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Endocrinology Vol. 145, No. 8 3647-3651
Copyright © 2004 by The Endocrine Society

Angiotensin II-Induced Insulin Resistance Is Enhanced in Adrenomedullin-Deficient Mice

Guangqun Xing, Tatsuo Shimosawa, Takehide Ogihara, Hiromitsu Matsui, Kanami Itakura, Xu Qingyou, Tomoichiro Asano, Katsuyuki Ando and Toshiro Fujita

Department of Internal Medicine (G.X., T.S., T.O., H.M., K.I., X.Q., T.A., K.A., T.F.), Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan; and Department of Nephrology (G.X.), affiliated hospital of Medical College, Qingdao University, Qingdao, China

Address all correspondence and requests for reprints to: Toshiro Fujita, M.D., Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: fujita-dis{at}h.u-tokyo.ac.jp.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
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.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
TYPE 2 DIABETES MELLITUS and hypertension are closely related disorders. Recently, oxidative stress has been considered as a possible key factor in the development of insulin resistance and hypertension. Studies in vitro have demonstrated that reactive oxygen species (ROS) can cause insulin resistance by several mechanisms, such as the impairment of insulin internalization in endothelial cells (1), the blocking of insulin receptor substrate (IRS)-1 phosphorylation, and the impairment of phosphatidylinositol (PI)-3 kinase activity in hepatocytes (2) and the translocation of glucose transporter (GLUT4) in adipocytes (3, 4). An in vivo study has also shown that the administration of ROS aggravates diabetes in diabetes-prone obese-Zucker rats (5). Moreover, treatments for reducing ROS can cause a secondary improvement in diabetes mellitus (6, 7).

Adrenomedullin (AM), discovered to be a potent vasodilator, has been recognized as a multipotent peptide that is especially known for its endogenous antioxidant effect (8, 9). Because AM-knockout homozygotes are embryonic lethal for an unknown reason (10), we have been examining AM-knockout heterozygous (AM+/–) mice, in which the serum and organ concentrations of AM is half of that seen in wild-type mice, and previously reported that angiotensin II (Ang II)-salt loading increases the level of oxidative stress (9).

In the present study, we further investigated the role of oxidative stress in the link between hypertension and diabetes using Ang II infusions in AM+/– mouse model with a high level of oxidative stress.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Eight-week-old male AM+/– mice with a disruption in the AM peptide (F10; n = 81) and C57BL/6J wild-type mice (n = 80) were used. The mice were handled in our accredited facility in accordance with the institutional animal care policies of the University of Tokyo, and all research protocols conformed to the guiding principles for animal experimentation as outlined by the Ethics Committee on Animal Research of the University of Tokyo, Faculty of Medicine.

Ang II (Sigma-Aldrich Japan, Tokyo, Japan) was administered ip using an osmotic minipump (Durect Corp., Cupertino, CA) at a dosage of 640 ng/kg·min for 28 d. 4-Hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl (hydroxy-TEMPOL) (Sigma-Aldrich Japan) at a dosage of 10 mmol/liter of drinking water was also administered for 4 wk. During the experimental period, the animals were fed a normal chow, and given free access to tap water. The mice were divided into eight groups: a wild-type control group, an AM+/– control group, a wild-type Ang II group, an AM+/– Ang II group, a wild-type+ hydroxyl-TEMPOL group, an AM+/–+ hydroxyl-TEMPOL group, a wild-type Ang II+ hydroxy-TEMPOL group, and an AM+/– Ang II+ hydroxy-TEMPOL group.

Blood pressure measurements
Systolic blood pressure (SBP) was measured using the tail-cuff method (BP98A, Softron Co., Tokyo, Japan) while the mice were in a conscious and unrestricted state. Systolic blood pressure was measured four times in each mouse for each time point, and the average value was calculated and used in farther analyses.

Measurement of fasting blood sugar (FBS) and serum insulin
Twenty-eight days after treatment, the mice were anesthetized with pentobarbital (1 g/kg body weight ip). Venous blood was drawn after 12 h fasting. FBS was assayed using the glucose oxidase method, and the plasma insulin level was measured using a RIA.

Measurement of 8-iso-prostaglandin F2{alpha} (isoprostane) and cAMP
Mice were placed in metabolic cages (KN-645, Natsume Co. Ltd., Tokyo, Japan) to collect their urine over a 24-h period for a consecutive 2 d beginning 26 d after osmotic pump implantation; urine samples were kept frozen until assay. Isoprostane was measured using the EIA method, according to the manufacturer’s instructions (Assay Designs, Inc., Ann Arbor, MI). The samples were diluted 100-fold. The total excretion level of isoprostane (nanograms per day) was then calculated. Urinary cAMP was measured using an RIA kit (cAMP kit, Yamasa Corp., Chiba, Japan).

Quantification of ROS
The level of O2– was measured in the soleus muscle, liver, and epididymal fat pad using electron spin resonance (ESR) spectroscopy with nitroxide radical hydroxy-TEMPOL as a spin probe (9). The ESR parameters were set as follows: a microwave power of 10 mW, an external magnetic field range of 10 milliTesla (mT), and a scan rate of 1 mT/sec; measurements were performed at room temperature using an ESR spectrometer (JES-FA-100; JEOL, Tokyo, Japan). Samples were weighed and homogenized in PBS containing protease inhibitors. The homogenate was immediately reacted with hydroxy-TEMPO (0.1 mmol/liter), and the resulting ESR spectrum was recorded every 2 min. The peak heights of the ESR spectra for hydroxy-TEMPO were measured, and a linear relation between the semilogarithmic plot of the peak signal intensity vs. time was observed. The rate of signal decay was calculated from the slope of this line, and the values obtained for the liver and adipose tissue, samples were standardized according to the tissue weight.

Insulin-stimulated glucose uptake into isolated soleus muscles
Glucose uptake into isolated muscles was measured as previously described (11). Mice were anesthetized with pentobarbital, and the soleus muscles were dissected free. Muscle strips were preincubated at 35 C for 60 min in Krebs-Henseleit bicarbonate (KHB) buffer supplemented with 8 mmol/liter glucose, 32 mmol/liter mannitol, and 0.1% BSA. Flasks were gassed continuously with 95% O2– 5%CO2 throughout the experiment. The muscles were then incubated for 20 min in oxygenated KHB buffer in the presence or absence of human insulin at concentrations of 0 or 0.2 mU/ml. The muscles were then rinsed and were incubated for 20 min at 29 C in 1.5 ml of KHB buffer containing 8 mM 2-deoxy-D-[1,2-3H(N)] glucose (2.25 mCi/ml), 32 mM [14C] mannitol (0.3 mCi/ml), 2 mM sodium pyruvate, and 0.1% BSA. Insulin was present throughout the wash and uptake incubation periods. After incubation, the muscles were rapidly blotted, weighed, and solubilized with 1 ml of Soluene 350. Radioactivity was counted in the samples using a liquid scintillation counter. 2-Deoxy-[3H] glucose uptake rates were corrected for extracellular trapping using the [14C] mannitol counts.

Measurement of AM content in the soleus muscle
Mice were anesthetized with pentobarbital, and the soleus muscles were dissected free. Samples were rapidly frozen and kept until assay. Using a previously described method employing polyclonal antibody (12), AM concentrations were measured, and the values were standardized according to tissue weight (grams).

Statistical analysis
All values were expressed as the mean ± SE. Comparisons among groups were analyzed using an ANOVA followed by Fisher’s method. Comparisons of SBP among groups were analyzed using an ANOVA with repeated measurements. Comparisons between two groups were made using unpaired Student’s t tests. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Blood pressure and insulin resistance
Ang II increased the AM content in skeletal muscle of both genotypes but was significantly higher in the wild-type Ang II group than in the AM+/– Ang II group (Fig. 1Go). Concomitantly with this finding, the urinary excretion of cAMP, a marker of the biological effects of AM that are increased by the infusion of Ang II, was also higher in wild-type animals (Table 1Go). Hydroxy-TEMPOL reduced cAMP excretion, compared with the results in the Ang II group, in both wild-type and AM+/– animals.



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  		FIG. 1. AM content in the skeletal muscles. Bars, Means ± SE. *, P < 0.05 vs. wild control group.

 

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  		TABLE 1. Physiological parameters

 
SBPs were significantly higher in the Ang II loading groups. No significant differences were observed between wild-type Ang II group and the AM+/– Ang II group throughout the experimental period (data not shown) or at the end of the experiment (Fig. 2Go).



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  		FIG. 2. Systolic blood pressure after Ang II and/or hydroxy-TEMPOL loading. Bars indicate means ± SE. Systolic blood pressures at the end of experiments were shown.

 
No significant changes in body weight after Ang II infusion were observed (Table 1Go). FBS levels were elevated by Ang II in both AM+/– and wild-type animals (Table 1Go), but the FBS level was significantly higher in AM+/– mice. However, no significant differences in serum insulin levels were observed among the four groups (Table 1Go). Thus, Ang II loading caused an abnormality in glucose metabolism that was enhanced in AM+/– mice.

To precisely examine insulin resistance, we measured the insulin-induced glucose uptake in the soleus muscle. With Ang II loading, 2-deoxyglucose uptake was significantly blunted (Fig. 3Go). The AM+/– Ang II group also showed a lower insulin sensitivity than the wild-type Ang II group (P < 0.05) (Fig. 3Go).



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  		FIG. 3. Changes of insulin-stimulated 2-deoxyglucose uptakes by Ang II. Bars indicate means ± SE. *, P < 0.05 vs. wild-type Ang II group.

 
Involvement of oxidative stress
Urinary excretion of isoprostane was significantly greater after Ang II loading (Fig. 4Go). To investigate the local ROS production in soleus muscles from Ang II-infused mice, we examined the tissues using ESR spectroscopy. The rate of ESR signal decay, an index of the amount of ROS, was significantly greater in AM+/– Ang II mice (0.030 ± 0.006/min, n = 6; P < 0.05) than in those from wild-type Ang II mice (0.013 ± 0.003/min, n = 6), suggesting increased oxidative stress in the soleus muscles of AM+/– Ang II mice (Fig. 5Go). In the liver but not in adipose tissue, the signal decay was significantly greater in samples from AM+/– Ang II mice (liver: 0.036 ± 0.006/min·100 mg tissue weight, n = 8; adipose tissue: 0.012 ± 0.003/min/10 mg tissue weight, n = 8) than in samples from wild-type Ang II mice (liver: 0.022 ± 0.008/min·100 mg tissue weight, n = 4; adipose tissue 0.009 ± 0.004/min·10 mg tissue weight, n = 4).



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  		FIG. 4. Total urinary excretion of isoprostane. Bars, Means ± SE. *, P < 0.10 vs. wild-type Ang II group.

 


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  		FIG. 5. ROS signal decay index measured by ESR method. Bars, Means ± SE.

 
Effects of a superoxide dismutase mimetic, hydroxy-TEMPOL, supplementation
Because ROS production in skeletal muscle was increased in AM+/– Ang II mice, we administered hydroxy-TEMPOL, a superoxide dismutase mimetic, to clarify the involvement of oxidative stress in the development of insulin resistance. When the SBP was evaluated using repeated ANOVAs at five time points during the experiment, hydroxy-TEMPOL did not significantly lower the SBP (n = 10 for each hydroxy-TEMPOL group) throughout the experiment (data not shown) or at the end of the experiments (Fig. 2Go).

Compared with the Ang II loading group, the urinary excretion of isoprostane decreased significantly (Fig. 4Go) with the administration of hydroxyl-TEMPOL. Also, a reduction in ROS in the skeletal muscle was confirmed using ESR (Fig. 5Go). In concordance with the normalization of the ROS level, the fasting glucose level tended to decrease in the wild-type and AM+/– hydroxyl-TEMPOL groups and was normalized in both the AM+/– Ang II+ hydroxy-TEMPOL group and the wild-type Ang II + hydroxy-TEMPOL group (Table 1Go). The insulin level decreased to an undetectable level in all groups (<0.1 ng/dl). Moreover, an ex vivo study of insulin sensitivity in skeletal muscle revealed that 2-deoxyglucose uptake had returned to its control level in both the AM+/– Ang II group (5.15 ± 0.38 nmol/mg tissue weight, n = 10) and in the wild-type Ang II group (5.29 ± 0.29 nmol/mg tissue weight, n = 10) (Fig. 3Go).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Insulin resistance has been shown to play an important role in the pathogenesis of hypertension and type 2 diabetes mellitus (13, 14). To treat these conditions, both insulin resistance and blood pressure should be managed simultaneously. Recent studies have revealed that oxidative stress can be linked to insulin resistance, hypertension, and related organ damages (15, 16). In the present study, we focused on the action of AM, a potent vasodilator and hypotensive peptide (17), as well as an antioxidant (8, 9). We examined the cause-result relationship of oxidative stress on insulin resistance and blood pressure. We applied Ang II to induce ROS generation and hypertension in young AM+/– mice. Disruption of the AM gene induces embryonic lethality in homozygous mice (10), but AM+/– mice grow normally and are fertile, although their AM level is half that of wild-type mice (9). As shown in this study, the AM contents of skeletal muscle from AM+/– mice was nearly half that of muscle from wild-type mice, and the AM content increased by about 3-fold with Ang II infusion in both wild-type and AM+/– mice. Thus, AM+/– mice remain deficient in AM even after Ang II loading.

Ang II loading elevated the blood pressure to the same extent in wild-type and AM+/– mice. The deficiency of AM did not further accelerate the elevation in blood pressure, probably because blood pressure is regulated by multiple factors, like NO, prostaglandins, and so on. On the other hand, the Ang II-induced insulin resistance was enhanced in AM+/– mice. Insulin resistance was evaluated by measuring 2-deoxyglucose uptake in the mice soleus muscle. Because skeletal muscle constitutes 30–40% of the body mass, skeletal muscle insulin resistance is a major determinant of overall insulin resistance (18). Furthermore, a skeletal muscle-specific inhibition of insulin signaling is adequate to cause insulin resistance (19, 20, 21).

In the present study, we have shown that Ang II loading induces insulin resistance together with an increased level of ROS, as measured by the urinary excretion of isoprostane, a marker for overall oxidative stress, and by ESR, in which ROS production was examined in specific tissues. Tissues involved in insulin resistance, liver as well as skeletal muscles were found to produce higher levels of ROS in AM-deficient mice after Ang II stimulation. Moreover, hydroxy-TEMPOL, an ROS scavenger, reversed the insulin resistance state in Ang II-infused mice, returning values to their control level. In groups without Ang II loading, ROS production was very small, and hydroxyl-TEMPOL did not alter the insulin- resistant state in these groups. These data suggest that Ang II impairs insulin signaling by inducing oxidative stress. AM has been shown to be up-regulated by ROS (22), which is consistent with our findings that Ang II increased the AM content and cAMP excretion and that hydroxyl-TEMPOL decreased these parameters (Fig. 1Go and Table 1Go). Furthermore, AM inhibits ROS production, and a deficiency of AM induces a higher oxidative stress by stimulating ROS production, but not by impairing the scavenging system that is regulated by AM (9). Thus, the AM-ROS axis may play a role in the pathophysiology of insulin resistance in the present model. ROS has been shown to impair insulin signaling in various organs through several mechanism: insulin internalization (1), the blocking of IRS phosphorylation, impairment of PI-3 kinase activity, and reduction of GLUT4 translocation (3, 4).

In addition to oxidative stress, Ang II has been reported to induce insulin resistance through several mechanisms: 1) by elevating blood pressure and decreasing the blood supply to skeletal muscles (23), and 2) by directly impairing the insulin signaling pathway (24, 25, 26). Hemodynamically, insulin resistance can be regarded as a prereceptor abnormality. Through structural vascular changes and an increase in vascular resistance, the skeletal muscle blood supply can be decreased, with a subsequent reduction in insulin delivery (23, 27). In the present study, Ang II loading elevated the blood pressure to the same extent in both wild-type and AM+/– mice, but the insulin resistance was severer in AM+/– mice. Moreover, hydroxy-TEMPOL treatment reversed the insulin resistance without affecting the blood pressure. These findings suggest that hemodynamic changes cannot explain the insulin resistance state in the present model.

Ang II can directly impair the insulin signaling pathway via several mechanisms, and numerous issues remain controversial. Some authors have reported that Ang II inhibits tyrosine phosphorylation and enhances serine phosphorylation of IRS-1, attenuating the binding of IRS-1 and PI-3 kinase (24, 25, 26). On the other hand, Ogihara et al. (28) reported that Ang II enhances tyrosine phosphorylation of IRSs, activating PI-3 kinase and Akt phosphorylation. In the present study, we did not examine the direct effects of Ang II on insulin signaling; however, hydroxy-TEMPOL reversed the insulin resistance, suggesting that oxidative stress plays a pivotal role in the induction of insulin resistance.

In conclusion, Ang II induced a higher level of oxidative stress in AM-deficient mice, leading to insulin resistance. This finding suggests that AM may not only be an intrinsic factor, but a potentially useful peptide for the treatment of insulin resistance and hypertension through its vasodilation and antioxidative effects.


   Footnotes
 
This study is partly sponsored by Sasagawa Scholarship (to G.X.).

Abbreviations: AM, Adrenomedullin; Ang II, angiotensin II; ESR, electron spin resonance; FBS, fasting blood sugar; hydroxy-TEMPOL, 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl; IRS, insulin receptor substrate; KHB, Krebs-Henseleit bicarbonate; PI, phosphatidylinositol; ROS, reactive oxygen species; SBP, systolic blood pressure.

Received January 12, 2004.

Accepted for publication April 13, 2004.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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