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Obesity: Original Article |
Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine (K.M.U., S.E.K.), Veterans Affairs Puget Sound Health Care System and Harborview Medical Center, University of Washington, Seattle, Washington 98108; Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Department of Medicine (D.B.C.), University of Washington, Seattle, Washington; and Medicine/Gerontology and Geriatric Medicine, Department of Medicine (S.M.B., R.S.S.), Harborview Medical Center and University of Washington, Seattle, Washington
Address all correspondence and requests for reprints to: Kristina M. Utzschneider, M.D., Veterans Affairs Puget Sound Health Care System (151), 1660 South Columbian Way, Seattle, Washington 98108. E-mail: kutzschn{at}u.washington.edu.
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Abstract |
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Introduction |
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Older subjects have lower insulin sensitivity and are more glucose intolerant when compared with younger individuals (2, 3, 4, 5, 6). These observed decreases in insulin sensitivity with aging are in large part related to increases in intraabdominal fat (IAF) (7, 8, 9) and a loss of sensitivity to dietary carbohydrate that also occurs with aging (10). In addition to decreases in insulin sensitivity, it has been shown that older subjects have impaired ß-cell function (2, 11, 12, 13). This impairment in ß-cell function that occurs with aging probably contributes to the increased incidence of IGT and diabetes observed in older populations.
The progression from normal glucose tolerance to IGT and diabetes involves a functional defect in the ability of the islet ß-cell to increase insulin secretion to adequately compensate for decreases in insulin sensitivity (14). Because the prevalence of obesity (15, 16) and diabetes (16) is increasing, recent focus has centered on ways to prevent the development of diabetes with lifestyle changes involving weight loss and/or exercise. Both the Finnish Diabetes Study (17) and the Diabetes Prevention Program (DPP) (18) demonstrated that lifestyle intervention aimed at weight reduction and increased physical activity reduced the incidence of the progression from IGT to diabetes by 58%. Of interest, in the DPP the lifestyle intervention was most effective in older subjects, with those at least 60 yr old demonstrating a 71% decrease in the incidence of progression to diabetes (18). Although several intervention studies have demonstrated that weight loss leads to improved glucose tolerance and increased insulin sensitivity (19, 20, 21, 22), none has systematically examined the effect of weight loss on ß-cell function in an older population. We hypothesized that weight loss leads to an improvement not only in insulin sensitivity but also in ß-cell function and that it is the improvement in both of these variables that could explain the effect of lifestyle on reducing the progression to diabetes in older subjects.
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Subjects and Methods |
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Nineteen overweight or obese, apparently healthy older men with normal fasting plasma glucose were recruited from the community to participate in a weight loss study. Subjects were all nonsmokers taking no medications, had no history of recent weight loss or gain, and were not participating in any exercise program. None of the subjects had a known history of IGT or diabetes. All subjects were screened with a routine medical history and physical examination, diet and exercise history, blood and urine chemistries, and a resting electrocardiogram. Informed consent was obtained before enrollment into the study, and all procedures were approved by the Human Subjects Review Committee at the University of Washington.
Weight loss protocol and weight stabilization
Subjects met with a registered dietician and were given instructions in a 1200-kcal/d diet that provided 50% of calories as carbohydrate, 30% as fat, and 20% as protein. All subjects also received a vitamin and mineral supplement. Subjects were instructed not to change their usual physical activity during the entire study. Compliance with this request was supported by a physical activity questionnaire. During the 3-month weight loss period, subjects were weighed on a metabolic scale three times a week at the University of Washington General Clinical Research Center (GCRC) and met with the dietitian at least weekly to discuss progress and/or problems.
All subjects underwent a 14-d period of weight stabilization before and after the weight loss protocol. During the weight stabilization period, subjects were weighed every weekday morning at the GCRC. Total caloric intake was adjusted to reduce weight fluctuation using a diet similar in macronutrient content to the weight reduction diet. During the weight stabilization period, all foods were prepared, packaged, and distributed by the research kitchen of the GCRC. During the last 7 d of this weight stabilization period, subjects’ weights did not change.
Measurements
Body composition measurements and computed tomography scans were performed on d 1 and 6 of the weight stabilization period, respectively. A frequently sampled iv glucose tolerance test (FSIGT) was performed on d 14 of the weight stabilization period, and a stepped arginine stimulation test was performed on d 15 to assess islet ß-cell function.
Body composition and body fat distribution
The percentage of body fat was determined by underwater weighing after a 12-h overnight fast, and fat mass and lean mass were calculated from total body weight as described previously (23). IAF and sc abdominal fat (SQAF) areas were quantified from a single abdominal computed tomography image obtained on inspiration at the level of the umbilicus (24). The amounts of IAF and SQAF measured at this level have been shown to correlate with total visceral and abdominal sc fat determined by multiple abdominal images (25, 26).
FSIGT
A tolbutamide-modified FSIGT was performed after an overnight fast to provide measures of insulin sensitivity, glucose effectiveness, insulin secretion, and glucose tolerance (27). Briefly, three basal samples were drawn for insulin and glucose at 5-min intervals before glucose administration. Glucose (11.4 g/m2 body surface area) was injected iv over 60 sec beginning at time zero. Then, tolbutamide (125 mg/m2 body surface area) was injected iv over 30 sec commencing 20 min after starting the glucose injection. Blood samples were drawn at 32 time points over the 4 h after glucose administration. Blood samples were separated, and the plasma was stored at –70 C before being assayed for glucose and immunoreactive insulin.
Arginine stimulation test
Fourteen subjects underwent a stepped arginine stimulation test. A glucose dose-response curve for the acute insulin response (AIR) to the nonglucose secretagogue arginine (AIRarg) was derived to characterize the relation of insulin release to glucose level. To do this, the AIRarg was measured at three different glucose concentrations: fasting, approximately 250 mg/dl (14 mM), and greater than 450 mg/dl (25 mM). A variable rate glucose infusion was used to achieve and maintain these elevated glucose concentrations. Because glucose is capable of priming the ß-cell (28, 29), a 2-h rest period occurred between the midrange and the higher hyperglycemic clamps, during which time no glucose was administered and the glucose level was allowed to return to the fasting level. Prestimulus samples were taken for glucose and insulin measurements at the fasting glucose level and 45 min after starting each of the hyperglycemic clamps, after which a maximal stimulatory dose (5 g) of arginine was administered iv. Samples for immunoreactive insulin measurement were taken at 2, 3, 4, and 5 min after each arginine injection. Plasma from these samples was also stored at –70 C before being assayed.
Assays and calculations
Plasma glucose concentrations were measured in triplicate using the glucose oxidase method. Plasma immunoreactive insulin was measured in duplicate using a modification of a double antibody RIA (30).
Using Bergman’s minimal model of glucose kinetics, two parameters were quantified using the glucose and insulin data obtained from the FSIGT (31). The first was the insulin sensitivity index (SI), which provides a measure of the ability of insulin to enhance glucose disposal; the second was glucose effectiveness at basal insulin, which is a measure of the ability of glucose to promote its own disposal. The administration of tolbutamide helps to improve parameter identifiability when the plasma glucose and insulin data are subject to analysis using this model (32).
The AIR to glucose (AIRg) was calculated as the mean incremental insulin response above basal between 2 and 10 min after the iv glucose bolus. The glucose disappearance constant (Kg), a measure of iv glucose tolerance, was calculated as the slope of the natural log of glucose from 10–19 min, expressed as the percentage of change per minute.
The AIRarg was calculated as the mean incremental insulin response above basal between 2 and 5 min after each arginine injection. These glucose dose-response data were then used to derive two additional measures of ß-cell function. The first is the maximal response obtained at a glucose level above 450 mg/dl (25 mM), known as AIRmax, which is a measure of ß-cell secretory capacity (33). Because the magnitude of the AIRarg is a linear function of the plasma glucose level when measured between plasma glucose levels of 60 mg/dl (3.4 mM) and 250 mg/dl (14 mM) (33, 34), a line segment can be drawn that connects the responses measured at these lower two glucose levels. The slope of this segment is known as the slope of glucose potentiation and describes the change in AIRarg divided by the change in plasma glucose level that produced it (
AIRarg/glucose). By using the equation for this line segment and the value for AIRmax, the second measure, which is an estimate of ß-cell sensitivity to glucose, can be calculated by solving for the glucose level at which 50% of AIRmax (PG50) occurred.
Because the magnitude of the insulin response is determined in part by the prevailing degree of insulin sensitivity (35), we also determined the disposition index (DI), which is calculated as the product of SI and AIRg. The calculation of this parameter is based on the known hyperbolic relationship between insulin sensitivity and the insulin response (35). Because AIRmax is also related to insulin sensitivity in a hyperbolic manner (35), we also calculated the product of SI x AIRmax. Percentiles were then calculated based on previously published equations (35) to compare SI x AIRg or SI x AIRmax in our older population before and after the weight loss intervention with that of a young, healthy population.
Statistical methods
All data are presented as mean ± SEM. Comparisons between baseline data and follow-up measures were made using two-tailed, paired Student’s t test. Simple linear regression was performed where indicated. All statistical analyses were performed using SPSS version 10 for Macintosh (SPSS Inc., Chicago, IL).
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Results |
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Each subject served as his own control for the weight loss intervention. The mean age and body mass index (BMI) at baseline were 65.4 yr (range, 60–75 yr) and 30.9 ± 0.6 kg/m2 (range, 27.2–37.3 kg/m2), respectively. The dietary intervention resulted in an average 10% loss of weight (95.6 ± 2.4 to 86.1 ± 2.5 kg; P < 0.001) with all subjects losing weight. Dietary weight loss was associated with significant reductions in the amount of body fat and its distribution as measured by percentage of fat, fat mass, IAF, and SQAF (Table 1
). Fat mass accounted for 84% of the overall decrease in body weight. Interestingly, with the intervention there were similar reductions in both SQAF and IAF of 23 and 24%, respectively.
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Fasting plasma glucose [97.3 ± 1.6 to 95.1 ± 1.3 mg/dl (5.4 ± 0.09 to 5.3 ± 0.07 mM); P = 0.05] and immunoreactive insulin [18.5 ± 1.3 to 12.2 ± 1.0 µU/ml (110.9 ± 7.7 to 73.5 ± 5.9 pM); P < 0.001] levels both declined after weight loss, with this decrease being 2 and 34%, respectively. All subjects exhibited a decline in their fasting insulin levels compatible with the 57% improvement in insulin sensitivity [SI, 1.59 ± 0.24 to 2.49 ± 0.32 x 10–4 min–1/(µU/ml) (2.65 ± 0.40 to 4.15 ± 0.54 x 10–5 min–1/pM); P < 0.001]. As illustrated in Fig. 1A, an improvement in insulin sensitivity occurred in 18 of the 19 subjects. In contrast, the other minimal model-derived measure, glucose effectiveness at basal insulin, which provides an estimate of insulin-independent glucose disposal, did not change (0.017 ± 0.001 to 0.019 ± 0.003 x 10–2 min–1). Kg also did not change significantly with the weight loss intervention (1.42 ± 0.10 to 1.44 ± 0.12%/min).
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). Arginine-stimulated insulin responses
Arginine testing was performed in 14 of the 19 subjects who participated in the weight loss intervention. In response to arginine, the AIRarg at the fasting glucose level did not change significantly [75.5 ± 12.3 to 68.3 ± 14.8 µU/ml (453 ± 74 to 410 ± 89 pM)]. At the midpoint glucose level, the glucose concentrations were clamped at 260.5 ± 8.3 mg/dl (14.5 ± 0.5 mM) before and 259.7 ± 8.3 mg/dl (14.4 ± 0.5 mM) after weight loss. At this glucose level, AIRarg tended to decrease [226.3 ± 27.8 µU/ml (1357.8 ± 166.5 pM) before and 204.5 ± 32.6 µU/ml (1227.2 ± 195.5 pM) after weight loss], although this did not reach statistical significance. The AIRmax, a measure of ß-cell secretory capacity, was determined at similar clamped glucose levels before [518.4 ± 10.8 mg/dl (28.8 ± 0.6 mM)] and after [520.2 ± 14.4 mg/dl (28.9 ± 0.8 mM)[rsqb] weight loss. At these matched glucose levels, AIRmax decreased from 314.3 ± 31.4 µU/ml (1886 ± 188 pM) before weight loss to 259.9 ± 33.4 µU/ml (1560 ± 200 pM) after weight loss (P < 0.05). This decrement occurred in nine of 14 subjects (Fig. 1C). Although AIRmax decreased, the ß-cell sensitivity to glucose (PG50) did not change significantly with the weight loss intervention [239.4 ± 32.4 mg/dl (13.3 ± 1.8 mM) vs. 198 ± 21.6 mg/dl (11.0 ± 1.2 mM); P = 0.14].
Measures of ß-cell function
Adjusting the insulin response for the prevailing level of insulin sensitivity, the DI was 9.63 ± 2.28 x 10–3 min–1 at baseline. After the 3-month weight loss intervention, the DI increased by 33% to 12.78 ± 2.58 x 10–3 min–1 (P < 0.05). As shown in Fig. 2A, this measure increased in 14 of the 19 subjects. SI x AIRmax at baseline was 51.01 ± 9.2 x 10–3 min–1 and improved with weight loss, increasing in 9 of the 14 subjects on average by 43% to 72.69 ± 13.4 x 10–3 min–1 (P < 0.05; Fig. 2B). Thus, although insulin sensitivity improved, the AIR decreased to a lesser degree, resulting in a net overall improvement in ß-cell function.
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Using calculated percentiles based on previously published equations (35), before the weight loss intervention the current group of men had a mean ranking that placed them on the seventh percentile for SI x AIRg when compared with a young, healthy population under the age of 45 yr, whereas after the 10% weight loss, their ranking increased to the 16th percentile as illustrated in Fig. 3A. The percentile ranking for SI x AIRmax compared with the young, healthy population was again very low, being at the eighth percentile at baseline and increasing to the 25th percentile after weight loss (Fig. 3B). The increments in percentile rankings for both of these parameters after weight loss is in keeping with an overall improvement in ß-cell function.
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Discussion |
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Although many studies have shown that insulin sensitivity improves with weight loss (21, 22, 36, 37), few have analyzed the effects of weight loss on ß-cell function in nondiabetic subjects. The few studies that have evaluated this parameter in nondiabetic subjects have used different investigational approaches, namely surgery (38) and medication (39), and have shown improved ß-cell function. Our study is unique in that we focused specifically on the older age population, and the weight loss was induced by a standard dietary intervention commonly used in the community for this purpose. The changes in insulin sensitivity, insulin responses, and ß-cell function that we observed are most likely related to the weight loss per se, rather than to any change in diet composition because all subjects were weight-stabilized for 2 wk both before and after the weight loss intervention on a diet with the same macronutrient composition. It is of interest that similar to our observation in nondiabetic subjects, weight loss produced by a very low-calorie diet (600 kcal/d for 6 wk) in obese subjects with type 2 diabetes resulted in changes in ß-cell function manifest as improved kinetics of insulin secretion (40, 41) and a partial reversal of abnormalities in pulsatile insulin release (42).
Our findings are particularly relevant in light of the findings in two recent large studies involving lifestyle intervention that showed a 58% reduction in the rate of development of diabetes with this form of intervention (17, 18). Although the combined lifestyle approaches used in the DPP (18) and the Finnish Diabetes Prevention Study (17) included counseling to increase physical activity as well as dietary modifications aimed at weight reduction, our study specifically examined the effects of dietary weight loss on insulin sensitivity and ß-cell function and did not include any exercise component. The findings of our study are also in keeping with additional analysis of the DPP data that showed that the effect of the lifestyle intervention to reduce the rate of conversion to diabetes was primarily the result of weight loss, and that the increased physical activity did not independently contribute to the beneficial effect of lifestyle change (43).
The lifestyle intervention studies that we have performed in older subjects comprising dietary weight loss in this study and exercise training in a previous study (44) provide further insight into the mechanisms by which the DPP and the Finnish Diabetes Prevention Study likely had their beneficial effects. With exercise training in older individuals, an improvement in insulin sensitivity was associated with a near-perfect compensatory decrease in insulin secretion so that no net change in the DI occurred (44). This near-perfect reciprocal change in SI and AIRg was also observed for SI and AIRmax. In contrast, the results of the dietary weight loss intervention reported here show that insulin sensitivity improves to a greater degree than the decline in the insulin response, resulting in an overall improvement in ß-cell function. The findings of our two studies therefore suggest that although changes in insulin sensitivity can regulate insulin responses, the effect of exercise or weight loss to change ß-cell function differs.
The mechanism whereby weight loss leads to improved ß-cell function is not known. Because adipose tissue mass decreases with weight loss, it is possible that factors secreted from fat, such as free fatty acids, IL-6, TNF-
, or adiponectin, may directly or indirectly impact ß-cell function. The possibility that substances secreted from fat may affect ß-cell function is also supported by cross-sectional human studies that have demonstrated that the increased IAF occurring with increasing age is associated not only with decreased insulin sensitivity (7, 8, 9, 45) but also with decreased ß-cell function (46) (Utzschneider, K., D. Carr, S. Kahn, and R. Knopp, unpublished observation). Clearly, determination of the responsible mechanism(s) that regulate adaptation of the ß-cell to changes in insulin sensitivity does require further study.
By performing the glucose dose-response curve with arginine, we were able to examine the ß-cell mechanism by which AIRg decreased with the weight loss intervention. From this assessment it appears that the decrease in AIRg is due to a decrease in ß-cell secretory capacity, as seen by the significant decrease in AIRmax after weight loss, rather than a change in the sensitivity of the ß-cell to glucose (PG50). The change in AIRmax without a change in PG50 is in keeping with two previous intervention studies. One study demonstrated reductions in both AIRg and AIRmax but no change in PG50 when insulin sensitivity was increased by exercise training (44), whereas the other showed increases in AIRg and AIRmax without a change in PG50 after experimental insulin resistance was induced with nicotinic acid (47). These intervention-based findings, along with our cross-sectional data (35), support the concept that changes in AIRg that are associated with differences in insulin sensitivity are more likely to be modulated by changes in ß-cell secretory capacity than by changes in ß-cell sensitivity to glucose.
We also determined ß-cell function by multiplying SI x AIRg and SI x AIRmax, based on the previous demonstration of a hyperbolic relationship between SI and AIRg and the use of this relationship as a means to determine ß-cell function (35). Although this relationship was first described using a cohort of young, healthy subjects less than 45 yr of age (35), it has been demonstrated to be similar in a small published study comparing young and elderly groups (48), and we have recently found this hyperbolic relationship to be present in a large cohort of older (ages 60–75 yr) subjects (Utzschneider, K., D. Carr, S. Kahn, and R. Knopp, unpublished observation). Based on the previously published hyperbolic relationship (35), the present findings at baseline of a low DI at the seventh percentile and low SI x AIRmax at the eighth percentile in our study group further underscore the reduced function of the ß-cell in these otherwise apparently healthy, older, overweight men and highlight their risk for progressing to develop diabetes.
It is of interest that despite all subjects achieving significant weight loss, some had very little change or showed an actual decline in measures of ß-cell function. This is likely due in part to the day-to-day variability of AIRg and SI, which in our hands are 20.6 and 16.9%, respectively (49). Despite this variability, on average ß-cell function was significantly improved with the dietary weight loss intervention. Three of the five subjects who had a decrease in the DI also had a decline in SI x AIRmax, but they otherwise did not show any unique features compared with the other subjects. Overall, with our sample size we were unable to identify any characteristics that would predict which subjects would have a greater response in insulin sensitivity or ß-cell function from the weight loss intervention.
In the current study, the DI improved, and therefore one might have expected iv glucose tolerance, measured as Kg, to increase. However, we failed to observe such a change. We believe this may well be due to the fact that we measured Kg from 10–19 min, and during this early time period insulin-independent glucose uptake is a major determinant of iv glucose tolerance (50). Thus, this time period may not reflect the effect of changes in insulin sensitivity and/or ß-cell function on glucose tolerance. Additionally, the day-to-day variability of Kg averages 14.5% (49), and this may have added to our inability to detect a significant change in this measure. Unfortunately, because of subject burden, we did not perform an oral glucose tolerance test. However, we would anticipate that had we done so, we would have been able to demonstrate an improvement in glucose tolerance using this approach because ß-cell function is a critical determinant of oral glucose tolerance (51, 52), and the two other studies that have examined ß-cell function after weight loss demonstrated an improvement in oral glucose tolerance (38, 39).
Although our study focused on men, based on the findings in other weight loss studies, we would expect that similar changes would have been observed in women. Although the DPP and the Finnish Diabetes Prevention Study did not specifically examine the mechanisms and the impact of gender thereon, both found that the reduction in the incidence of progression from IGT to diabetes with lifestyle intervention was similar in men and women (17, 18), supporting the lack of a differential effect of gender. Furthermore, studies evaluating the effects of weight loss after bariatric surgery (38) and weight loss medication (39) involved mostly women, and both found improvements in insulin sensitivity and ß-cell function.
In summary, our results demonstrate that weight loss in an older, overweight to obese male population can significantly improve not only insulin sensitivity but also ß-cell function. This improvement in ß-cell function along with the enhancement of insulin sensitivity may be an important mechanism whereby lifestyle intervention is capable of reducing glucose levels and delaying the progression from IGT to diabetes in older subjects, a segment of the population that has an increased prevalence of IGT and is at increased risk of developing diabetes.
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Acknowledgments |
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Footnotes |
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Abbreviations: AIR, Acute insulin response; AIRarg, AIR to arginine; AIRg, AIR to iv glucose; AIRmax, maximal glucose-potentiated insulin response; BMI, body mass index; DI, disposition index; DPP, Diabetes Prevention Program; FSIGT, frequently sampled iv glucose tolerance; GCRC, General Clinical Research Center; IAF, intraabdominal fat; IGT, impaired glucose tolerance; Kg, glucose disappearance constant; PG50, glucose level at 50% AIRmax; SI, insulin sensitivity index; SQAF, sc abdominal fat.
Received October 20, 2003.
Accepted January 19, 2004.
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