help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Meneilly, G. S.
Right arrow Articles by Elahi, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Meneilly, G. S.
Right arrow Articles by Elahi, D.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH
Hazardous Substances DB
*GLUCAGON
Medline Plus Health Information
*Seniors' Health
The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 8 2925-2932
Copyright © 1998 by The Endocrine Society

Original Studies

The Effect of Age and Glycemic Level on the Response of the ß-Cell to Glucose-Dependent Insulinotropic Polypeptide and Peripheral Tissue Sensitivity to Endogenously Released Insulin1

Graydon S. Meneilly, Alice S. Ryan, Kenneth L. Minaker and Dariush Elahi

Department of Medicine (G.S.M., K.L.M., D.E.), Division of Gerontology, Beth Israel Hospital, Harvard Medical School, Boston, Massachusetts 02215; Geriatric Medicine Unit (K.L.M., D.E.), Division of General Internal Medicine, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114; Department of Medicine (G.S.M.), Division of Geriatric Medicine, University of British Columbia, Vancouver V6T 1Z3 British Columbia; Department of Medicine (A.S.R., D.E.), University of Maryland School of Medicine and Geriatrics Research Education and Clinical Center/Baltimore Veterans’ Administration Medical Center, Baltimore, Maryland 21201

Address all correspondence and requests for reprints to: Dariush Elahi, Ph.D., Geriatrics Research Laboratory, GRJ 1215, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114-2696.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Normal aging is characterized by a progressive impairment in glucose tolerance. An important mechanism underlying the glucose intolerance of aging is an impairment in glucose-induced insulin release. These studies were conducted to determine whether the age-related impairment in insulin release was caused by a decreased ß-cell sensitivity to glucose-dependent insulinotropic polypeptide (GIP). Thirty-one Caucasian men were divided into four groups: two young groups (age range: 19–26 yr, n = 15) and two old groups (age range: 67–79 yr, n = 16). Each volunteer participated in three studies (n = 93 clamps). Hyperglycemic clamps were conducted at two doses [basal plasma glucose (G) + 5.4 mmol/L and G + 12.8 mmol/L] for 120 min. In the initial hyperglycemic clamp, only glucose was infused. In subsequent studies, GIP was infused at a final rate of 2 or 4 pmol/kg-1·min-1 from 60–120 min. Basal plasma insulin and GIP levels were similar in the young (41 ± 6 and 51 ± 6 pmol/L) and the old subjects (42 ± 6 and 66 ± 12 pmol/L) in all studies. First- and second-phase insulin responses were similar during the control study and during the first 60 min of each GIP infusion study in both groups. The 90–120 min GIP values were similar between groups and between hyperglycemic plateaus during the 2 and 4 pmol/kg-1·min-1 GIP infusion (young: 342 ± 28 and 601 ± 44 pmol/L, old: 387 ± 45 and 568 ± 49 pmol/L). In response to the GIP infusions, significant increases in insulin occurred in young and old at both glucose levels (P < 0.01). The potentiation of the insulin response caused by GIP was greater in the young subjects than in the old, in the G + 5.4 mmol/L studies (P < 0.05). However, the insulin response to GIP was similar in both young and old during the G + 12.8 mmol/L clamps. The insulinotropic effect of the incretin was higher in the young and in the old, in the G + 12.8 mmol clamps, than in the G + 5.4 mmol/L clamps.

We conclude that normal aging is characterized by a decreased ß-cell sensitivity to GIP during modest hyperglycemia, which may explain, in part, the age-related impairment in glucose-induced insulin release. We also find that the insulinotropic effect of GIP is increased with increasing levels of hyperglycemia.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE INSULIN response to oral glucose, which is greater than that from IV glucose (1), is caused by the glucose-stimulated secretion of gut hormones that potentiate the insulin response. Several hormones have been identified as candidates for this effect and are termed: incretins. Glucose-dependent insulinotropic polypeptide (GIP, formerly known as gastric inhibiting polypeptide), isolated and characterized by Brown (2) in the early 1970s, is one of the leading candidates for this incretin effect. GIP is secreted from the gut in response to oral glucose, fat, or protein (3) and stimulates insulin release from the pancreas in the presence of hyperglycemia (4, 5, 6). Although the glucose dependency of this peptide for its insulinotropic effect has been known for several years, a dose response curve for GIP at different levels of glycemia has not been determined.

Normal aging is characterized by a progressive impairment in carbohydrate intolerance (7). The glucose intolerance of aging predisposes the elderly to type 2 diabetes. There is evidence suggesting that one of the mechanisms underlying this age-related glucose intolerance is an impairment in the glucose-induced insulin release from the ß-cell (8). It is possible that the decreased insulin responses to glucose that occur with age are caused, in part, by altered responses to GIP. The following study was performed to assess whether normal aging is characterized by a decreased ß-cell sensitivity to GIP.


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

Thirty-one Caucasian men volunteered to participate in 93 clamp studies. The men were divided into 4 groups; 2 young groups (age range: 19–26 yr, n = 15) and 2 old groups (age range: 67–79 yr, n = 16) (Table 1Go). All subjects were nonsmokers, were free of underlying disease, and were not on any medications. Subjects were screened by a detailed medical history, a thorough physical examination, a routine biochemical assessment of blood and urine samples, and an oral glucose tolerance test (OGTT). The oral glucose dose was 40 g/m2 body surface area. All subjects had a normal OGTT, as judged by the National Diabetes Data Group plasma glucose concentration criteria (9). All methods and procedures were approved by the Committee on Clinical Investigations, New Procedures, and New Forms of Therapy at the Beth Israel Hospital and by the Human Experimentation Committee of the University of British Columbia, for 3 separate studies, which were completed at least 3 weeks apart. All tests were performed after an overnight fast and were begun by 0730 h. In all studies, a hyperglycemic clamp was performed for 2 h. At 120 min, the glucose infusion was terminated, and all parameters were followed for an additional 30 min. Hyperglycemic clamps were conducted at 2 doses (basal plasma glucose (G) + 5.4 mmol/L and G + 12.8 mmol/L, corresponding to an approximate level of 11 and 18 mmol/L, Table 1Go). Subjects were assigned to the G + 5.4 or G + 12.8 mmol/L studies using a table of random numbers. During the initial hyperglycemic clamp, only glucose was infused. In the remaining two studies, sterile, pyrogen free, porcine GIP was infused in a primed-constant infusion manner from 60–120 min at a final infusion rate of 2 or 4 pmol/kg-1·min-1. The priming dose lasted 10 min. From 60–63, 63–67, and 67–70 min, the rates were 2.71, 1.93, and 1.41 times the constant rate. The porcine GIP for these studies was obtained from Bachem Laboratories (Torrance, Ca).


View this table:
[in this window]
[in a new window]
  		Table 1. Subject characteristics

 
In each clamp study, glucose production and utilization rates were determined by means of the primed constant-rate infusion technique, with tritiated glucose. A priming dose of 8.5 kBq/kg of sterile, pyrogen free 3-3H-glucose (New England Nuclear, Boston, MA) was administered at -120 min, followed by a constant iv infusion of 85 Bq/kg-1·min-1 for the duration of the experiment. Four arterialized blood samples (10) were taken from a dorsal hand vein enclosed in a box heated to 68–70 C, at 10 min intervals starting at -30 min, to assess basal metabolic parameters. At 0 min, employing the hyperglycemic clamp technique (11) and using an infusion of 20% glucose solution (Travenol, Dearfield, IL), a square wave of hyperglycemia was created and maintained for 120 min (12).

Analytical techniques. Blood samples were collected in heparinized syringes. Samples were obtained every 5 min for plasma glucose determination and every 10 min for determination of plasma insulin, GIP, glucagon, and glucose specific activity. To assess first-phase insulin responses, samples were obtained every 2 min for the initial 10-min period of the clamp. Plasma glucose was immediately assayed by the glucose oxidase method (Beckman Glucose Analyzer II, Beckman Instruments, Inc., Fullerton, CA). Blood samples were collected in a prechilled test tube containing kallikrein-trypsin inhibitor (Trasylol, FBA Pharmaceuticals, New York, NY) and EDTA, as previously described (6). Plasma samples were aliquoted for determination of glucose specific activity and hormones. All determinations were performed in duplicate. Plasma insulin, GIP, glucagon, and the specific activity of glucose were determined as previously described (6, 13, 14, 15).

Statistical analyses. The rate of total appearance (Ra) and disappearance rate of glucose (Rd) were calculated according to the nonsteady-state equations of Steele (16). The volume of distribution of glucose was assumed to be 210 mL/kg (17). Endogenous glucose production was estimated as the difference between the calculated Ra and the exogenous glucose infusion for the appropriate time interval during the clamp (18). MCR, the volume of plasma from which glucose is completely and irreversibly removed in unit time, was calculated as Rd divided by the concentration of glucose for the specific interval (mL/kg-1·min-1) (19).

The mean concentration of glucose, insulin, glucagon, GIP, Ra, and Rd were calculated for each time point for the clamp studies. The trapezoidal rule was used to calculate the integrated responses, over 30-min intervals, for each subject. The integrated response was divided by its time interval, resulting in a mean concentration or value. Means of these individual values were calculated for Ra, Rd, MCR, glucose, insulin, GIP, and glucagon. The differences between and within studies and groups were evaluated with the paired and unpaired t test and repeated-measures ANOVA (20). Correlation coefficients were calculated according to the method of least squares. A sigmoidal-logistic curve fitting technique (21) was employed to examine the dose-response relationships between plasma insulin and glucose use. Except where otherwise stated, results are presented as mean ± SEM.


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

Basal + 5.4 mmol/L. Fasting glucose values were slightly lower in the young group than in the old (Table 2Go). During the clamp, plasma glucose levels were maintained stable in all studies, both before and after the GIP infusion, for each subject. The mean plasma glucose level during the 120-min clamp period was computed for each individual study and expressed as a percentage of the desired goal. The mean glucose level for all hyperglycemic studies at G + 5.4 mmol/L was 10.5 ± 0.2 and 11.2 ± 0.2 mmol/L for the young and old groups, respectively. The mean ± SD plasma glucose concentration for the entire study period was maintained at a percentage of the desired goal for the young and old groups in all studies (99.1 ± 1.4 and 100.4 ± 1.0%). The coefficient of variation (CV) of the glucose concentration during the clamp was also computed for each individual study. The mean CV for all of the studies of the young and old groups were 5.2 ± 2.1 and 3.0 ± 0.9 (SD), respectively.


View this table:
[in this window]
[in a new window]
  		Table 2. Basal glucose and hormone values

 
Basal plasma insulin and GIP levels were similar in young and old volunteers (Table 2Go). Figure 1Go illustrates the plasma insulin and GIP levels for young and old volunteers during the G + 5.4 mmol/L clamps. In response to the square wave of hyperglycemia, a bimodal release of plasma insulin occurred in each subject. The 30–60 min and 90–120 min insulin and GIP values are shown in Table 3Go. The 30–60 min GIP values were similar in young and old subjects in all studies. In the control study, the 90–120 min GIP levels were not different from 30–60 min values in either group. However, during the GIP infusion studies, square waves of GIP levels were detected. The 90–120 min GIP values were similar between groups during the 2 and during the 4 pmol/kg-1·min-1 GIP infusion (Table 3Go).



View larger version (26K):
[in this window]
[in a new window]
  		Figure 1. Plasma insulin (log scale) and GIP levels during G + 5.4 mmol/L hyperglycemic clamps (mean ± SEM). See Subjects and Methods for details of each study.

 

View this table:
[in this window]
[in a new window]
  		Table 3. Insulin and GIP values (pmol/L) during the hyperglycemic clamp study

 
The 30–60 min insulin values were similar in all studies in both age groups (Table 3Go). During the control studies, 90–120 min insulin values were not significantly different between young and old volunteers (Table 3Go). As shown in Fig. 1Go, in response to the GIP infusion, whereas plasma glucose was unchanged, significant increases in insulin occurred in both groups (P < 0.01). The 90–120 min insulin responses were less in the elderly during the 2 (P < 0.08) and during the 4 (P < 0.05) pmol/kg-1·min-1 GIP studies. In the old group, the insulin response tended to decrease during this time, despite continued high levels of GIP. The potentiation of the insulin response caused by GIP was calculated for each individual subject as the difference between 90–120 min insulin values in the GIP infusion and control studies. This insulin response was greater in the young subjects during the 2 (young: 674 ± 126 vs. old: 406 ± 133 pmol/L) and 4 (young: 883 ± 170 vs. old: 433 ± 102 pmol/L, P < 0.05) pmol/kg-1·min-1 GIP infusion. When the 90–120 min insulin response was expressed as a percentage of basal insulin, the insulin response was reduced in the elderly at both the 2 (young: 2862 ± 555 vs. old: 1304 ± 340%, P < 0.05) and 4 (young: 2481 ± 539 vs. old: 1204 ± 200%, P < 0.05) pmol/kg-1·min-1 GIP infusions. Despite the doubling of the dose of GIP, there was no significant augmentation of the insulin response in either group.

Basal + 12.8 mmol/L. Basal glucose levels in the young and old groups were not different (Table 2Go). Plasma glucose levels were maintained stable in all studies throughout the 120-min period. The mean glucose level for all hyperglycemic studies at G + 12.8 mmol/L was 17.9 ± 0.3 and 18.2 ± 0.3 mmol/L for the young and old groups, respectively. The percentages of the desired goal for the young and old groups in all studies were 98.8 ± 1.7 and 99.7 ± 1.2% (SD). The mean CV for all of the studies of the young and old groups were 4.8 ± 1.8 and 3.9 ± 0.9 (SD), respectively.

Basal plasma insulin levels in the old group were significantly higher than in the young group (P < 0.05), but basal GIP levels were similar in the two groups (Table 2Go). Figure 2Go illustrates the plasma insulin and GIP levels for the young and old subjects during the G + 12.8 mmol/L clamps. In response to the square wave of hyperglycemia, a bimodal release of plasma insulin occurred in each subject. The 30–60 min and 90–120 min insulin and GIP values are shown in Table 3Go. The 30–60 min GIP values were similar in young and old subjects in all studies. In the control study, the 90–120 min GIP levels were not different from 30–60 min in either group. During the GIP infusion studies, 90–120 min GIP values were similar between groups during the 2 and 4 pmol/kg-1·min-1 GIP infusions (Table 3Go).



View larger version (24K):
[in this window]
[in a new window]
  		Figure 2. Plasma insulin (log scale) and GIP levels during G + 12.8 mmol/L hyperglycemic clamps (mean ± SEM). See Subjects and Methods for details of each study.

 
The 30–60 min insulin values were greater in the elderly (Table 3Go). During the control studies, 90–120 min insulin values were also greater in the old (Table 3Go). As shown in Fig. 2Go, in response to GIP infusion, whereas plasma glucose was unchanged, significant increases in insulin occurred in both groups (P < 0.01). The 90–120 min insulin responses were similar in young and old during the 2 and 4 pmol/kg-1·min-1 GIP infusion. The potentiation of the insulin response caused by GIP was similar in the young and the old subjects during the 2 (1886 ± 335 vs. 1856 ± 451 pmol/L) and during the 4 (young: 2242 ± 394 and old: 1937 ± 609 pmol/L) pmol/kg-1·min-1 GIP infusions and was not different between the two doses of GIP. In addition, when the 90–120 min insulin response was expressed as a percentage of basal insulin, the insulin response was similar in both young and old at each GIP infusion rate (2 pmol GIP: young, 6694 ± 1076 vs. old, 5827 ± 1429%; 4 pmol GIP: young, 6952 ± 1317 vs. old, 6011 ± 1705%). In contrast to the hyperglycemic clamps at 11 mmol/L, the insulin response did not wane in the old group during the GIP infusion at either dose.

Glucagon levels. For each hyperglycemic plateau, basal glucagon levels were similar in the young and old groups (Table 2Go). In response to the hyperglycemia, plasma glucagon levels were similarly suppressed by 60 min in all studies and averaged 106 ± 8 pmol/L in the young and 126 ± 10 pmol/L in the old. No further suppression occurred during the remainder of the clamps, even after GIP infusions in either group.

Glucose turnover. Basal Ra in the control and GIP infusion studies were similar between studies in both groups and averaged 12.1 ± 0.7 and 11.9 ± 0.5 µmol/kg-1·min-1 in the young and old groups. In response to hyperglycemia, Ra was suppressed in both groups, and the 30–60 min rates in the young and old groups were 1.9 ± 1.2 and -1.2 ± 1.0 µmol/kg-1·min-1. Because Ra was essentially completely suppressed, no further suppression was observed during the subsequent hour in any of the studies, with or without GIP. Essentially identical results were obtained during the G + 12.8 mmol/L studies.

In response to hyperglycemia and the concomitant hyperinsulinemia, Rd increased in both groups during each glycemic plateau (Fig. 3Go). During the lower hyperglycemic plateau, the increase during the first hour was similar between control and GIP studies and, during 30–60 min, averaged 31.1 ± 4.1 and 20.0 ± 1.7 µmol/kg-1·min-1 in the young and old groups, indicating a significantly higher Rd in the young than in the old (P < 0.05). During the control study, Rd further increased in the second hour, and the 90–120 min rates were again higher in the young than in the old subjects (56.7 ± 5.8 vs. 27.3 ± 4.2 µmol/kg-1·min-1, P < 0.05). During the lower-dose GIP infusion, the increase in Rd was essentially 2-fold higher than the control study, and the 90–120 min rates were significantly higher in the young than in the old subjects (102.4 ± 6.7 vs. 42.5 ± 4.2 µmol/kg-1·min-1, P < 0.001). This was a significant increase, compared with the control study, in both groups (P < 0.03). At the lower hyperglycemic plateau during the higher-dose GIP infusion, no further increase in Rd was observed in either group for the 90–120 min period, compared with the lower-dose GIP infusion. However, comparisons between groups (young: 102.2 ± 5.6 vs. old: 52.7 ± 5.4 µmol/kg-1·min-1, P < 0.001) and with the control study (P < 0.005) were again significantly different.



View larger version (25K):
[in this window]
[in a new window]
  		Figure 3. Whole-body glucose disposal rates (Rd) during hyperglycemic clamps (mean ± SEM). See Subjects and Methods for details of each study.

 
During the higher hyperglycemic plateau, the increase during the first hour was similar between control and GIP studies and, during 30–60 min, averaged 64.8 ± 6.9 and 50.0 ± 3.7 µmol/kg-1·min-1 in the young and old (Fig. 3Go). During the control study, Rd further increased in the second hour, and the 90–120 min rates were again higher in the young than the old subjects (106.0 ± 12.7 vs. 73.8 ± 5.4 µmol/kg-1·min-1, P < 0.05). During the lower dose GIP infusion, the increase in Rd was essentially 2-fold higher than in the control study, and the 90–120 min rates were significantly higher in the young than old (184.6 ± 17.1 vs. 100.9 ± 7.5 µmol/kg-1·min-1, P < 0.001). This was a significant increase, compared with the control study, in both groups (P < 0.02). During the higher-dose GIP infusion, no further increase in Rd was observed in either group for the 90–120 min period. However, comparisons between groups (young: 168.5 ± 12.5 vs. old: 102.9 ± 7.3 µmol/kg-1·min-1, P < 0.01) and with the control study were again significantly different (P < 0.001).

Rd, during the higher hyperglycemic plateau, was significantly greater than during the lower hyperglycemic plateau during each phase of the clamp, as well as during each GIP infusion (P < 0.005). To compare glucose disposals during both hyperglycemic plateaus, in the presence or absence of GIP, MCRs of glucose were calculated. Integrated responses were calculated for the basal period (n = 1) and the three succeeding 30-min intervals, from 30–60 to 90–120 min for each control study, during each hyperglycemic plateau (n = 6) in each group. In addition, the 60–90 and 90–120 min MCRs were calculated only for the 2 pmol/kg-1·min-1 dose, again during each hyperglycemic plateau (n = 4),because no statistically significant differences were observed between the 2 doses of the incretin infusion. Thus, 11 unique integrated MCR responses were examined, as a function of the corresponding plasma insulin levels, in each group. As illustrated in Fig. 4Go, there is a statistically significant dose-response relationship in the old group (r2 = 0.93, P < 0.001) and in the young group (r2 = 0.87, P < 0.001). Furthermore, there is both a shift to the right and a lower maximal response in the old, compared with the young group. The ED50 values for insulin for the young and old groups were 438 and 862 pmol/L, respectively.



View larger version (17K):
[in this window]
[in a new window]
  		Figure 4. Dose response relationship of glucose MCRs vs. plasma insulin levels in young and old volunteers. Each point represents the mean ± SEM for plasma insulin and MCR for a 30-min interval. See Subjects and Methods for details.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In the present study, the effect of two doses of GIP at two levels of hyperglycemia was examined in young and old normal male volunteers. At the lower glycemic plateau, the insulinotropic effect of each dose of GIP was equal, but the effect of GIP was greater in the young than the old. At the higher glycemic plateau, the two doses of GIP were again equally insulinotropic in young and old volunteers. The insulin response was higher than at the lower glycemic plateau.

One of the mechanisms postulated as a cause for the carbohydrate intolerance of normal aging is a reduction in glucose-induced insulin release from the ß-cell. Most studies have found that the insulin responses to oral glucose are increased in the elderly (7, 22). However, because glucose values were also higher in the elderly during these studies, the higher glucose levels may explain the higher insulin levels. Conceivably, the insulin responses to an equivalent oral glucose challenge would be reduced in the elderly if glucose levels were similar in both age groups. Although several studies have found that insulin responses to iv glucose are similar in young and old (23, 24, 25), more recent studies, conducted on healthy older subjects, have found that the insulin responses to iv glucose infusion are reduced in the elderly (8, 26, 27, 28, 29). Even in the studies that report that peripheral insulin responses to glucose infusion are equivalent in young and old subjects, glucose-induced insulin release was likely impaired in the elderly because of an age-related impairment in insulin clearance (24). Indeed, Pacini et al. (24) recently found that, although peripheral insulin levels were similar in young and old during a frequently sampled intravenous glucose tolerance test, C-peptide responses were reduced in the aged, suggesting reduced insulin secretion from the ß-cell and decreased hepatic insulin extraction in the aged. Our study suggests that the decrease in glucose-induced insulin release with normal aging may be caused, in part, by a decreased ß-cell sensitivity to GIP.

We have previously reported that a 1 pmol/kg-1·min-1 infusion of GIP at a hyperglycemic level of approximately 11 mmol/L (plasma GIP levels of 190 pmol/L) had a minimal effect on glucose-stimulated insulin secretion (30). In the current study, at the same level of glycemia, GIP levels of approximately 350 and 600 pmol/L had a marked (but essentially similar) effect on insulin secretion. From our previous and current hyperglycemic clamp studies, we can conclude that the maximally effective GIP level is between 190 and 350 pmol/L, when plasma glucose levels are increased by approximately 5 mmol/L. The incremental insulin responses to GIP were much greater during the 18 mmol/L study, consistent with our previous data that indicates that progressively higher levels of plasma glucose increase the sensitivity of the ß-cell to GIP (6).

The lower level of hyperglycemia was chosen because it represents the upper concentration of normal glycemic excursion that is encountered daily in normal elderly subjects. The upper level of hyperglycemia was chosen because it represents a value commonly seen after meals in moderately well-controlled elderly subjects with type 2 diabetes. The 2 pmol/kg-1·min-1 GIP infusion rates resulted in plasma GIP levels observed after glucose ingestion in normal subjects (31), whereas the 4 pmol/kg-1·min-1 GIP levels are observed in patients with type 2 diabetes but are rarely seen in normal subjects.

The effect of aging on the response to GIP has not been fully elucidated. Basal GIP levels are unchanged with age (31, 32). Using the IV oral variant of the hyperglycemic clamp, we have shown that, whereas the GIP response to oral glucose is similar in young and old, the insulin response to endogenous GIP may be reduced in the elderly (33). Our current data suggests that normal aging is characterized by an impairment in the ß-cell response to GIP during modest hyperglycemia. When plasma glucose is raised to higher levels, the insulinotropic effect of GIP in the elderly is equal to that of the young. This suggests that the GIP/glucose dose response curve is shifted to the right in the elderly, which is analogous to the rightward shift that occurs in the dose response curve for glucose utilization observed during exogenous infusion of insulin (22, 34, 35).

The similar Ra values in young and old are consistent with our previous data that shows that hepatic glucose production is normally regulated by insulin in the elderly (35). The lower Rd values found during the 11 mmol/L hyperglycemic clamps may, in part, reflect the reduced insulin responses in the elderly. However, Rd values were also lower during the 18 mmol/L hyperglycemic clamp, when plasma insulin levels were essentially equal between the two groups. In the elderly, there was both a shift to the right and a reduction in the maximal response in the dose response curve for plasma insulin and MCR of glucose. Previous reports have demonstrated impaired glucose utilization during exogenously induced hyperinsulinemia, in older subjects, during euglycemia (22, 34, 35). Our data demonstrates, for the first time, that during endogenously stimulated hyperinsulinemia and hyperglycemia, glucose utilization is markedly impaired in the elderly.

In this study, different young and old subjects participated in the 11 mmol/L and 18 mmol/L clamps. It is possible that the differences we report between studies may reflect differences in subject populations, rather than age-related differences. In particular, fasting insulin levels were higher in the elderly before the 18 mmol/L clamp, implying that these subjects were more insulin resistant than the other subject groups. Ideally, we would have liked to perform 11 mmol/L and 18 mmol/L clamps in the same subjects. Because of our concern, and that of our ethics committee, about performing multiple studies with substantial phlebotomy and administration of radioactivity, especially in elderly subjects, we elected not to enroll subjects in both protocols. However, the elderly subjects in both studies were free of underlying disease, took no medication, and had normal OGTT’S. Despite differences in basal insulin, we believe that our findings reflect age-related changes and not random differences between subject groups.

In summary, normal aging is characterized by a decreased ß-cell response to GIP during modest hyperglycemia. The age-related impairment in the response to GIP may be an important cause of the glucose intolerance of aging, a precursor for diabetes in this age group. The insulinotropic effect of GIP is increased with increasing levels of glycemia, and the defect in the ß-cell response to GIP disappears when plasma glucose is increased to higher levels.


   Acknowledgments
 
Our sincere gratitude is extended to the men who participated in this study. We also thank Gail Chin, Linda Morse, and Christine Yakura for their excellent technical assistance; plus the staff of the Clinical Research Center for their invaluable assistance. We gratefully acknowledge the support of the Pacific Command, Royal Canadian Legion, the Allan McGavin Geriatric Endowment at the University of British Columbia, and the Jack Bell Geriatric Endowment at Vancouver Hospital and Health Science Centre.


   Footnotes
 
1 This work was supported, in part, by National Institutes of Health Grants AG-00599, PGO-AG-12583, and RR-01032, and by grants from the Medical Research Council of Canada and the British Columbia Health Research Foundation. Back

Received October 10, 1997.

Revised March 19, 1998.

Accepted April 17, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. McIntyre N, Holdsworth CC, Turner DS. 1964 New interpretation of oral glucose tolerance. Lancet. 2:20–21.[CrossRef]
  2. Brown JC. 1971 A gastric inhibitory polypeptide: the amino acid composition and the tryptic peptides. Can J Biochem. 49:255–261.[CrossRef][Medline]
  3. Cleator IGM, Gourlay RH. 1975 Release of immunoreactive GIP by oral ingestion of food substance. Am J Surg. 130:128–134.[CrossRef][Medline]
  4. Andersen DK, Elahi D, Brown JL, Tobin JD, Andres R. 1978 Oral glucose augmentation of insulin secretion: interactions of gastric inhibitory polypeptide with ambient glucose and insulin levels. J Clin Invest. 62:152–161.
  5. Dupre J, Ross SA, Watson D, Brown JC. 1973 Stimulation of insulin secretion by gastric inhibitory polypeptide. J Clin Endocrinol Metab. 37:826–828.[Medline]
  6. Elahi D, Andersen DK, Brown JC, et al. 1979 Pancreatic {alpha} and ß-cell responses to GIP infusion in normal man. Am J Physiol. 237:E185–191.
  7. Davidson M. 1979 The effect of aging on carbohydrate metabolism: a review of the English literature and a practical approach to the diagnosis of diabetes mellitus in the elderly. Metabolism. 28:688–705.[CrossRef][Medline]
  8. Chen M, Bergman RN, Pacini G, Porte D. 1985 Pathogenesis of age-related glucose intolerance in man: insulin resistance and decreased ß-cell function. J Clin Endocrinol Metab. 60:13–20.[Abstract]
  9. National Diabetes Data Group. 1979 Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes. 28:1039–1057.[Medline]
  10. McGuire EAH, Helderman JH, Tobin JD, Andres R, Berman M. 1976 Effects of arterial vs. venous sampling on analysis of glucose kinetics in man. J Appl Physiol. 41:565–573.[Abstract/Free Full Text]
  11. Elahi D. 1996 In praise of the hyperglycemic clamp: a method for assessment of ß-cell sensitivity and insulin resistance. Diabetes Care. 19:278–286.[Abstract]
  12. Andres R, Swerdloff R, Pozesky T, Coleman D. 1966 Manual feedback technique for control of glucose concentration. In: Skeggs Jr LT, ed. Automation in analytical chemistry. New York: Medaid; 486–501.
  13. Soeldner JS, Slone D. 1965 Critical variables in the radioimmunoassay of serum insulin using the double antibody technique. Diabetes. 14:771–779.[Medline]
  14. Faloona GR, Unger RH. 1974 Glucagon. In: Jaffe BM, Behrman HR, eds. Methods of hormone radioimmunoassay. New York: Academy Press; 317–334.
  15. Somogyi M. 1984 Determination of blood sugar. J Biol Chem. 10:69–73.
  16. Steele R. 1959 Influences of glucose loading and injected insulin on hepatic glucose output. Ann NY Acad Sci. 82:420–430.
  17. Insel PA, Liljenquist JE, Tobin JD, et al. 1975 Insulin control of glucose metabolism in man: a new kinetic analysis. J Clin Invest. 55:1057–1066.
  18. Radzuik J, Norwich KH, Vranic M. 1974 Measurement and validation of non-steady turnover rates with application to the insulin and glucose systems. Fed Proc. 33:1855–1865.[Medline]
  19. Riggs DS. 1963 The mathematical approach to physiological problems. Cambridge, MA: The M.I.T. Press; 168–172.
  20. Snedecor GW, Cochran WG. 1979 Statistical methods. Ames, IA: Iowa University Press; 59–65.
  21. DeLean A, Munson PJ, Rodbard D. 1978 Simultaneous analysis of families of sigmoidal dose-response curves: application to bioassay, radioligand assay, and physiological dose-response curves. Am J Physiol. 235:E97–E102.
  22. Fink RI, Kolterman OG, Griffin J, Olefsky JM. 1983 Mechanisms of insulin resistance of aging. J Clin Invest. 71:1523–1535.
  23. DeFronzo RA. 1979 Glucose intolerance and aging. Diabetes. 28:1095–1101.[Medline]
  24. Pacini G, Beccaro F, Valero A, Nosadine R, Crepaldi G. 1990 Reduced ß-cell secretion and insulin hepatic extraction in healthy elderly subjects. J Am Geriatr Soc. 38:1283–1289.[Medline]
  25. Elahi D, Muller DC, McAloon-Dyke M, Tobin JD, Andres R. 1993 The effect of age on insulin response and glucose utilization during four hyperglycemic plateaus. Exp Gerontol. 28:393–409.[CrossRef][Medline]
  26. Gumbiner B, Polonsky KS, Beltz WF, Wallace P, Brechtel G, Fink R. 1989 Effect of aging on insulin secretion. Diabetes. 38:1549–1556.[Abstract]
  27. Beccaro F, Paine G, Valero A, Nosadini R, Crepaldi G. 1990 Age and glucose tolerance in healthy subjects. Aging. 2:277–282.[Medline]
  28. Frank SA, Roland DC, Sturis J, et al. 1995 Effects of aging on glucose regulation during wakefulness and sleep. Am J Physiol. 269:32:E1006–E1016.
  29. Scheen AJ, Sturis J, Polonsky KS, Van Cauter E. 1996 Alterations in the ultradian oscillations of insulin secretion and plasma glucose in aging. Diabetologia. 39:564–572.[Medline]
  30. Elahi D, McAloon-Dyke M, Fukagawa N, et al. 1994 The insulinotropic actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like polypeptide -1 (7–37) in normal and diabetic subjects. Regul Pept. 51:63–74.[CrossRef][Medline]
  31. McConnell JG, Alam MJ, O’Hare MM, Buchanen KD, Stout RW. 1993 The effect of age and sex on the response of enteropancreatic polypeptide to oral glucose. Age Aging. 12:54–62.[Abstract/Free Full Text]
  32. Groop PH. 1989 The influence of body weight, age and glucose tolerance on the relationship between GIP secretion and ß-cell function in man. Scand J Clin Lab Invest. 49:367–379.[Medline]
  33. Elahi D, Andersen DK, Miller DC, Tobin JD, Brown JC, Andres R. 1984 The enteric enhancement of glucose-stimulated release: the role of GIP in aging, obesity, and non-insulin-dependent diabetes mellitus. Diabetes. 33:950–957.[Abstract]
  34. Rowe JW, Minaker KL, Pallotta JA, Flier JS. 1983 Characterization of the insulin resistance of aging. J Clin Invest. 71:1581–1587.
  35. Meneilly GS, Minaker KL, Elahi D, Rowe JW. 1989 Insulin action in aging man: tissue-specific difference at low physiologic insulin levels. J Gerontol. 42:196–201.



This article has been cited by other articles:


Home page
 Diabetes CareHome page
R. E. Pratley, J. Rosenstock, F. X. Pi-Sunyer, M. A. Banerji, A. Schweizer, A. Couturier, and S. Dejager
Management of Type 2 Diabetes in Treatment-Naive Elderly Patients: Benefits and risks of vildagliptin monotherapy
Diabetes Care, December 1, 2007; 30(12): 3017 - 3022.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
A. M. Chang, M. J. Smith, A. T. Galecki, C. J. Bloem, and J. B. Halter
Impaired {beta}-Cell Function in Human Aging: Response to Nicotinic Acid-Induced Insulin Resistance
J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3303 - 3309.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
A. M. Chang and J. B. Halter
Aging and insulin secretion
Am J Physiol Endocrinol Metab, January 1, 2003; 284(1): E7 - E12.
[Abstract] [Full Text] [PDF]

Home page
 J. Gerontol. A Biol. Sci. Med. Sci.Home page
J. Korosi, C. H.S. McIntosh, R. A. Pederson, H.-U. Demuth, J. F. Habener, R. Gingerich, J. M. Egan, D. Elahi, and G. S. Meneilly
Effect of Aging and Diabetes on the Enteroinsular Axis
J. Gerontol. A Biol. Sci. Med. Sci., September 1, 2001; 56(9): M575 - 579.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Meneilly, G. S.
Right arrow Articles by Elahi, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Meneilly, G. S.
Right arrow Articles by Elahi, D.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH
Hazardous Substances DB
*GLUCAGON
Medline Plus Health Information
*Seniors' Health

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals