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Clinical Studies |
Department of Geriatric Medicine and Metabolic Diseases, Institute of Endocrinology (A.D.B., M.R., C.C.), II University of Naples, Naples, Italy
Address all correspondence and requests for reprints to: Giuseppe Paolisso, M.D., Department of Geriatric Medicine and Metabolic Diseases, Servizio di Astanteria Medica, Piazza Miraglia 2, I-80138 Naples, Italy.
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Abstract |
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Introduction |
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Previous studies have demonstrated that healthy centenarians have better anthropometric characteristics (8) and glucometabolic profiles (9) than aged subjects and not different from those in healthy adults. As IGF-I may have a regulatory role on body composition (10), plasma lipid concentration (11), and insulin action (12), it cannot be excluded that IGF-I or the IGF-I/IGFBP-3 molar ratio affects such anthropometric and metabolic characteristics in healthy centenarians.
In light of such findings, we sought answers to the following questions. 1) Is there any difference in plasma IGF-I, IGFBP-3, and/or IGF-I/IGFBP-3 molar ratio between aged subjects and centenarians? If yes, 2) is any change in plasma IGF-I, IGFBP-3, and IGF-I/IGFBP-3 molar ratio related to body composition, plasma leptin and lipid concentrations, and insulin action in healthy centenarians? For this reasons in 79 healthy subjects with a large age range (21–106 yr), fasting plasma IGF-I and IGFBP-3, leptin, and lipid concentrations were determined, body composition was assessed by bioimpedance analysis, and insulin-mediated glucose uptake was evaluated by euglycemic hyperinsulinemic glucose clamp.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Seventy-nine subjects (42 males and 37 females) with a wide age range (21–106 yr) were studied. The whole group of subjects was categorized in 3 groups: 1) adults (<50 yr; n = 30), 2) aged subjects (75–99 yr; n = 30), and 3) centenarians (>100 yr; n = 19). Premenopausal women were all studied in the follicular phase. All subjects were normotensive, were taking no medications, were not smokers, and had no evidence of metabolic or cardiovascular disease. Oral glucose tolerance (13) (75 g glucose) was tested in all volunteers before they were enrolled in the study. Subjects with a family history of noninsulin-dependent diabetes mellitus, obesity [body mass index (BMI), >30], or hypertension were excluded from the study. No woman was taking hormone replacement therapy before or during the study. No subject was hypertensive or used drugs that affect insulin secretion and/or action or plasma lipid levels in the 3 weeks preceding the tests. Subjects with a change in body weight of more than 2 kg during the preceding year and/or with Alzheimer’s disease or secondary dementia were excluded from the study. Each subject (or their relatives for healthy centenarians) was asked to record intake of foods and beverages as well as cigarette smoking during the 3 days preceding the metabolic investigations. Daily physical activity was recorded and evaluated according to the method of Haskel (14). All tests were conducted in the morning and after an overnight fast (at least 12 h). After a clear explanation of the potential risks of the study, all volunteers (as well as their relatives for centenarians) provided informed consent to participate in the study, which was approved by the ethical committee of our institutions.
Anthropometric determination
Weight and height were measured using a standard beam balance scale. Fat-free mass (FFM) and body fat (BF) were measured using a four-terminal bioimpedance analyzer (RJL Spectrum Bioelectrical Impedance-BIA 101/SC Akern, RJL-System, Florence, Italy) (15) as previously reported (8). Waist and hip circumferences were measured to the nearest 0.5 mm with a plastic tape, and the waist/hip ratio (WHR) was calculated.
Metabolic tests
Insulin action was measured using the euglycemic hyperinsulinemic glucose clamp technique as previously reported (9).
Geriatric assessment
In aged subjects and centenarians, geriatric assessment was performed by the Mini Mental State Examination (MMSE) (16) and Instrumental Activities Daily Living (IADL) scale (17). Subjects with MMSE scores of 20 or less were considered to have mild to severe cognitive impairment (16). Subjects with a severe degree of disability were those with IADL score of 8 or less (17).
Analytical methods
Plasma glucose was determined by the glucose oxidase method (Beckman Glucose Autoanalyzer, Fullerton, CA). Plasma lipid concentrations were determined from fresh samples drawn after a 12-h overnight fast. Plasma high density lipoprotein (HDL) cholesterol concentrations were determined after precipitation of low density lipoprotein (LDL) and very low density lipoprotein (VLDL) with dextran sulfate and magnesium chloride (18). Commercial enzymatic methods were used in the determination of serum cholesterol (Monotest, Boehringer Mannheim, Milan, Italy) (19) and triglycerides (Peridecrome, Boehringer Mannheim) (20). Serum LDL cholesterol levels were calculated by the Friedwald formula (21). Subjects with total triglycerides greater than 4.5 mmol/L were not included in the study. The interassay coefficient of variation was less than 3.8% for total cholesterol, less than 5.0% for HDL cholesterol, and less than 2.5% for triglycerides. Plasma free fatty acid (FFA) concentrations were determined by spectrophotometric methods as reported by Miles et al. (22). After centrifugation, plasma insulin (Sorin Biomedical, Milan, Italy; coefficient of variation, 3.3 \ 0.2%), IGF-I (Active IGF-I, with extraction, Diagnostic System Laboratories, Webster, TX), and IGFBP-3 (Active IGFBP-3, Diagnostic System Laboratories), and leptin (Linco Research, St. Louis, MO) concentrations were determined by RIA.
Calculations and statistical analyses
For molar comparisons between IGF-I and IGFBP-3, the following molecular masses were used in the calculation: IGF-I, 7.5 kDa; and IGFBP-3, 30.5 kDa.
Whole body glucose disposal (WBGD) was calculated during the final 60 min of the clamp, according to the following formula (23): WBGD = glucose infusion rate pool correction, and when no entry of glucose in plasma from the liver occurs (24).
To approximate normal distributions, plasma insulin, leptin, triglycerides, IGF-I, and IGFBP-3 concentrations and IGF-I/IGFBP-3 molar ratios were log transformed and used in all calculations. Differences among the groups were determined by ANOVA. When P < 0.05 was found, Scheffe’s test was also used. Analysis of covariance allowed adjustment of each variable for covariates. Pearson product-moment correlations were calculated to test the association among variables. Partial correlation tested associations between two variables independently of a covariate. Multivariate analyses tested the independent association of different variables with WBGD. Before performing the data analysis in the whole sample of subjects (n = 79), the nQuery test was used for predicting the adequacy of sample size. A group of 75 subjects was found to be statistically enough large. Further, analysis of 95% regression confidence intervals showed very narrow ranges, thus confirming the nQuery test prediction. Statistical analyses were performed using the SOLO (BMDP, Cork, Ireland) software package. All values are presented as the mean \ SD.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Subject characteristics are given in Table 1
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Centenarians had significantly lower BMI, FFM, and BF than aged
subjects and adults. BF was also more peripherally distributed in
centenarians than in aged subjects, but was not different from that in
adults. The fasting plasma leptin concentration was greater in
centenarians than adults even if aged subjects had the greatest plasma
leptin concentration. Differences in plasma leptin concentration among
the groups persisted after adjustment for the amount of BF and WHR
(P < 0.05 among all groups). The plasma albumin
concentration was unaffected by advancing age. Centenarians had the
lowest plasma lymphocytes concentrations. Fasting plasma urea,
creatinine, liver enzymes, and total protein concentrations were
similar in the three studied groups and within the normal range (data
not shown). Smoking and alcohol drinking were similar in adults and
centenarians, but remarkably higher in aged subjects (data not shown).
Fat intake was lower in centenarians (48.1 \ 2.1 g/day) than
those in adults (78.9 \ 3.5 g/day; P < 0.001)
and aged subjects (63.5 \ 3.9 g/day; P < 0.01).
In contrast, daily carbohydrate intake in centenarians (45 \ 8%
equivalent to 46.4 \ 3.4 g/day) was not different from that in
aged subjects (43 \ 4% equivalent to 76.2 \ 3.6 g/day) or
adults (47 \ 4% equivalent to 88.6 \ 4.4 g/day) as the
percentage of total energy intake, but was the lowest as an absolute
value (P < 0.01 for all comparisons).
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. Comparing healthy centenarians to aged subjects, the
former had a less atherogenic plasma lipid profile. In fact, fasting
plasma triglycerides, FFA, and LDL cholesterol concentrations were
significantly lower in centenarians than aged subjects, whereas plasma
HDL cholesterol had the opposite trend. Differences between
centenarians and aged subjects in plasma triglycerides, FFA, and LDL
cholesterol concentrations were independent of daily fat and
carbohydrate intake and amount of daily physical activity
(P < 0.05 for all parameters). Centenarians had also
WBGD greater than that in aged subjects, but similar to that in adults.
Again, differences in WBGD between centenarians and aged subjects
persisted even after adjustment for BF, daily fat and carbohydrate
intake, smoking and alcohol drinking, and amount of daily physical
activity (P < 0.05).
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Fasting plasma IGF-I, IGFBP-3, and IGF-I/IGFBP-3 molar ratio in
the three study groups are reported in Fig. 1. IGF-I
declined with advancing age, but no differences between aged subjects
and centenarians were found. IGFBP-3 had a trend similar to that of
IGF-I, but in centenarians lower values were present than in aged
subjects. As expected, the IGF-I/IGFBP-3 molar ratio declined in the
elderly; nevertheless, centenarians had a plasma IGF-I/IGFBP-3 molar
ratio greater than that in aged subjects. The difference in the plasma
IGF-I/IGFBP-3 molar ratio between centenarians and aged subjects was
independent of nutritional status, liver enzyme concentration, or daily
physical activity (P < 0.05). The IGF-I/IGFBP-3 molar
ratio was significantly correlated with plasma IGF-I in centenarians
(n = 19; r = 0.66; P < 0.001), aged subjects
(n = 30; r = 0.55; P < 0.001), and adults
(n = 30; r = 0.57; P < 0.001).
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In centenarians, the IGF-I/IGFBP-3 molar ratio correlated with BMI
(r = -0.55; P < 0.009), the amount of BF (r
= -0.62; P < 0.003), FFM (r = 0.56;
P < 0.008), and the fasting plasma leptin
concentration (r = -0.63; P < 0.004; Fig. 2). The correlation between the plasma IGF-I/IGFBP-3
molar ratio and the plasma leptin concentration was independent of the
amount of BF (r = -0.57; P < 0.01). The plasma
IGF-I/IGFBP-3 molar ratio also correlated with fasting plasma glucose
(r = -0.46; P < 0.02) and insulin (r =
-0.54; P < 0.01) concentrations. The relationship
between the fasting plasma IGF-I/IGFBP-3 molar ratio and fasting plasma
lipid concentrations and insulin action is reported in Fig. 3. The plasma IGF-I/IGFBP-3 molar ratio was associated
with WBGD (r = 0.64; P < 0.005), fasting plasma
triglycerides (r = -0.58; P < 0.01), FFA (r
= -0.64; P < 0.005), and LDL cholesterol (r =
-0.59; P < 0.009) concentrations. All correlations
were independent of daily fat and carbohydrate intake and WBGD
(P < 0.05 for all). No significant correlations
between the IGF-I/IGFBP-3 molar ratio and plasma total (r = 0.31;
P = NS) and HDL (r = 0.34; P = NS)
cholesterol concentrations were present. The correlation between the
plasma IGF-I/IGFBP-3 molar ratio and WBGD persisted after adjustment
for BF, fasting plasma insulin concentration, daily carbohydrate and
fat intake, and daily physical activity (r = 0.55;
P < 0.009), but not after further adjustment for the
plasma FFA concentration (r = 0.30; P = 0.17).
Furthermore, the correlation between the plasma IGF-I/IGFBP-3 molar
ratio and plasma triglycerides (r = -0.44; P <
0.05) and FFA (r = -0.53; P < 0.03) persisted
even after adjustment for WBGD, daily fat intake, and daily physical
activity.
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MMSE (27 \ 2.1 vs. 18.3 \ 3.1; P < 0.02) and IADL (26 \ 2.6 vs. 8.4 \ 4.1; P < 0.001) were significantly different in aged subjects and centenarians, respectively. The fasting plasma IGF-I/IGFBP-3 molar ratio correlated with MMSE (r = 0.53; P < 0.03), but not with IADL (r = 0.33; P = NS).
Data analysis in the whole sample of subjects (n = 79)
In the whole group of subjects (n = 79), the IGF-I/IGFBP-3 molar ratio correlated with advancing age (r = -0.66; P < 0.001), BMI (r = -0.44; P < 0.001), fasting plasma leptin (r = -0.36; P < 0.001), insulin (r = -0.29; P < 0.009), and IGF-I (r = 0.69; P < 0.001) concentrations and WBGD (r = 0.36; P < 0.001). After controlling for age, sex, BF, FFM, and WHR, the plasma IGF-I/IGFBP-3 molar ratio was still correlated with plasma leptin (r = -0.33; P < 0.007) and WBGD (r = 0.30; P < 0.008). In the whole group of subjects aged more than 75 yr (n = 49), a significant correlation between the MMSE score and plasma IGF-I (r = 0.43; P < 0.002) and the IGF-I/IGFBP-3 molar ratio (r = 0.48; P < 0.001) was found. After adjustment for age and sex, the MMSE score was still correlated with plasma IGF-I (r = 0.35; P < 0.01) and the plasma IGF-I/IGFBP-3 molar ratio (r = 0.48; P < 0.008). In the multivariate analysis a model made by age, sex, BF, FFM, WHR, and the plasma IGF-I/IGFBP-3 molar ratio explained 54% of WBGD variability, with age (P < 0.05), BF (P < 0.03), FFM (P < 0.05), and the IGF-I/IGFBP-3 molar ratio (P < 0.007) significantly and independently associated with WBGD. Similar results were obtained when fasting plasma IGF-I instead of the IGF-I/IGFBP-3 molar ratio was used.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The main finding of our study was that healthy centenarians have fasting plasma IGF-I/IGF-BP3 molar ratios more elevated than those in aged subjects. If one considers that GH and IGF-I concentrations decline with advancing age, the more elevated plasma IGF-I/IGFBP-3 molar ratio in centenarians compared to that in aged subjects appears very striking. The reasons for such results need to be investigated. A specific genetic background, a natural selection of subjects with those hormonal characteristics, and a further age-related reduction in GH secretory status can be hypothesized. With regard to genetics, evidence has been accumulated that in children, the plasma IGF-I concentration is more tightly regulated by genetic factors; nevertheless, data in old subjects are lacking. In contrast, the plasma IGFBP-3 concentration mainly depends on the plasma GH concentration (25). Alternatively, an effect of insulin should be taken into account. In fact, insulin enhances the bioavailability of IGF-I, as it increases the plasma IGF-I concentration without affecting the plasma IGFBP-3 concentration (26). Due to the difference in insulin action between aged subjects and centenarians, one can suggest that the preserved insulin action in centenarians might be responsible for a more appropriate IGF-I production while the plasma IGFBP-3 concentration is left to decline. Thus, the net final effect is an increase in the plasma IGF-I/IGFBP-3 molar ratio.
An interesting question is whether preservation of IGF status is somehow related to the ability of the centenarians to have survived beyond 100 yr. Our study has a cross-sectional design; thus, it was unable to provide a cause-effect response. Further, one should point out that in centenarians possible deleterious effects on survival of various lifestyle factors were absent, and thus, they could be confounders related to IGF status.
The relationship among IGF-I, anthropometric parameters, and aging is well known (10, 27, 28). Cross-sectional studies have demonstrated an increase in adiposity as a possible metabolic contributor to the decrease in IGF-I in the presence (27, 28) or absence (29) of advancing age. Our study provides further evidence for an inverse correlation between the amount of BF and the plasma IGF-I/IGFBP-3 molar ratio. Interestingly enough, our study also demonstrates that aged subjects have the greatest plasma leptin concentration, compared to those in adults and centenarians. Furthermore, a significant relationship between plasma leptin and the plasma IGF-I/IGFBP-3 ratio was observed in the whole population studied and not only centenarians. Plasma leptin is the product of the ob gene, which has been shown to regulate body weight and food intake in mice (30). However, the physiological role of leptin in human deserves further investigation. Our results indicate that the unbound form of IGF-I might be a regulatory factor of plasma leptin independently of the effect of IGF-I on BF. As IGF-I may act in an autocrine and paracrine manner (1) and promotes the differentiation of adipocytes (1, 31), a modulatory role of unbound IGF-I on the production of plasma leptin by adipose cells cannot be ruled out. Nevertheless, future research will need to better clarify this point.
In a previous study, healthy centenarians have been shown to have a better insulin action than aged subjects, even after appropriate correction for the body composition (9). The reason for such a difference is not fully understood. It should be pointed out that BMI and bioimpedance analysis are not very appropriate nutritional indexes for studying very old subjects and/or centenarians. Alternatively, differences in unbound plasma IGF-I concentration might provide a potential explanation. In our study, a direct relationship between the plasma IGF-I/IGFBP-3 molar ratio and WBGD disposal in healthy centenarians was found. Such a relationship was independent of the main confounders affecting insulin action. The relationship between IGF-I and insulin-mediated glucose uptake has been object of numerous investigations. In vitro, it has shown that IGF-I can bind to the insulin receptor, but with an affinity only 1–5% that of insulin (1, 12). Among the other possible molecular mechanisms, IGF-I may improve insulin action through an interaction between the insulin signal transduction pathway and the IGF-I signal transduction pathway (32, 33). Finally, the occurrence of a hybrid insulin/IGF-I receptor has been reported in certain tissue (34). These receptors have a greater affinity for IGF-I than for insulin and thus require lower free IGF-I levels for activation than would insulin receptors. In vivo, the strongest data related to the effect of IGF-I on insulin action came from the studies investigating the metabolic effects of recombinant human IGF-I (rhIGF-I) administration. Hussain et al. (35) demonstrated that a 5-day infusion of rhIGF-I increased both the plasma FFA concentration and insulin sensitivity in normal volunteers. Contrasting data were reported by Boulware et al. (36), who demonstrated that an acute infusion of rhIGF-I suppressed FFA levels in nondiabetic subjects. Moses et al. (32) also found a substantial reduction in the fasting triglyceride concentration, a result consistent with that reported by Zenobi et al. (32). In our study we also found an inverse relationship between the plasma IGF-I/IGFBP-3 molar ratio and plasma triglycerides and FFA concentrations, which was independent of WBGD. According to Boulware et al. (36), one can hypothesize that an elevated plasma IGF-I or IGF-I/IGFBP-3 molar ratio is associated with accelerated triglyceride and FFA metabolism and, thus, with an inhibition of the Randle cycle. Alternatively, an effect of IGF-I on hepatic glucose output (HGO) can be also taken into account. In fact, we found an inverse relationship between the plasma IGF-I/IGFBP-3 molar ratio and the fasting glucose concentration. Such a relationship suggests that IGF-I decreases HGO, the major determinant of fasting plasma glucose (12, 32). Nevertheless, in our study HGO was not determined, and thus, the effect of IGF-I at the liver site remains to be confirmed.
With regard to the relationship between plasma IGF-I/IGFBP-3 molar ratio and plasma LDL cholesterol, previous data have shown an improvement of plasma lipid profile by IGF-I treatment in noninsulin-dependent diabetes mellitus patients (37, 38). It has been hypothesized that IGF-I decreases the secretion of insulin into the portal vein, so that VLDL triglyceride synthesis and secretion are diminished. Because VLDL are metabolized to LDL particles, the net result of IGF-I is a considerable fall in the VLDL triglyceride level and later also in the LDL cholesterol concentration (37).
Finally, in our study a positive association between the plasma IGF-I/IGFBP-3 molar ratio and the degree of cognitive function was also found. Such results are in agreement with those reported by Papadakis et al. (39) and might be explained by the fact that IGF-I receptors are widely distributed in the brain (40).
In conclusion, our study demonstrates that healthy centenarians have plasma IGF-I/IGFBP-3 molar ratios greater than those in aged subjects. In centenarians, a more favorable plasma IGF-I/IGFBP-3 molar ratio was always found associated with improved insulin action and plasma lipid concentration.
Received December 5, 1996.
Revised March 12, 1997.
Accepted March 20, 1997.
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