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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2004-2100
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 11 6251-6256
Copyright © 2005 by The Endocrine Society

Deconvolution Analysis of Rapid Insulin Pulses before and after Six Weeks of Continuous Subcutaneous Administration of Glucagon-Like Peptide-1 in Elderly Patients with Type 2 Diabetes

Graydon S. Meneilly, Johannes D. Veldhuis and Dariush Elahi

Division of Geriatric Medicine (G.S.M.), Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4E3; Department of Medicine (J.D.V.), Mayo Clinic, Rochester, Minnesota 55905; and Department of Surgery (D.E.), University of Massachusetts Medical School, Worcester, Massachusetts 01655

Address all correspondence and requests for reprints to: Dariush Elahi, Ph.D., Department of Surgery, Endocrinology and Metabolism Laboratory, University Campus, 55 Lake Avenue North, Worcester, Massachusetts 01655. E-mail: dariush.elahi{at}umassmed.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Insulin is secreted in a pulsatile fashion with measurable orderliness (low entropy). Normal aging and diabetes in middle-aged patients is characterized by alterations in pulsatile insulin release.

Objectives: We undertook the current studies to determine whether disruptions in pulsatile insulin release also accompany diabetes in the elderly.

Design: Two studies were performed. In the first study, insulin values were sampled every minute for 1 h under fasting conditions. In the second study, subjects underwent a 2-h hyperglycemic glucose clamp (glucose 5.4 mM above basal). From 60–120 min, insulin was sampled every 1 min. Secretory pulse analysis was conducted using a multiparameter deconvolution technique.

Setting: The study was conducted in a general clinical research center and during outpatient visits.

Patients: Volunteers were healthy young [n = 10; body mass index (BMI), 23 ± 1 kg/m2; age, 23 ± 1 yr] and elderly (n = 10; BMI, 24 ± 1 kg/m2; age, 78 ± 2 yr) volunteers and elderly patients with diabetes (n = 8; BMI, 28 ± 1 kg/m2; age, 73 ± 2 yr).

Intervention: Five of the older patients with type 2 diabetes (BMI, 29 ± 1 kg/m2; age, 72 ± 2 yr) were treated with continuous sc glucagon-like peptide-1 (GLP-1) (7–36) amide infusion for 6 wk, and a second 2-h hyperglycemic clamp was performed.

Main Outcome Measures: Insulin burst mass, pulsatile insulin secretion, and entropy were measured.

Results: Under fasting conditions, elderly patients with diabetes had a reduction in insulin burst mass (P < 0.05) that was similar to normal elderly. During hyperglycemia, elderly patients with diabetes had an even greater impairment in insulin burst mass (P < 0.05) and basal (P < 0.05) and pulsatile insulin secretion (P < 0.05) than normal elderly. Approximate entropy, a measure of irregularity of insulin release, was increased to a greater extent in older diabetes patients than normal elderly, signifying loss of orderliness of insulin secretion (P < 0.05). In response to treatment with GLP-1, insulin burst mass (P < 0.05) and pulsatile insulin secretion (P < 0.05) improved significantly in elderly patients with diabetes.

Conclusions: We conclude that alterations in pulsatile insulin release can be improved in elderly patients with diabetes by the administration of sc GLP-1.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE PREVALENCE OF diabetes increases with age (1). Although there have been extensive studies regarding the metabolic changes in middle aged patients with diabetes (2, 3), there is limited information regarding metabolic alterations in elderly patients with this disease (4, 5, 6). Insulin is secreted in a pulsatile and orderly fashion. Rapid, low amplitude pulses occur every 8–15 min (7, 8). Rapid insulin pulses, as well as the orderliness of the insulin release process (entropy), show disruption in disease states characterized by altered glucose metabolism, including impaired glucose tolerance, obesity, type 2 diabetes mellitus, and normal aging (7, 8). Here, we tested the hypothesis that diabetes in the elderly is accompanied by alterations in pulsatile and entropic (orderly) insulin secretion. We also determined whether prolonged infusion of the insulinotropic incretin peptide, glucagon-like peptide-1 (GLP-1), could improve these alterations in pulsatile insulin secretion.


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

These studies were performed in 10 healthy young and 10 healthy elderly subjects and eight elderly patients with type 2 diabetes. The data from the experiments in these subjects has not been published previously. Five of the patients with diabetes were treated with a continuous sc GLP-1 infusion for 6 wk (see Experimental protocol). Healthy young and old subjects had a normal history and physical examination, screening laboratory tests, electrocardiogram, and an oral glucose tolerance test (glucose dose, 40 gm/m2; National Diabetes Data Group criteria). None of the healthy young or old subjects had a family history of diabetes or was taking medication known to influence glucose homeostasis. All patients with diabetes were being treated with metformin before commencing the study, but none were receiving insulin or insulin secretogogues. This study was approved by the Committee on Human Investigation at the University of British Columbia. All subjects provided written informed consent before participation.

Experimental protocol

Studies were conducted in the Clinical Research Center at the University of British Columbia. Body composition was estimated using bioelectric impedance methodology (RJL Systems, Detroit, MI). The percentage of body fat was calculated from impedance values as described elsewhere (9). Subjects refrained from strenuous physical activity and ate a diet containing at least 150 g of carbohydrates per day for 3 d before glucose and insulin assessments. In patients with diabetes, metformin was stopped 72 h before each study. Studies commenced at 0730 h, after an overnight fast. In each study, an iv catheter was inserted into a hand vein for sampling of "arterialized" venous blood (10). Each subject underwent two studies. In the first study, insulin was sampled every 1 min and glucose every 2 min for 60 min. All volunteers subsequently underwent a 120-min hyperglycemic glucose clamp study [increment above basal 5.4 mM (98 mg/dl)] according to the method of Andres et al. (11). Insulin and glucose were sampled every 5 min from 0–60 min. From 60–120 min, insulin was sampled every 1 min and glucose every 2 min. Five of the diabetic patients were then treated with a continuous sc infusion of GLP-1 for 6 wk and then underwent a second hyperglycemic glucose clamp study, as described above. Metformin was withheld 3 d before the first study and during the entire 6 wk of GLP-1 infusion. The peptide was administered by continuous sc infusion into the periumbilical region using a MiniMed (Sylmar, CA) infusion pump [100 pmol·kg–1·h–1 (330 ng·kg–1·h–1)] as previously described (12). If mean fasting plasma glucose levels were not less than 8 mM (144 mg/dl) or if mean premeal sugars were not less than 11 mM (198 mg/dl) after 1 wk of therapy with GLP-1, the infusion rate was increased by 25%. The mean initial and final GLP-1 dose were 330 ± 32 and 433 ± 49 ng·kg–1·h–1. The GLP-1 infusion was terminated 24 h before the second clamp.

Analytical methods

An aliquot of the blood sample was used to measure plasma glucose by the glucose oxidase method using a YSI glucose analyzer (Yellow Springs Instruments, Yellow Springs, OH). Blood was placed in prechilled test tubes containing Aprotonin (400 KIU/ml) and EDTA (1.5 mg/ml) and centrifuged at 4 C. The plasma was stored promptly at –70 C until assay. All samples from each subject were analyzed in the same RIA. For the insulin assays, equal numbers of young, old, and diabetic subjects were included in each assay. Assays were performed in duplicate using a human insulin RIA kit from Linco Research (St. Louis, MO), which is specific and sensitive. There is less than 1% cross reactivity with proinsulin. The interassay coefficient of variation was 11% and the mean intraassay coefficient of variation was 6%. The sensitivity was 10 pmol/liter (~2 µU/ml).

Pulse analysis

Insulin pulse profiles were analyzed for rapid insulin pulsatility with a multiparameter deconvolution technique (8, 13). This technique quantitatively describes insulin profiles as a collection of the following inputs: 1) a finite number of discrete insulin secretory bursts occur at specific times; 2) individual secretory-burst amplitudes (maximal rates of secretion in a burst); 3) a common burst half-duration (duration of an algebraically gaussian secretory pulse at half-maximal amplitude), with secretory bursts superimposed on 4) a basal time-invariant insulin secretory rate, assuming a nominal insulin half-life of 2.5 min. The following parameters were calculated: secretory burst frequency (the number of significant secretory pulses per 60 min); interburst interval (time in minutes separating successive pulses); burst mass (the mass or area of the calculated secretory bursts); basal (constitutive) insulin secretion rate; pulsatile insulin secretion rate; fractional pulsatile insulin secretion; as well as mean and integrated insulin concentration.

In addition to deconvolution analysis, the data were evaluated by a recently developed scale and model-independent statistic, approximate entropy (ApEn) (8, 14). ApEn provides a measure of regularity (orderliness) of insulin release that can be compared between groups. This estimate is complementary to deconvolution analysis.

Data analysis

Glucose use during the 90–120 min of the hyperglycemic clamp, i.e. glucose metabolized, was calculated from the glucose infusion rate during that time corrected for plasma glucose space and the amount of urinary glucose loss (if any) as previously described (15, 16). We used the trapezoidal rule to calculate the integrated insulin response for the 90- to 120-min interval. The integrated responses were divided by 30 min, resulting in a mean concentration or value. All data were analyzed using SAS (SAS Institute, Inc., Cary, NC).

Values of P < 0.05 were regarded as indicating statistical significance. Differences between subjects were determined by repeated measures ANOVA. All data are presented as the mean ± SEM.


   Results
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 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The physical characteristics and metabolic profile of each group is presented in Table 1Go. The two healthy groups had a similar body mass index (BMI), although the healthy elderly subjects had a greater percentage of fat. The diabetic group had a higher BMI as well as higher percentage of fat than both the healthy elderly and the young group. The diabetic group was well controlled with Metformin as well as with GLP-1 as judged by the glycosylated hemoglobin. Healthy elderly subjects had normal glucose tolerance tests, but, as expected, their 2-h glucose values were higher than in the young. Fasting insulin values were elevated in patients with diabetes but similar in healthy young and old. The plasma insulin response during the last 30 min of the clamp (90–120 min) was greatest in the young and was approximately 60% higher than the healthy elderly group. In the elderly diabetic group, plasma insulin response was only 28% of the healthy elderly group. After GLP-1 treatment, the plasma insulin response during the 90- to 120-min period was increased by more than 2-fold. Glucose metabolized during the last 30 min of the clamp was greatest in the young followed by healthy elderly followed by the diabetic groups, suggesting progressive insulin resistance in the three groups.


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  		TABLE 1. Physical and metabolic characteristics of each group

 
Five-minute plasma glucose and insulin levels for the young, healthy elderly, and elderly diabetic group for the basal 60-min study are shown in Fig. 1Go, and rapid insulin pulse parameters under fasting conditions are summarized in Table 2Go. Plasma glucose and insulin levels are remarkably similar in the healthy groups, although the diabetic group has both a higher plasma glucose and insulin levels. Burst mass was significantly greater in healthy young, but was not different between healthy elderly and elderly patients with diabetes (P < 0.05). ApEn increased between groups, indicating that normal aging and diabetes are characterized by progressive alterations in the regularity of insulin secretion. There were no significant differences in any other insulin pulse parameter.



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  		FIG. 1. Five-minute plasma glucose and insulin levels during the basal study (means ± SE). {triangleup}, Young (n = 10); {circ}, healthy elderly (n = 10); •, elderly diabetics (n = 8).

 

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  		TABLE 2. Deconvolution analysis of rapid insulin pulses under fasting conditions

 
Five-minute plasma glucose and insulin levels during the hyperglycemic clamp in the young, healthy elderly, and elderly diabetic group are shown in Fig. 2Go, and rapid insulin pulse parameters during hyperglycemia are shown in Table 3Go. Plasma glucose levels were again similar in the healthy groups, whereas the diabetic group had higher glucose levels, although the incremental increase in glucose in all three groups was the same. Plasma insulin response during both the first- and second-phase release was 2-fold higher in the young group compared with the healthy elderly. In the diabetic group, first-phase insulin response was absent and the second-phase insulin release was 3-fold lower compared with the healthy elderly group. Mean and integrated insulin concentration, burst mass, and basal and pulsatile insulin secretion decreased progressively between groups (all P < 0.05). ApEn was increased in both older groups, but was not significantly different between normal elderly and older patients with diabetes.



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  		FIG. 2. Two-minute (0–10) and 5-min (10–120) plasma glucose and insulin levels during hyperglycemic clamp (means ± SE). Plasma glucose level = 5.4 mM (98 mg/dl) above basal level. {triangleup}, Young (n = 10); {circ}, healthy elderly (n = 10); •, elderly diabetics (n = 8).

 

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  		TABLE 3. Deconvolution analysis of rapid insulin pulses under hyperglycemic conditions

 
Five-minute plasma glucose and insulin levels during the hyperglycemic clamp in five diabetic patients before and after GLP-1 treatment are shown in Fig. 3Go, and the effect of prolonged GLP-1 infusion on insulin pulse parameters is shown in Table 4Go. Plasma glucose levels are similar in both clamps. Second-phase insulin response was increased more than 2-fold by GLP-1 infusion. As can be seen in Table 4Go, GLP-1 increased mean and integrated insulin concentration, burst mass, and pulsatile insulin secretion (both P < 0.05). However, basal insulin secretion remained below normal and ApEn did not decrease.



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  		FIG. 3. Two-minute (0–10) and 5-min (10–120) plasma glucose and insulin levels during hyperglycemic clamp in five diabetics before and after 6 months of GLP-1 administration (means ± SE). Plasma glucose levels = 5.4 mM (98 mg/dl) above basal level. •, Pre-GLP-1; {circ}, post-GLP-1.

 

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  		TABLE 4. Deconvolution analysis of rapid insulin pulses before and after GLP-1 infusion in older patients with type 2 diabetes

 
The insulin pulse profile for the basal, pre-GLP-1 hyperglycemic, and post-GLP-1 hyperglycemic clamp studies for a volunteer is shown in Fig. 4Go. As can be seen, GLP-1 resulted in a substantial increase in pulsatile insulin secretion.



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  		FIG. 4. Individual insulin profiles for concentration and secretion for a diabetic volunteer. Left panels, 0- to 60-min profile during the basal study; middle panels, 60- to 120-min profile during the hyperglycemic clamp pre-GLP-1 administration; and right panels, 60- to 120-min profile during the hyperglycemic clamp post-GLP-1 administration.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Two previous studies have evaluated rapid insulin pulses during fasting in the elderly (17, 18). Matthews et al. (17) reported that the apparent regularity of pulses was reduced and interpulse interval was increased in the aged compared with healthy young. We found that fasting insulin burst mass was reduced and ApEn was increased in the elderly (18), and our current findings are consistent with these results. There was a striking similarity in the impairment in insulin burst mass in the elderly patients with diabetes relative to healthy elderly controls. We also report that the irregularity of insulin secretion is further increased in elderly patients with diabetes relative to age-matched controls, implying a greater disorderliness of insulin secretion in these patients.

In the current study, we also evaluated insulin pulse parameters in response to stable hyperglycemia in elderly patients with diabetes and compared their responses to those in healthy young and old. Consistent with our previous report (19), we found that normal aging is characterized by a reduction in mean and integrated insulin secretion, basal and pulsatile insulin production rate, and mass of rapid insulin secretory pulses. In addition, we demonstrated that diabetes in the elderly is characterized by a further reduction in these parameters. Hyperglycemia improved the regularity of insulin secretion in both healthy elderly and elderly patients with diabetes, but both groups still had more disorderly insulin secretion than young controls.

In normal subjects, it has been demonstrated that GLP-1 infusion increases the mass of insulin pulses but not their orderliness or frequency (20). Two previous studies have evaluated the effect of GLP-1 infusion on pulsatile insulin secretion in middle aged patients with diabetes. Juhl et al. (21) found that short-term GLP-1 infusion increased basal insulin secretion and insulin burst mass with no change in ApEn. Ritzel et al. (22) gave an overnight GLP-1 infusion and found an increase in burst mass, but no change in basal insulin secretion, interpulse interval, burst frequency or ApEn. We have previously shown that prolonged sc GLP-1 infusion enhances glucose-induced insulin secretion in elderly patients with diabetes (12). In the current study, we demonstrate for the first time that prolonged infusion of GLP-1 in elderly obese type 2 diabetic patients improves pulsatile insulin secretion. The mechanism for this effect is unclear, but it may relate to the effect of reduced glucose toxicity on the ß-cell. However, it should be acknowledged that improved pulsatile secretion in the elderly diabetic did not restore insulin secretion to age-related norms. Since these patients were obese and insulin resistant relative to age-matched controls, their insulin responses would need to be substantially higher to qualify as normal.

Several methodological concerns should be addressed. Of course changes in plasma glucose can influence insulin response. We do not believe this can explain the differences observed in the different groups, as glucose levels were remarkably stable both in the basal as well as the hyperglycemic states. Our calculations assumed that insulin half-life, volume of distribution, and clearance are unchanged with age, an assumption which is supported by the literature (23, 24, 25). We did not compare insulin secretion rates calculated from C-peptide values with insulin parameters calculated by deconvolution. We did not think that this significantly affects our findings since previous studies have found that temporal variations in insulin levels closely parallel changes in insulin secretion rates in young and old (24). Finally, it previously has been demonstrated that peripheral sampling fails to detect a significant portion of high frequency pulses detected by portal sampling (7, 8, 26). We believe we optimized other factors known to effect pulse detection in our study (frequency and duration of sampling as well as type of pulse detection algorithm) (7, 8, 26). There is a strong correlation between the pulse parameters detected by portal vs. peripheral sampling (7, 8, 26). Thus, because insulin clearance is unchanged with age, we believe that, even though we may have failed to detect the absolute number of pulses in all age groups, relative changes in young and old should be similar.

In conclusion, rapid insulin pulses during fasting and in response to hyperglycemia are altered with normal aging and diabetes. Prolonged GLP-1 infusion in obese type 2 diabetic patients can be used to improve pulsatile insulin secretion implying that this peptide may have great therapeutic utility in the elderly.


   Acknowledgments
 
We thank Rosemarie Torressani, Gail Tedder, Gail Chin, Christine Lockhart, Kandace Bradford, and Benjamin Weirich for their assistance in conducting and preparing these studies.


   Footnotes
 
This work was supported by a grant from the Canadian Diabetes Association and by Grant NIA-AG00599 from the National Institutes of Health. We gratefully acknowledge the support of the Allan McGavin Geriatric Endowment at the University of British Columbia, and the Jack Bell Geriatric Endowment Fund at Vancouver Hospital and Health Science Centre.

First Published Online August 9, 2005

Abbreviations: ApEn, Approximate entropy; BMI, body mass index; GLP-1, glucagon-like peptide-1.

Received October 22, 2004.

Accepted August 1, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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