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Independent Influence of Age on Basal Insulin Secretion in Nondiabetic Humans

Consiglio Nazionale delle Ricerche Institute of Clinical Physiology (P.I.), 56126 Pisa, Italy

Address all correspondence and requests for reprints to: Patricia Iozzo, M.D., CNR Institute of Clinical Physiology, Via Savi, 8, 56126 Pisa, Italy. E-mail: pisamet{at}po.ifc.pi.cnr.it

	Abstract

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Glucose tolerance deteriorates with aging. To test whether age per se impairs basal ß-cell function, we analyzed retrospective clamp data from a large group (n = 957) of nondiabetic Europeans over the 18–85 yr age range (the European Group for the Study of Insulin Resistance database). In this cohort, the fasting posthepatic insulin delivery rate [IDR, obtained as the product of clamp-derived posthepatic insulin MCR and fasting plasma insulin concentration] was 8.9 (6.6) mU/min (median and interquartile range), and it gradually increased with age. In univariate association, IDR was positively related to body mass index (P < 0.0001), fasting plasma glucose (P < 0.01), and waist-to-hip ratio (P < 0.001), and negatively related to insulin sensitivity (P < 0.0001). After controlling for these factors in a multivariate model, IDR declined significantly with age (P < 0.0001). This intrinsic effect of age on IDR was similar in men and women, and it averaged 25% between 18–85 yr. In the same statistical model, insulin MCR (but not fasting plasma insulin concentration) showed a significant (P < 0.0001) inverse relation to age. We conclude that, in nondiabetic Caucasian subjects of either sex, senescence per se is associated with a progressive decline in both insulin clearance and basal insulin release.

	Introduction

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THE PREVALENCE of type 2 diabetes has been estimated to increase linearly with age, both in men and in women (1). More in general, the notion that glucose tolerance progressively worsens with advancing age seems to be beyond controversy (2). Though suggestive, this evidence does not necessarily imply a contributory role of age per se, and the pathophysiologic mechanism(s) underlying age-induced glucose intolerance remain incompletely understood (3). Because insulin is the main regulator of glucose homeostasis, age-related defects involving both insulin action and insulin secretion have been sought.

Several in vivo studies have reported a significant age-dependent diminution of glucose-stimulated insulin secretion (4, 5, 6), whereas others have been unable to document any change (7, 8, 9). In vitro, decreased (10), unchanged (11, 12), or even increased (13) ß-cell responses to a glucose challenge with age have been described. The insulin responses to glyburide (14), isoproterenol (15), and glyceraldehyde (16) seem to be unaffected by aging; whereas the response to tolbutamide (17), arginine (17), or leucine (18) may be reduced, and that to gastric inhibitory polypeptide has been found to be either decreased (19) or unchanged (20). Fasting insulin secretion has received considerably less attention. Whereas fasting plasma insulin concentrations are unanimously recognized to be increased in the elderly (5, 21, 22), subtler disturbances of basal insulin release, with a reduction in the amplitude and mass of rapid pulses and a decreased frequency of ultradian pulses, seem to characterize normal aging (23).

Large-scale data on the influence of age on insulin release in man are lacking. In human population studies, the progressive changes in anthropometric and metabolic variables that occur with age mask the intrinsic effect of age on insulin secretion. In the present work, we used the database of the European Group for the Study of Insulin Resistance (including 957 clamp studies carried out in healthy Caucasian subjects ranging in age from 18–85 yr) in an attempt to delineate the age-related pattern of basal insulin secretion while controlling for the effects of changes in body mass and composition and insulin sensitivity.

	Subjects and Methods

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Subjects

Twenty clinical research centers in Europe agreed to pool their available clamp studies, on the condition that the study subjects met the following criteria: 1) no clinical or laboratory evidence of cardiac, renal, liver, or endocrine disease; 2) a fasting plasma glucose concentration less than 6.7 mmol/L and normal glucose tolerance by WHO criteria (24); 3) normal blood pressure (<160/95 mm Hg); 4) no recent change (10%) in body weight; and 5) no current medication. The present analyses were based on a total of 957 cases, of which 407 originated in northern Europe (Finland, Sweden, and the United Kingdom), 217 in central Europe (Denmark, Germany, and Switzerland), and 333 in southern Europe (Italy, Yugoslavia, and Greece). At each center, the protocol was reviewed and approved by the local ethics committee, and informed consent was obtained from all subjects before their participation.

Protocol

The minimum of information required for each case was: age, anthropometric variables, fasting and steady-state (i.e. final 40 min of a 2-h clamp, see below) plasma glucose, and insulin measurements. Height was measured to the nearest centimeter, weight to the nearest kilogram. The waist-to-hip circumference ratio (WHR), which was available in a subset of 529 subjects from 11 centers, was determined by measuring the waist circumference at the narrowest part of the torso, and the hip circumference in a horizontal plane at the level of the maximal extension of the buttocks.

Insulin action was measured in all subjects, by the euglycemic insulin clamp technique (25), using an insulin infusion rate of 1 mU·min^-1 per kilogram of body weight, as previously described (26).

Analytical procedures

Plasma glucose was measured by the glucose oxidase method. Plasma insulin concentrations were measured by RIA.

Data analysis

The body mass index (BMI) was obtained by dividing body weight (in kilograms) by the square of height (in meters). The insulin-stimulated total glucose disposal rate, as measured during steady-state euglycemic hyperinsulinemia (last 40 min of the clamp), was normalized per kilogram of lean body mass (M_lbm); the latter was calculated by Hume’s formula (27). In a subgroup of 457 subjects, direct measurements of lean body mass, by electrical bioimpedance [or the equivalent labeled water technique (28)], were available. The measured and estimated values were very well correlated with one another (r = 0.77, P < 0.0001). The estimated LBM value was therefore used to normalize M values in the entire database.

The rate at which endogenous insulin is delivered to the systemic circulation after transhepatic passage (termed posthepatic insulin delivery rate, IDR) was obtained as the product of fasting systemic plasma insulin concentration and posthepatic insulin clearance rate (MCRi). The latter was measured from the clamp experiment as the ratio of the exogenous insulin infusion rate to the plasma insulin concentration attained during the final 40 min of the 2-h clamp. The rationale of this measurement is that, because of the fast metabolic clearance rate of insulin, a primed-constant infusion of exogenous hormone, lasting 120 min, results in steady-state plasma insulin levels. Under these conditions, the ratio of exogenous insulin infusion rate to steady-state plasma concentration equals the metabolic clearance rate of systemically administered insulin, provided that endogenous insulin release ceases. Fink and co-workers (29) have validated this approach by showing that physiological insulin infusions under clamp conditions cause a prompt (60 min) and profound (>70%) inhibition of endogenous C-peptide levels equally in elderly and nonelderly subjects. The further assumption is made that the insulin clearance measured during the clamp, i.e. at plasma insulin concentrations in the range of 50–150 µU/mL in the present studies, applies to the fasting range of peripheral plasma insulin concentrations (3–35 µU/mL). This assumption has been verified in studies using the euglycemic insulin clamp technique, in which liver saturation of insulin extraction occurred for prehepatic plasma insulin levels in excess of 150–200 µU/mL (30). In turn, the systemic (or posthepatic) insulin clearance (MCRis) is related to the clearance rate of endogenous insulin entering the circulation through the portal vein (MCRip) through the following relationship: MCRis = MCRip (1 - h), where h is the hepatic fractional extraction of the hormone. Similarly, IDR equals the fasting rate of insulin release from the ß-cell multiplied by (1 - h) (31). Thus, IDR is proportional to pancreatic release through a factor represented by first-pass hepatic insulin extraction. The interindividual variability of IDR is a compound of the variability of ß-cell release and that of fractional hepatic extraction of insulin.

Statistical analysis

Data are presented as mean ± SD. Fasting plasma insulin concentration, MCRi, IDR, and M_lbm were transformed into their natural logarithms to normalize their distributions; these data are summarized as median, and interquartile range. The log-transformed values of these variables were used in all statistical analyses. Group comparisons were carried out by ANOVA. Simple- and multiple-regression analyses were carried out by standard techniques. To formally account for intercenter variability, dummy variables [(n-1) for n centers] were included in all regression models.

	Results

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The general characteristics of the whole cohort were: age 43 ± 17 yr; BMI 25.7 ± 4.8 kg·m^-2; WHR 0.91 ± 0.08 and 0.86 ± 0.10 for men and women, respectively; fasting plasma glucose 5.05 ± 0.51 mmol/L; fasting plasma insulin 8.5 (5.6) µU/mL; insulin sensitivity (M_lbm) 48.6 (22.6) µmol·min^-1·kg^-1; MCRi 1.1 (0.4) 1·min^-1; and fasting posthepatic IDR 8.9 (6.6) mU/min. When these characteristics were stratified by gender-specific age quartiles (Table 1), in both men and women, there was a trend for BMI, MCRi, and fasting plasma insulin concentrations to increase between the first and third quartile and to decrease in the last quartile. WHR increased steadily across the age quartiles in men and women alike, whereas fasting plasma glucose concentrations rose in men but were stable in women. IDR also showed a biphasic age pattern in men, as well as in women, whereas insulin sensitivity changed as the mirror image of IDR.

View larger version (17K): [in this window] [in a new window]   Figure 1. Posthepatic IDR, as a function of age, in 957 nondiabetic subjects. Lines are predictions from a multiple-regression model, adjusting for gender, BMI, fasting plasma glucose, and insulin sensitivity (calculated at the mean population values and drawn within the actual age range of the study population). The dotted line is the predicted dependence of IDR on age, after further adjustment by WHR.

In the whole dataset, the posthepatic insulin clearance rate was found to be significantly related to insulin sensitivity (Fig. 2). Furthermore, after adjusting for insulin sensitivity and also for gender, BMI, and fasting plasma glucose, insulin clearance was significantly (P < 0.0001) related to age in an inverse fashion, whereas similarly adjusted fasting plasma insulin levels were stable throughout the age range (P = 0.63) (Fig. 3).

View larger version (30K): [in this window] [in a new window]   Figure 2. Direct relationship between posthepatic insulin clearance and insulin sensitivity of glucose uptake in 957 nondiabetic subjects. FFM, .

View larger version (20K): [in this window] [in a new window]   Figure 3. Age-related changes in posthepatic insulin clearance rate and fasting plasma insulin concentration in 957 nondiabetic subjects. Data are point estimates, by decade of age, from a multiple regression model adjusting by center, gender, BMI, fasting plasma glucose, and insulin sensitivity. Insulin clearance (P < 0.0001), but not plasma insulin levels (P = 0.63), declines with age.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

The present analyses are based on data from nondiabetic subjects of either sex, covering a wide range of age (18–85 yr) and BMI (15–55 kg/m^-2). Though not a random population sample, the European Group for the Study of Insulin Resistance cohort reproduces the salient characteristics of a general population of nondiabetic subjects, as previously detailed (32). By selection, our study group did not include persons with impaired glucose tolerance or overt diabetes, i.e. those individuals in whom ß-cell dysfunction may have a specific genetic basis, the expression of which is affected by the process of aging (33, 34). In a nondiabetic population, the impact that normal senescence per se exerts on insulin secretion can be adequately assessed. Clearly, cross-sectional data can only provide inferences on the effects of aging; longitudinal observations over a time span of approximately 70-yr, on the other hand, are virtually impossible to carry out.

ß-cell function is expressed in a variety of responses, such as early- and late-phase insulin response to iv or oral glucose, potentiation of glucose-induced insulin secretion by substrates other than glucose and by gastrointestinal hormones, insulin response to mixed meals, priming and potentiation of glucose-induced insulin release, and entraining of spontaneous oscillatory cycles (23, 35). Although basal insulin release is just one of ß-cell functional modes, consistent evidence shows that, in nondiabetic subjects, stimulated insulin secretion is roughly proportional to fasting insulin release (35, 36). By way of example, in a subset of the present cohort (n = 34) in whom the insulin response to oral glucose was available, the fasting rate of insulin delivery was closely related to glucose-stimulated insulin delivery (Fig. 4). Consequently, interindividual differences and correlates of basal insulin release may be safely assumed to apply also to stimulated ß-cell responses.

View larger version (17K): [in this window] [in a new window]   Figure 4. Direct relationship between fasting and post-OGTT rates of posthepatic insulin delivery in a subgroup of nondiabetic subjects.

Main findings

A larger body mass, insulin resistance, and a higher fasting plasma glucose concentration all were independently associated with higher IDR values; once these factors were controlled for, IDR showed a substantial decline over a time span of approximately 70 yr of age. This effect was similar in men and women and was stronger when the positive influence of fat distribution on IDR was taken into account.

The finding of higher IDR values in obese or insulin-resistant subjects is consistent with known physiological mechanisms. Thus, obesity leads to ß-cell hypertrophy (38) and enhanced insulin secretory capacity in the basal state, as well as in response to secretagogues (39). Resistance to insulin action on glucose utilization, on the other hand, feeds back to the ß-cell through multiple signals, the most important of which is an elevation in plasma glucose concentration. Because of the size of the present study sample, even the fasting plasma glucose concentration, which is a highly homeostatic variable, emerged as a positive determinant of fasting insulin release. The further impact of central fat accumulation on IDR is a novel concept that has emanated from a previous analysis of this database (26). In the aggregate, the current data provide a paradigm for the operation of opposing physiological influences on a key homeostatic function: the rate of basal insulin release is the sum of positive stimuli (BMI, WHR, insulin resistance, and plasma glucose) countering the negative influence of age per se. Because, in this cohort (much like the general population), BMI, WHR, and glucose levels rose with age, the reciprocal association between age and IDR was completely masked, because the unadjusted IDR values generally increased with age.

Importantly, the intrinsic influence of age on basal insulin release could not be inferred from the fasting plasma insulin concentrations, because these did not show any significant decrease with age, even after adjustment for confounders (Fig. 3). This result is explained by the concomitant age-related decrease in posthepatic insulin clearance, which maintains peripheral insulin levels in the face of decreasing insulin release (Fig. 3). The effect of aging on insulin clearance has been previously described in a comparison of a group (n = 14) of nonobese subjects with a mean age of 70 yr, with a younger group (mean age = 35 yr) (29). The current data confirm and extend the finding by showing that the impact of age on insulin clearance is present in both sexes through an ample age range and is independent of both obesity and insulin sensitivity.

Thus, senescence is associated with a specific reduction in the ability of ß-cells to sustain basal insulin release and a reduced capacity of peripheral tissues (mostly, the liver) to degrade circulating insulin. The age-related changes in body size and composition impose a chronic secretory strain on the endocrine pancreas. That such a functional overload may exhaust the ß-cell, eventually resulting in impaired glucose tolerance, is plausible; this possibility, however, cannot be tested in this database that only included individuals with preserved glucose tolerance. Presumably, subjects carrying a high genetic risk of ß-cell dysfunction went on to develop glucose intolerance and were therefore selected out of this cohort.

Our results reconcile previous studies (4, 5, 6, 7, 8, 9, 14, 15, 16, 17, 18, 19, 20), in which either the small sample size or failure to correct for confounders led to contrasting conclusions. It should also be mentioned that, in many studies, insulin secretion has been estimated from plasma insulin concentrations alone (4, 5, 6, 7, 8, 9) or from model-derived indices of ß-cell function (40). Of note is that, in the only other large series of simultaneous measurements of insulin sensitivity and insulin secretion (obtained in 380 healthy young subjects studied by the modified intravenous glucose tolerance test-minimal model analysis), the acute insulin response to iv glucose was negatively modulated by age, even within the narrow age range explored (18–32 yr) (41).

Among the wealth of studies that have attempted to define the pathophysiology of the deterioration of glucose tolerance that typically accompanies senescence (2), many have focused on glucose-stimulated ß-cell function (4, 5, 6, 7, 8, 9), rather than basal insulin release. However, experimental manipulations of basal ß-cell function have a profound impact on glucose homeostasis. Thus, inhibition of basal insulin release in the dog (42), as well as in healthy (43) or type 2 diabetic subjects (44), has been shown to up-regulate hepatic glucose production and down-regulate peripheral glucose uptake and intracellular glucose oxidation. These effects can be reversed by basal insulin supplementation in type 2 diabetic patients (45). These observations support the notion that an age-related decrease in basal insulin release (such as that shown in the present analysis) can make a substantial contribution to the development of glucose intolerance in the elderly. In turn, both insulin deficiency and glucose intolerance have been implicated in the progression of senescence, the former by accelerating protein catabolism (46), the latter by raising the level of circulating reducing sugars (47).

In summary, our data are compatible with the conclusion that aging per se is associated with a continuous decrease in basal insulin release, beginning early in life. The size of the age effect is such as to increase the likelihood of developing glucose intolerance. Modifiable anthropometric and metabolic factors (body mass, fat distribution, and insulin sensitivity) contribute to sustain insulin release during the aging process but are likely to impose a further burden on ß-cell function, thereby enhancing the risk of ß-cell exhaustion.

	Footnotes

 
¹ H. Beck-Nielsen (University of Odense, Denmark), P. Bell (University of Belfast, United Kingdom), E. Bonora (University of Verona, Italy), B. Capaldo (Federico II University, Naples, Italy), P. Cavallo-Perin (University of Turin, Italy), S. Del Prato (University of Padova, Italy), E. Ferrannini (CNR Institute of Clinical Physiology, Pisa, Italy), D. Fliser (University of Heidelberg, Germany), A. Golay (University of Geneva, Switzerland), L.C. Groop (Lund University, Sweden), S. Jacob (Stadtklinik, Baden-Baden, Germany), M. Laakso (University of Kuopio, Finland), N. Lalic (University of Belgrade, Yugoslavia), G. Mingrone (Catholic University, Rome, Italy), A. Mitrakou (University of Athens, Greece), G. Paolisso (University of Naples II, Napoli, Italy), K. Rett (University of München, Germany), U. Smith (University of Göteborg, Sweden), M. Weck (Kreischa, Germany), H. Yki-Järvinen (University of Helsinki, Finland).

Received August 14, 1998.

Revised November 23, 1998.

Accepted December 4, 1998.

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