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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 3 819-823
Copyright © 1998 by The Endocrine Society

Original Studies

Effect of Troglitazone on B Cell Function, Insulin Sensitivity, and Glycemic Control in Subjects with Type 2 Diabetes Mellitus1

Ronald L. Prigeon, Steven E. Kahn and Daniel Porte, Jr.

Division of Metabolism, Endocrinology, and Nutrition and Veterans Affairs Puget Sound Health Care System, University of Washington, Seattle, Washington 98108

Address all correspondence and requests for reprints to: Ronald L. Prigeon, M.D., Veterans Administration Puget Sound Health Care System (151), 1660 South Columbian Way, Seattle, Washington 98108.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
We studied the effects of troglitazone (200–800 mg daily) or placebo on carbohydrate metabolism in 18 subjects with type 2 diabetes (mean age, 66 yr; body mass index, 27.7 kg/m2) at baseline and after taking medication for 12 weeks. We measured fasting proinsulin (PI) and immunoreactive insulin (IRI) levels in all subjects. Thirteen subjects underwent additional metabolic studies, including injection of arginine to determine the acute insulin response, and an iv glucose tolerance test to measure the insulin sensitivity index (SI) and glucose effectiveness at zero insulin using the minimal model, iv glucose tolerance, and acute insulin response to glucose. Troglitazone treatment resulted in a decrease in fasting plasma glucose from 11.2 ± 0.7 to 9.6 ± 0.9 mmol/L (P = 0.02). This was associated with a decrease in the fasting IRI concentration (111 ± 20 to 82 ± 13 pmol/L; P = 0.02) and a trend toward a decrease in the fasting PI concentration (43 ± 11 to 25 ± 4 pmol/L; P = 0.06). A significant decrease in PI/IRI was observed (38.3 ± 3.6% to 32.6 ± 3.2%; P = 0.04). Troglitazone therapy was also associated with a decrease in the acute insulin response to arginine (226 ± 34 to 167 ± 25 pmol/L; P = .01) and a near-significant percent increase in SI (75 ± 35%; P = 0.06). Glucose effectiveness at zero insulin, iv glucose tolerance, and acute insulin response to glucose did not change. Thus, we found that the decrease in plasma glucose during troglitazone therapy is associated with a dose-related decrease in PI/IRI and an increase in SI, suggesting that changes in both B cell function and insulin sensitivity contribute to the improvement in metabolic status.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
TYPE 2 diabetes mellitus is characterized by insulin resistance and B cell dysfunction, including reduced insulin secretion (1, 2) and an elevated ratio of proinsulin to immunoreactive insulin (PI/IRI) (3, 4, 5, 6). Troglitazone is a new oral insulin-sensitizing agent from the thiazolidinedione group of compounds that has been shown to be effective in reducing fasting glucose levels in subjects with type 2 diabetes (7, 8) and improving insulin sensitivity in experimental animals (9) and human subjects (10, 11, 12). However, the effect of troglitazone administration on B cell function in persons with type 2 diabetes has not been fully evaluated. Therefore, we performed a comprehensive evaluation of the metabolic effects of troglitazone on factors that are important in glucose tolerance, including B cell function, insulin sensitivity, and glucose effectiveness.


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

The study group consisted of 18 subjects (4 women and 14 men) with type 2 diabetes treated with either diet or a sulfonylurea medication. The average subject age was 66 yr (range, 45–82 yr), and average body mass index was 27.7 kg/m2 (range, 20.1–37.8). Aside from sulfonylurea treatment, no subjects were taking medication known to alter glucose metabolism, and all were otherwise in good health. The protocol was approved by the human subjects review committee of the University of Washington, and informed consent was obtained from all subjects. The results of the baseline study for 9 of the 18 subjects was previously reported (13).

Procedures

Subjects taking a sulfonylurea medication were withdrawn from their medication, and all subjects underwent a 4-week stabilization period before initiation of troglitazone therapy. Subjects were randomly assigned to receive either placebo or troglitazone at a dose of 200, 400, 600, or 800 mg/day, taken as a single dose in the morning.

Samples for fasting glucose were obtained 1 week before and immediately before troglitazone therapy and after 11 and 12 weeks of therapy, and the fasting glucose level was taken as the average of the 2 measurements. Samples for fasting IRI and PI were obtained immediately before the first troglitazone dose and after 12 weeks of therapy. In 13 subjects, 2 additional metabolic tests were performed; measurement of the acute insulin response to arginine (AIRarg) and an iv glucose tolerance test (IVGTT).

The AIRarg procedure was performed at each subject’s spontaneous fasting glucose concentration and consisted of obtaining baseline samples at -10, -5, and -1 min followed by injection of 5 g arginine HCl over a 30-s period. Samples for glucose and IRI measurement were obtained 2, 3, 4, and 5 min after arginine injection.

The IVGTT consisted of the collection of basal samples, followed by iv injection of 11.4 g/m2 glucose over 60 s commencing at time zero. The IVGTT was modified by the injection of human regular insulin (Novolin, Novo-Nordisk, Bagsvaard, Denmark) beginning at 20 min, with approximately half the insulin injected as a bolus, and the remainder infused over 5 min (14, 15). The total insulin dose was between 0.035–0.060 U/kg based on body mass index, the goal being to equalize insulin action among subjects. Thirty-two blood samples for glucose and insulin measurements were collected over a 4-h period after glucose administration at 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 19, 22, 23, 24, 25, 27, 30, 35, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 220, and 240 min.

All studies were performed on the metabolic ward of the Veterans Affairs Puget Sound Health Care System, Seattle Division, after an overnight fast. Subjects remained supine for the AIRarg and IVGTT studies, and the AIRarg procedure was performed first, followed 30 min later by the IVGTT. Blood samples were arterialized by wrapping the entire forearm and hand with a heated pad, and infusates were administered through a similar catheter inserted in the contralateral arm. Both catheters were kept patent by infusion of 0.9% saline. For the five subjects who did not participate in the additional metabolic studies, the fasting blood sample was obtained from a forearm vein with the subject seated in a chair.

Assays

All samples were placed on ice until plasma was separated and stored at -20 C. Plasma glucose concentrations were measured using a hexokinase method. Plasma IRI was measured in duplicate using a modification of a double antibody RIA (16). The insulin antibody employed in this assay cross-reacts with PI and PI conversion intermediates on an equimolar basis to insulin (17); thus, this assay measures IRI, which includes insulin, PI, and PI conversion intermediates. PI and intermediates were measured using a two-step procedure, as previously described (17). Thus, PI refers to PI and PI conversion intermediates. The intraassay coefficients of variation for glucose, IRI, and PI were less than 1.3%, 5%, and 10%, respectively. All IRI samples from an individual were measured in a single assay.

Computations and statistics

On days on which the IVGTT and AIRarg procedures were performed, fasting glucose, IRI, and PI levels were calculated as the average of three baseline samples. PI/IRI was computed as the molar ratio. AIRarg was computed as the mean increment of IRI 2, 3, 4, and 5 min after arginine injection. The acute insulin response to glucose (AIRglucose) was computed from the IVGTT results as the mean increment above baseline 2, 3, 4, 5, 6, 8, and 10 min after the glucose injection. The glucose disappearance constant (Kg) was computed as the slope of the linear least square regression line to the natural logarithm of the glucose concentration vs. time from 10–19 min after the administration of glucose. The insulin sensitivity index (SI) and glucose effectiveness at zero insulin (GEZI) were obtained from IVGTT results by identification of minimal model parameters using a nonlinear least square technique (18, 19).

The effect of troglitazone therapy was determined using three statistical methods. The first method compared pretreatment to during treatment parameter values using a paired t test with subjects who received placebo excluded from the analysis. Due to a skewed distribution, the change in fasting PI was also compared with the Wilcoxon’s rank sum test. The second procedure evaluated whether a dose-dependent effect was present by computing the regression of change in parameter value against dose. For this analysis, subjects who received placebo are included. As a linear dose-response cannot be differentiated from a dose threshold effect due to the relatively small sample size, the data were also analyzed by comparing the changes observed in a high dose group (600 and 800 mg/day) to those in low dose and placebo groups (200 and 400 mg/day and placebo) using unpaired t tests. Two-tailed tests were used for all comparisons, and P < 0.05 was considered significant. Because of marked heteroscedasticity, insulin sensitivity data were analyzed as a percent change from the baseline value. Data are expressed as the mean ± SE.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
All 18 subjects completed the study, and individual results are listed in Tables 1Go and 2Go. A significant decrease in the fasting glucose concentration was observed in those subjects treated with troglitazone (11.2 ± 0.7 to 9.6 ± 0.9 mmol/L; P = 0.02). Troglitazone therapy was also associated with a decrease in the fasting IRI concentration (111 ± 20 to 82 ± 13 pmol/L; P = 0.02) and a trend toward a decrease in the fasting PI concentration (43 ± 11 to 25 ± 4 pmol/L; P = 0.06). Using a Wilcoxon test, a significant decrease in PI was observed (P < 0.01). The PI/IRI ratio showed a decrease that was significant (38.3 ± 3.6% to 32.6 ± 3.2%; P = 0.04).


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  		Table 1. Individual results for fasting, glucose stimulation, and arginine stimulation studies

 

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  		Table 2. Individual IVGTT results

 
The percent change in insulin sensitivity was computed for each subject, and a near-significant increase in this measure was obtained (+75 ± 35%; P = 0.06). As there is no hypothesis that troglitazone would cause a decrease in SI, we believe that it is appropriate to use a one-tailed test that would result in a significant P value of 0.03. Kg increased from 0.76% to 0.85%/min; however, this increment was not significant. AIRarg decreased from 226 ± 34 to 167 ± 25 pmol/L (P = 0.01), but no change was observed in AIRglucose.

The dose-response effects of troglitazone therapy on PI/IRI are shown in Fig. 1Go. A significant relationship between PI/IRI and dose was observed using linear regression analysis (r2 = 0.43; P = 0.003) and also when the results from a high dose group (600 and 800 mg/day) were compared to results from other subjects (P = 0.002). A significant relationship was also observed between dose and change in fasting glucose concentration (r2 = 0.33; P = 0.01, by linear regression; P = 0.02, by group comparison) as well as a near-significant relationship between dose and percent change in SI (r2 = 0.25; P = 0.08, by linear regression).



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  		Figure 1. Relationship between troglitazone dose and the change in the basal PI/IRI ratio.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The B cell in normal individuals efficiently converts PI to insulin, resulting in a PI/IRI of approximately 15% in the basal state. In patients with type 2 diabetes, this ratio is doubled (4, 20), which may reflect dysfunctional B cell processing of the prohormone, and is associated with a reduction in B cell secretory capacity (21). Thus, this ratio has been used as a marker for B cell dysfunction per se. The ratio of PI to IRI rather than the absolute PI concentration appears to reflect B cell dysfunction, because PI/IRI remains normal or decreased whereas the PI concentration increases in normoglycemic persons with hyperinsulinemia from obesity (5) and from experimentally induced insulin resistance (22). Additionally, an increase in PI/IRI was observed with streptozocin-induced B cell dysfunction in primates (23).

In the present study, we found that troglitazone treatment lowered PI/IRI in subjects with type 2 diabetes, suggesting an improvement in B cell function. There are several potential explanations for this effect. The increased insulin sensitivity with troglitazone treatment should lead to a decrease in B cell demand because of the effect of insulin sensitivity to modulate B cell responsiveness (22). As B cell demand has been hypothesized as a contributor to the increased PI/IRI observed in type 2 diabetes (24, 25, 26), the troglitazone-associated decrease in B cell demand could potentially lead to a lowering of PI/IRI. However, several studies performed in our and other laboratories suggest that a change in PI/IRI may not be due to changes in B cell demand. No change in PI/IRI was seen with increased B cell demand from nicotinic acid-induced insulin resistance (22), insulin secretagogues (27), or mild, sustained hyperglycemia (28). These findings would not support the conclusion that the 75% increase in SI and the associated decrease in secretory demand resulting from troglitazone treatment are likely to explain the observed change in PI/IRI. However, it is possible that B cells in subjects with type 2 diabetes respond differently to reduced B cell demand than normoglycemic subjects.

It has also been hypothesized that hyperglycemia can alter PI processing secondary to an increase in secretory demand or due to a direct toxic effect on the B cell. Thus, it would be expected that lowering plasma glucose levels may lead to an improvement in glucose toxicity and reduce PI/IRI. However, countering this theory is our recently published study assessing the effect of sulfonylureas on PI/IRI (13). In that study, we found that a sulfonylurea-induced decrease in plasma glucose levels did not affect PI/IRI, even though the change in glucose level was greater than the decrease induced by troglitazone in the present study.

Alternatively, it is possible that troglitazone has a direct effect on the B cell to improve its function. In keeping with this possibility, Inoue et al. (29) have shown an increase in insulin content in B cells in 90% of pancreatectomized rats treated with troglitazone, whereas Masuda et al. (30) have shown an increase in insulin secretion in isolated pancreatic islets and in HIT cells treated with troglitazone as well as evidence for binding of troglitazone to B cell membranes. Finally, Fujiwara et al. (31) showed marked regranulation of the B cells and other structural changes in troglitazone-treated db/db mice suggestive of an increase in insulin synthesis. Thus, although no in vitro study has examined the direct effect of troglitazone on PI processing, the above findings suggest that troglitazone may have direct effects on B cell function.

Additionally, this study demonstrates both a decrease in fasting plasma glucose and an increase in insulin sensitivity in response to troglitazone therapy. Similar findings have been made previously in experimental animals and humans (7, 8, 9, 10, 11, 32, 33). However, we did not observe a significant change in GEZI, a measure of insulin-independent glucose disposal. This finding is somewhat unexpected in light of the in vitro study by Ciaraldi et al. (34), in which troglitazone produced a doubling of glucose transport in cultured L6 muscle cells in medium devoid of insulin, but is in keeping with the lack of change in glucose effectiveness at basal insulin 5g in women at high risk for the development of type 2 diabetes (12) and in women with polycystic ovary syndrome (11). It is possible that we were unable to detect small changes in GEZI, or that the in vitro and in vivo effects of the drug are different.

In this study we have also demonstrated a decrease in both fasting and arginine-stimulated B cell insulin release. It is likely that two factors are responsible for these decreases in hormone levels. First, the insulin response to a nonglucose secretagogue is known to be dependent on the prevailing plasma glucose level in normal and diabetic subjects (1); thus, a lower glucose level should produce a smaller insulin response. Second, the reduced insulin secretion could be the result of an adaptation of B cell response to changes in insulin sensitivity. This adaptive effect has been observed in young normal subjects as an increase in insulin responses to challenge after a decrease in SI (22), and in older subjects as a decrease in B cell responses after an exercise-induced increase in SI (35). Similar adaptive change may be at work in our investigation.

Despite the lower plasma glucose levels and increased SI, only an 11% increase in Kg was observed with troglitazone therapy, and this change did not reach statistical significance. This finding can be explained by noting that in the absence of a first phase insulin response, Kg is predominately determined by GEZI (36). The lack of change of Kg in the present study is, therefore, consistent with the lack of change in GEZI and the absence of a first phase insulin response.

In conclusion, troglitazone therapy lowers fasting plasma glucose and improves SI, an index of insulin sensitivity. Additionally, drug treatment was associated with lower PI/IRI, suggesting improved B cell function. The B cell function changes may be due to a direct effect of the drug on the B cell, adaptive changes to the increase in insulin sensitivity, alterations in the prevailing glucose concentration, or a combination of these factors.


   Acknowledgments
 
We thank Richard Chan, Ruth Hollingsworth, Susan Loewen, Hong Nguyen, and Jira Wade, who provided technical help in performing the studies and in assaying the samples. Thanks also go to the study participants. Eli Lilly Co. kindly donated the PI standards.


   Footnotes
 
1 This work was supported by the Medical Research Service of the Department of Veterans Affairs, NIH Grants DK-12829 and DK-17047, and a grant-in-aid from Parke-Davis Pharmaceuticals. Back

Received April 14, 1997.

Revised November 7, 1997.

Accepted November 20, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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G. Kwon, G. Xu, C. A. Marshall, and M. L. McDaniel
Tumor Necrosis Factor alpha -induced Pancreatic beta -Cell Insulin Resistance Is Mediated by Nitric Oxide and Prevented by 15-Deoxy-Delta 12,14-prostaglandin J2 and Aminoguanidine. A ROLE FOR PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR gamma  ACTIVATION AND iNOS EXPRESSION
J. Biol. Chem., June 25, 1999; 274(26): 18702 - 18708.
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