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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 9 3350-3356
Copyright © 1998 by The Endocrine Society

Original Studies

Age-Related Reduction in Glucose Elimination Is Accompanied by Reduced Glucose Effectiveness and Increased Hepatic Insulin Extraction in Man1

Bo Ahrén and Giovanni Pacini

Department of Medicine (B.A.), Lund University, S-205 02 Malmö, Sweden; and Institute of Systems Science and Biomedical Engineering (G.P.) (LADSEB-CNR), I-35127 Padua, Italy

Address all correspondence and requests for reprints to: Dr. Bo Ahrén, Department of Medicine, Malmö University Hospital, S-205 02 Malmö, Sweden. E-mail: bo.ahren{at}medforsk.mas.lu.se


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
This study examined whether insulin secretion, insulin sensitivity, glucose effectiveness (SG), and hepatic extraction (HE) of insulin are altered by age when glucose tolerance is normal. A frequently sampled iv glucose tolerance test was performed in 20 elderly (E, 10/10 male/female, all 63 yr old) and in 20 young subjects (Y, 10/10 male/female, all 27 yr old), who were similar in body mass index and 2-h blood glucose during oral glucose tolerance test. E exhibited impaired glucose elimination (iv tolerance index, 1.31 ± 0.10 vs. 1.70 ± 0.12% min-1; P = 0.019). First-phase insulin secretion and SI did not differ between the groups, whereas E had lower glucose sensitivity of second-phase insulin secretion (0.40 ± 0.07 vs. 0.70 ± 0.08 (pmol/L)min-2/(mmol/L), P = 0.026), lower SG, 0.017 ± 0.002 vs. 0.025 ± 0.002 min-1, P = 0.004), and higher HE (81.3 ± 2.4 vs. 73.2 ± 2.1%, P = 0.013). Across both groups, SG correlated positively with glucose tolerance index (r = 0.58, P < 0.001) and negatively with HE (r = -0.54, P < 0.001). Plasma leptin and glucagon did not change by age, whereas plasma pancreatic polypeptide (PP) was higher in E (122 ± 18 vs.66 ± 6 pg/mL, P = 0.004). PP did not, however, correlate to any other parameter. We conclude that E subjects with normal oral glucose tolerance have reduced SG, impaired second-phase insulin secretion, and increased HE, whereas SI and first-phase insulin secretion seem normal. SG seems most related to age-dependent impairment of glucose elimination, whereas leptin, glucagon, and PP do not seem to contribute.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GLUCOSE tolerance is progressively reduced by age (1, 2, 3, 4, 5, 6, 7). Therefore, the incidence of impaired glucose tolerance (IGT) and its accompanying increased risk for the development of type 2 diabetes are increased in older age groups (8). The mechanism underlying the age-related development of glucose intolerance is not clear. Several studies have reported that the tissue sensitivity to the action of insulin is reduced by age. This conclusion has been based on measuring insulin sensitivity with the hyperinsulinemic euglycemic clamp technique (4, 5, 6, 7), the forearm glucose uptake technique (9, 10), or the frequently sampled iv glucose tolerance test (FSIGT), which determines the insulin sensitivity index (SI) (11). In contrast, by using the same methods, several other studies have not been able to demonstrate any reduction in tissue insulin sensitivity with age (12, 13, 14, 15, 16). There seems also to be no consensus regarding the potential role of insulin secretion in glucose intolerance in old age. In fact, several studies have shown no reduction in insulin secretion in old subjects (4, 10, 12), whereas other studies have demonstrated impaired second-phase insulin secretion ({phi}2) (11, 17).

Potential explanations for these different results might be offered. First, many studies lack an age standardization in the different study groups and have included a large age range in the respective young (Y) and elderly (E) age groups. This could increase the variability of the results because the cut-off age for altered insulin sensitivity or secretion is unknown. Second, a difference in degree of other age-related variables between the studied groups, like obesity or physical activity, might be of importance because such factors age-independently affect the tissue sensitivity to insulin (18, 19). Third, a significantly higher 2-h glucose value in the oral glucose tolerance test (OGTT) in the older group exists in some studies, even though the older subjects did not meet the criteria for IGT (5, 11, 12). This might complicate interpretation of the results because, in IGT, a combination of low insulin sensitivity and insulin secretion is usually found (11, 20). This would imply that changes in insulin secretion and insulin action are not necessarily caused by the aging process per se but to the glucose intolerance.

The purpose of this study was to explore whether insulin secretion and insulin sensitivity are altered by age when the influences of glucose intolerance, as judged by OGTT and body mass index (BMI), are strictly controlled. Furthermore, the study also controlled for gender influences and (by studying Caucasians only) for possible influences caused by differences in ethnic origin of the subjects. The FSIGT with minimal model analysis was performed to obtain measurements of SI, insulin secretion, SG, and hepatic extraction of insulin (21, 22). The metabolic parameters were also related to circulating levels of leptin [the adipocyte hormone that, in rodents, has been shown to regulate body weight by reducing food intake and increasing energy expenditure (23, 24)] and the islet hormones, glucagon and pancreatic polypeptide (PP), because the potential impact of these hormones on the age-related changes in glucose metabolism has not been determined before.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

We studied two different groups of Caucasian subjects. Both groups were recruited from a health-screening program in the city of Malmö. The E group consisted of 20 subjects [10 women and 10 men; age, 63 yr plus 6 months (±5 months, means ± SD)], and the Y group consisted of 20 subjects [10 women and 10 men; age, 27 yr plus 10 months (±10 months, means ± SD)]. The BMI was 25.2 ± 1.7 kg/m2 in the E group and 24.9 ± 2.1 kg/m2 in the Y group (mean ± SD, not significantly different). A 75-g OGTT, using WHO criteria (25), was undertaken in all subjects. For this test, the subjects attended the clinic in the morning, after an overnight fast. Capillary blood glucose samples were obtained directly before and 2 h after a 75-g oral glucose load. The 2 h were spent in a semirecumbent position. All subjects were found to have normal glucose tolerance, defined using WHO reference values (25; 2-h blood glucose after oral glucose load <7.8 mmol/L). All subjects were healthy, without any current or past history of any significant illness (including endocrine disorders, ischemic heart disease, or hypertension). All subjects had normal liver and thyroid function tests; none were taking any medication known to affect glucose tolerance; none had a family history of diabetes. All subjects received oral and written information concerning the aims and methods of the study, and they signed a consent declaration before the start of the study. The study protocol was approved by the Ethics Committee of Lund University.

FSIGT

FSIGT was undertaken in all subjects 6–8 weeks after the OGTT. Subjects attended the clinic in the morning, after an overnight fast. A catheter was inserted into an antecubital vein for blood sampling and into a contralateral antecubital vein for glucose injection. Basal samples were drawn at -10 min and at -1 min. At time 0, glucose (300 mg/kg) was injected in 1 min, and then additional samples were collected at 3, 4, 5, 6, 8, 10, 15, 20, 25, 30, 40, 60, 80, 100, 120, 150, and 180 min.

Analyses

Capillary blood glucose samples from the OGTT were chilled at 4 C and sent to the central laboratory at the hospital, where they were analyzed using an automatic glucose oxidase method. Samples for measurement of insulin were taken in prechilled tubes, for determination of glucose, leptin, and PP in prechilled tubes containing 0.084 mL EDTA (0.34 mol/L) and for determination of C-peptide and glucagon in prechilled tubes containing 0.084 mL EDTA (0.34 mol/L) and aprotinin (250 kallikrein-inhibiting units/mL blood; Bayer, Leverkusen, Germany). Leptin, PP, and glucagon were determined in fasting samples only. A total of 390 mL blood were taken during the test. All blood samples were immediately centrifuged at 5 C, and serum or plasma was frozen at -20°C until analyses. Serum insulin concentrations were analyzed with a double-antibody RIA technique. Guinea pig antihuman insulin antibodies, human insulin standard, and mono-125I-tyr-human insulin tracer (Linco Res. Inc., St. Charles, MO) were used. Plasma C-peptide concentrations were analyzed with a double-antibody RIA technique using guinea pig antihuman C-peptide antibodies, 125I-labeled human C-peptide, and human C-peptide standard (Linco). Plasma glucose concentrations were determined using the glucose oxidase method. Baseline samples, i.e. before injecting glucose, were also taken for analysis of leptin, glucagon, and PP. Plasma leptin was analyzed with a double-antibody RIA using rabbit antihuman leptin antibodies, 125I-labeled human leptin as tracer and human leptin (Linco) as standard (26). Glucagon levels were measured with a double-antibody RIA, in duplicate, using guinea pig antihuman glucagon antibodies specific for pancreatic glucagon, 125I-glucagon as tracer, and glucagon standard (Linco). PP was determined with a double-antibody RIA using rabbit antihuman PP antibodies (Linco), 125I-labeled human PP (Peninsula Laboratories, Merseyside, England), and human PP (Linco) standard (27). All measurements were performed in duplicate.

Data analysis

FSIGT data were analyzed with the minimal model technique (21, 22, 28, 29) that provides parameters SI and SG (glucose effectiveness). SG can be factored out into two components: SG at basal insulin (BIE) and SG at zero insulin, i.e. glucose disappearance rate per se (GEZI) (30). The C-peptide minimal model (22) and that of posthepatic insulin provide the parameters BSR (basal B cell secretion rate), the fractional clearance of C-peptide, and first-phase insulin secretion ({phi}1) and {phi}2, which are the dynamic suprabasal first- and second-phase B cell sensitivity to glucose, respectively. Total B cell insulin secretion was calculated per unit volume as the integral of C-peptide secretion rate throughout the 3-h duration of the experiment, and hepatic insulin extraction as the percent difference between total B cell insulin secretion and the posthepatic insulin delivery (22). The areas under the curve (AUC) for insulin and C-peptide were calculated using the trapezoidal rule. The acute insulin response to glucose (AIRG) and the acute C-peptide response to glucose (ACPG) were calculated by averaging the suprabasal concentration of insulin or C-peptide between 3 and 10 min after glucose injection. We also calculated two indices: the disposition index, by multiplying SI times AIRG (31); and the B cell adaptation index, by multiplying SI times {phi}1 (20). The disposition index (SI times AIRG) weighs SI with the ambient peripheral insulin during the first phase. It is a peripheral measurement and does not necessarily reflect pancreatic secretion of insulin. The adaptation index (SI times {phi}1), on the other hand, relates SI directly to a descriptor of B cell function, because {phi}1 is a direct prehepatic variable that derives from C-peptide (22) and involves the active mechanism of the B cells to release insulin under a glucose stimulation. The adaptation index, therefore, tells us how the pancreas reacts to a possible alteration in SI. It should be emphasized that the FSIGT was performed without additional injection of tolbutamide or insulin (21), because it was recently shown that SI is the same in the different protocols (32), providing that there is sufficient insulin, as was the case in our study; whereas SG may be different, because it depends upon the amount of insulin present (32, 33). In our case, however, SG estimations also can be used, because insulin pattern and amount are not different in the two groups.

Statistics

Model parameters were calculated by the computer program MINMOD (34) and by a specific program for B cell secretion (35). The iv glucose elimination rate was quantified with the glucose tolerance index, KG, calculated as the slope of the natural logarithm of glucose concentration vs. time from 10–30 min. Statistical analysis was performed with the SPSS (Statistical Package for the Social Sciences) for Windows system. Differences in mean values between groups were analyzed by means of ANOVA for repeated measurements for the glucose, insulin, and C-peptide concentrations during the FSIGT, and of unpaired Student’s t test for the clinical parameters and parameters calculated from the FSIGT. Statistical significant difference was assumed at P < 0.05. Pearson’s product-moment correlation was used to estimate linear relationships between variables. All data and results are given as mean ± SEM, unless otherwise stated.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Glucose, insulin, and C-peptide

Fasting blood glucose levels in the E subjects were 4.9 ± 0.1 mmol/L vs. 4.5 ± 0.1 mmol/L in the Y subjects (P = 0.040) when performing the OGTT. The respective 2-h blood glucose values were 6.1 ± 0.3 mmol/L and 6.1 ± 0.3 mmol/L (not significant). Plasma C-peptide levels were higher in the E subjects (P = 0.034), whereas serum insulin levels did not differ between the two groups (Table 1Go).


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  		Table 1. Fasting levels of glucose, insulin, and C-peptide and metabolic parameters calculated from FSIGT for the two different groups

 
FSIGT

Immediately after the glucose injection, plasma glucose, serum insulin, and plasma C-peptide rose rapidly, with peak levels after 3 min; then the levels declined (Fig. 1Go). Plasma glucose levels were higher in E than in Y individuals at each individual time point from min 15 after glucose administration through min 120 (P = 0.028 or less), and KG was significantly lower in E than in Y subjects (P = 0.019). Serum insulin levels did not differ significantly between the groups at any individual time point, whereas plasma C-peptide levels were significantly elevated in the E subjects, both at basal preglucose injection and at all time points from 60 min after glucose challenge and throughout the 180-min study period (P = 0.030 or less). Similarly, AIRG, ACPG, and AUCinsulin did not differ between the two groups, whereas AUCC-peptide was higher in the E subjects (P = 0.020). The parameter {phi}1 did not differ between the groups (P = 0.952), whereas {phi}2 was lower in the E subjects (P = 0.034). Furthermore, BSR showed a higher value in E subjects than in Y subjects (P = 0.026), whereas total amount of released insulin throughout the 180-min study period did not differ between the groups.



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  		Figure 1. Concentrations of plasma glucose (upper panel), serum insulin (middle panel), and plasma C-peptide (lower panel) during the iv glucose test (300 mg/kg) in two groups of healthy subjects with normal glucose tolerance, consisting of E subjects (64 yr old, 10 females and 10 males) or Y subjects (27 yr old, 10 females and 10 males). Means ± SEM are shown.

 
SI was similar in the two groups. In contrast, SG was lower in the E than in the Y subjects (P = 0.004), because of a significantly lower GEZI (P = 0.007) (Table 2Go). Furthermore, hepatic insulin extraction was higher in the E than in the Y subjects (P = 0.013). Finally, both the disposition index (SI x AIRG; 184 ± 22 10-4 min-1 in E subjects vs. 242 ± 47 10-4 min-1 in the Y subjects, P = 0.277) and the adaptation index (SI x {phi}1; 102 ± 14 min-2/mmol/L in E vs. 98 ± 12 min-2/mmol/L in Y subjects, P = 0.83) were not different between the groups. In contrast, the product SI x {phi}2 was lower in the E subjects (0.38 ± 0.06 10-4 min-3/(mmol/L) vs. 0.74 ± 0.13 10-4 min-3/(mmol/L) of Y subjects, P = 0.016).


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  		Table 2. Plasma levels of leptin, glucagon, and PP in the two different groups

 
Relationships among the metabolic parameters and the iv KG

To study whether parameters from the FSIGT could explain the reduced KG, a univariate correlation analysis was undertaken across both groups, correlating the parameters that were altered by age (i.e. baseline plasma glucose levels, SG, {phi}2, and hepatic insulin extraction rate) with KG. It was found that SG correlated positively (r = 0.579, P < 0.001) and hepatic insulin extraction correlated negatively (r = -0.414, P = 0.003) with KG, whereas no significant correlation was found between KG and baseline plasma glucose (r = -0.21, P = 0.136) or {phi}2 (r = 0.13, P = 0.369). It was also found that SG correlated negatively with hepatic insulin extraction (r = -0.54, P < 0.001). A partial correlation analysis revealed that SG and KG correlated significantly with each other also when removing the correlation that is caused by their mutual association with hepatic insulin extraction (r = 0.508, P = 0.001). Also, estimates of {phi}1 correlated with KG, such as AIRG (r = 0.433, P = 0.005), serum insulin at min 3 (r = 0.431, P = 0.005), and the increase in serum insulin at min 3 (r = 0.452, P = 0.003). Furthermore, both the disposition index (r = 0.633, P < 0.001) and the adaptation index (r = 0.443, P = 0.004) correlated with KG.

Adaptation to reduced SI

Plotting AIRG vs. SI, we obtained the characteristic hyperbolic function, which did not differ between E and Y subjects (Fig. 2Go). There was also a similar significant negative correlation between SI and {phi}1 in the two groups (in E subjects, r = -0.46, P = 0.046; in Y subjects, r = -0.52, P = 0.018). This shows that neither SI nor its relation to {phi}1 was disturbed in the E subjects.



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  		Figure 2. The relationship between SI and AIRG in two groups of healthy subjects with normal glucose tolerance, consisting of E subjects (64 yr old, 10 females and 10 males) or Y subjects (27 yr old, 10 females and 10 males).

 
Leptin, glucagon, and PP

Plasma levels of leptin and glucagon did not differ between E and Y subjects, whereas plasma PP was significantly higher in E subjects (Table 2Go). Plasma leptin was, as expected, higher in females than in males (Table 2Go) and correlated significantly to BMI in both males (r = 0.717, P < 0.001) and females (r = 0.789, P < 0.001). After adjustment for BMI, plasma leptin levels correlated significantly to fasting insulin and C-peptide, to AUCinsulin and AUCC-peptide, to AIRG, and to fasting glucagon in both genders (P < 0.05). Plasma glucagon showed significant correlation with baseline circulating levels of insulin (r = 0.57, P < 0.001) and C-peptide (r = 0.54, P < 0.001), as well as with AIRG (r = 0.58, P < 0.001), ACPG (r = 0.54, P < 0.001), AUCinsulin (r = 0.49, P = 0.001), AUCC-peptide (r = 0.43, P = 0.006), SI (r = -0.41, P = 0.008), and plasma leptin (r = 0.36, P = 0.037) but not with other metabolic parameters obtained in the FSIGT or with plasma PP (r = 0.03, P = 0.854). Plasma PP did not display any gender difference (89.0 ± 10.6 pg/mL in males vs. 99.2 ± 17.6 pg/mL in females, P = 0.625) and did not show any significant correlation with BMI, with the metabolic parameters obtained in the FSIGT, or with plasma leptin or glucagon.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study exercised great care when recruiting the subjects for the examinations. Therefore, the age variation is negligible within the two groups that have identical numbers of males and females, and the 2-h blood glucose level after a 75-g OGTT and BMI were not different between the groups. It may be argued that equivalent oral glucose tolerance and BMI have different clinical implications in E vs. Y age groups, given that aging might influence glucose metabolism differently in different tissue types and that the body fat percentage might be different in different age groups, in spite of identical BMI (36). However, it is also known that manifest IGT is more related to obesity than to aging (4, 37, 38); and thus, differences in BMI between different age groups might be a most important confounder. Therefore, although no measures on degree of central adiposity or fat percentage are available in our study groups, we standardized BMI (in addition to age, gender, and oral glucose tolerance) when selecting the groups, to avoid different body weight as a confounder. Our results showed that, in spite of a normal 2-h glucose in OGTT, KG and SG were reduced in E subjects. Regarding the parameters characterizing the B cell activity, total posthepatic delivery of C-peptide increased, whereas glucose sensitivity of the {phi}2 decreased by age. In contrast, glucose sensitivity of {phi}1, posthepatic delivery of insulin, and SI were not altered in the E subjects. Finally, hepatic insulin extraction increased by age.

The most impressive difference between the E and Y subjects was the low SG in the E subjects. Previous studies also including subjects with IGT have not demonstrated any age-related influence on SG (11, 13), whereas one study has shown impairment of insulin-independent glucose uptake under basal conditions in elderly subjects (39). The clinical importance of the reduced SG in the E subjects in our study is supported by the finding that SG correlated to the glucose elimination rate. In the E subjects in the present study, it was GEZI that was reduced, when compared with the Y subjects. This means that the impairment seems to be ascribed to the totally insulin-independent processes. Other evidences for this are the unchanged insulin sensitivity indices, both at BIE and under dynamic insulin conditions (SI). Theoretically, the reduced SG might reside in the liver (decreased glucose uptake or failure of suppression of glucose production), in the peripheral muscle tissue (decreased glucose uptake), or in the central nervous system. It might be speculated that the reduced glucose uptake is executed in the central nervous system, because it has been demonstrated that the brain weight is reduced by aging, being 7% less at 80 than at 20 yr of age (40); and the glucose transport in the brain is reduced by aging in rats (41). However, the minimal model does not allow differentiation between the potential sites for the reduced SG in the elderly. The reduction of SG, in studies using the minimal model, has recently been a topic stimulating discussions as to whether it is a true physiological phenomenon or just a model artifact (32, 33, 42, 43). In fact, reduction of SG might be accompanied by, and may be caused by, a reduction of the prevailing insulin concentrations, (32, 33, 43). In the present study, however, insulin was not different between the groups; and therefore, the observed differences in SG between the two groups seem to be valid, and its reduction seems to be unrelated to factors other than age.

Several previous studies have demonstrated reduced insulin sensitivity in old age (3, 4, 5, 6, 7, 8, 9, 10, 11), whereas several other studies, using the same methodological protocols, failed to demonstrate any reduction in tissue insulin sensitivity by age (12, 13, 14, 15, 16). A difference between the FSIGT and hyperinsulinemic euglycemic clamp techniques is that they measure tissue sensitivity to insulin at different insulin levels: in the FSIGT, insulin concentrations are at lower, more physiological levels; whereas in the clamp studies, plasma insulin levels are usually elevated to 800–1000 pmol/L (3, 4, 5, 6, 7, 44). Studies using hyperinsulinemic clamp techniques have reported inhibition of insulin sensitivity in-old age groups by approximately 30% (45), whereas studies using lower rates of insulin have reported a higher degree of inhibition at old age (5, 6, 11). This would imply that it would be easier to detect changes in insulin sensitivity in old-age groups by techniques using lower levels of insulin, such as the FSIGT. Therefore, the lack of any difference in our present study seems to have other explanations. A possible explanation is that the subjects in our study all had normal 2-h glucose values in OGTT, whereas in previous studies, the older subjects have had manifest glucose intolerance (11). Therefore, it is possible that reduction in insulin sensitivity in several previous studies on subjects of old age (3, 4, 5, 6, 7, 45), is a sign of manifest oral glucose intolerance, rather than an effect of aging per se.

Under normal conditions, insulin secretion and insulin sensitivity display a hyperbolic relation, in that insulin secretion experiences a compensatory increase when insulin sensitivity is reduced (21, 36, 44). In IGT, the increase in insulin secretion is inadequate when insulin sensitivity is reduced (44), and it is primarily the first phase insulin secretion that is inadequately increased (20, 46). We found that in the E subjects, the measures of {phi}1 were not significantly different from those of Y subjects (AIRG and {phi}1), confirming previous studies (4, 10, 11, 12, 17); and the hyperbolic relation between SI and {phi}1 was not different between E and Y subjects (Fig. 2Go). Hence, it seems that the E subjects had normal {phi}1 and normal adaptive capacity for changes in SI.

In contrast, the E group had a diminished glucose sensitivity for the second phase insulin secretion, which begins approximately 10–15 min after glucose administration, confirming previous reports (10, 17). The molecular basis for this B cell defect remains to be established. It could be speculated that this B cell defect in the E subjects would contribute to the reduced glucose elimination rate, in spite of the normal {phi}1. This, in turn, would make these subjects more vulnerable for deterioration of the glucose tolerance if tissue sensitivity to insulin is reduced, even though the first phase insulin secretion would experiences a compensatory increase. In spite of the glucose sensitivity in the second phase insulin secretion being reduced in old age, the total amount of insulin released during the second phase was increased, as evident by the increased AUCC-peptide. It could be argued that the reduction of {phi}2, despite an increase of the total AUCC-peptide, may be interpreted as a model biased result. However, our evidence is justified by reminding that the sensitivity to glucose of the second-phase B cell secretion ({phi}2) quantifies a dynamic process, i.e. the ability of the pancreas to suprabasally release insulin under a dynamic stimulation (22, 28, 35). Because of the simultaneously increase of hepatic extraction of insulin, the resulting peripheral serum insulin levels were not significantly different between the groups. This should have provided a similar glucose-lowering effect in the two groups. Hence, the physiological significance of the reduced glucose sensitivity of second-phase B cell secretion in the E subjects remains to be established.

In the E group, the 180-min plasma C-peptide levels after glucose administration were elevated, as compared with the Y group. This may give the impression that the disappearance rate of C-peptide was reduced in the E subjects. However, this was caused by elevated baseline levels, because plasma C-peptide at 180 min had returned to baseline levels in all subjects. Also, the model-derived clearance of C-peptide was not different in the two groups. This study also demonstrated an increased hepatic insulin extraction in the E subjects. This increased extraction rate correlated to the reduction in SG and, therefore, also to the reduction in glucose elimination, which yields the speculation that there is a direct link between these two parameters. However, more studies are required to establish these mechanisms and to clarify how this increase occurs and to identify the signals that generate it. A hepatic insulin extraction rate of 70–80% might seem high, because it is known that the liver degrades approximately 50% of insulin during the first passage (47). However, our figure represents the extraction rate of insulin during the entire 180-min period, which is the integrated result of several passages through the liver.

In this study, we also measured leptin and the two islet hormones, glucagon and PP. We found that leptin levels were higher in females than in males and correlated to insulin and glucagon, which are well-known phenomena (24, 48, 49). We found, however, that leptin levels were not different in the Y and E subjects, suggesting that, in humans, there is no age-related change in circulating leptin. Similarly, plasma glucagon levels were not different between the two age groups. Although it is well established that glucagon increases circulating glucose levels and also stimulates insulin secretion (50), its potential involvement in glucose intolerance is not known. However, a close relationship between insulin and glucagon secretion seems to exist under normal conditions, and consequently, we confirmed that plasma glucagon correlates to parameters of insulin secretion. We found also that fasting glucagon correlated negatively with SI but did not correlate to SG.

An interesting observation in this study, was that plasma levels of PP were significantly elevated in the E subjects without any relation to gender or to the parameters of the FSIGT. This is a novel finding, the relevance of which needs to be studied. The function of PP is not completely known. Its circulating levels are increased during hypoglycemia (51), and circulating PP has been shown to reflect vagal nerve activity (52). Whether the increase in PP in old age might be involved in the reduction in SG and glucose elimination rate is possible, but no evidences confirming such an assumption were found in this study, because circulating PP did not correlate to SG or to glucose elimination rate.

We conclude that, in carefully selected elderly (64 yr) and young (27 yr) subjects of both genders and with no difference in glucose tolerance between the groups, old age is associated with reduced SG, increased hepatic insulin extraction, and a reduced glucose sensitivity in the second phase of insulin secretion. Old age is also associated with high plasma PP levels but no change in plasma leptin or glucagon. We suggest that the impaired elimination of glucose in old subjects with maintained normal glucose tolerance is caused mainly by reduced SG and impaired second phase insulin secretion.


   Acknowledgments
 
The authors are grateful to Lilian Bengtsson, Ulrika Gustavsson, Eva Holmström, and Margaretha Persson for expert technical assistance.


   Footnotes
 
1 This work was supported by the Swedish Medical Research Council (Grant 14X-6834); Ernhold Lundström, Albert Påhlsson and Novo Nordic Foundations, Swedish Diabetes Association, Malmö University Hospital, and the Faculty of Medicine, Lund University. Back

Received March 23, 1998.

Revised June 3, 1998.

Accepted June 9, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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