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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 8 3794-3800
Copyright © 2003 by The Endocrine Society

Influence of Rosiglitazone Treatment on ß-Cell Function in Type 2 Diabetes: Evidence of an Increased Ability of Glucose to Entrain High-Frequency Insulin Pulsatility

Claus B. Juhl, Malene Hollingdal, Niels Pørksen, Åge Prange, Frederik Lönnqvist and Ole Schmitz

Medical Department M (Endocrinology and Diabetes) (C.B.J., M.H., N.P., O.S.), Århus University Hospital, 8000 Århus, Denmark; Medical Department (C.B.J., A.P.), Kolding Sygehus, 6000 Kolding, Denmark; Center for Metabolism and Endocrinology (F.L.), Huddinge University Hospital, Karolinska Institute, 17177 Stockholm, Sweden; and Institute of Clinical Pharmacology (O.S.), University of Århus, Århus, Denmark

Address all correspondence and requests for reprints to: Claus B. Juhl, M.D., Medical Department M (Endocrinology and Diabetes), Århus University Hospital, Nørrebrogade 44, 8000 Århus C, Denmark. E-mail: cbj{at}dadlnet.dk.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Thiazolidinediones have well-established insulin-sensitizing effects. Their impact on insulin secretion is less clarified. Consequently, we sought to determine potential effects of a thiazolidinedione (rosiglitazone) on the ß-cell function. Twenty type 2 diabetic individuals were randomized to receive rosiglitazone (rosi) 4 mg twice daily or placebo (pla) for 13 wk. Before treatment and at the end of the treatment period, the patients underwent an iv glucose tolerance test (0.3 g/kg), a hyperglycemic (15 mmol/liter) clamp with arginine (5 g) stimulation, assessment of baseline high-frequency insulin pulsatility, and glucose-entrained insulin pulsatility (6 mg/kg·min every 10 min), and a hyperinsulinemic euglycemic clamp. Fasting plasma glucose was reduced (pla, 8.2 ± 2.1 vs. 8.8 ± 2.6 mmol/liter; rosi, 8.6 ± 7.1 vs. 7.1 ± 1.2 mmol/liter; P < 0.01), and insulin sensitivity was increased by rosiglitazone treatment (M value: pla, 5.3 ± 1.8 vs. 5.4 ± 1.6 mg/kg·min; rosi, 5.9 ± 2.2 vs. 7.4 ± 1.3 mg/kg·min; P = 0.05). First-phase insulin secretion and insulin secretory capacity were unaffected. Glucose-entrained insulin secretion was increased as assessed by spectral power analysis (P = 0.05). In conclusion, rosiglitazone treatment for 3 months in type 2 diabetic patients exerts no action on insulin secretion per se. Improved glucose-entrained high-frequency insulin pulsatility suggests an increased ability of the ß-cell to sense and respond to glucose changes within the physiological range.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
INSULIN RESISTANCE AND ß-cell dysfunction are features of type 2 diabetes. The evaluation of the effect of antidiabetic agents in these patients, therefore, requires an evaluation of both. Failure to antidiabetic therapy, however, is frequent (1). Consequently, there is a strong need for new antidiabetic agents to improve metabolic control and prevent progression of the disease. Thiazolidinediones (TZDs) is a recently introduced class of oral antihyperglycemic compounds. Their glucose-lowering effect is believed to arise from an increased insulin action in the adipose tissue, skeletal muscle, and liver (2, 3, 4, 5). Despite a widespread use of TZDs, however, possible ß-cell actions have been only sparsely elucidated in humans (6, 7). In subjects with impaired glucose tolerance increased insulin secretory rate and enhanced entrainment of ultradian glucose oscillations have been demonstrated after TZD exposure (8). Furthermore, studies in diabetic animal models, isolated pancreas, and ß-cells have indicated an increased glucose stimulated insulin secretion and increased entrainment of insulin secretion to oscillatory glucose infusion, but the results have been conflicting (9, 10, 11, 12, 13). TZDs have been shown to reduce lipid storage in the ß-cell (14) and prevent loss of ß-cell mass in an animal model of type 2 diabetes (15), thus providing a theoretical basis of improved ß-cell function after TZD treatment. Finally, a direct action of troglitazone on the ATP-sensitive channel has been suggested (10). The ß-cell function in terms of the pulsatile insulin release during baseline conditions and the prompt insulin response to exogenous glucose supply is disturbed in type 2 diabetes (16, 17, 18) and ß-cell function should be evaluated at baseline as well as in response to glucose-stimuli (19). The present study was, therefore, undertaken to evaluate the effect of 3 months of rosiglitazone treatment vs. placebo on the ß-cell abnormality in type 2 diabetic individuals as assessed by a panel of ß-cell test.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
The protocol was performed in accordance with the Helsinki Declaration and approved by the local ethical committees in Århus and Vejle counties. Before entering the study, written informed consent was obtained after written and oral information.

The study was conducted as a two-site, double blind, placebo-controlled, parallel-group study. The study was performed in the research units of the Medical Department of Århus University Hospital and Kolding Sygehus. Twenty patients with type 2 diabetes were equally randomized to receive either rosiglitazone or placebo. Sixteen patients were diet treated only, and the four patients treated with oral antidiabetic agents (repaglinide, n = 3; glibenclamide, n = 1) went through a 6-wk washout period before inclusion. None of the patients received medication with known influence on insulin secretion or insulin sensitivity in addition to the study drug.

The patients were asked to maintain their dietary and physical activity habits throughout the study period. The patients received rosiglitazone 4 mg or placebo twice daily for 13 wk. Before the treatment and at the end of the treatment period, the patients underwent two study days (1 and 2, respectively) as described below. After 4 wk of treatment, a safety visit was performed to ensure that severe hyperglycemia or hypoglycemic periods were not present.

Study days

A schematic presentation of the study days is shown in Fig. 1Go. At arrival to the Clinical Research Unit, cannulae were placed in an antecubital vein and the ipsilateral hand vein (study d 1) or in both antecubital veins (study d 2) for infusion and sampling purposes. The forearm was heated at the side of blood sampling in both study days. Additional study procedures were initiated 30 min later (t = 0).



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  		FIG. 1. The study was performed as a double-blind, placebo-controlled trial. The procedures performed on the study days are outlined on the figure. Study d 1 and 2 were completed approximately 1 wk apart at baseline (pretreatment) and at the end of the 13-wk treatment period (posttreatment).

 
Study d 1 (1 wk before and + 12 wk relative to start of medication). First-phase insulin secretion was assessed by infusion of glucose 0.3 g/kg body weight over 2 min (from -2 to 0 min). Blood was collected for the analysis of insulin and glucose at -10, -5, 1, 3, 5, 7, and 10 min relative to the end of the glucose infusion. Areas under the curve (AUC)1–10 min for insulin and peak insulin1–10 min values were recorded. Hereafter, a hyperinsulinemic, euglycemic clamp was performed: Insulin was infused with an initial rate of 3 mU/kg·min from t = 30–90 min, followed by 1.5 mU/kg·min until t = 240 min. Plasma glucose was allowed gradually to fall to 5.5 mmol/liter, and then the glucose level was maintained stable by the infusion of 20% glucose. The coefficient of variation of the glucose infusion rate during the last 30 min of the clamp was 3.0% (range, 0.7–5.5%). The mean glucose infusion rate and serum insulin for the last 30 min of the clamp were used for the calculation of the insulin sensitivity.

Study d 2 (immediately before and +13 wk relative to start of study medication). Baseline (nonstimulated) high-frequency insulin pulsatility was assessed by collection of blood samples every minute for 60 min by the study procedure described previously (20). Fasting insulin was calculated as the mean of the first three insulin measurements. Hereafter the ability of the ß-cell to sense and respond to minor glucose oscillations (entrainment) was evaluated during repeated punctuated glucose infusions every 10 min (pulse duration 1 min, glucose infusion rate 6 mg/kg·min) by similar high-frequency blood sampling for 60 min. The resultant insulin concentration time series was analyzed by deconvolution analysis and time series analysis as described below. Insulin secretory capacity was subsequently evaluated by a hyperglycemic clamp analysis from t = 150–230 achieved by variable glucose infusion targeting a glycemic value of 15 mmol/liter. Absolute and incremental (relative to baseline) AUC of insulin and glucagon were calculated for the period t = 200–230 min. To further stimulate islet hormone-release 5 g L-arginine was infused over 30 sec at t = 230 min, and blood samples were obtained at 0, 5, 10, 15, 20, and 30 min relative to infusion. Absolute and incremental (relative to baseline) AUC for insulin and glucagon were calculated for this 30 min period t = 230–260 min).

Biochemical analyses

All biochemical analyses were performed in duplicate. Plasma glucose was measured on a glucose analyzer (Beckman, Palo Alto, CA) using the glucose oxidation technique. All other blood samples were stored at -20 C and analyzed within a month. Serum insulin concentration was measured by using a two-site immunospecific insulin ELISA. The intra- and interassay coefficients of variation were 3% and 5%, respectively. Samples for glucagon measurement were collected in tubes with aprotinin/EDTA solution in an ice bath and frozen immediately. Measurements were performed by RIA (21). Free fatty acids were measured by a calorimetric method (WAKO, Trichem, Frederiksund, Denmark). C-peptide was measured by a two-site monoclonal-based ELISA (K6218; Dako Diagnostics Ltd., Cambridgeshire, UK). This assay has an intra- and interassay coefficient of variation (in triplicates) of 2% and 3%, respectively.

Data analysis

Deconvolution analysis. Serum insulin concentration time series were analyzed in a blinded manner by deconvolution analysis to quantitate insulin secretory burst mass, burst amplitude, basal secretion, and interpulse interval (22). The analysis was performed as described earlier (23). Results are expressed relative to the distribution volume.

Detrending. To eliminate the effects of nonstationarity in the data, approximate entropy (ApEn), spectral analysis, and autocorrelation analysis were performed on the residuals after subtraction of an 11-point centered moving average process (24, 25, 26). This length of the moving average process was chosen to ensure optimal detrending also in the entrainment studies where a frequency of 10 min was to be expected.

ApEn. Regularity of insulin concentration time series during baseline and glucose-entrained conditions was assessed by ApEn (27). ApEn measures the likelihood that patterns repeat throughout the time series. Precise mathematical definition was described elsewhere (27). ApEn depends on the choice of the input parameters m (the length of the patterns compared) and r (an interval calculated as a fraction of the SD in the time series within which data points are considered equal). By application of a small r value (e.g. r = 0.2 x SD), ApEn evaluates fine (sub) patterns in the time series, and a larger r value (e.g. r = 1.0 x SD) is applied to evaluate more coarse patterns (28). A higher ApEn value indicates a more irregular time series. ApEn is little affected by noise that lies within the defined r value.

Spectral analysis and autocorrelation analysis. The ability of glucose infusion to entrainment insulin release was measured by spectral analysis and autocorrelation analysis.

By spectral analysis insulin concentration time series is described by sinus waves of different frequencies to evaluate the magnitude of a 10-min frequency. The analysis was performed using noncommercial software. A Tukey window of 25 data points was used, and spectra were normalized, assuming that the total variance in each time series was 100%. This enables comparison of spectral estimates despite the different absolute values of insulin. The spectral power of the 10-min frequency during placebo and rosiglitazone treatment was compared statistically. Autocorrelation analysis was performed using SPSS version 10.0 (SPSS Inc., Chicago, IL). Autocorrelation coefficients at lag time = 10 min were transformed to Z values by Fischers Z transformation. Mean values were calculated and transformed to r values by the inverse procedure before statistical comparison.

Statistical comparison. Statistical analyses were performed by unpaired t tests of {delta} (after pretreatment) values between the rosiglitazone and placebo group. AUC for the stimulation tests were calculated by summing successive trapezes. The disposition index was calculated as M*AUCfirst phase insulin secretion. All statistical tests were two-tailed. Cut-off value for statistical significance was defined as 5%.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Clinical parameters

Baseline subject characteristics are given in Table 1Go. There were no statistically significant differences between the two study groups. Fasting plasma glucose was significantly reduced from 8.6–7.1 mmol/liter (P < 0.01), and fasting serum insulin was reduced by approximately 25% (P = 0.09) after rosiglitazone treatment (Table 2Go). Fasting plasma glucagon was not influenced by the treatment. The rosiglitazone-treated individuals experienced a weight gain averaging 2 kg (pla, 95.0 ± 10.5 vs. 94.7 ± 9.4; rosi, 91.7 ± 7.0 vs. 93.7 ± 8.4 kg; P = 0.02).


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  		TABLE 1. Subject characteristics (mean ± SD) of the two study groups

 

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  		TABLE 2. Baseline values, IVGTT, and hyperglycemic clamp including arginine stimulation

 
First-phase insulin secretion

The first phase insulin release was unchanged after rosiglitazone and placebo treatment as calculated by the maximal insulin concentration and absolute and incremental AUC of insulin (Table 2Go and Fig. 2Go).



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  		FIG. 2. Mean insulin concentration during the IVGTT. Glucose (0.3 g/kg) was infused over 2 min as illustrated by the block arrow. A, Results from the placebo-treated group. B, Results from rosiglitazone-treated group.

 
Hyperglycemic clamp

Mean insulin level rose from approximately 65 pmol/liter at baseline to approximately 175 pmol/liter during hyperglycemia (Table 2Go and Fig. 3Go). The glucose stimulated insulin release was unaltered by rosiglitazone treatment as calculated by absolute and incremental AUC of insulin during the last 30 min of hyperglycemia. Plasma glucagon was suppressed by approximately 50% during hyperglycemia. This suppression was not altered by rosiglitazone treatment (Table 2Go). A marked stimulatory effect of insulin release was observed after iv arginine bolus, and this was likewise unaffected by the rosiglitazone.



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  		FIG. 3. Mean insulin concentration during baseline (0–30 min), hyperglycemia (200–230 min), and arginine stimulation (230–360 min). A, Results from the placebo-treated group. B, Results from the rosiglitazone-treated group (pretreatment, open symbols; posttreatment, black symbols). Average insulin response was unaltered after rosiglitazone treatment, compared with placebo.

 
Insulin sensitivity

Insulin sensitivity was improved by rosiglitazone treatment as assessed by hyperinsulinemic euglycemic clamp technique (M: pla, 5.3 ± 1.8 vs. 5.4 ± 1.6; rosi, 5.9 ± 2.2 vs. 7.4 ± 1.3 mg/kg·min; P = 0.05) also when adjusted for the actual mean insulin value during the steady-state period (M/I ratio: pla, 0.23 ± 0.10 vs. 0.23 ± 0.09; rosi, 0.22 ± 0.08 vs. 0.28 ± 0.06; P = 0.04). The increase in insulin sensitivity in the rosiglitazone-treated group correlated positively to the reduction in fasting plasma glucose in the rosiglitazone treatment group (Pearsons r = 0.64, P < 0.05), but no such correlation was observed in the placebo group. Free fatty acids tended to be reduced (pla, 0.63 ± 0.15 vs. 0.59 ± 0.22; rosi, 0.64 ± 0.26 vs. 0.42 ± 0.20; P = 0.07) despite a lower insulin level, suggesting improved adipose tissue insulin sensitivity. The disposition index was not significantly changed after rosiglitazone treatment but tended to be increased (pla, 71 ± 51 vs. 66 ± 38; rosi, 68 ± 28 vs. 81 ± 39).

Pulsatile insulin secretion and glucose entrainment

The overall insulin release was insignificantly suppressed by approximately 25% in the rosiglitazone treatment group (Table 3Go and Fig. 4Go). This effect was ascribable to a significant (25–30%) reduction in insulin secretory burst mass and burst amplitude, whereas the baseline insulin release was unaffected by rosiglitazone treatment. The pulse frequency was not affected. One representative example of a deconvolved insulin concentration time series during baseline conditions is shown in Fig. 4Go. The regularity of the insulin release pattern was assessed by approximate entropy analysis and was found to be unaltered after 12 wk of rosiglitazone treatment.


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  		TABLE 3. Deconvolution analysis and regularity analyses of insulin concentration time series during baseline (nonstimulated) and glucose-entrained conditions

 


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  		FIG. 4. Example of deconvolution analysis of baseline (nonentrained) insulin concentration time series from a patient receiving rosiglitazone treatment. A and C, The pretreatment assessments. B and D, Posttreatment assessments. A and B, Insulin concentration time series obtained (open symbols) along with a best fit line (black line) estimated by least square analysis. C and D, Calculated insulin secretory rate. Overall decrease in insulin release is seen to originate from decreased insulin secretory burst mass, but basal secretion and pulse frequency are unaltered.

 
Glucose entrainment was significantly improved by rosiglitazone treatment as assessed by spectral analysis (Fig. 5AGo). A similar trend was found when data were analyzed by autocorrelation analysis and approximate entropy analysis, although none of these latter findings were statistically significant. Figure 5Go shows one example of a placebo-treated subject (Fig. 5BGo) and rosiglitazone-treated subject (Fig. 5CGo).



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  		FIG. 5. Example of insulin concentration profiles and mean results from time series analysis of glucose-entrained insulin concentration series. A, Delta (post- to pretreatment) differences of the mean spectral power and autocorrelation coefficient at 10 min periodicity after placebo (open bars) and rosiglitazone (hatched bars) treatment. B, Lack of entrainment after placebo treatment. C, Increased ability of the ß-cell to sense and respond to exogenous oscillatory glucose supply after rosiglitazone treatment. Note the apparent synchrony of insulin oscillation relative to the timing of glucose infusion indicated by arrows (pretreatment, open triangles; posttreatment, black circles). *, P < 0.05.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present study provides a detailed assessment of insulin secretion after TZD treatment of type 2 diabetic subjects. The TZDs are believed to act primarily through an increase in insulin sensitivity. Acknowledging the close relationship between insulin sensitivity and insulin secretion, however, possible direct effects on the ß-cell function are important to improve glycemic control (29).

Fasting serum insulin was reduced by approximately 25% by rosiglitazone treatment. Although this was not statistically significant, it is comparable with previous reports (6). A down-regulation of insulin synthesis and secretory capacity may consequently be expected. In line with this hypothesis reduced maximal insulin release during iv glucose tolerance test (IVGTT) has been reported along with reduced fasting insulin after troglitazone treatment in hyperlipidemic, diabetic rabbits (11). In contrast, enhanced ß-cell function as estimated by IVGTT has been reported after troglitazone treatment in subjects with IGT known to have a blunted but still evident first-phase insulin response to IVGTT (8, 30). Furthermore, we observed a trend toward an improved disposition index in this rather small number of patients after rosiglitazone treatment. This is in line with the observation by Buchanan et al. (31) in which a marked increase in the disposition index was demonstrated in Hispanic women with previous gestational diabetes mellitus treated with troglitazone. In the current study, we observed no absolute changes in the insulin secretion after rosiglitazone treatment as assessed by first-phase insulin secretion test or hyperglycemic clamp including arginine stimulation. Reduced fasting insulin, which has been reported, thus reflects an adaptation to the reduced glycemia and the improved insulin sensitivity and not a reduced insulin release capacity.

In addition to conventional ß-cell tests in which supraphysiological stimuli are applied, we assessed ß-cell function by baseline and glucose entrained insulin pulsatility. Overnight ß-cell rest induced by somatostatin infusion has been shown to improve baseline insulin pulsatility in type 2 diabetic patients (32). Likewise improved metabolic control could be expected to improve insulin pulsatility. We have recently demonstrated increased insulin secretory burst mass in type 2 diabetic patients treated with sulfonylurea for 5 wk. The study, however, failed to demonstrate improved regularity despite improved glycemic control (33). It is plausible that such a direct ß-cell stimulus in itself induces changes in ß-cell release regularity as has been demonstrated by repaglinide treatment (26). The tendency to reduce baseline (i.e. nonglucose stimulated) insulin release was achieved by a significant reduction of the insulin secretory burst mass, but the basal (nonpulsatile) insulin secretion and the pulse frequency were unaltered. Adjustment of the baseline insulin release was thus predominantly achieved by modulation of the pulsatile insulin secretion, which is similar to what has previously been reported for insulin secretagogues (25, 26, 33, 34).

By application of repeated glucose stimuli of physiological amplitudes (35), we found increased regularity of the induced insulin response in rosiglitazone-treated subjects. The improved ß-cell function might be related to reduced glucose toxicity after improved glycemic control or improved insulin sensitivity. Because first-phase insulin release and maximal insulin secretory capacity both were unaltered, the improvement seems to be related to increased ß-cell sensitivity rather than to increased secretory capacity. Pioglitazone has been shown to improve glucose entrainment in ZDF rats only if intervention has been applied early in the development of the disease. This finding indicates that reversibility depends on the preexisting condition of the ß-cell (13) and might explain why only some of the patients regained ability to entrain glucose oscillations. Entrainment is a sensitive tool for assessing differences in insulin release between health and type 2 diabetes (36). The present study is, to our knowledge, the first to compare this method with conventional ß-cell tests in which supraphysiological doses of glucose or nonglucose secretagogues are applied. Although laborious and expensive, insulin pulsatility studies might thus be useful in uncovering smaller differences or subtle changes that are not readily detectible by other ß-cell tests.

In conclusion, we found that 3 months of rosiglitazone treatment of type 2 diabetic patients did not alter insulin secretory capacity as assessed by a panel of different ß-cell tests. However, the results expand the evidence that TZD may improve the ability of the ß-cell to sense and respond to changes in glucose concentrations, suggesting a protective role of rosiglitazone treatment on the ß-cell either via improved metabolic control or through direct drug actions.


   Acknowledgments
 
The expert technical assistance of Anette Mengel and Lene Kristensen is gratefully acknowledged.


   Footnotes
 
This work was supported by Glaxo-SmithKline. F.L. was employed at Glaxo-SmithKline at the time of study conductance.

Abbreviations: ApEn, Approximate entropy; AUC, area(s) under the curve; IVGTT, iv glucose tolerance test; TZD, thiazolidinedione.

Received August 1, 2002.

Accepted April 10, 2003.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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