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Effects of low intensity exercise therapy on early phase insulin secretion in overweight subjects with impaired glucose tolerance and type 2 diabetes mellitus
diabetes research and clinical practice 82 (2008) 291–297
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journal homepage: www.elsevier.com/locate/diabres
Effects of low intensity exercise therapy on early phase insulin secretion in overweight subjects with impaired glucose tolerance and type 2 diabetes mellitus Ryoma Michishita a,*, Naoko Shono b,c, Takaki Kasahara a, Toshiyuki Tsuruta a a
Clinic of Tsuruta Orthopaedic Surgery, Saga, Japan Institute of Lifestyle Medical Science, Saga, Japan c Department of Cardiovascular and Renal Medicine, Saga University, Faculty of Medicine, Saga, Japan b
article info
abstract
Article history:
This study was designed to evaluate effects of exercise therapy on early phase insulin
Received 2 June 2008
secretion in overweight subjects with impaired glucose tolerance (IGT) and type 2 diabetes
Received in revised form
mellitus (DM). The subjects consisted of overweight subjects with normal glucose tolerance
11 August 2008
(NGT, n = 10), IGT (n = 10) and DM (n = 10) (age: 51.1 8.2, 56.3 8.8 and 58.5 6.2 years,
Accepted 14 August 2008
respectively). All of these patients performed exercise therapy at lactate threshold intensity
Published on line 14 October 2008
for 12 weeks. Before intervention, area under the glucose curve (AUCPG) was higher in DM,
Keywords:
secretion as calculated by insulinogenic index was higher in the NGT group than in either
Insulin secretion
the IGT or DM groups ( p < 0.05). After exercise therapy, the insulin sensitivity, AUCPG and
IGT and NGT groups, and area under the insulin curve (AUCIRI) and the early phase insulin
Insulin sensitivity
AUCIRI improved in three groups ( p < 0.05, respectively). The insulinogenic index increased
Exercise therapy
in IGT and DM groups ( p < 0.05, respectively), but the changes in the insulinogenic index
Impaired glucose tolerance
showed no significant differences between IGT and DM groups. These results suggest that
Type 2 diabetes mellitus
the ß-cell function in subjects with IGT and DM could therefore improve after exercise therapy. Moreover, AUCPG, AUCIRI and insulin sensitivity were also improved no relation to NGT, IGT and DM. # 2008 Elsevier Ireland Ltd. All rights reserved.
1.
Introduction
There is accumulating evidence that insulin response after an oral glucose load plays a pivotal role in the pathogenesis of various stages of type 2 diabetes mellitus (DM) [1,2]. Physical inactivity, unbalanced diet and aging induce visceral fat accumulation and reduction of the insulin sensitivity in liver and skeletal muscle. The decreased insulin sensitivity causes compensated hyperinsulinemia though the reduction in the control of the glucose production by secreted insulin from ßcell. Moreover, continuing reduction of insulin function induces
slow and excessive insulin secretion by irritation of postprandial hyperglycemia. Finally, long-term hyperglycemia and slow and excessive insulin secretion cause insulin secretion failure. Several studies [2–4] have observed that the level of insulin at 30 min after an oral glucose load is lower than normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and DM despite no significant differences in the total insulin concentration. One characteristic finding of early DM development is the reduction of early phase insulin secretion. On the other hand, there have been several studies [5–8] on the effect of exercise therapy for improving insulin sensitivity
* Corresponding author at: 174-8 Kamitogawa Ushizumachi, Saga 849-0305, Japan. Tel.: +81 952 51 5611; fax: +81 952 51 5432. E-mail address: [email protected] (R. Michishita). 0168-8227/$ – see front matter # 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2008.08.013
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diabetes research and clinical practice 82 (2008) 291–297
and early phase insulin secretion. However, at present, no difference in the effects of exercise therapy on early phase insulin secretion with regard to overweight subjects with NGT, IGT and DM has been elucidated. We therefore hypothesize that the effects of exercise therapy on glucose metabolism may differ between subjects with NGT, IGT and DM. This study was designed to clarify differences in the effects of the exercise therapy on the improvement in glucose metabolism in overweight subjects with NGT, IGT and DM.
2.
Materials and methods
2.1.
Subjects
The study enrolled 10 overweight subjects with NGT (2 men and 8 women: mean age, 51.1 8.2 years; mean body mass index (BMI), 29.7 4.2 kg/m2), 10 overweight subjects with IGT (2 men and 8 women, including 4 with an impaired fasting glucose: mean age, 56.3 8.8 years; BMI, 28.1 3.4 kg/m2) and 10 overweight subjects with DM (3 men and 7 women: mean age, 58.5 6.2 years; BMI, 30.2 2.2 kg/m2). NGT, IGT and DM were divided according to the criteria of Japan Diabetes Society (IGT, fasting glucose 110–125 mg/dl or 2-h glucose 140–199 mg/ dl; DM, fasting glucose 126 mg/dl or 2-h glucose 200 mg/dl) [9]. All of the IGT and DM subjects were newly diagnosed in our clinic, unfortunately, the period of prevalence in IGT and DM subjects before undergoing a medical examination in our clinic was unclear. Following recruitment, all these patients participated in an exercise therapy program. Any patients who were taking cardioactive drugs such as anti-hypertensive drugs, statins or hypoglycemic agents, or patients with a history of cerebrovascular disease, coronary artery disease, or diabetic complication (diabetic neuropathy, diabetic nephropathy and diabetic retinopathy) were excluded from the analysis because we focused on the effects of only exercise training without the influence of these medications. The local institutional review board approved the study protocol, and written informed consent was obtained from each patient prior to commencement of the study.
2.2.
Blood sampling and anthropometric measurements
Blood samples were collected early in the morning by venipuncture from an antecubital vein, after at least 12 h of fasting. The fasting blood samples were used to measure the following parameters: plasma glucose levels by enzymatic methods, serum insulin level by the enzyme immunoassay method, and hemoglobin A1c (HbA1c) by high performance liquid chromatography. Next, the 75 g oral glucose tolerance test (OGTT) was performed to analyze plasma glucose and serum insulin concentration. Blood samples were taken at 30, 60, 90 and 120 min after the administration of an oral glucose load. Plasma glucose and serum insulin levels were measured and the sums of the levels at fasting state, 30, 60, 90 and 120 min were calculated (area under the glucose curve (AUCPG) and area under the insulin curve (AUCIRI)). The insulin resistance was assessed using Matthews’s homeostasis model assessment (HOMA-IR) [10] based on the following formula: fasting glucose
(mg/dl) fasting insulin (mU/ml)/405. The capacity of early phase insulin secretion was determined by the insulinogenic index [11] and Matthews’s homeostasis model assessment (HOMA-ß cell) by the following formula: insulinogenic index = plasma glucose at 30 min after the administration of an oral glucose load fasting glucose/serum insulin at 30 min after the administration of an oral glucose load fasting insulin, and HOMA-ß cell = 360 fasting insulin/fasting glucose 63. The insulin sensitivity index was calculated using the method of Matsuda and DeFronzo [12] based on the following formula: insulin sensitivity index = 10,000/square root of (fasting glucose fasting insulin) (mean glucose mean insulin during OGTT). Obesity, hypertension, IGT or DM and dyslipidemia were defined as coronary risk factors, and the total number of risk factors was also calculated for each subject. The BMI was calculated as the ratio of body weight (kg) to height squared (m2). Waist circumference was measured at the level of umbilicus.
2.3.
Exercise test
A multistage graded submaximal exercise test was performed on each subject using an electric bicycle ergometer. The workload was increased every 4 min, depending on their daily activity levels. A CM5-lead ECG (ML-1800, Fukuda Denshi, Tokyo, Japan) was recorded continuously during exercise testing. The following parameters were measured at rest and during the last 1 min of each stage: the rate of perceived exhaustion, blood pressure (FB-300, Fukuda Denshi, Tokyo, Japan), and blood lactate concentration (Lactate Pro, Arkray, Kyoto, Japan). The workload at the first breaking point of the blood lactate level was used to determine the lactate threshold (LT). When no clear LT could be obtained, then the LT was determined by the method of Beaver et al. [13]. The workload at LT adjusted for the body weight was as the index for the relative intensity because the workload on the bicycle ergometer was supposed to be influenced by the body weight (LT (W)/body weight). Maximal ˙ 2 max) was estimated by the nomogram of oxygen uptake (VO ˚ trand and Ryhming [14] using the heart rate measured at three A different submaximal workloads. The end point of exercise testing was determined based on either achieving a blood lactate concentration 4 mmol/l or the criteria described in the guidelines of the American College of Sports Medicine [15].
2.4.
Exercise therapy
The exercise therapy using electric bicycle ergometer at the LT level was carried out for 30–60 min per day, 1–6 times per week for 12 weeks. We recommended patients to try to exercise for 180 min per week as a target exercise volume. The exercise training protocol was performed within the possible limits (duration and frequency) for each subject. The exercise volume was evaluated by the averaged total exercise duration per week. All of the subjects were instructed to maintain consistent daily activity and eating styles during the period of exercise therapy.
2.5.
Statistical analysis
The data were expressed as the means S.D. The statistical analyses were performed using the StatView 5.0 software
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diabetes research and clinical practice 82 (2008) 291–297
Table 1 – Comparison of the patients’ characteristics before and after 12 weeks exercise therapy in overweight subjects with normal glucose tolerance, impaired glucose tolerance and type 2 diabetes mellitus NGT group (n = 10)
Age (years) Sex (men/women) Smoking habit (yes/no) Drinking habit (yes/no) Dyslipidemia (yes/no) Hypertension (yes/no) Number of the coronary risk factors BMI (kg/m2) Waist circumference (cm) ˙ 2 max/LBM (ml/kg/min) Estimated VO LT (W)/body weight Exercise duration per week (min/week)
IGT group (n = 10)
DM group (n = 10)
Before
After
Before
After
Before
51.1 8.2 2/8 1/9 1/9 3/7 0/10 1.5 0.7 29.7 4.2 94.4 10.2 44.3 4.4 0.61 0.16 –
– – – – – – – 29.0 3.4 91.0 8.1* 45.7 5.7 0.89 0.26* 158.9 72.5
56.3 8.8 2/8 0/10 2/8 7/3 7/3y 2.2 1.3 28.1 3.4 90.4 7.7 39.4 3.0 0.59 0.13 –
– – – – – – – 27.4 2.9 86.1 7.0* 41.3 5.1 0.84 0.20* 166.0 98.4
58.5 6.2 3/7 0/10 3/7 6/4 8/2y 3.0 0.8y 30.2 2.2 98.8 5.6 39.4 3.0y 0.53 0.19 –
After – – – – – – – 29.7 2.3 96.1 6.3* 41.3 5.1 0.76 0.24* 165.1 77.1
Data are expressed as mean S.D. yp < 0.05, compared with NGT group before exercise therapy. *p < 0.05,comparison to before the exercise therapy in each groups. NGT, normal glucose tolerance; IGT, impaired glucose tolerance; DM, type 2 diabetes mellitus; BMI, body mass index; ˙ 2 max, maximal oxygen uptake; LBM, lean body mass; LT, lactate threshold. VO Obesity, hypertension, impaired glucose tolerance or type 2 diabetes mellitus and dyslipidemia were defined as coronary risk factors, and the total number of risk factors was also calculated for each subject.
package. The inter-multiple group relationships were determined using a repeated measure analysis of variance (ANOVA). Pearson’s simple regression analysis was performed to determine the association between the changes in glucose metabolism indices and exercise duration per week. The percent changes were expressed as follows: (values after exercise therapy baseline values before exercise therapy)/ baseline values before exercise therapy 100. A probability value of <0.05 was considered to be statistically significant.
3.
Results
Tables 1 and 2 show comparisons of the patients’ characteristics before and after 12 weeks exercise therapy in overweight subjects with NGT, IGT and DM. There were no significant
differences in the age, sex, smoking habit, drinking habit and exercise duration per week among NGT, IGT and DM groups (158.9 72.5, 166.0 98.4, 165.1 77.1 min, respectively). The prevalence of hypertension was significantly higher in IGT and DM groups than in NGT group ( p < 0.05). Number of the coronary risk factors was significantly higher and estimated ˙ 2 max/LBM was significantly lower in DM group than in NGT VO group ( p < 0.05). HbA1c, fasting glucose, 2-h glucose and AUCPG were significantly higher and insulin sensitivity was significantly lower in DM group than in IGT and NGT groups ( p < 0.05). Fasting insulin, AUCIRI and insulinogenic index were significantly lower in DM group than in NGT group ( p < 0.05). HOMA-IR was significantly higher in the NGT and DM groups than in the IGT group ( p < 0.05). HOMA-ß cell was significantly lower in the IGT and DM groups than in the NGT group ( p < 0.05).
Table 2 – Comparison of glucose metabolism indices before and after 12 weeks exercise therapy in overweight subjects with normal glucose tolerance, impaired glucose tolerance and type 2 diabetes mellitus NGT group (n = 10) Before HbA1c (%) Fasting glucose (mg/dl) 2-h glucose (mg/dl) AUCPG (mg/dl) Fasting insulin (mU/ml) AUCIRI (mU/ml) HOMA-IR HOMA-ß cell (%) Insulinogenic index Insulin sensitivity index
5.2 0.4 94.7 7.9 120.1 14.3 629.8 73.0 17.8 10.5 447.6 192.0 4.24 2.74ô 203.1 112.4 2.13 1.44 3.15 1.53
After 5.2 0.3 94.2 8.5 106.4 16.3* 570.7 78.6* 14.2 8.2* 342.7 79.8* 3.41 2.30* 169.0 86.5 1.96 0.93 3.93 1.75*
IGT group (n = 10) Before 5.5 0.3 102.8 13.6 161.2 19.5y 787.2 89.8y 14.4 7.3 319.6 94.3 2.24 1.07 91.0 55.3y 0.54 0.24y 3.59 1.14
After 5.3 0.4 98.0 12.1 127.8 31.8* 669.0 120.9* 13.0 7.4 281.4 77.7* 1.89 1.36 90.6 58.6 0.99 0.37* 4.79 1.56*
DM group (n = 10) Before y,ô
6.8 0.4 129.9 11.8y,ô 208.7 43.1y,ô 993.4 148.1y,ô 8.8 3.6y 247.1 81.5y 4.47 2.10ô 84.5 51.3y 0.44 0.22y 2.34 1.75y,ô
After 6.5 0.3 118.6 9.3* 157.2 47.1* 837.0 140.0* 7.8 5.1 209.6 44.9 3.82 2.26 85.9 44.9 0.93 0.45* 3.08 1.29*
Data are expressed as mean S.D. yp < 0.05, compared with NGT group before exercise therapy. ôp < 0.05, comparison to IGT group before exercise therapy. *p < 0.05, compared with before the exercise therapy in each groups. NGT, normal glucose tolerance; IGT, impaired glucose tolerance; DM, type 2 diabetes mellitus; HbA1c, hemoglobin A1c; AUCPG, area under the glucose curve; AUCIRI, area under the insulin curve; HOMA-IR and HOMA-ß cell, insulin resistance and insulin secretion indices by homeostasis model assessment.
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diabetes research and clinical practice 82 (2008) 291–297
Fig. 1 – Plasma glucose responses fasting and after the administration of an oral glucose load before and after 12 weeks exercise therapy in overweight subjects with NGT, IGT and DM groups. Data are expressed as the mean W S.D. yp < 0.05, in compared with NGT group. ôp < 0.05, in compared with IGT group. *p < 0.05, in comparison to before the exercise therapy in each groups.
Figs. 1 and 2 show the plasma glucose and serum insulin responses after fasting and after the administration of an oral glucose load before and after 12 weeks exercise therapy in NGT, IGT and DM groups. Plasma glucose after the administration of an oral glucose load was higher in DM, IGT and NGT (DM > IGT > NGT), and serum insulin after the administration of an oral glucose load was higher in NGT, IGT and DM (NGT > IGT > DM, p < 0.05, respectively). After 12 weeks of exercise therapy, fasting glucose decreased in only DM group ( p < 0.05). Waist circumference, 2-h glucose, AUCPG, insulin sensitivity index and LT (W)/body weight improved in all of the groups ( p < 0.05, respectively). AUCIRI decreased in NGT and IGT groups ( p < 0.05, respectively). Insulinogenic index increased in IGT and DM groups ( p < 0.05, respectively). Fig. 3 shows comparisons of the percent changes in glucose metabolism indices in NGT, IGT and DM groups. There were no significant differences in the changes in AUCPG, AUCIRI, and insulin sensitivity index among three groups. The change in insulinogenic index showed a significantly greater increase in
IGT and DM groups than in NGT group ( p < 0.05), but no significant differences between IGT and DM groups. In addition, the association between the improvement in the glucose metabolism indices and the exercise duration per week was investigated (Table 3). In the NGT group, the exercise duration per week was negatively correlated with the changes in AUCIRI (r = 0.790, p < 0.01), and positively with the changes in the insulin sensitivity index (r = 0.652, p < 0.05). In IGT group, exercise duration was negatively associated with the changes in 2-h glucose (r = 0.634, p < 0.05), AUCPG (r = 0.691, p < 0.05), and positively with the changes in the insulin sensitivity index (r = 0.634, p < 0.05). In DM group, exercise duration was positively correlated with the changes in insulinogenic index (r = 0.661, p < 0.05). Moreover, in the IGT group combined with the DM group, the exercise duration per week was negatively related to the changes in 2-h glucose (r = 0.455, p < 0.05) and AUCPG (r = 0.560, p < 0.05), and positively with the changes in insulinogenic index (r = 0.451, p < 0.05) and the insulin sensitivity index (r = 0.450, p < 0.05).
Fig. 2 – Serum insulin responses fasting and after the administration of an oral glucose load before and after 12 weeks exercise therapy in overweight subjects with NGT, IGT and DM groups. Data are expressed as the mean W S.D. yp < 0.05, in compared with NGT group. *p < 0.05, in comparison to before the exercise therapy in each groups.
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Fig. 3 – Comparison of the changes in the glucose metabolism indices by low intensity exercise therapy in overweight subjects with NGT, IGT and DM groups. Data are expressed as the mean W S.D. The percent changes were expressed as follows: (values after exercise therapy S baseline values before exercise therapy)/baseline values before exercise therapy T 100. *p < 0.05, in comparison to the NGT group.
4.
Discussion
The major finding of this study was that the insulinogenic index in overweight subjects with IGT and DM could improve after low intensity exercise therapy. In addition, the change in the insulinogenic index correlated with exercise duration per week in the IGT group combined with the DM groups. There have been several studies [5–8] performed to elucidate the effect of exercise therapy for improving insulin sensitivity and early phase insulin secretion. Oshida et al. [5] demonstrated
that insulin sensitivity by long-term mild jogging increased ˙ 2 max and BMI. Dela et al. [7] observed despite no changes in VO that the increment of early phase insulin secretion by exercise training does not require changes in insulin sensitivity and HbA1c in patients with DM. However, at present, the effects of improvement in the serum insulin response after glucose load by exercise therapy with regard to the difference in overweight subjects with NGT, IGT and DM have yet to be elucidated. Moreover, the relationship between the improvement in the ß-cell function and exercise duration per week is still
Table 3 – Association between the changes in glucose metabolism indices and exercise duration per week calculated by simple regression analysis
HbA1c (%) Fasting glucose (%) 2-h glucose (%) AUCPG (%) Fasting insulin (%) AUCIRI (%) HOMA-IR (%) HOMA-ß cell (%) Insulinogenic index (%) Insulin sensitivity index (%)
NGT group
IGT group
DM group
0.363 0.302 0.160 0.205 0.228 0.790* 0.282 0.042 0.629 0.652y
0.196 0.065 0.634y 0.691y 0.279 0.467 0.241 0.169 0.365 0.634y
0.103 0.198 0.195 0.308 0.081 0.133 0.039 0.178 0.661y 0.079
Data are expressed as a regression coefficient. yp < 0.05, *p < 0.01. Abbreviations as shown in Table 2.
IGT + DM group 0.044 0.029 0.455y 0.560y 0.156 0.280 0.161 0.055 0.451y 0.450y
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diabetes research and clinical practice 82 (2008) 291–297
unknown though it has been observed that insulin sensitivity increased depending on the exercise volume and intensity [16]. Therefore, our results may suggest that the insulin secretion improved depending on the exercise volume in overweight subjects with IGT and DM. As a result, although the AUCPG, AUCIRI and insulin sensitivity index improved in three groups, there were no significant differences of the changes in these parameters in three groups. In addition, the insulinogenic index increased in only IGT and DM groups, but the percent change in the insulinogenic index showed no significant differences between IGT and DM groups. Although the waist circumference and LT (W)/body weight improved in this study, there ˙ 2 were no significant changes in HbA1c, BMI and estimated VO max in all of the groups. Therefore, our results suggest that the improvement in the insulin sensitivity and AUCIRI by low intensity exercise therapy demonstrated no relationship to the NGT, IGT and DM and improvement in the HbA1c, BMI and ˙ 2 max. Moreover, the major differences in the characteristic VO of the effects of low intensity exercise therapy in three groups were the changes in early phase insulin secretion. The Diabetes Prevention Program (DPP) Research Group [17] demonstrated that a change in lifestyle could reduce the incidence of DM, while also improving the insulin sensitivity and insulin secretion in comparison to the metformin in Caucasian populations. It is well known that the Japanese population shows a lower insulin secretion in comparison to other ethnic groups. However, regardless of a small number of subjects in our data in comparison to the DPP, the results of DPP and our data were similar. Namely, from several studies, the effects of low intensity exercise therapy on the process of improvement in the serum insulin response after glucose load were different depending upon the insulin secretion pattern and total exercise volume during exercise period, while showing no relationship to ethnic groups. In the present study, the prevalence of hypertension and number of the coronary risk factors were significantly higher in the IGT and DM groups than in the NGT group before exercise therapy. Fkukuda-Akita et al. [18] demonstrated the insulinogenic index to be lower in the non-metabolic syndrome subjects in comparison to the metabolic syndrome subjects. It has been postulated that hyperinsulinemia might be an etiologic cause of obesity, hypertension, DM and arteriosclerosis [19]. The common association of obesity, hypertension, DM and arteriosclerosis has been thought to be attributable to hyperinsulinemia and insulin resistance. Therefore, as a result, ß-cell dysfunction was thus considered to be associated with long-term hyperinsulinemia and insulin resistance may also induce the accumulation of other coronary risk factors.
4.1.
Study limitation and clinical implication
There are several limitations in this study. First, a small number of subjects, predominately middle-aged females, comprised the study subjects. Second, the insulin sensitivity index and insulinogenic index were evaluated using less sensitive indices than a euglycemic hyperinsulinemic clamp ˙ 2 max in our and minimal model technique. Third, the VO ˚ strand and study was estimated using the nomogram of A
Ryhming. And finally, there is the possibility that the subjects had an unconscious reduction of caloric intake and increased daily activity even though they were instructed to maintain their daily activity excluding exercise therapy. However, this study is first report to evaluate the improvement in the serum insulin after glucose load by exercise therapy with regard to the difference in overweight subjects with NGT, IGT and DM. Therefore, the present study may help to demonstrate that low intensity exercise therapy without the use of hypoglycemic agents, may possibly improve the ß-cell function in subjects with IGT and DM.
Notice of grant support This study was supported in part by a grant from the Japanese Ministry of Education, Culture, Sports, Science and Technology (No. 16500445).
Conflict of Interest None.
references
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available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/diabres
Effects of low intensity exercise therapy on early phase insulin secretion in overweight subjects with impaired glucose tolerance and type 2 diabetes mellitus Ryoma Michishita a,*, Naoko Shono b,c, Takaki Kasahara a, Toshiyuki Tsuruta a a
Clinic of Tsuruta Orthopaedic Surgery, Saga, Japan Institute of Lifestyle Medical Science, Saga, Japan c Department of Cardiovascular and Renal Medicine, Saga University, Faculty of Medicine, Saga, Japan b
article info
abstract
Article history:
This study was designed to evaluate effects of exercise therapy on early phase insulin
Received 2 June 2008
secretion in overweight subjects with impaired glucose tolerance (IGT) and type 2 diabetes
Received in revised form
mellitus (DM). The subjects consisted of overweight subjects with normal glucose tolerance
11 August 2008
(NGT, n = 10), IGT (n = 10) and DM (n = 10) (age: 51.1 8.2, 56.3 8.8 and 58.5 6.2 years,
Accepted 14 August 2008
respectively). All of these patients performed exercise therapy at lactate threshold intensity
Published on line 14 October 2008
for 12 weeks. Before intervention, area under the glucose curve (AUCPG) was higher in DM,
Keywords:
secretion as calculated by insulinogenic index was higher in the NGT group than in either
Insulin secretion
the IGT or DM groups ( p < 0.05). After exercise therapy, the insulin sensitivity, AUCPG and
IGT and NGT groups, and area under the insulin curve (AUCIRI) and the early phase insulin
Insulin sensitivity
AUCIRI improved in three groups ( p < 0.05, respectively). The insulinogenic index increased
Exercise therapy
in IGT and DM groups ( p < 0.05, respectively), but the changes in the insulinogenic index
Impaired glucose tolerance
showed no significant differences between IGT and DM groups. These results suggest that
Type 2 diabetes mellitus
the ß-cell function in subjects with IGT and DM could therefore improve after exercise therapy. Moreover, AUCPG, AUCIRI and insulin sensitivity were also improved no relation to NGT, IGT and DM. # 2008 Elsevier Ireland Ltd. All rights reserved.
1.
Introduction
There is accumulating evidence that insulin response after an oral glucose load plays a pivotal role in the pathogenesis of various stages of type 2 diabetes mellitus (DM) [1,2]. Physical inactivity, unbalanced diet and aging induce visceral fat accumulation and reduction of the insulin sensitivity in liver and skeletal muscle. The decreased insulin sensitivity causes compensated hyperinsulinemia though the reduction in the control of the glucose production by secreted insulin from ßcell. Moreover, continuing reduction of insulin function induces
slow and excessive insulin secretion by irritation of postprandial hyperglycemia. Finally, long-term hyperglycemia and slow and excessive insulin secretion cause insulin secretion failure. Several studies [2–4] have observed that the level of insulin at 30 min after an oral glucose load is lower than normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and DM despite no significant differences in the total insulin concentration. One characteristic finding of early DM development is the reduction of early phase insulin secretion. On the other hand, there have been several studies [5–8] on the effect of exercise therapy for improving insulin sensitivity
* Corresponding author at: 174-8 Kamitogawa Ushizumachi, Saga 849-0305, Japan. Tel.: +81 952 51 5611; fax: +81 952 51 5432. E-mail address: [email protected] (R. Michishita). 0168-8227/$ – see front matter # 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2008.08.013
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and early phase insulin secretion. However, at present, no difference in the effects of exercise therapy on early phase insulin secretion with regard to overweight subjects with NGT, IGT and DM has been elucidated. We therefore hypothesize that the effects of exercise therapy on glucose metabolism may differ between subjects with NGT, IGT and DM. This study was designed to clarify differences in the effects of the exercise therapy on the improvement in glucose metabolism in overweight subjects with NGT, IGT and DM.
2.
Materials and methods
2.1.
Subjects
The study enrolled 10 overweight subjects with NGT (2 men and 8 women: mean age, 51.1 8.2 years; mean body mass index (BMI), 29.7 4.2 kg/m2), 10 overweight subjects with IGT (2 men and 8 women, including 4 with an impaired fasting glucose: mean age, 56.3 8.8 years; BMI, 28.1 3.4 kg/m2) and 10 overweight subjects with DM (3 men and 7 women: mean age, 58.5 6.2 years; BMI, 30.2 2.2 kg/m2). NGT, IGT and DM were divided according to the criteria of Japan Diabetes Society (IGT, fasting glucose 110–125 mg/dl or 2-h glucose 140–199 mg/ dl; DM, fasting glucose 126 mg/dl or 2-h glucose 200 mg/dl) [9]. All of the IGT and DM subjects were newly diagnosed in our clinic, unfortunately, the period of prevalence in IGT and DM subjects before undergoing a medical examination in our clinic was unclear. Following recruitment, all these patients participated in an exercise therapy program. Any patients who were taking cardioactive drugs such as anti-hypertensive drugs, statins or hypoglycemic agents, or patients with a history of cerebrovascular disease, coronary artery disease, or diabetic complication (diabetic neuropathy, diabetic nephropathy and diabetic retinopathy) were excluded from the analysis because we focused on the effects of only exercise training without the influence of these medications. The local institutional review board approved the study protocol, and written informed consent was obtained from each patient prior to commencement of the study.
2.2.
Blood sampling and anthropometric measurements
Blood samples were collected early in the morning by venipuncture from an antecubital vein, after at least 12 h of fasting. The fasting blood samples were used to measure the following parameters: plasma glucose levels by enzymatic methods, serum insulin level by the enzyme immunoassay method, and hemoglobin A1c (HbA1c) by high performance liquid chromatography. Next, the 75 g oral glucose tolerance test (OGTT) was performed to analyze plasma glucose and serum insulin concentration. Blood samples were taken at 30, 60, 90 and 120 min after the administration of an oral glucose load. Plasma glucose and serum insulin levels were measured and the sums of the levels at fasting state, 30, 60, 90 and 120 min were calculated (area under the glucose curve (AUCPG) and area under the insulin curve (AUCIRI)). The insulin resistance was assessed using Matthews’s homeostasis model assessment (HOMA-IR) [10] based on the following formula: fasting glucose
(mg/dl) fasting insulin (mU/ml)/405. The capacity of early phase insulin secretion was determined by the insulinogenic index [11] and Matthews’s homeostasis model assessment (HOMA-ß cell) by the following formula: insulinogenic index = plasma glucose at 30 min after the administration of an oral glucose load fasting glucose/serum insulin at 30 min after the administration of an oral glucose load fasting insulin, and HOMA-ß cell = 360 fasting insulin/fasting glucose 63. The insulin sensitivity index was calculated using the method of Matsuda and DeFronzo [12] based on the following formula: insulin sensitivity index = 10,000/square root of (fasting glucose fasting insulin) (mean glucose mean insulin during OGTT). Obesity, hypertension, IGT or DM and dyslipidemia were defined as coronary risk factors, and the total number of risk factors was also calculated for each subject. The BMI was calculated as the ratio of body weight (kg) to height squared (m2). Waist circumference was measured at the level of umbilicus.
2.3.
Exercise test
A multistage graded submaximal exercise test was performed on each subject using an electric bicycle ergometer. The workload was increased every 4 min, depending on their daily activity levels. A CM5-lead ECG (ML-1800, Fukuda Denshi, Tokyo, Japan) was recorded continuously during exercise testing. The following parameters were measured at rest and during the last 1 min of each stage: the rate of perceived exhaustion, blood pressure (FB-300, Fukuda Denshi, Tokyo, Japan), and blood lactate concentration (Lactate Pro, Arkray, Kyoto, Japan). The workload at the first breaking point of the blood lactate level was used to determine the lactate threshold (LT). When no clear LT could be obtained, then the LT was determined by the method of Beaver et al. [13]. The workload at LT adjusted for the body weight was as the index for the relative intensity because the workload on the bicycle ergometer was supposed to be influenced by the body weight (LT (W)/body weight). Maximal ˙ 2 max) was estimated by the nomogram of oxygen uptake (VO ˚ trand and Ryhming [14] using the heart rate measured at three A different submaximal workloads. The end point of exercise testing was determined based on either achieving a blood lactate concentration 4 mmol/l or the criteria described in the guidelines of the American College of Sports Medicine [15].
2.4.
Exercise therapy
The exercise therapy using electric bicycle ergometer at the LT level was carried out for 30–60 min per day, 1–6 times per week for 12 weeks. We recommended patients to try to exercise for 180 min per week as a target exercise volume. The exercise training protocol was performed within the possible limits (duration and frequency) for each subject. The exercise volume was evaluated by the averaged total exercise duration per week. All of the subjects were instructed to maintain consistent daily activity and eating styles during the period of exercise therapy.
2.5.
Statistical analysis
The data were expressed as the means S.D. The statistical analyses were performed using the StatView 5.0 software
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Table 1 – Comparison of the patients’ characteristics before and after 12 weeks exercise therapy in overweight subjects with normal glucose tolerance, impaired glucose tolerance and type 2 diabetes mellitus NGT group (n = 10)
Age (years) Sex (men/women) Smoking habit (yes/no) Drinking habit (yes/no) Dyslipidemia (yes/no) Hypertension (yes/no) Number of the coronary risk factors BMI (kg/m2) Waist circumference (cm) ˙ 2 max/LBM (ml/kg/min) Estimated VO LT (W)/body weight Exercise duration per week (min/week)
IGT group (n = 10)
DM group (n = 10)
Before
After
Before
After
Before
51.1 8.2 2/8 1/9 1/9 3/7 0/10 1.5 0.7 29.7 4.2 94.4 10.2 44.3 4.4 0.61 0.16 –
– – – – – – – 29.0 3.4 91.0 8.1* 45.7 5.7 0.89 0.26* 158.9 72.5
56.3 8.8 2/8 0/10 2/8 7/3 7/3y 2.2 1.3 28.1 3.4 90.4 7.7 39.4 3.0 0.59 0.13 –
– – – – – – – 27.4 2.9 86.1 7.0* 41.3 5.1 0.84 0.20* 166.0 98.4
58.5 6.2 3/7 0/10 3/7 6/4 8/2y 3.0 0.8y 30.2 2.2 98.8 5.6 39.4 3.0y 0.53 0.19 –
After – – – – – – – 29.7 2.3 96.1 6.3* 41.3 5.1 0.76 0.24* 165.1 77.1
Data are expressed as mean S.D. yp < 0.05, compared with NGT group before exercise therapy. *p < 0.05,comparison to before the exercise therapy in each groups. NGT, normal glucose tolerance; IGT, impaired glucose tolerance; DM, type 2 diabetes mellitus; BMI, body mass index; ˙ 2 max, maximal oxygen uptake; LBM, lean body mass; LT, lactate threshold. VO Obesity, hypertension, impaired glucose tolerance or type 2 diabetes mellitus and dyslipidemia were defined as coronary risk factors, and the total number of risk factors was also calculated for each subject.
package. The inter-multiple group relationships were determined using a repeated measure analysis of variance (ANOVA). Pearson’s simple regression analysis was performed to determine the association between the changes in glucose metabolism indices and exercise duration per week. The percent changes were expressed as follows: (values after exercise therapy baseline values before exercise therapy)/ baseline values before exercise therapy 100. A probability value of <0.05 was considered to be statistically significant.
3.
Results
Tables 1 and 2 show comparisons of the patients’ characteristics before and after 12 weeks exercise therapy in overweight subjects with NGT, IGT and DM. There were no significant
differences in the age, sex, smoking habit, drinking habit and exercise duration per week among NGT, IGT and DM groups (158.9 72.5, 166.0 98.4, 165.1 77.1 min, respectively). The prevalence of hypertension was significantly higher in IGT and DM groups than in NGT group ( p < 0.05). Number of the coronary risk factors was significantly higher and estimated ˙ 2 max/LBM was significantly lower in DM group than in NGT VO group ( p < 0.05). HbA1c, fasting glucose, 2-h glucose and AUCPG were significantly higher and insulin sensitivity was significantly lower in DM group than in IGT and NGT groups ( p < 0.05). Fasting insulin, AUCIRI and insulinogenic index were significantly lower in DM group than in NGT group ( p < 0.05). HOMA-IR was significantly higher in the NGT and DM groups than in the IGT group ( p < 0.05). HOMA-ß cell was significantly lower in the IGT and DM groups than in the NGT group ( p < 0.05).
Table 2 – Comparison of glucose metabolism indices before and after 12 weeks exercise therapy in overweight subjects with normal glucose tolerance, impaired glucose tolerance and type 2 diabetes mellitus NGT group (n = 10) Before HbA1c (%) Fasting glucose (mg/dl) 2-h glucose (mg/dl) AUCPG (mg/dl) Fasting insulin (mU/ml) AUCIRI (mU/ml) HOMA-IR HOMA-ß cell (%) Insulinogenic index Insulin sensitivity index
5.2 0.4 94.7 7.9 120.1 14.3 629.8 73.0 17.8 10.5 447.6 192.0 4.24 2.74ô 203.1 112.4 2.13 1.44 3.15 1.53
After 5.2 0.3 94.2 8.5 106.4 16.3* 570.7 78.6* 14.2 8.2* 342.7 79.8* 3.41 2.30* 169.0 86.5 1.96 0.93 3.93 1.75*
IGT group (n = 10) Before 5.5 0.3 102.8 13.6 161.2 19.5y 787.2 89.8y 14.4 7.3 319.6 94.3 2.24 1.07 91.0 55.3y 0.54 0.24y 3.59 1.14
After 5.3 0.4 98.0 12.1 127.8 31.8* 669.0 120.9* 13.0 7.4 281.4 77.7* 1.89 1.36 90.6 58.6 0.99 0.37* 4.79 1.56*
DM group (n = 10) Before y,ô
6.8 0.4 129.9 11.8y,ô 208.7 43.1y,ô 993.4 148.1y,ô 8.8 3.6y 247.1 81.5y 4.47 2.10ô 84.5 51.3y 0.44 0.22y 2.34 1.75y,ô
After 6.5 0.3 118.6 9.3* 157.2 47.1* 837.0 140.0* 7.8 5.1 209.6 44.9 3.82 2.26 85.9 44.9 0.93 0.45* 3.08 1.29*
Data are expressed as mean S.D. yp < 0.05, compared with NGT group before exercise therapy. ôp < 0.05, comparison to IGT group before exercise therapy. *p < 0.05, compared with before the exercise therapy in each groups. NGT, normal glucose tolerance; IGT, impaired glucose tolerance; DM, type 2 diabetes mellitus; HbA1c, hemoglobin A1c; AUCPG, area under the glucose curve; AUCIRI, area under the insulin curve; HOMA-IR and HOMA-ß cell, insulin resistance and insulin secretion indices by homeostasis model assessment.
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Fig. 1 – Plasma glucose responses fasting and after the administration of an oral glucose load before and after 12 weeks exercise therapy in overweight subjects with NGT, IGT and DM groups. Data are expressed as the mean W S.D. yp < 0.05, in compared with NGT group. ôp < 0.05, in compared with IGT group. *p < 0.05, in comparison to before the exercise therapy in each groups.
Figs. 1 and 2 show the plasma glucose and serum insulin responses after fasting and after the administration of an oral glucose load before and after 12 weeks exercise therapy in NGT, IGT and DM groups. Plasma glucose after the administration of an oral glucose load was higher in DM, IGT and NGT (DM > IGT > NGT), and serum insulin after the administration of an oral glucose load was higher in NGT, IGT and DM (NGT > IGT > DM, p < 0.05, respectively). After 12 weeks of exercise therapy, fasting glucose decreased in only DM group ( p < 0.05). Waist circumference, 2-h glucose, AUCPG, insulin sensitivity index and LT (W)/body weight improved in all of the groups ( p < 0.05, respectively). AUCIRI decreased in NGT and IGT groups ( p < 0.05, respectively). Insulinogenic index increased in IGT and DM groups ( p < 0.05, respectively). Fig. 3 shows comparisons of the percent changes in glucose metabolism indices in NGT, IGT and DM groups. There were no significant differences in the changes in AUCPG, AUCIRI, and insulin sensitivity index among three groups. The change in insulinogenic index showed a significantly greater increase in
IGT and DM groups than in NGT group ( p < 0.05), but no significant differences between IGT and DM groups. In addition, the association between the improvement in the glucose metabolism indices and the exercise duration per week was investigated (Table 3). In the NGT group, the exercise duration per week was negatively correlated with the changes in AUCIRI (r = 0.790, p < 0.01), and positively with the changes in the insulin sensitivity index (r = 0.652, p < 0.05). In IGT group, exercise duration was negatively associated with the changes in 2-h glucose (r = 0.634, p < 0.05), AUCPG (r = 0.691, p < 0.05), and positively with the changes in the insulin sensitivity index (r = 0.634, p < 0.05). In DM group, exercise duration was positively correlated with the changes in insulinogenic index (r = 0.661, p < 0.05). Moreover, in the IGT group combined with the DM group, the exercise duration per week was negatively related to the changes in 2-h glucose (r = 0.455, p < 0.05) and AUCPG (r = 0.560, p < 0.05), and positively with the changes in insulinogenic index (r = 0.451, p < 0.05) and the insulin sensitivity index (r = 0.450, p < 0.05).
Fig. 2 – Serum insulin responses fasting and after the administration of an oral glucose load before and after 12 weeks exercise therapy in overweight subjects with NGT, IGT and DM groups. Data are expressed as the mean W S.D. yp < 0.05, in compared with NGT group. *p < 0.05, in comparison to before the exercise therapy in each groups.
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Fig. 3 – Comparison of the changes in the glucose metabolism indices by low intensity exercise therapy in overweight subjects with NGT, IGT and DM groups. Data are expressed as the mean W S.D. The percent changes were expressed as follows: (values after exercise therapy S baseline values before exercise therapy)/baseline values before exercise therapy T 100. *p < 0.05, in comparison to the NGT group.
4.
Discussion
The major finding of this study was that the insulinogenic index in overweight subjects with IGT and DM could improve after low intensity exercise therapy. In addition, the change in the insulinogenic index correlated with exercise duration per week in the IGT group combined with the DM groups. There have been several studies [5–8] performed to elucidate the effect of exercise therapy for improving insulin sensitivity and early phase insulin secretion. Oshida et al. [5] demonstrated
that insulin sensitivity by long-term mild jogging increased ˙ 2 max and BMI. Dela et al. [7] observed despite no changes in VO that the increment of early phase insulin secretion by exercise training does not require changes in insulin sensitivity and HbA1c in patients with DM. However, at present, the effects of improvement in the serum insulin response after glucose load by exercise therapy with regard to the difference in overweight subjects with NGT, IGT and DM have yet to be elucidated. Moreover, the relationship between the improvement in the ß-cell function and exercise duration per week is still
Table 3 – Association between the changes in glucose metabolism indices and exercise duration per week calculated by simple regression analysis
HbA1c (%) Fasting glucose (%) 2-h glucose (%) AUCPG (%) Fasting insulin (%) AUCIRI (%) HOMA-IR (%) HOMA-ß cell (%) Insulinogenic index (%) Insulin sensitivity index (%)
NGT group
IGT group
DM group
0.363 0.302 0.160 0.205 0.228 0.790* 0.282 0.042 0.629 0.652y
0.196 0.065 0.634y 0.691y 0.279 0.467 0.241 0.169 0.365 0.634y
0.103 0.198 0.195 0.308 0.081 0.133 0.039 0.178 0.661y 0.079
Data are expressed as a regression coefficient. yp < 0.05, *p < 0.01. Abbreviations as shown in Table 2.
IGT + DM group 0.044 0.029 0.455y 0.560y 0.156 0.280 0.161 0.055 0.451y 0.450y
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unknown though it has been observed that insulin sensitivity increased depending on the exercise volume and intensity [16]. Therefore, our results may suggest that the insulin secretion improved depending on the exercise volume in overweight subjects with IGT and DM. As a result, although the AUCPG, AUCIRI and insulin sensitivity index improved in three groups, there were no significant differences of the changes in these parameters in three groups. In addition, the insulinogenic index increased in only IGT and DM groups, but the percent change in the insulinogenic index showed no significant differences between IGT and DM groups. Although the waist circumference and LT (W)/body weight improved in this study, there ˙ 2 were no significant changes in HbA1c, BMI and estimated VO max in all of the groups. Therefore, our results suggest that the improvement in the insulin sensitivity and AUCIRI by low intensity exercise therapy demonstrated no relationship to the NGT, IGT and DM and improvement in the HbA1c, BMI and ˙ 2 max. Moreover, the major differences in the characteristic VO of the effects of low intensity exercise therapy in three groups were the changes in early phase insulin secretion. The Diabetes Prevention Program (DPP) Research Group [17] demonstrated that a change in lifestyle could reduce the incidence of DM, while also improving the insulin sensitivity and insulin secretion in comparison to the metformin in Caucasian populations. It is well known that the Japanese population shows a lower insulin secretion in comparison to other ethnic groups. However, regardless of a small number of subjects in our data in comparison to the DPP, the results of DPP and our data were similar. Namely, from several studies, the effects of low intensity exercise therapy on the process of improvement in the serum insulin response after glucose load were different depending upon the insulin secretion pattern and total exercise volume during exercise period, while showing no relationship to ethnic groups. In the present study, the prevalence of hypertension and number of the coronary risk factors were significantly higher in the IGT and DM groups than in the NGT group before exercise therapy. Fkukuda-Akita et al. [18] demonstrated the insulinogenic index to be lower in the non-metabolic syndrome subjects in comparison to the metabolic syndrome subjects. It has been postulated that hyperinsulinemia might be an etiologic cause of obesity, hypertension, DM and arteriosclerosis [19]. The common association of obesity, hypertension, DM and arteriosclerosis has been thought to be attributable to hyperinsulinemia and insulin resistance. Therefore, as a result, ß-cell dysfunction was thus considered to be associated with long-term hyperinsulinemia and insulin resistance may also induce the accumulation of other coronary risk factors.
4.1.
Study limitation and clinical implication
There are several limitations in this study. First, a small number of subjects, predominately middle-aged females, comprised the study subjects. Second, the insulin sensitivity index and insulinogenic index were evaluated using less sensitive indices than a euglycemic hyperinsulinemic clamp ˙ 2 max in our and minimal model technique. Third, the VO ˚ strand and study was estimated using the nomogram of A
Ryhming. And finally, there is the possibility that the subjects had an unconscious reduction of caloric intake and increased daily activity even though they were instructed to maintain their daily activity excluding exercise therapy. However, this study is first report to evaluate the improvement in the serum insulin after glucose load by exercise therapy with regard to the difference in overweight subjects with NGT, IGT and DM. Therefore, the present study may help to demonstrate that low intensity exercise therapy without the use of hypoglycemic agents, may possibly improve the ß-cell function in subjects with IGT and DM.
Notice of grant support This study was supported in part by a grant from the Japanese Ministry of Education, Culture, Sports, Science and Technology (No. 16500445).
Conflict of Interest None.
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