IR. A cut-off value of AM at 52 pg/mL could differentiate obese children with and without left ventricular hypertrophy at a sensitivity of 94.32% and specificity of 92.45%.. Plasma AM levels may be elevated in obese children particularly those with LV hypertrophy and is correlated with higher blood pressure and insulin resistance. Measurement of plasma AM levels in obese children may help to identify those at high risk of developing LV hypertrophy and dysfunction.

Topics: Adrenomedullin; Area Under Curve; Biomarkers; Body Mass Index; Case-Control Studies; Child; Developing Countries; Echocardiography; Egypt; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Incidence; Insulin Resistance; Male; Pediatric Obesity; Reference Values; Risk Assessment; ROC Curve

MHC class II (MHCII) antigen presentation in adipocytes was reported to trigger early adipose inflammation and insulin resistance. However, the benefits of MHCII inhibition in adipocytes remain largely unknown. Here, we showed that human plasma polypeptide adrenomedullin 2 (ADM2) levels were negatively correlated with HOMA of insulin resistance in obese human. Adipose-specific human ADM2 transgenic (aADM2-tg) mice were generated. The aADM2-tg mice displayed improvements in high-fat diet-induced early adipose insulin resistance. This was associated with increased insulin signaling and decreased systemic inflammation. ADM2 dose-dependently inhibited CIITA-induced MHCII expression by increasing Blimp1 expression in a CRLR/RAMP1-cAMP-dependent manner in cultured adipocytes. Furthermore, ADM2 treatment restored the high-fat diet-induced early insulin resistance in adipose tissue, mainly via inhibition of adipocyte MHCII antigen presentation and CD4(+) T-cell activation. This study demonstrates that ADM2 is a promising candidate for the treatment of early obesity-induced insulin resistance.

Topics: 3T3-L1 Cells; Adipocytes; Adipose Tissue; Adrenomedullin; Animals; Bone Marrow Transplantation; Cells, Cultured; Genes, MHC Class II; Humans; Inflammation; Insulin Resistance; Mice; Mice, Inbred C57BL; Mice, Transgenic; Models, Biological; Obesity; Peptide Hormones; Positive Regulatory Domain I-Binding Factor 1; Receptor Activity-Modifying Protein 1; Transcription Factors

To determine the therapeutic effects of adrenomedullin (ADM) on vascular calcification and related molecular mechanism in fructose-induced insulin resistance rats.. Rats received ordinary drinking water or 10% fructose in drinking water for 12 weeks and subcutaneous injection of normal saline or ADM (3.6 μg kg(-1) ) twice a day for the last 4 weeks. Levels of ADM, calcitonin receptor-like receptors (CRLR), receptor activity-modifying proteins (RAMP) as well as calcium content, alkaline phosphatase (ALP) activity, osteoblastic and contractile smooth muscle markers in aortic media were measured.. The levels of ADM, CRLR, RAMP2 and RAMP3 in aortic media were increased in fructose-fed rats. ADM treatment attenuated the fructose-induced insulin resistance, increased blood pressure, fasting glucose, insulin, triglycerides and cholesterol levels. It improved VSMCs proliferation and disordered arrangement and hyperplasia of elastic fibres in fructose-fed rats. Calcium deposits, calcium content and ALP activity in the aortic media were increased in fructose-fed rats, which were attenuated by ADM treatment. The osteoblastic markers such as osteopontin (OPN), bone morphogenetic protein 2 (BMP2) proteins and core binding factor alpha-1 (Cbfα-1) protein and mRNA expressions were increased in fructose-fed rats. ADM treatment increased the OPN protein expression, but reduced the BMP2 protein, Cbfα-1 protein and mRNA expression. Contractile smooth muscle markers such as α-actin and smooth muscle 22α (SM-22α) were downregulated in fructose-fed rats, which were recovered by ADM treatment.. Administration of ADM attenuates insulin resistance, calcium deposition and osteogenic transdifferentiation in aortic media in fructose-fed rats.

Topics: Adrenomedullin; Animals; Aorta; Biomarkers; Blood Glucose; Blood Pressure; Cell Transdifferentiation; Cholesterol; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Fructose; Insulin; Insulin Resistance; Male; Osteogenesis; Rats; Rats, Sprague-Dawley; Signal Transduction; Triglycerides; Vascular Calcification

Topics: Adrenomedullin; Animals; Aorta; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Insulin Resistance; Male; Vascular Calcification

The aim of the study was to investigate adrenomedullin (ADM) levels and its relation with insulin resistance in women with polycystic ovary syndrome (PCOS). Twenty-nine women with PCOS and 29 age- and body mass index (BMI)- matched control subjects were included in the study. PCOS was defined according to criteria by the Rotterdam European Society of Human Reproduction and Embryology/American Society for Reproductive Medicine (ESHRE/ASRM)-sponsored PCOS consensus workshop group. A full clinical and biochemical examination including basal hormones and metabolic profile was performed. Insulin resistance was calculated by using the homeostasis model assessment of insulin resistance index (HOMA-IR). Plasma ADM levels were measured by high performance liquid chromatographic (HPLC) method. Plasma ADM, fasting insulin levels and HOMA-IR were significantly higher in patients with PCOS than the control group. ADM levels were positively correlated with insulin levels and HOMA-IR index. The best cut-off value of ADM levels to identify the presence of insulin resistance (HOMA-IR≥2.7) was 30.44 ng/ml. Calculated odds ratio of insulin resistance by using logistic regression analysis, as predicted by ADM, was 0.15 (95% confidence interval, 0.037-0.628; p=0.009). In multiple regression analysis, ADM level was an independent predictor of HOMA-IR index. Our finding indicated that ADM levels increased in women with PCOS in accordance with HOMA-IR. ADM could be a significant independent determinant of insulin resistance in women with PCOS.

Topics: Adrenomedullin; Adult; Biomarkers; Blood Glucose; Body Mass Index; Case-Control Studies; Female; Humans; Insulin Resistance; Lipids; Polycystic Ovary Syndrome; Young Adult

New-onset diabetes in patients with pancreatic cancer is likely to be a paraneoplastic phenomenon caused by tumor-secreted products. We aimed to identify the diabetogenic secretory product(s) of pancreatic cancer.. Using microarray analysis, we identified adrenomedullin as a potential mediator of diabetes in patients with pancreatic cancer. Adrenomedullin was up-regulated in pancreatic cancer cell lines, in which supernatants reduced insulin signaling in beta cell lines. We performed quantitative reverse-transcriptase polymerase chain reaction and immunohistochemistry on human pancreatic cancer and healthy pancreatic tissues (controls) to determine expression of adrenomedullin messenger RNA and protein, respectively. We studied the effects of adrenomedullin on insulin secretion by beta cell lines and whole islets from mice and on glucose tolerance in pancreatic xenografts in mice. We measured plasma levels of adrenomedullin in patients with pancreatic cancer, patients with type 2 diabetes mellitus, and individuals with normal fasting glucose levels (controls).. Levels of adrenomedullin messenger RNA and protein were increased in human pancreatic cancer samples compared with controls. Adrenomedullin and conditioned media from pancreatic cell lines inhibited glucose-stimulated insulin secretion from beta cell lines and islets isolated from mice; the effects of conditioned media from pancreatic cancer cells were reduced by small hairpin RNA-mediated knockdown of adrenomedullin. Conversely, overexpression of adrenomedullin in mice with pancreatic cancer led to glucose intolerance. Mean plasma levels of adrenomedullin (femtomoles per liter) were higher in patients with pancreatic cancer compared with patients with diabetes or controls. Levels of adrenomedullin were higher in patients with pancreatic cancer who developed diabetes compared those who did not.. Adrenomedullin is up-regulated in patients with pancreatic cancer and causes insulin resistance in β cells and mice.

Topics: Adenocarcinoma; Adrenomedullin; Aged; Animals; Cell Line, Tumor; Cells, Cultured; Diabetes Mellitus, Type 2; Female; Glucose; Humans; In Vitro Techniques; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Mice; Mice, Nude; Middle Aged; Models, Animal; Pancreas; Pancreatic Neoplasms; Rats; RNA, Small Interfering; Transplantation, Heterologous; Up-Regulation

Adrenomedullin (ADM) has been recognized as a multipotent multifunctional peptide. To explore the pathophysiological roles of ADM in insulin resistance (IR), we studied the changes in ADM mRNA level in the myocardium and vessels and the effect of ADM supplementation on rats with IR induced by fructose feeding. Rats were fed 4% fructose in drinking water for 8 weeks, and ADM was administered subcutaneously in pure water through an Alzet Mini-osmotic Pump at 300 ng/kg/h for the last 4 weeks. Compared with controls, rats with IR showed increased levels of fasting blood sugar and serum insulin, by 95% and 67%, respectively (all P<0.01), and glycogen synthesis and glucose transport activity of the soleus decreased by 54% and 55% (all P<0.01). mRNA level and content of brain natriuretic peptide (BNP) in myocardial were all increased significantly. Fructose-fed rats showed increased immunoreactive-ADM content in plasma by 110% and in myocardia by 55% and increased mRNA level in myocardia and vessels (all P<0.01). ADM administration ameliorated the induced IR and myocardial hypertrophy. The glycogen synthesis and glucose transport activity of the soleus muscle increased by 41% (P<0.01) and 32% (P<0.05). ADM therapy attenuated myocardial and soleus lipid peroxidation injury and enhanced the antioxidant ability. Our results showed upregulation of endogenous ADM during fructose-induced IR and the protective effect of ADM on fructose-induced IR and concomitant cardiovascular hypertrophy probably by its antioxidant effect, which suggests that ADM could be an endogenous protective factor in IR.

Topics: Adrenomedullin; Animals; Blood Glucose; Cardiomegaly; Cardiotonic Agents; Fructose; Glycogen; Infusion Pumps; Infusions, Subcutaneous; Insulin; Insulin Resistance; Lipid Peroxidation; Male; Malondialdehyde; Muscle, Skeletal; Myocardium; Natriuretic Peptide, Brain; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Although adrenomedullin (AM) is a potent hypotensive peptide that acts mainly as a vasodilative and proliferation inhibitory factor, there have been few hemodynamic studies on AM in humans, especially concerning arterial stiffness and hormonal effects. In addition, AM is a suppressive factor in insulin resistance, suggesting that the effects of AM in a state of insulin resistance are important. To evaluate the effects of AM in humans, 28 participants were intravenously administered AM (5 pmol min(-1) kg(-1)) for 90 min. They also received a representative vasodilator drug, nicardipine, as a reference drug. Blood pressure, heart rate, pulse wave velocity (PWV) and blood flow were monitored throughout the experiment. Hormonal changes were also monitored by blood tests. The effects of AM were compared with those of nicardipine. In addition, the effects of AM were re-evaluated against insulin resistance state. AM and nicardipine produced the same level of hypotension, but AM showed a more potent ability to increase heart rate, blood flow and cardiac output and reduce PWV. AM and nicardipine similarly stimulated plasma noradrenaline and renin activity. However, in the state of insulin resistance, favorable effects of AM on aortic stiffness were blunted and differences between AM and nicardipine disappeared. Furthermore, there was a significant correlation between maximum changes in the PWV induced by AM and the homeostasis model assessment of insulin resistance index (r=0.58, P=0.001). Our results suggest that AM may improve arterial stiffness and act as a compensatory factor against arterial sclerosis. Moreover, decreased reactivity of AM may participate in the progression of arterial sclerosis in insulin resistance.

Topics: Adrenomedullin; Adult; Arteries; Compliance; Hemodynamics; Humans; Insulin Resistance; Middle Aged; Vasodilator Agents

We recently reported that long-term treatment with pioglitazone restored cardiac Akt phosphorylation in response to hyperthermia (HT) and subsequent cardiac heat-shock protein 72 (HSP72) expression, in heredity insulin resistance rats via improvement of insulin sensitivity. Because adrenomedullin (AM) promotes Akt phosphorylation and attenuates myocardial ischemia/reperfusion injury, we tested the hypothesis that pretreatment with AM before HT could restore depressed Akt activation and cardiac HSP72 expression, thereby enhancing protection against ischemia/reperfusion injury in this model. At 16 wk of age, male insulin-resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rats and control Long-Evans Tokushima Otsuka (LETO) rats were treated with AM (0.05 microg/kg . /min iv) or vehicle for 60 min. Thereafter, HT (43 C for 20 min) or normothermia (NT; 37 C for 20 min) was applied. The heart was isolated 1 and 24 h after HT. 1) Either AM or HT induced myocardial Akt phosphorylation in a phosphatidylinositol 3-kinase-dependent manner, which was augmented by their combination. 2) Akt phosphorylation induced by HT, or a combination of HT and AM, was attenuated in insulin-resistant OLETF rat hearts. 3) The levels of Akt phosphorylation in response to AM and/or HT correlated with reperfusion-induced left ventricular functional recovery and amount of released creatine kinase during reperfusion. 4) AM protected the hearts of OLETF rats and LETO rats. Our results suggest that AM pretreatment could enhance HT-induced myocardial Akt phosphorylation and subsequent HSP72 expression in a phosphatidylinositol 3-kinase-dependent manner, in association with tolerance against ischemia/reperfusion injury. This intervention was effective even in insulin-resistant hearts.

Topics: Adrenomedullin; Animals; Blood Pressure; Cardiotonic Agents; Drug Evaluation, Preclinical; Heart; HSP72 Heat-Shock Proteins; Insulin Resistance; Male; Myocardium; Oncogene Protein v-akt; Phosphatidylinositol 3-Kinases; Phosphorylation; Rats; Rats, Inbred OLETF; Rats, Long-Evans; Recovery of Function; Reperfusion Injury; Ventricular Function, Left

We generated preadipocyte cell lines impaired in adrenomedullin production through integration of an adrenomedullin small interfering RNA expression vector. The reduction of adrenomedullin synthesis strongly accelerated adipose differentiation. These results were bolstered when overexpression of active adrenomedullin peptide led to delayed differentiation. Therefore, we propose that adrenomedullin is an antiadipogenic factor. Moreover, we checked whether insulin, a proadipogenic factor, regulates expression of adrenomedullin. We observed that insulin had an inhibitory effect on adrenomedullin expression in isolated human adipocyte cells. This response was dose dependent and was reversed by resistin, a new anti-insulin agent. We quantified circulating adrenomedullin in healthy obese patients and observed a threefold increase of adrenomedullin compared with lean patients. Furthermore, adrenomedullin plasma levels are negatively correlated to plasma insulin levels in these obese patients. The insulin inhibitory response was also observed in vivo in Sprague-Dawley rats but not in the insulin-resistant Zucker rat, suggesting that adrenomedullin expression is upregulated in insulin-resistant adipose cells. Using adrenomedullin promoter-luciferase reporter gene constructs, we have shown that the adrenomedullin response to insulin is mediated by insulin-responsive elements. These findings provide new insight into fat mass development and the relationship between obesity and elevated circulating adrenomedullin levels in diabetic patients.

Topics: Adipocytes; Adipogenesis; Adrenomedullin; Adult; Animals; Cell Differentiation; Cell Line; Down-Regulation; Female; Gene Expression Regulation; Gene Silencing; Genetic Markers; Humans; Insulin; Insulin Resistance; Male; Mice; Middle Aged; Obesity; Promoter Regions, Genetic; Rats; Rats, Sprague-Dawley; Rats, Zucker; RNA, Messenger; RNA, Small Interfering; Transcription, Genetic

Insulin resistance and hypertension are common disorders that are closely related. Among several factors, oxidative stress has been reported to be intimately related to these diseases. To elucidate the involvement of oxidative stress in the development of insulin resistance in a hypertensive model, we administered angiotensin II (Ang II), which raises blood pressure and induces reactive oxygen radicals, to adrenomedullin (AM)-knockout heterozygous mice and examined the resulting changes in blood pressure and insulin resistance. Ang II was administered ip at a dosage of 640 ng/kg.min for 4 wk. The systolic blood pressure was significantly elevated in both AM-knockout heterozygous and wild-type mice to the same extent. On the other hand, Ang II attenuated insulin sensitivity more strongly in AM-knockout heterozygous mice than in wild-type mice, when measured using 2- deoxyglucose uptakes in the soleus muscle. Ang II also induced a higher urinary excretion of isoprostane, a marker of oxidative stress. Furthermore, the production of oxidative stress in the soleus muscles of angiotensin-treated mice, measured using electronic spin resonance, was significantly higher than that in AM-knockout heterozygous mice. Moreover, 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl, a superoxide scavenger mimetic, normalized the insulin resistance induced by Ang II without affecting the blood pressure in both groups. The present results suggest that, in an Ang II-treated mouse model, insulin resistance is induced by oxidative stress through a mechanism that is independent of blood pressure, and that AM can act as a protective peptide against insulin resistance via its intrinsic antioxidant effect.

Topics: Adrenomedullin; Angiotensin II; Animals; Blood Pressure; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Peptides; Piperidines

This animal experiment was aimed at the questions whether high glucose concentration inhibits insulin secretion (glucose toxicity, GT) of beta-cell of islets from SHR and Wistar-Kyoto (WKY) rat and whether adrenomedullin (AM) enhances GT. Ten 6-week-old SHRs (test group) and ten 10-week-old Wistar-Kyoto rats (WKY) (control group) were selected. RAMI-1640 medium containing 5.6 mM glucose (normal glucose group) and 20 mM glucose (high glucose group) were applied. Various concentrations of AM (0, 10(-8), 10(-7), 10(-6) M) and RPMI-1640 medium containing high glucose were mixed, respectively. The isolated islets from rats were put into 12-well plates (90 islets/well). The islets were incubated in RAMI-1640 medium containing normal or high glucose for one hour. Then the supernatants from both incubations were determined by RIA for insulin. In SHR group, the insulin concentration in supernatants gained from high glucose group without AM was lower than that from normal glucose group (19.9+/-6.6 vs 60.9+/-33.6 mU/L, P<0.05). With the increment of the concentration of AM, insulin concentration in supernatants from islets incubated in high glucose and various concentrations of AM tended to be low further (19.9+/-6.6 vs 22.2+/-8.0 vs 21.5+/-5.6 vs 17.9+/-3.6 mU/L). The changing tendency in control group was the same as in SHR group. When the islets were incubated in normal glucose and high glucose medium, the insulin concentration in supernatant significantly decreased in SHR group compared with that in control group (P<0.01). The insulin secretion was inhibited by high glucose in beta-cell of islets from SHR and WKY. The results suggest GT to beta-cell of islets from SHR and WKY. AM tended to inhibit insulin secretion in a dose-dependent manner in beta-cell of islets from SHR and WKY. The inhibition of insulin secretion caused by high glucose in beta-cell of islets from SHR was more remarkable than from WKY. This may be related to secretion dysfunction in beta-cell of islets from SHR.

Topics: Adrenomedullin; Animals; Blood Glucose; Cells, Cultured; Female; Glucose; Hyperglycemia; Hypertension; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Male; Peptides; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Hypertension, insulin resistance, and obesity are common age-related metabolic disorders that are often associated with increased oxidative stress and the resultant vascular damage. Underlying mechanisms have been suggested, and age-related overproduction of oxidative stress is one possible candidate. Since we recently found a vasoactive peptide, adrenomedullin, to be an endogenous antioxidant that potently inhibits oxidative stress-induced vascular damage, in the current study we evaluated oxidative stress-induced changes in aged mice. Insulin sensitivities in young and aged adrenomedullin-deficient mice were measured by means of the hyperinsulinemic-euglycemic clamp method; insulin resistance was apparent in aged adrenomedullin-deficient mice with increased urinary excretion of 8-iso-prostaglandin F2alpha, a marker of oxidative stress, but not in young adrenomedullin-deficient mice. Concomitantly, only aged adrenomedullin-deficient mice not only showed increased production of muscular reactive oxygen species, as demonstrated by the electron spin resonance method, but also had significantly decreased insulin-stimulated glucose uptake into the soleus muscle associated with impairment of insulin signals such as insulin receptor substrate-1,2 and phosphatidylinositol-3 kinase activities. In turn, these abnormalities could be nearly reversed by either treatment with 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl, a membrane-permeable superoxide dismutase mimetic, or adrenomedullin supplementation. Evidence presented in this report suggests that age-related accumulation of oxidative stress is involved in blood pressure regulation and insulin resistance in aged adrenomedullin-deficient mice, and adrenomedullin is thus an endogenous substance counteracting oxidative stress-induced insulin resistance associated with aging.

Topics: Adrenomedullin; Aging; Animals; Antioxidants; Blood Pressure; Body Weight; Cyclic N-Oxides; Deoxyglucose; Female; Genotype; In Vitro Techniques; Insulin; Insulin Resistance; Isoprostanes; Male; Mice; Mice, Knockout; Muscle, Skeletal; Oxidative Stress; Peptides

It has recently been shown that deficiency of adrenomedullin (AM), a potent vasodilator peptide, leads to insulin resistance. We studied expression of AM in NIH 3T3-L1 adipocytes and compared it with expression of resistin, an adipocyte-derived peptide hormone that is proposed to cause insulin resistance. Moreover, we studied the effects of tumor necrosis factor-alpha (TNF-alpha), a known mediator of insulin resistance, on the expression of AM and resistin in 3T3-L1 adipocytes.. 3T3-L1 cells were induced to differentiate to adipocytes by insulin, dexamethasone and 3-isobutyl-1-methylxanthine. Expression of AM mRNA and resistin mRNA was examined by Northern blot analysis. Immunoreactive AM in the medium was measured by RIA.. AM mRNA was expressed in preadipocytes, but barely detectable in adipocytes. Immunoreactive AM was detected in the medium of both preadipocytes and adipocytes, with about 2.5 times higher levels found in preadipocytes. In contrast, resistin mRNA was expressed in adipocytes, whereas it was not detected in preadipocytes. Treatment with TNF-alpha increased AM expression in both adipocytes and preadipocytes, whereas it decreased resistin mRNA levels in adipocytes.. The present study has shown that AM expression was down-regulated and resistin expression was up-regulated during adipocyte differentiation of 3T3-L1 cells. TNF-alpha acted as a potent negative regulator of resistin expression and a potent positive regulator of AM expression in adipocytes, raising the possibility that in addition to its known actions in causing insulin resistance, TNF-alpha may also have actions against insulin resistance through AM and resistin.

Topics: 1-Methyl-3-isobutylxanthine; 3T3 Cells; Adipocytes; Adrenomedullin; Animals; Blotting, Northern; Cell Differentiation; Dexamethasone; Dose-Response Relationship, Drug; Gene Expression Regulation; Glucocorticoids; Hormones, Ectopic; Humans; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Interferon-alpha; Interleukin-1; Mice; Nerve Growth Factor; Peptides; Proteins; Recombinant Proteins; Resistin; RNA, Messenger; Tumor Necrosis Factor-alpha

Rat adrenomedullin is a peptide vasodepressor that may be of importance in the pathogenesis of hypertensive disease. Because of the known link between obesity and hypertension, we hypothesized that decreased responsiveness to adrenomedullin might be seen in an obese rodent model. In this study, the in vivo vasodilator actions of exogenous adrenomedullin were compared in anesthetized lean (n = 7) and obese (fa/fa) Zucker rats (n = 8). Adrenomedullin dose dependently lowered mean arterial pressure in both phenotypes, but the half-maximal dose (ID50) was 2-fold higher in fa/fa rats (1.7 +/- 0.22 vs. 0.83 +/- 0.06 nmol/kg). Moreover, the duration of effect was markedly reduced in the fa/fa rats, to 1-2 min from about 5 min in the lean animals. There was no evidence for an increased rate of degradation of adrenomedullin in the fa/fa rats. Although the rats used in this study were not hypertensive, adrenomedullin had reduced sensitivity and duration of action. The evidence suggests possible defects at the target receptor or altered metabolism of adrenomedullin in obesity.

Topics: Adrenomedullin; Animals; Blood Pressure; Hypertension; Insulin Resistance; Male; Obesity; Peptides; Rats; Rats, Zucker; Vasodilator Agents