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Combined effect of ACE inhibitor and exercise training on insulin resistance in type 2 diabetic rats
Life Sciences 70 (2002) 1811 – 1820
Combined effect of ACE inhibitor and exercise training on insulin resistance in type 2 diabetic rats Nagakatsu Harada, Eiko Takishita, Noriko Ishimura, Asako Minami, Sadaichi Sakamoto, Yutaka Nakaya* Department of Nutrition, School of Medicine, The University of Tokushima, 3-18-15, Kuramoto-cho, Tokushima City, 770-8503, Japan Received 12 June 2001; accepted 31 October 2001
Abstract The aim of this study was to investigate whether a combined treatment of ACE inhibitor and exercise training is more effective than either treatment alone in alleviating the insulin resistant states in the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a model of type 2 diabetes. OLETF rats (25 weeks old) were randomly divided into 5 groups; sedentary control, exercise-trained, temocapril (ACE inhibitor; 2 mg/kg/day)-treated, with and without exercise, and losartan (AT1 receptor antagonist; 1 mg/kg/day)-treated. Long-Evans Tokushima Otsuka rats were used as a non-diabetic control. Body weight, the amount of abdominal fat and blood pressure were higher for OLETF rats than for control rats. However, glucose infusion rate (GIR), an index of insulin resistance, was decreased greatly in OLETF rats. The fasting levels of blood glucose, insulin and lipids were also increased in the diabetic strain. In OLETF rats, both temocapril and losartan reversed hypertensive states significantly, whereas GIR and hyperlipidemia were improved when rats were treated with ACE inhibitors, but not with the AT1 receptor antagonist. Exercise training decreased body weight and the amount of abdominal fat, and also increased GIR in parallel with improved dislipidemia. The combination of the ACE inhibitor with exercise training also improved obesity, hyperinsulinemia, dislipidemia and fasting level of blood glucose, and this combination resulted in the greatest improvement of insulin resistance. These results suggest that the combination of ACE inhibitor and exercise training may be a beneficial treatment for mixed diabetic and hypertensive conditions. D 2002 Elsevier Science Inc. All rights reserved. Keywords: Angiotensin; Diabetes mellitus; Exercise; Insulin
* Corresponding author. Tel.: +81-88-633-7090; fax: +81-88-633-7113. E-mail address: [email protected] (Y. Nakaya). 0024-3205/02/$ – see front matter D 2002 Elsevier Science Inc. All rights reserved. PII: S 0 0 2 4 - 3 2 0 5 ( 0 2 ) 0 1 4 9 5 - 9
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Introduction Most patients with essential hypertension show insulin resistance [1,2]. Thus, antihypertensive drugs are expected to provide the additional benefit of reducing insulin resistance. The effects of antihypertensive drugs on glucose metabolism have been widely studied and many reports have shown angiotensin converting enzyme (ACE) inhibitors [3–5] and alpha 1-blockers [6] to have strong effects in this regard. The precise mechanisms underlying the improvement of insulin resistance by ACE inhibitors are still unknown. However, suppression of the production of angiotensin II, which causes vasoconstriction or stimulates a release of noradrenaline, is thought to play a role. Also, bradykinin, which facilitates glucose utilization directly [7] or indirectly [8], is degraded by ACE, which is also known as kininase 2 [9]. The involvement of bradykinin action in ACE inhibitor-mediated improvement of glucose metabolism has been well demonstrated [10]. Exercise training is also effective in the treatment of diabetes and obesity. Decreasing body weight, in particular the amount of abdominal fat, decreases the levels of various factors derived from fat tissue, such as TNF-alpha and free fatty acids (FFAs), both of which cause insulin resistance [11,12]. Exercise also causes a variety of metabolic changes in the body, and enhances the uptake of glucose into skeletal muscle tissues, leading to improved insulin sensitivity [13,14]. Several factors are candidates, i.e. intracellular Ca2+, protein kinase C (PKC), 50 –AMP-activated protein kinase (AMPK), adenosine, glycogen, nitric oxide (NO) and bradykinin [15]. The involvement of these factors in exercise-induced glucose uptake has been investigated widely from old times to today, although the mechanisms are not made still clearly. Recently, it has been reported that the combined treatment of ACE inhibition with exercise training caused great improvement of oral glucose tolerance and of insulinstimulated muscle transport of glucose than either treatment alone in the diabetic, obese Zucker rats [16]. However, it remains unclear whether whole-body insulin resistance is also further reversed by such combined treatment. Using another type 2 diabetic model rat, OLETF (Otsuka Long-Evans Tokushima Fatty rat), we have examined the effects of an ACE inhibitor, AT1 receptor antagonist and exercise training, alone or in combination, on impaired glucose homeostasis. The results show that exercise training or ACE inhibitor, but not AT1 receptor antagonist, improved insulin resistance in OLETF rats and that the combination of exercise training and ACE inhibitor resulted in greatly improved insulin resistance, suggesting that such a combination may be a beneficial treatment for diabetic conditions associated with hypertension.
Materials and methods Animals Four-week-old male type 2 diabetic rats (OLETF) were provided from the Tokushima Research Institute (Otsuka Pharmaceutical, Tokushima, Japan). Rats were housed singly at a constant room temperature (22 ± 2 C) with a 12-hour light/dark cycle, and were fed standard
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rat diet (Oriental Yeast, Tokyo, Japan). Food and water were available ad libitum and rats had grown satisfactorily throughout their lifespan. At the age of 25 weeks, they were randomly assigned to the following 5 groups; sedentary control (n = 8), exercise-trained (n = 8), temocapril (ACE inhibitor; 2 mg/kg/day)-treated (n = 8), temocapril (2 mg/kg/day)-treated and exercise-trained (n = 7), and losartan (AT1 receptor antagonist; 1 mg/kg/day)-treated (n = 7). Body weight and fasting blood glucose levels were not significantly different among groups at the beginning of the experiment. A non-diabetic rat strain (Long-Evans Tokushima Otsuka; LETO) was used as the age-matched control. At 29 weeks, systolic blood pressure was measured by using the tail-cuff method (Neuroscience, Tokyo, Japan). Exercise training of the rats was performed by placing rats in an individual cage with an exercise wheel (Nishin, Tokushima, Japan). Rats were allowed to run at their own pace. The running activity was measured by recording the number of revolutions of the wheel (1.15 m/cycle) per day. The mean running distances were 592 ± 51 m / day or 579 ± 81 m / day in groups with or without temocapril treatment, respectively (not significant between two groups). Oral glucose tolerance test (OGTT) and euglycemic insulin clamp studies At 29 weeks, OGTT was performed after an overnight fast. Glucose solution (2 g/kg body weight) was administered orally, and at 0, 30, 60, and 120 min, blood was drawn from a tail vein in order to measure the plasma glucose level. At 30 weeks, insulin-mediated whole-body glucose uptake was determined using a hyperinsulinemic euglycemic clamp study. After an overnight fast, rats were anesthetized by intraperitoneal injection of pentobarbital, and catheters were inserted in the carotid artery and vein. Rats received a 1-hour infusion of insulin (60 pmol/kg/min). The duration of the study was sufficient to examine whole body glucose disposal, as described in our previous reports [17]. A glucose solution (100 g/l) was initiated at time 0, and the rate was adjusted to maintain the plasma concentration of glucose at approximately 6.1 mmol/l. The total body glucose uptake represents the mean glucose infusion rate (GIR) during the last 20 min. Table 1 Body weight, abdominal fat and systolic blood pressure Body weight (g) Non-diabetic OLETF
Sedentary Exercised Temocapril Temo + exercised Losartan
544.0 689.2 603.3 659.8 580.3 686.0
Data are means ± SE. SBP: Systolic blood pressure, Temo: temocapril. * p < 0.05 vs. non-diabetic rats. y p < 0.05 vs. OLETF-sedentary rats. z p < 0.05 vs. OLETF rats treated with temocapril.
± ± ± ± ± ±
11.6 13.4* 29.5y 10.0 16.3y,z 11.4
Abdominal fat (g/100 g BW) 4.7 15.0 11.4 13.6 10.3 15.1
± ± ± ± ± ±
0.6 0.6* 0.9y 0.3 0.7y,z 0.5
SBP (mmHg) 122 152 136 124 126 133
± ± ± ± ± ±
5 4* 9 3y 3y 3y
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Blood chemicals and measurement of the amount of abdominal fat Before the beginning of the clamp studies, blood samples were collected from the carotid artery. The plasma level of glucose was determined by the glucose oxidase method (Toecho Super, Kyoto Daiichi Kagaku, Kyoto, Japan). The plasma levels of insulin and lipids were measured by using commercial kits (Wako, Tokyo, Japan). After the insulin clamp studies, mesenteric, epididymal, and retroperitoneal fats were collected and the total amount of abdominal fat was measured. Statistical analysis Data are expressed as the mean ± SE. Data were analyzed by analysis of variance plus Bonferroni multiple comparison tests. A p level of < 0.05 was accepted as statistically significant.
Results Body weight, abdominal fat and systolic blood pressure The mean body weight, amount of visceral fat and systolic blood pressure of each group at 30 weeks of age are shown in Table 1. Body weight and the total amount of abdominal fat were significantly greater in OLETF-sedentary rats than in age-matched non-diabetic rats. Exercise training significantly decreased both body weight and total fat weight in the abdominal cavity of OLETF rats, whereas each drug treatment did not. Systolic blood pressure of OLETF sedentary rats was also higher than that of non-diabetic rats. Temocapril and losartan, but not exercise-training, significantly decreased the blood pressure of OLETF rats.
Table 2 Plasma level of glucose, insulin and lipids Glucose (m mol/l) Non-diabetic OLETF Sedentary Exercised Temocapril Temo+exercised Losartan
5.91 7.79 7.63 7.05 6.40 7.75
± ± ± ± ± ±
0.30 0.24* 0.38 0.25 0.17y 0.29
Insulin (n mol/l) 0.85 1.89 0.75 1.96 0.83 1.89
± ± ± ± ± ±
Data are means ± SE. Temo: temocapril. * p < 0.05 vs. non-diabetic rats. y p < 0.05 vs OLETF-sedentary rats. z p < 0.05 vs. OLETF rats treated with temocapril.
0.13 0.26 0.07y 0.23 0.09y,z 0.25
Free fatty Triacylglycerol Total cholesterol acid (m mol/l) (m mol/1) (m mol/1) 0.52 1.09 0.91 0.85 0.87 0.92
± ± ± ± ± ±
0.07 0.04* 0.10 0.11 0.09 0.13
0.61 3.79 2.31 1.79 0.79 3.39
± ± ± ± ± ±
0.20 0.71* 0.44 0.19y 0.14y 0.60
1.48 3.24 2.31 2.46 1.81 3.60
± ± ± ± ± ±
0.22 0.32* 0.19y 0.08 0.12y 0.34
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Fig. 1. Changes in the plasma level of glucose before and throughout the time course from 30 to 120 min after glucose (2 g/kg) administered orally in each rat group. Blood samples were collected from a tail vein without anesthesia. Data are means ± SE. * p < 0.05 vs. non-diabetic rats. y p < 0.05 vs. OLETF-sedentary rats.
Fig. 2. Glucose infusion rate (GIR) in each group during the euglycemic hyperinsulinemic clamp studies. The rate was adjusted to maintain the plasma concentration of glucose at approximately 6.1 mmol/l for 20 min. Data are means ± SE. * p < 0.05 vs. non-diabetic rats. y p < 0.05 vs. OLETF-sedentary rats. z p < 0.05 vs. OLETF rats treated with each treatment alone.
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Plasma levels of glucose, insulin and lipids Table 2 shows the fasting plasma levels of glucose, insulin and lipids of each group at 30 weeks of age. In OLETF sedentary rats, these parameters were significantly augmented compared to that of non-diabetic rats. Exercise training decreased the plasma insulin and cholesterol levels significantly, whereas temocapril treatment prevented the increase in the level of triacylglycerol. The combination of temocapril treatment and exercise training significantly decreased the fasting level of plasma glucose. There were no significant changes in any of the measured parameters in losartan-treated rats. Glucose tolerance and in vivo glucose disposal Time courses during OGTT show that OLETF sedentary rats had significantly higher levels of blood glucose than non-diabetic rats after glucose administration (Fig. 1). In OLETF rats, the increase in the glucose level was significantly attenuated by the treatment with temocapril. The GIR was decreased in OLETF sedentary rats compared with non-diabetic rats (Fig. 2). Temocapril treatment or exercise training significantly augmented the GIR, and the combination of both further increased the glucose disposal. On the other hand, no change in glucose intolerance was observed in the group with losartan treatment.
Discussion An increased body weight, accumulation of abdominal fat and decreased insulin sensitivity are factors contributing to, and features of, the type 2 diabetic rat model, OLETF [17]. Blood pressure is also higher in OLETF rats compared to that of the non-diabetic strain [18]. In the present study, temocapril, an inhibitor of ACE, improved GIR in OLETF rats, whereas losartan, an antagonist of the AT1 receptor, failed to reverse the insulin resistant states, although both drugs decreased the level of blood pressure. Exercise training by itself also improved insulin resistance and decreased the amount of abdominal fat in OLETF. However, the most important finding in this study is that the combination of exercise and ACE inhibition has the greatest ability to improve the impaired glucose metabolism in OLETF rats. It has been reported that ACE inhibitors have a beneficial effect on insulin resistance [3–5]. This effect was once considered to be attributable to an increased blood flow leading to a higher rate of delivery of glucose and insulin to the peripheral tissues [19,20]. Shimamoto et al. [21] showed, in a high-fructose-induced diabetic rat model, that the increased insulin sensitivity induced by ACE inhibitor, delapril, was due to prevention of the production of angiotensin II. These improvements might involve a suppression of angiotensin II actions such as vascular constriction or of stimulating noradrenaline release from the ends of sympathetic nerves, which worsen insulin resistance [22]. On the other hand, insulin itself also increases blood flow and capillary recruitment in skeletal muscle, and such increases might contribute to the metabolic action of insulin [23]. In this regard, Rattigan et al. demonstrated that the vasoconstrictor a– methylserotonin (a– met5HT) caused insulin
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resistance in perfused muscle by preventing insulin’s action to recruit nutritive capillaries [24]. At present, however, there is no evidence that angiotensin II has such preventing effect on insulin-induced capillary recruitment. In the present study, losartan failed to improve glucose intolerance in OLETF rats. Consistent with our study, losartan had no effect on insulin sensitivity or glucose metabolism in a rat model of hypertension with or without diabetes [10,25]. The effects of AT1 receptor antagonism on glucose metabolism are still controversial, and the differences in the effects of these drugs are possibly due to the variability among the types of drugs or animals used. In in vitro and in vivo studies, it has been reported that the stimulatory effects of ACE inhibitors on glucose utilization were blocked by the application of kinin antagonist [10,26]. These findings suggest a contribution of the kinins to increased insulin sensitivity. The inhibition of ACE, i.e. of kininase 2, leads to accumulation of bradykinin and its metabolic products, such as prostaglandins [27]. In muscle, bradykinin enhances the phosphorylation of the insulin receptor beta subunit and insulin receptor substrate-1 without affecting the number or affinity of insulin receptors, thus leading to increased insulin-mediated glucose transporter 4 (GLUT4) translocation [8]. A similar observation was also reported using captopril but not losartan, suggesting an indirect role for bradykinin in regulating glucose metabolism [28]. On the other hand, insulin-mediated GLUT4 translocation itself is also impaired in the muscle of diabetic, obese Zucker rats [29]. Recently, we have reported that bradykinin directly triggers translocation of GLUT4 in various tissues via an insulin-independent pathway [7]. Thus, the observed improvement of glucose metabolism by ACE inhibitors might be due to direct or indirect actions of increased endogenous bradykinin. Exercise has been demonstrated to increase the uptake of glucose into skeletal muscle [13,14] or into the whole body [17]. In the present study, exercise training also improved insulin resistance in OLETF rats. Increased translocation of GLUT4 by skeletal muscle cell membranes following exercise was reported in experiments with humans [30] and animals [31,32]. A study involving the use of rats showed that increased levels of GLUT4 induced by exercise did not decline during a five day period after the cessation of the exercise [33]. It was also reported that the signaling pathways related to the increased glucose uptake are different between insulin- and exercise- mediated stimulation [14,34], although insulinstimulated glucose uptake was observed to be increased after exercise [32]. This may explain the fact that exercise training increases the uptake of glucose even in persons with insulin resistance [14]. In the present study, treatment with the combination of ACE inhibitor and exercise training showed greater improvement in glucose metabolism than either treatment alone in the OLETF rats. The result is consistent with that of a recent study in which such combined treatment greatly improved diabetic conditions of obese Zucker rats [16]. However, factors mediating interactions between these two treatments are yet unknown. One mechanism of improved insulin resistance by exercise may be a decrease in abdominal fat tissues which largely produce or release a variety of antagonizing factors to insulin, such as FFAs [12]. In this regard, Steen et al. demonstrated, using Zucker rats, that exercise training significantly decreased the plasma level of FFAs, although this effect was not enhanced by the combined treatment with ACE inhibitor trandolapril [16]. Since we failed to observe any change in the
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plasma FFA level neither by exercise training nor by ACE inhibition, FFAs appear not to be directly involved in the synergistic effect of the combined treatment. Alternatively, several other factors could be mediators. Muscle contraction enhances the release of bradykinin [35], whereas exercise training has been reported to increase the level of bradykinin in plasma [36]. If it is so, the level of bradykinin which is increased by exercise training might be maintained by ACE inhibitors for a long time. On the other hand, muscle contraction also activates several enzymes in the cell signaling pathways, such as PKC [37] and AMPK [38,39], both of which have been considered to be involved in accelerated muscle glucose uptake during exercise [15]. In addition, the increase in the production of NO or in the proportion of nutritive capillary flow in muscle tissue during exercise contributes to increased glucose disposal from the circulation [17,40]. Whether these factors are involved in the effect of ACE inhibition alone or of that in combination with exercise training, however, has not been determined in this study. In conclusion, our results indicate that the combination of ACE inhibitor and exercise training would be an effective treatment for hypertensive states with insulin resistance. To understand this phenomenon more deeply, the precise mechanisms underlying such greatest improvement of insulin resistance need to be clarified in the future.
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Combined effect of ACE inhibitor and exercise training on insulin resistance in type 2 diabetic rats Nagakatsu Harada, Eiko Takishita, Noriko Ishimura, Asako Minami, Sadaichi Sakamoto, Yutaka Nakaya* Department of Nutrition, School of Medicine, The University of Tokushima, 3-18-15, Kuramoto-cho, Tokushima City, 770-8503, Japan Received 12 June 2001; accepted 31 October 2001
Abstract The aim of this study was to investigate whether a combined treatment of ACE inhibitor and exercise training is more effective than either treatment alone in alleviating the insulin resistant states in the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a model of type 2 diabetes. OLETF rats (25 weeks old) were randomly divided into 5 groups; sedentary control, exercise-trained, temocapril (ACE inhibitor; 2 mg/kg/day)-treated, with and without exercise, and losartan (AT1 receptor antagonist; 1 mg/kg/day)-treated. Long-Evans Tokushima Otsuka rats were used as a non-diabetic control. Body weight, the amount of abdominal fat and blood pressure were higher for OLETF rats than for control rats. However, glucose infusion rate (GIR), an index of insulin resistance, was decreased greatly in OLETF rats. The fasting levels of blood glucose, insulin and lipids were also increased in the diabetic strain. In OLETF rats, both temocapril and losartan reversed hypertensive states significantly, whereas GIR and hyperlipidemia were improved when rats were treated with ACE inhibitors, but not with the AT1 receptor antagonist. Exercise training decreased body weight and the amount of abdominal fat, and also increased GIR in parallel with improved dislipidemia. The combination of the ACE inhibitor with exercise training also improved obesity, hyperinsulinemia, dislipidemia and fasting level of blood glucose, and this combination resulted in the greatest improvement of insulin resistance. These results suggest that the combination of ACE inhibitor and exercise training may be a beneficial treatment for mixed diabetic and hypertensive conditions. D 2002 Elsevier Science Inc. All rights reserved. Keywords: Angiotensin; Diabetes mellitus; Exercise; Insulin
* Corresponding author. Tel.: +81-88-633-7090; fax: +81-88-633-7113. E-mail address: [email protected] (Y. Nakaya). 0024-3205/02/$ – see front matter D 2002 Elsevier Science Inc. All rights reserved. PII: S 0 0 2 4 - 3 2 0 5 ( 0 2 ) 0 1 4 9 5 - 9
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Introduction Most patients with essential hypertension show insulin resistance [1,2]. Thus, antihypertensive drugs are expected to provide the additional benefit of reducing insulin resistance. The effects of antihypertensive drugs on glucose metabolism have been widely studied and many reports have shown angiotensin converting enzyme (ACE) inhibitors [3–5] and alpha 1-blockers [6] to have strong effects in this regard. The precise mechanisms underlying the improvement of insulin resistance by ACE inhibitors are still unknown. However, suppression of the production of angiotensin II, which causes vasoconstriction or stimulates a release of noradrenaline, is thought to play a role. Also, bradykinin, which facilitates glucose utilization directly [7] or indirectly [8], is degraded by ACE, which is also known as kininase 2 [9]. The involvement of bradykinin action in ACE inhibitor-mediated improvement of glucose metabolism has been well demonstrated [10]. Exercise training is also effective in the treatment of diabetes and obesity. Decreasing body weight, in particular the amount of abdominal fat, decreases the levels of various factors derived from fat tissue, such as TNF-alpha and free fatty acids (FFAs), both of which cause insulin resistance [11,12]. Exercise also causes a variety of metabolic changes in the body, and enhances the uptake of glucose into skeletal muscle tissues, leading to improved insulin sensitivity [13,14]. Several factors are candidates, i.e. intracellular Ca2+, protein kinase C (PKC), 50 –AMP-activated protein kinase (AMPK), adenosine, glycogen, nitric oxide (NO) and bradykinin [15]. The involvement of these factors in exercise-induced glucose uptake has been investigated widely from old times to today, although the mechanisms are not made still clearly. Recently, it has been reported that the combined treatment of ACE inhibition with exercise training caused great improvement of oral glucose tolerance and of insulinstimulated muscle transport of glucose than either treatment alone in the diabetic, obese Zucker rats [16]. However, it remains unclear whether whole-body insulin resistance is also further reversed by such combined treatment. Using another type 2 diabetic model rat, OLETF (Otsuka Long-Evans Tokushima Fatty rat), we have examined the effects of an ACE inhibitor, AT1 receptor antagonist and exercise training, alone or in combination, on impaired glucose homeostasis. The results show that exercise training or ACE inhibitor, but not AT1 receptor antagonist, improved insulin resistance in OLETF rats and that the combination of exercise training and ACE inhibitor resulted in greatly improved insulin resistance, suggesting that such a combination may be a beneficial treatment for diabetic conditions associated with hypertension.
Materials and methods Animals Four-week-old male type 2 diabetic rats (OLETF) were provided from the Tokushima Research Institute (Otsuka Pharmaceutical, Tokushima, Japan). Rats were housed singly at a constant room temperature (22 ± 2 C) with a 12-hour light/dark cycle, and were fed standard
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rat diet (Oriental Yeast, Tokyo, Japan). Food and water were available ad libitum and rats had grown satisfactorily throughout their lifespan. At the age of 25 weeks, they were randomly assigned to the following 5 groups; sedentary control (n = 8), exercise-trained (n = 8), temocapril (ACE inhibitor; 2 mg/kg/day)-treated (n = 8), temocapril (2 mg/kg/day)-treated and exercise-trained (n = 7), and losartan (AT1 receptor antagonist; 1 mg/kg/day)-treated (n = 7). Body weight and fasting blood glucose levels were not significantly different among groups at the beginning of the experiment. A non-diabetic rat strain (Long-Evans Tokushima Otsuka; LETO) was used as the age-matched control. At 29 weeks, systolic blood pressure was measured by using the tail-cuff method (Neuroscience, Tokyo, Japan). Exercise training of the rats was performed by placing rats in an individual cage with an exercise wheel (Nishin, Tokushima, Japan). Rats were allowed to run at their own pace. The running activity was measured by recording the number of revolutions of the wheel (1.15 m/cycle) per day. The mean running distances were 592 ± 51 m / day or 579 ± 81 m / day in groups with or without temocapril treatment, respectively (not significant between two groups). Oral glucose tolerance test (OGTT) and euglycemic insulin clamp studies At 29 weeks, OGTT was performed after an overnight fast. Glucose solution (2 g/kg body weight) was administered orally, and at 0, 30, 60, and 120 min, blood was drawn from a tail vein in order to measure the plasma glucose level. At 30 weeks, insulin-mediated whole-body glucose uptake was determined using a hyperinsulinemic euglycemic clamp study. After an overnight fast, rats were anesthetized by intraperitoneal injection of pentobarbital, and catheters were inserted in the carotid artery and vein. Rats received a 1-hour infusion of insulin (60 pmol/kg/min). The duration of the study was sufficient to examine whole body glucose disposal, as described in our previous reports [17]. A glucose solution (100 g/l) was initiated at time 0, and the rate was adjusted to maintain the plasma concentration of glucose at approximately 6.1 mmol/l. The total body glucose uptake represents the mean glucose infusion rate (GIR) during the last 20 min. Table 1 Body weight, abdominal fat and systolic blood pressure Body weight (g) Non-diabetic OLETF
Sedentary Exercised Temocapril Temo + exercised Losartan
544.0 689.2 603.3 659.8 580.3 686.0
Data are means ± SE. SBP: Systolic blood pressure, Temo: temocapril. * p < 0.05 vs. non-diabetic rats. y p < 0.05 vs. OLETF-sedentary rats. z p < 0.05 vs. OLETF rats treated with temocapril.
± ± ± ± ± ±
11.6 13.4* 29.5y 10.0 16.3y,z 11.4
Abdominal fat (g/100 g BW) 4.7 15.0 11.4 13.6 10.3 15.1
± ± ± ± ± ±
0.6 0.6* 0.9y 0.3 0.7y,z 0.5
SBP (mmHg) 122 152 136 124 126 133
± ± ± ± ± ±
5 4* 9 3y 3y 3y
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Blood chemicals and measurement of the amount of abdominal fat Before the beginning of the clamp studies, blood samples were collected from the carotid artery. The plasma level of glucose was determined by the glucose oxidase method (Toecho Super, Kyoto Daiichi Kagaku, Kyoto, Japan). The plasma levels of insulin and lipids were measured by using commercial kits (Wako, Tokyo, Japan). After the insulin clamp studies, mesenteric, epididymal, and retroperitoneal fats were collected and the total amount of abdominal fat was measured. Statistical analysis Data are expressed as the mean ± SE. Data were analyzed by analysis of variance plus Bonferroni multiple comparison tests. A p level of < 0.05 was accepted as statistically significant.
Results Body weight, abdominal fat and systolic blood pressure The mean body weight, amount of visceral fat and systolic blood pressure of each group at 30 weeks of age are shown in Table 1. Body weight and the total amount of abdominal fat were significantly greater in OLETF-sedentary rats than in age-matched non-diabetic rats. Exercise training significantly decreased both body weight and total fat weight in the abdominal cavity of OLETF rats, whereas each drug treatment did not. Systolic blood pressure of OLETF sedentary rats was also higher than that of non-diabetic rats. Temocapril and losartan, but not exercise-training, significantly decreased the blood pressure of OLETF rats.
Table 2 Plasma level of glucose, insulin and lipids Glucose (m mol/l) Non-diabetic OLETF Sedentary Exercised Temocapril Temo+exercised Losartan
5.91 7.79 7.63 7.05 6.40 7.75
± ± ± ± ± ±
0.30 0.24* 0.38 0.25 0.17y 0.29
Insulin (n mol/l) 0.85 1.89 0.75 1.96 0.83 1.89
± ± ± ± ± ±
Data are means ± SE. Temo: temocapril. * p < 0.05 vs. non-diabetic rats. y p < 0.05 vs OLETF-sedentary rats. z p < 0.05 vs. OLETF rats treated with temocapril.
0.13 0.26 0.07y 0.23 0.09y,z 0.25
Free fatty Triacylglycerol Total cholesterol acid (m mol/l) (m mol/1) (m mol/1) 0.52 1.09 0.91 0.85 0.87 0.92
± ± ± ± ± ±
0.07 0.04* 0.10 0.11 0.09 0.13
0.61 3.79 2.31 1.79 0.79 3.39
± ± ± ± ± ±
0.20 0.71* 0.44 0.19y 0.14y 0.60
1.48 3.24 2.31 2.46 1.81 3.60
± ± ± ± ± ±
0.22 0.32* 0.19y 0.08 0.12y 0.34
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Fig. 1. Changes in the plasma level of glucose before and throughout the time course from 30 to 120 min after glucose (2 g/kg) administered orally in each rat group. Blood samples were collected from a tail vein without anesthesia. Data are means ± SE. * p < 0.05 vs. non-diabetic rats. y p < 0.05 vs. OLETF-sedentary rats.
Fig. 2. Glucose infusion rate (GIR) in each group during the euglycemic hyperinsulinemic clamp studies. The rate was adjusted to maintain the plasma concentration of glucose at approximately 6.1 mmol/l for 20 min. Data are means ± SE. * p < 0.05 vs. non-diabetic rats. y p < 0.05 vs. OLETF-sedentary rats. z p < 0.05 vs. OLETF rats treated with each treatment alone.
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Plasma levels of glucose, insulin and lipids Table 2 shows the fasting plasma levels of glucose, insulin and lipids of each group at 30 weeks of age. In OLETF sedentary rats, these parameters were significantly augmented compared to that of non-diabetic rats. Exercise training decreased the plasma insulin and cholesterol levels significantly, whereas temocapril treatment prevented the increase in the level of triacylglycerol. The combination of temocapril treatment and exercise training significantly decreased the fasting level of plasma glucose. There were no significant changes in any of the measured parameters in losartan-treated rats. Glucose tolerance and in vivo glucose disposal Time courses during OGTT show that OLETF sedentary rats had significantly higher levels of blood glucose than non-diabetic rats after glucose administration (Fig. 1). In OLETF rats, the increase in the glucose level was significantly attenuated by the treatment with temocapril. The GIR was decreased in OLETF sedentary rats compared with non-diabetic rats (Fig. 2). Temocapril treatment or exercise training significantly augmented the GIR, and the combination of both further increased the glucose disposal. On the other hand, no change in glucose intolerance was observed in the group with losartan treatment.
Discussion An increased body weight, accumulation of abdominal fat and decreased insulin sensitivity are factors contributing to, and features of, the type 2 diabetic rat model, OLETF [17]. Blood pressure is also higher in OLETF rats compared to that of the non-diabetic strain [18]. In the present study, temocapril, an inhibitor of ACE, improved GIR in OLETF rats, whereas losartan, an antagonist of the AT1 receptor, failed to reverse the insulin resistant states, although both drugs decreased the level of blood pressure. Exercise training by itself also improved insulin resistance and decreased the amount of abdominal fat in OLETF. However, the most important finding in this study is that the combination of exercise and ACE inhibition has the greatest ability to improve the impaired glucose metabolism in OLETF rats. It has been reported that ACE inhibitors have a beneficial effect on insulin resistance [3–5]. This effect was once considered to be attributable to an increased blood flow leading to a higher rate of delivery of glucose and insulin to the peripheral tissues [19,20]. Shimamoto et al. [21] showed, in a high-fructose-induced diabetic rat model, that the increased insulin sensitivity induced by ACE inhibitor, delapril, was due to prevention of the production of angiotensin II. These improvements might involve a suppression of angiotensin II actions such as vascular constriction or of stimulating noradrenaline release from the ends of sympathetic nerves, which worsen insulin resistance [22]. On the other hand, insulin itself also increases blood flow and capillary recruitment in skeletal muscle, and such increases might contribute to the metabolic action of insulin [23]. In this regard, Rattigan et al. demonstrated that the vasoconstrictor a– methylserotonin (a– met5HT) caused insulin
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resistance in perfused muscle by preventing insulin’s action to recruit nutritive capillaries [24]. At present, however, there is no evidence that angiotensin II has such preventing effect on insulin-induced capillary recruitment. In the present study, losartan failed to improve glucose intolerance in OLETF rats. Consistent with our study, losartan had no effect on insulin sensitivity or glucose metabolism in a rat model of hypertension with or without diabetes [10,25]. The effects of AT1 receptor antagonism on glucose metabolism are still controversial, and the differences in the effects of these drugs are possibly due to the variability among the types of drugs or animals used. In in vitro and in vivo studies, it has been reported that the stimulatory effects of ACE inhibitors on glucose utilization were blocked by the application of kinin antagonist [10,26]. These findings suggest a contribution of the kinins to increased insulin sensitivity. The inhibition of ACE, i.e. of kininase 2, leads to accumulation of bradykinin and its metabolic products, such as prostaglandins [27]. In muscle, bradykinin enhances the phosphorylation of the insulin receptor beta subunit and insulin receptor substrate-1 without affecting the number or affinity of insulin receptors, thus leading to increased insulin-mediated glucose transporter 4 (GLUT4) translocation [8]. A similar observation was also reported using captopril but not losartan, suggesting an indirect role for bradykinin in regulating glucose metabolism [28]. On the other hand, insulin-mediated GLUT4 translocation itself is also impaired in the muscle of diabetic, obese Zucker rats [29]. Recently, we have reported that bradykinin directly triggers translocation of GLUT4 in various tissues via an insulin-independent pathway [7]. Thus, the observed improvement of glucose metabolism by ACE inhibitors might be due to direct or indirect actions of increased endogenous bradykinin. Exercise has been demonstrated to increase the uptake of glucose into skeletal muscle [13,14] or into the whole body [17]. In the present study, exercise training also improved insulin resistance in OLETF rats. Increased translocation of GLUT4 by skeletal muscle cell membranes following exercise was reported in experiments with humans [30] and animals [31,32]. A study involving the use of rats showed that increased levels of GLUT4 induced by exercise did not decline during a five day period after the cessation of the exercise [33]. It was also reported that the signaling pathways related to the increased glucose uptake are different between insulin- and exercise- mediated stimulation [14,34], although insulinstimulated glucose uptake was observed to be increased after exercise [32]. This may explain the fact that exercise training increases the uptake of glucose even in persons with insulin resistance [14]. In the present study, treatment with the combination of ACE inhibitor and exercise training showed greater improvement in glucose metabolism than either treatment alone in the OLETF rats. The result is consistent with that of a recent study in which such combined treatment greatly improved diabetic conditions of obese Zucker rats [16]. However, factors mediating interactions between these two treatments are yet unknown. One mechanism of improved insulin resistance by exercise may be a decrease in abdominal fat tissues which largely produce or release a variety of antagonizing factors to insulin, such as FFAs [12]. In this regard, Steen et al. demonstrated, using Zucker rats, that exercise training significantly decreased the plasma level of FFAs, although this effect was not enhanced by the combined treatment with ACE inhibitor trandolapril [16]. Since we failed to observe any change in the
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plasma FFA level neither by exercise training nor by ACE inhibition, FFAs appear not to be directly involved in the synergistic effect of the combined treatment. Alternatively, several other factors could be mediators. Muscle contraction enhances the release of bradykinin [35], whereas exercise training has been reported to increase the level of bradykinin in plasma [36]. If it is so, the level of bradykinin which is increased by exercise training might be maintained by ACE inhibitors for a long time. On the other hand, muscle contraction also activates several enzymes in the cell signaling pathways, such as PKC [37] and AMPK [38,39], both of which have been considered to be involved in accelerated muscle glucose uptake during exercise [15]. In addition, the increase in the production of NO or in the proportion of nutritive capillary flow in muscle tissue during exercise contributes to increased glucose disposal from the circulation [17,40]. Whether these factors are involved in the effect of ACE inhibition alone or of that in combination with exercise training, however, has not been determined in this study. In conclusion, our results indicate that the combination of ACE inhibitor and exercise training would be an effective treatment for hypertensive states with insulin resistance. To understand this phenomenon more deeply, the precise mechanisms underlying such greatest improvement of insulin resistance need to be clarified in the future.
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