Loss of entrainment of high-frequency plasma insulin oscillations in type 2 diabetes is likely a glucose-specific {beta}-cell defect

Catherine S. Mao, Nancy Berman, and Eli Ipp

Depts. Of Medicine and Pediatrics, Research and Education Institute at Harbor-UCLA Medical Center, Torrance, California 90502

Submitted 8 December 2003 ; accepted in final form 24 February 2004


    ABSTRACT
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 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
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Spontaneous high-frequency insulin oscillations are easily entrainable to exogenous glucose in vitro and in vivo, but this property is lost in type 2 diabetes (2-DM). We hypothesized that this lack of entrainment in 2-DM would be specific to glucose. This was tested in nine control and ten 2-DM subjects. Serial blood sampling at 1-min intervals was carried out for 60 min in the basal state and for 120 min while small (1–60 mg/kg) boluses of arginine were injected intravenously at exactly 29-min intervals. Samples were analyzed for insulin concentrations, and time series analysis was carried out using spectral analysis. In control subjects, the mean period of basal plasma insulin oscillations was 10.3 ± 1.3 min and was entrained by arginine to a mean period of 14.9 ± 0.6 min (P < 0.00001 vs. basal). Similarly, in 2-DM subjects, spontaneous insulin oscillations were entrained by arginine; mean basal insulin period was 10.0 ± 1.0 min and 14.5 ± 1.8 min with arginine boluses (P < 0.00001). All of the primary peaks observed in spectral analysis were statistically significant (P < 0.05). Percent total power of primary peaks ranged from 17 to 68%. Thus arginine boluses entrain spontaneous high-frequency insulin oscillations in 2-DM subjects. This represents a distinct and striking difference from the resistance of the {beta}-cell to glucose entrainment in 2-DM. We conclude that loss of entrainment of spontaneous high-frequency insulin oscillations in 2-DM is likely a glucose-specific manifestation of {beta}-cell secretory dysfunction.

{beta}-cell dysfunction


ABNORMALITIES IN PULSATILITY of hormone secretion have been implicated in secretory dysregulation in many endocrine systems (32). High-frequency insulin oscillations, normally an example of a regular hormonal rhythm (5, 8, 10, 14, 15, 17, 24, 25, 30), are disturbed in disease. Abnormalities in oscillations take a number of different forms, including loss of regularity, a decrease or increase in amplitude, or an alteration in frequency (1, 9, 12, 16, 19, 20). It has also been suggested that a loss of regularity in high-frequency plasma insulin oscillations might represent an early secretory defect that can be demonstrated before the development of diabetes (2, 21, 27).

Spontaneous high-frequency insulin oscillations are easily entrainable to an exogenous rhythm by small changes in glucose concentration in vitro (4). In vitro studies using isolated rat islets demonstrated spontaneous high-frequency insulin oscillations that were easily entrained to the rhythm of glucose pulses delivered at a different frequency (4). In vivo, high-frequency plasma insulin oscillations are also entrainable with exogenous glucose (18, 23). However, in type 2 diabetic (2-DM) patients, there is a complete loss of entrainment to glucose stimulation (11, 18). The present study was designed to determine whether the loss of entrainment of insulin oscillations is a glucose-specific defect in 2-DM. Other abnormalities in {beta}-cell function are recognized to be glucose specific (22). We therefore hypothesized that the lack of entrainment of spontaneous insulin oscillations in 2-DM would be specific to glucose and that insulin oscillations in diabetic subjects would be entrainable by other insulin secretagogues, e.g., arginine. Using a similar approach to the one we used for the study of glucose entrainment (18), we evaluated the susceptibility to entrainment of spontaneous high-frequency insulin oscillations by exogenous arginine in nondiabetic subjects and subjects with 2-DM in vivo.


    SUBJECTS AND METHODS
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 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
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Subjects. Nine control subjects and ten subjects with 2-DM were studied. The control subjects consisted of three women and six men with mean age (±SD) 37.6 ± 16.2 yr (range 20–64 yr) and mean body mass index (BMI) 26.5 ± 6.2 kg/m2 (range 18.8–36.1 kg/m2). The 2-DM subjects consisted of five women and five men with diabetes of duration that extended from new diagnosis to 20 yr. Their mean age was 49.8 ± 13.5 yr (range 33–74 yr) with mean BMI 27.2 ± 4.4 kg/m2 (range 22.3–34.5 kg/m2). All studies were performed at the General Clinical Research Center at Harbor-UCLA Medical Center. All patients gave their informed consent to participate in these studies, which were approved by the Institutional Review Board.

Procedures. Control and diabetic subjects were studied after an overnight fast. Subjects with 2-DM were either diet controlled or treated with oral hypoglycemic agents. 2-DM subjects taking oral hypoglycemic agents discontinued these medications for 7 days before being tested. All subjects were instructed to maintain a diet with ≥200 g of carbohydrates per day for the 3 days preceding the study. All studies were initiated between 9:00 and 10:00 AM. Subjects assumed a resting recumbent position and remained so throughout the test period. Blood was sampled through a 23-gauge needle that was inserted retrograde in a dorsal hand vein heated for arterialization (13). For the entrainment studies, subjects had cannulation of a deep vein in the contralateral arm for arginine injections. After a 15- to 30-min rest period, arterialized venous blood sampling was carried out at 1-min intervals for 180 min.

Protocols. Serial blood sampling at 1-min intervals was carried out for 60 min in the basal state and for 120 min while small (1–60 mg/kg) boluses of arginine were injected intravenously at exactly 29-min intervals. Initially, plasma arginine concentrations were measured before and 2 min after each arginine injection to determine the dose-dependent change in plasma arginine concentrations. The dose and frequency of the injections were then designed to cause the smallest possible perturbation in insulin concentrations. Arginine injections were given as a 10% solution over 30 s and flushed with 5 ml of normal saline. Blood samples were placed on ice immediately and centrifuged at 4°C within 1 h, and plasma was stored at –20°C immediately after separation.

Arginine bolus. The initial experiments were dose-finding studies. We used a regimen of increasing doses, with 15, 30, 45, and 60 mg/kg arginine injected sequentially in control (n = 2) and diabetic (n = 3) subjects. Because of the large change in arginine levels even with the lowest dose, the arginine dose was decreased to 3, 6, 9, and 12 mg/kg in control (n = 3) and diabetic subjects (n = 2; data not shown) and further to 0.5, 1, 2, 3 mg/kg in one control subject; and 1.25 mg/kg x 4 doses in one diabetic subject. On the basis of the results of these studies, we chose 1 mg/kg arginine x 4 doses as the optimal regimen that caused the smallest possible perturbation in insulin concentrations, and this was used for all subsequent studies in control (n = 3) and diabetic (n = 6) subjects. [Note that 2 diabetic subjects were studied twice with each of the 2 high-dose regimens and showed identical entrainment; thus only 1 (the 1st) set of data was used]. Because there was no difference in the entrainment response by use of any of the different dosage regimens, all of the data are grouped and presented together for each of the control and diabetic groups.

Analysis. All samples from an individual study were measured in duplicate in the same assay. Plasma glucose was measured using the hexokinase method with an Abbott autoanalyzer (7). The intra-assay coefficient of variation was 1–2%. Plasma insulin was measured by sensitive radioimmunoassay (33). The intra-assay coefficient of variation for the insulin assay was 5–6%, with a lower limit of sensitivity of 1 µU/ml. Plasma arginine was measured using an HPLC method with a Beckman 6300 series high-performance amino acid analyzer.

Statistical analysis. The time series results were analyzed as previously described (18). In brief, the time series for each individual data set was smoothed using a 3-point moving average to reduce rapid fluctuations in the data due to assay or experimental noise. Time series analysis was carried out using spectral analysis with SAS (SAS Institute). Any linear time trends and low-frequency oscillations in plasma glucose and insulin were eliminated by using linear regression analysis (detrending) to filter out peaks with periods >20 min. Spectral analysis results were represented by the spectral power of the dominant peak expressed as the percentage of total power in the time series. Differences between groups were evaluated using the Student's t-test. Fisher's test was used to determine whether the dominant peaks were significantly different from noise (28). Data are presented as means ± SD.


    RESULTS
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 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
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 REFERENCES
 
Subject characterization. Table 1 shows the demographic information and fasting plasma glucose, insulin, and arginine for each individual subject. The mean fasting plasma glucose was 87.3 ± 5.0 mg/dl for the control subjects and 211.5 ± 52.5 mg/dl for the subjects with diabetes (P < 0.00005). The mean fasting plasma insulin was 7.2 ± 3.0 µU/ml for the control subjects and 24.3 ± 26.8 µU/ml for the subjects with diabetes (P = 0.077). The mean fasting plasma arginine was 124.6 ± 41.8 µM/l for the control subjects (n = 8) and 138.0 ± 67.6 µM/l for the subjects with diabetes (n = 6, P = 0.68).


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Table 1. Patient characteristics

 
Basal studies. During the basal studies, regular oscillations of plasma insulin concentrations were observed in control and 2-DM subjects (Table 2). Figure 1 shows the 3-point moving average of basal plasma insulin concentrations over 60 min for a representative control and 2-DM subject. The results of spectral analysis performed using the 3-point moving averages of plasma insulin concentrations in basal studies for all subjects are summarized in Table 2. The mean period of basal plasma insulin oscillations was 10.3 ± 1.3 min in the control subjects and 10.0 ± 1.0 min in the 2-DM subjects as determined by spectral analysis. Every subject showed at least one peak on spectral analysis that was significantly different from noise (P < 0.05). The percentage of total power in all subjects tested (n = 18) ranged from 22 to 68%.


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Table 2. Results of spectral analysis in basal and entrainment studies in control and 2-DM subjects

 


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Fig. 1. Three-minute moving average of basal plasma insulin concentrations in a control subject (A) and a diabetic subject (B). The data are detrended.

 
Entrainment studies. In response to sequential arginine bolus injections, plasma insulin concentrations in control subjects responded with a rapid increase that followed each bolus, resulting in a series of insulin peaks that fell rapidly to baseline. This was followed by a smaller, secondary peak of insulin, half-way between the larger, arginine-induced peaks. This pattern is very similar to that seen with entrainment by glucose when injected in similar bolus fashion at the same intervals (18). Figure 2 shows a time series of the 3-point moving average of plasma insulin response to arginine boluses for a representative control subject and a 2-DM subject. This was associated with an obvious change in the period of basal plasma insulin oscillations in control subjects. High-frequency insulin oscillations were entrained to the period of the exogenously injected arginine, from 10.3 ± 1.3 min in the basal state to a period of 14.9 ± 0.6 min (P < 0.00001 vs. basal).



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Fig. 2. Three-minute moving average of plasma insulin concentrations in a control subject (A) and a diabetic subject (B) injected with intravenous arginine at 29-min intervals (arrows). The data are detrended and presented with a fitted sine wave, using the frequency and amplitude of the dominant period, as determined by spectral analysis. Note that the data in this figure are taken from experiments performed in the same subjects shown in Fig. 1.

 
Similarly, in the diabetic subjects, spontaneous insulin oscillations were entrained by arginine boluses. The insulin period in the 2-DM subjects was 10.0 ± 1.0 min in the basal state and 14.5 ± 1.8 min with arginine injections (P < 0.00001). One diabetic subject (Table 2, subject 18) did not entrain basal plasma insulin oscillations to arginine stimulation despite good insulin responses to the arginine boluses.

All of the primary peaks observed in spectral analysis were statistically significant (P < 0.05). The results of spectral analysis performed using 3-point moving averages of plasma insulin concentrations in bolus studies for all subjects are also summarized in Table 2. Every subject showed at least one peak that was significantly different from noise (P < 0.05) in all entrainment studies. The percentage of total power for all subjects in the entrainment studies ranged from 17 to 39%.

The repeated arginine bolus injections were designed to induce entrainment of insulin oscillations. To ensure that there was no unintended effect of the experimental design upon overall insulin and glucose homeostasis over the duration of the study, plasma insulin and glucose concentrations were evaluated at the start and end of the study (Table 2). No consistent effect of the repeated bolus injections was observed. Nonsignificant, small decreases in mean insulin concentrations from start to finish were observed in both groups and in glucose concentrations in the 2-DM subjects.


    DISCUSSION
 TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
This study was designed to determine whether the loss of entrainment of high-frequency insulin oscillations in 2-DM is a glucose-specific defect. Our previous studies had demonstrated that high-frequency plasma insulin oscillations are entrainable with exogenous glucose in normal subjects with the use of an identical protocol with glucose as the entraining stimulus. The period of insulin oscillations was consistently entrained, shifting from a mean of ~10 min to a period of close to 15 min (18). Our first goal in this study was, therefore, to test whether arginine was also able to entrain insulin oscillations in control subjects. The response was almost identical. Arginine induced a 50% lengthening of the period, from a mean of 10.3 to 14.9 min, similar to that seen when control subjects were exposed to glucose. We therefore demonstrated that this protocol was successful in inducing clearly demonstrable entrainment of high-frequency insulin oscillations with glucose or arginine in normal control subjects.

However, in 2-DM subjects, our data demonstrate a distinct difference between the effects of glucose and arginine to entrain high-frequency insulin oscillations. Glucose was unable to entrain insulin oscillations in 2-DM, as demonstrated previously in all subjects whom we studied (18). There was no shift in phase or period of insulin oscillations, indicating a failure of glucose recognition by the {beta}-cell of the process(es) that regulate(s) both of these oscillation parameters. In contrast, this study shows that arginine was able to entrain insulin oscillations even in subjects with 2-DM. Also in this group, the mean period of insulin oscillations was shifted from a mean of ~10 to 14.5 min, similar to the shift in period caused by arginine in control subjects. Thus a normal physiological response to arginine was retained in the diabetic state. The successful entrainment of high-frequency insulin oscillations by arginine, coupled with our previous observations that glucose fails to entrain in diabetic subjects, provides strong evidence that loss of entrainment is a glucose-specific defect of the {beta}-cell.

The mechanisms for spontaneous high-frequency insulin oscillations and their entrainment are not well understood. In vitro studies of isolated islets provide evidence for oscillations of glycolysis in the {beta}-cell, consistent with its occurrence in many other mammalian cells, and it has been suggested that these may be the underlying pulse generator for insulin oscillations (3, 31). Also in isolated islets, it has been demonstrated that {beta}-cells are very sensitive to entrainment by glucose, responding to small fluctuations in glucose concentrations (4). On the basis of those two observations, Mao et al. (18) hypothesized that glucose entrainment of insulin oscillations occurs when a sudden increase in glucose delivered to the {beta}-cell overrides ongoing spontaneous oscillatory activity in the glycolytic pathway and resets the phase of the oscillations and possibly also their frequency. Failure to entrain in response to glucose in diabetic subjects can then be explained by a failure of responsiveness in the glycolytic pathway. This hypothesis is consistent with our present results in that the nonglucose secretagogue arginine, which bypasses glycolytic signaling to activate the insulin-secretory pathway (29, 31), successfully entrained insulin oscillations where glucose failed.

Arginine has long been known to stimulate insulin secretion and has been used as a prototypical agent to represent a nonglucose stimulus of {beta}-cell function (6, 26). Typically, arginine has been shown to retain secretagogue activity even when glucose-stimulated insulin secretion is lost, as in 2-DM. Arginine exerts its insulin-stimulating action by elevating intracellular calcium concentrations as a consequence of its own electrogenic transport into the {beta}-cell (29), thus effectively bypassing the glycolytic pathway. A defect in the glycolytic pathway might not only explain the glucose specificity of entrainment failure but conceivably could play a role in other similar phenomena, such as the loss in diabetes of first-phase insulin secretion that is well known to have glucose-specific properties (26).

A single observation of particular interest that may contribute toward understanding mechanisms for entrainment is the unusual response of one of the ten 2-DM subjects tested (subject 18, Table 2). In this case, arginine failed to entrain insulin oscillations despite a clear insulin-secretory response to arginine, indicating {beta}-cell recognition of the stimulus. Although this observation was made in the study of only one subject, it occurred repeatedly in that experiment, demonstrating a clear distinction between stimulus-secretion coupling (observed in this case) and initiation of entrainment (which was lost), suggesting that these are physiological phenomena with distinct regulatory pathways. In the glucose studies, it was not possible to distinguish between these, because failure of both stimulus-secretion coupling and entrainment occurred concurrently (11, 18). It is also unclear at this time whether dissociation of the secretory events seen in this one instance is a physiological or a pathological finding; more data are required to evaluate how commonly this occurs and the mechanisms involved.

In summary, the results of this study demonstrate 1) that exogenous arginine results in entrainment of spontaneous high-frequency insulin oscillations in control subjects and 2) that arginine also entrains most subjects with type 2 diabetes. 3) This represents a distinct and striking difference from the lack of responsiveness of the {beta}-cell to glucose entrainment in diabetic subjects. We conclude that loss of entrainment of spontaneous high-frequency insulin oscillations in diabetes is likely to be a glucose-specific manifestation of {beta}-cell secretory dysfunction.


    GRANTS
 TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
These studies were supported in part by a grant from the National Institutes of Health (NIH) to support the General Clinical Research Center at Harbor-UCLA Medical Center (M01-RR-00425). C. S. Mao was the recipient of a Clinical Associate Physician Grant from the NIH National Center for Research Resources (M01-RR-00425–27S8) and a grant from the Endocrine Fellows Foundation.


    ACKNOWLEDGMENTS
 
We are indebted to the nurses, dietary staff, and core laboratory technicians of the Clinical Study Center at Harbor-UCLA Medical Center for their assistance in the performance of these studies.


    FOOTNOTES
 

Address for reprint requests and other correspondence: E. Ipp, Harbor-UCLA Medical Center, Box 16, 1000 W. Carson St., Torrance, CA 90509–2910 (E-mail: ipp{at}gcrc.rei.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


    REFERENCES
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 DISCUSSION
 GRANTS
 REFERENCES
 

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