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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 12 6048-6053
Copyright © 2004 by The Endocrine Society

Rosiglitazone, But Not Glyburide, Reduces Circulating Proinsulin and the Proinsulin:Insulin Ratio in Type 2 Diabetes

Stephen A. Smith, Lisa E. Porter, Nandita Biswas and Martin I. Freed

Scientific Affairs (S.A.S.), Diabetes, GlaxoSmithKline, Harlow, Essex, CM19 5AW, United Kingdom; and Cardiovascular and Metabolism Clinical Development (L.E.P., N.B., M.I.F.), GlaxoSmithKline, King of Prussia, Pennsylvania 19406

Address all correspondence and requests for reprints to: Stephen A. Smith, GlaxoSmithKline, New Frontiers Science Park (South), Third Avenue, Harlow, Essex, CM19 5AW, United Kingdom. E-mail: stephen.a.smith{at}gsk.com.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
An elevation in the ratio of proinsulin (PI) to immunoreactive insulin (IRI) is inversely related to ß-cell function in type 2 diabetes, and increased PI is an independent risk factor for coronary heart disease. An objective of the present studies was to assess the effects of the thiazolidinedione insulin sensitizer, rosiglitazone, on indirect markers of ß-cell function and cardiovascular risk in people with type 2 diabetes by measuring plasma PI and the PI:IRI ratio. Parameters of insulin processing, including plasma PI and PI:IRI ratios, were determined in type 2 diabetes patients enrolled in two randomized double-blind studies comparing the effects of rosiglitazone (4 or 8 mg/d) with placebo (study 1, 26-wk treatment) or the sulfonylurea glyburide (study 2, 52-wk treatment). Treatment with rosiglitazone for 26 wk (study 1) produced significant dose-dependent decreases in both plasma PI concentrations (18–29%) and the PI:IRI ratio compared with baseline (7–14%) and placebo (19–29%) (P < 0.001). A significant increase in the PI:IRI ratio in placebo-treated patients occurred (P < 0.001). In study 2, rosiglitazone also significantly reduced both plasma PI and the PI:IRI ratio compared with baseline (P < 0.001). In contrast, glyburide significantly increased both plasma PI (45%; P < 0.001) and the PI:IRI ratio (10%) (P < 0.05 vs. baseline). These results show that rosiglitazone and glyburide have differential effects on absolute PI levels and the PI:IRI ratio in people with type 2 diabetes.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
INSULIN RESISTANCE AND impaired pancreatic ß-cell function are the twin hallmarks of type 2 diabetes. The normal reciprocal relationship between insulin sensitivity and insulin secretion is disrupted such that impaired sensitivity to insulin in target tissues is combined with inappropriately low ß-cell function (1). During the progression from normal glucose control, through impaired glucose tolerance, to overt hyperglycemia, patterns of insulin secretion change. Initially, compensation for peripheral insulin resistance occurs via expansion of the ß-cell mass combined with increased insulin secretion (the resultant hyperinsulinemia is adequate to maintain normoglycemia). Susceptible individuals are unable to maintain the compensatory hyperinsulinemia in the long term, ß-cell function gradually deteriorates, and hyperglycemia eventually becomes established. Moreover, the United Kingdom Prospective Diabetes Study using an indirect measure, homeostasis model of assessment (HOMA) analysis, showed that the progressive decline in ß-cell function was not modified by any of the established treatments for type 2 diabetes: diet and exercise, sulfonylureas, or metformin. This may be one reason why none of these current therapies are able to provide sustained glycemic control (2).

The synthesis and release of insulin from ß-cells is a complex process. The primary gene product, preproinsulin, is sequentially processed via proinsulin (PI), through intermediate proteolytic cleavage products, to insulin and C-peptide before release from the ß-cell granule by exocytosis. In nondiabetic subjects, the conversion of PI to insulin is very efficient [plasma PI:immunoreactive insulin (IRI) ratio, approximately 0.1 (3)]; but in type 2 diabetes, levels of PI are elevated disproportionately, by about 3-fold, and consequently there is an increase in the ratio PI:IRI to about 0.3 (3, 4).

The PI:IRI ratio has been used as an indirect marker of ß-cell function. For example, elevation of the PI:IRI ratio correlates with a decreased acute insulin response to glucose in type 2 diabetics (3) and is also predictive of the development of type 2 diabetes (5, 6, 7). It is recognized that increased PI:IRI ratios do not reflect just an increased secretory demand on the ß-cell (imposed, for example, by peripheral insulin resistance) because, in a number of insulin-resistant conditions, compensatory hyperinsulinemia is not accompanied by alteration in the PI:IRI ratio (8, 9, 10, 11, 12).

Increased plasma PI may not only be a reflection of disordered ß-cell function, but it is also associated with adverse cardiovascular effects. Very recently, elevated PI concentrations have been found, in the nondiabetic population, to predict death and morbidity from coronary heart disease, independently of other cardiovascular risk factors (13). Interestingly, risk of coronary heart disease was increased at plasma PI levels significantly lower than those reported in people with type 2 diabetes.

Oral antidiabetic agents exert differential effects on ß-cell function in type 2 diabetes. Sulfonylureas increase the sensitivity of ß-cells to glucose, thereby increasing insulin secretion (14, 15); but because these agents do not change the PI:IRI ratio, absolute concentrations of PI are also increased (16, 17). This suggests that sulfonylureas do not correct the underlying ß-cell disorder: this is borne out by their failure to provide durable glycemic control (2). Metformin reduces hyperproinsulinemia, but this probably occurs as a secondary consequence of improved glycemic control rather than from a direct action to improve ß-cell performance, because diet and exercise produces similar reductions in PI levels (18, 19).

The insulin-sensitizing thiazolidinediones have been reported to alter insulin processing. In a small study in 18 type 2 diabetic subjects, 12 wk of troglitazone therapy reduced both plasma insulin and the PI:IRI ratio, but the absolute concentration of PI was not significantly suppressed (20). In a similarly small study in Japanese patients, pioglitazone significantly reduced both plasma insulin and PI but, unlike troglitazone, did not improve the PI:IRI ratio (21).

In view of the importance of preserving ß-cell function to maintain durable glycemic control, together with the emerging role of PI as a cardiovascular risk factor, we have investigated the effects of the potent insulin-sensitizing thiazolidinedione, rosiglitazone, on parameters of insulin processing in people with type 2 diabetes. Insulin processing was assessed from a post hoc analysis of measurements of plasma insulin and PI, using assays specific for each product, in patients with type 2 diabetes enrolled in two large clinical trials. The first (study 1) was a placebo-controlled study in which patients were treated with rosiglitazone for 6 months. The second (study 2) was a 1-yr comparator trial in which patients received either rosiglitazone or the sulfonylurea glyburide. The primary glycemic endpoints and adverse event profiles from each of these studies have been published (22, 23).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Two double-blind, randomized, multicenter trials were conducted, one in the United States (study 1, 42 centers) and the other in Europe (study 2, 71 centers). The studies were conducted in accordance with the Declaration of Helsinki (1989 amendment), Title 21 of the U.S. Code of Federal Regulations, and Good Clinical Practice Guidelines. The Institutional Review Board at each center approved the protocol, and participants provided informed consent before study enrollment. Men and women who were 36–81 yr old with a diagnosis of type 2 diabetes were eligible to participate if their fasting plasma glucose was between 140 mg/dl (7.8 mmol/liter) and 299 mg/dl (16.6 mmol/liter) (study 1) or 126 mg/dl (7.0 mmol/liter) and 270 mg/dl (15.0 mmol/liter) (study 2), their fasting plasma C-peptide level exceeded 0.79 ng/ml (0.26 nmol/liter), and their body mass index was between 22 and 38 kg/m2 at the time of screening (22, 23).

In both studies, eligible patients were discontinued from all antidiabetic medication for 2 wk before starting a 4-wk, single-blind, placebo baseline period. In study 1, patients were then randomly assigned to 26 wk of double-blind treatment with placebo, rosiglitazone (4 mg/d; 2 mg twice daily) or rosiglitazone (8 mg/d; 4 mg twice daily). In study 2, patients were randomly assigned to receive 52 wk of double-blind treatment with placebo plus rosiglitazone (4 mg/d; 2 mg twice daily), placebo plus rosiglitazone (8 mg/d; 4 mg twice daily), or placebo plus glyburide. During the first 12 wk of treatment, the dose of glyburide was titrated in 2.5-mg increments (range, 2.5–15 mg) to provide optimal glycemic control, and the dose (median, 7.5 mg/d) was then held constant for the remainder of the study. A double-dummy system enabled titration of administered rosiglitazone without changing the daily dose.

Assays

All laboratory tests, with the exception of the insulin assays, were performed by SmithKline Beecham Clinical Laboratories (Van Nuys, CA). Blood samples for the determination of plasma analytes were taken from overnight fasted subjects. Assessment of glycemic and lipid parameters has been described previously (22). Insulin and insulin precursor molecules were assayed at Addenbrookes National Health Service Trust Hospital, Cambridge, United Kingdom. Plasma samples were maintained at –70 C before assay. Specific insulin concentrations were measured by a one-step immunoenzymatic assay (24, 25) [Access Ultrasensitive Immunoassay System, Sanofi Diagnostics Pasteur, Guildford, UK; normal reference range, 2.2–10.2 µU/ml (13–61 pmol/liter)]. Plasma insulin concentrations determined in the two studies therefore represent "true" insulin only. Thus, absolute values quoted may differ from those in other publications in which nonspecific assays were used and IRI consists of insulin, PI, and split products.

Intact PI was determined using a two-site immunometric assay with time-resolved fluorescence detection (Delfia, Wallac, Inc., Turku, Finland). The assay was linear to at least 400 pmol/liter. C-peptide was determined by RIA (Diagnostic Products, Los Angeles, CA).

Statistical analysis

Analysis was based on the efficacy population, defined as all patients who were randomized and had at least one valid on-therapy value for measured parameters. For patients who withdrew from the study or had missing values, the last on-therapy observation was carried forward to all subsequent visits for which data were missing.

For both studies, the efficacy endpoint was evaluation of glycemic control in terms of change in glycosylated hemoglobin (HbA1c) from baseline to study endpoint compared with placebo or glyburide (22, 23). In study 2, rosiglitazone treatment was compared with glyburide treatment for the efficacy endpoint of fasting plasma glucose from baseline to wk 52. In both studies, the assessment of differences between treatment groups for insulin, PI, and C-peptide was performed using the general linear model with terms for treatment and baseline measurement. The data for individual parameters are highly skewed and therefore were log-transformed before statistical analysis. Results were then back-transformed to provide geometric means and were expressed both as percentage difference from control and percentage change from baseline. Treatment comparisons for change from baseline in the PI:IRI ratio were made using nonparametric methods (Wilcoxon rank sum test). Changes from baseline were examined using a signed-rank test.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The baseline characteristics of patients were similar in all treatment groups in both studies (Table 1Go). In study 1, 533 patients were randomized to treatment with an efficacy-evaluable population of 493 (22). In study 2, 598 patients were randomized to treatment with an efficacy-evaluable population of 587 (23). Subjects in study 1 had been diagnosed with diabetes for approximately 5 yr; whereas in study 2, the mean duration of diagnosed diabetes was approximately 6 yr.


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  		TABLE 1. Demographic and baseline characteristics of efficacy populations

 
In study 1, fasting plasma glucose in the placebo group rose from a mean of 228 mg/dl (12.71 mmol/liter) to 248 mg/dl (13.75 mmol/liter), and HbA1c increased by 0.9% over the 26-wk treatment period (22). By contrast, rosiglitazone reduced fasting glucose by a mean of 58 mg/dl (3.22 mmol/liter) at 4 mg/d and by 76 mg/dl (4.22 mmol/liter) at 8 mg/d, compared with placebo. Rosiglitazone (2 and 4 mg twice daily) decreased mean HbA1c relative to placebo by 1.2 and 1.5 percentage points, respectively.

Baseline and wk-26 insulin-parameter values for rosiglitazone and placebo for study 1 are shown in Table 2Go. After 26 wk of treatment with rosiglitazone (4 or 8 mg/d), the mean change from baseline was statistically significant (P < 0.01) for all insulin-related parameters (Table 2Go). Mean reductions in PI after rosiglitazone (4 or 8 mg/d) were significant compared with placebo (P < 0.01), whereas the mean changes in insulin levels were not significantly different from placebo. PI was reduced in a dose-dependent manner, by 18 and 29%, relative to placebo at 4 and 8 mg rosiglitazone, respectively.


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  		TABLE 2. Summary of changes in insulin parameters

 
In study 2, glyburide reduced HbA1c by a mean of 0.72%, from a baseline of 8.15% over the 52-wk treatment period, whereas rosiglitazone reduced HbA1c by 0.27% and 0.53% at 2 and 4 mg twice daily, respectively. The glycemic improvement produced by 4 mg twice daily rosiglitazone was not significantly different from that produced by optimally tritrated glyburide (23).

Baseline and wk-52 insulin-parameter values for study 2 are shown in Table 2Go. Glyburide treatment significantly increased plasma insulin concentrations, but C peptide was not significantly altered. Importantly, glyburide increased the absolute PI concentration by 45%, from 16.4 pg/ml (17.5 pmol/liter) to 23.8 pg/ml (25.3 pmol/liter). In this study, rosiglitazone produced dose-dependent significant reductions from baseline (P < 0.001) in plasma insulin and C-peptide. As detected in study 1, and in direct contrast to glyburide, rosiglitazone produced a dose-dependent decrease in absolute plasma PI concentrations. The magnitude of the fall in PI was comparable with that in study 1. Compared with glyburide, rosiglitazone treatment was associated with statistically significant (P < 0.001) reductions in insulin, PI, and C-peptide levels.

To gain an indirect estimate of ß-cell function, PI:IRI ratios were calculated in both studies. In study 1, treatment with rosiglitazone (4 or 8 mg/d) resulted in significant (P < 0.05) dose-dependent decreases in the PI:IRI ratio compared with baseline (7–14% reduction) and placebo (19–29% reduction) (Table 3Go). Conversely, treatment for 26 wk with placebo was associated with a significant (P < 0.001) increase in the PI:IRI ratio (13% increase) (Table 3Go). The measured PI:IRI ratios in this study population, of about 0.3, are very comparable with those reported previously in the literature (3, 4).


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  		TABLE 3. Estimates of ß-cell function–PI:IRI ratio

 
In study 2, similar dose-dependent decreases in the PI:IRI ratio were observed after 52 wk of treatment with rosiglitazone compared with baseline (–14%: P < 0.001 for rosiglitazone, 8 mg/d) (Table 3Go). Reductions in the PI:IRI ratio were statistically significant (P < 0.001) for rosiglitazone both at 4 mg (–17%) and at 8 mg/d (–21%), compared with glyburide (Table 3Go). In contrast, 52 wk of treatment with glyburide resulted in a significant (P < 0.05) 10% increase in the PI:IRI ratio compared with baseline (Table 3Go).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
It is now well established that thiazolidinediones primarily improve glycemic control in type 2 diabetes by reducing insulin resistance, primarily in skeletal muscle (26, 27). Although many studies using a variety of animal models of type 2 diabetes have shown that the thiazolidinediones exert powerful ß-cell protective properties (28, 29, 30), there is much less evidence of this in humans. In the present report, the data from the two large clinical trials clearly show that rosiglitazone produces favorable changes in insulin processing and that may provide an indirect indication that ß-cell function is improved.

As previously detailed, clinically and statistically significant reductions in HbA1c and fasting plasma glucose were achieved in study 1 after 26 wk and in study 2 after 52 wk of treatment with rosiglitazone (4 and 8 mg/d) (22, 23). The beneficial effects on glycemic control were accompanied by dose-dependent decreases in levels of insulin, PI, and C-peptide, as well as significant reductions of the PI:IRI ratio, an established, albeit indirect, marker of ß-cell function. These observations are also consistent with the favorable changes in HOMA estimates of ß-cell function (49 and 60% increases compared with placebo in rosiglitazone 4 and 8 mg/d groups, respectively, after 26-wk treatment) measured in study 1 (22).

The precise mechanism by which rosiglitazone induces a decrease in the PI:IRI ratio is, at present, unknown. However, this effect is unlikely to be attributable simply to the reduction in hyperglycemia, because in study 2, glyburide produced a degree of glycemic control similar to that achieved with rosiglitazone but, in contrast, produced a significant increase in both PI as well as the PI:IRI ratio. The rosiglitazone-mediated decreases in insulin and PI levels are also unlikely to be due to stimulation of peptide clearance, because insulin is cleared more rapidly than PI, and therefore, a rise in PI:IRI ratio would have been expected (31, 32).

A potential mechanism by which rosiglitazone may improve estimates of ß-cell function is via a reduction in circulating free fatty acids. Elevated plasma free fatty acids are proposed as a major factor in the development of insulin resistance in type 2 diabetes (33). In addition to inhibition of insulin-stimulated glucose uptake, an increase in plasma free fatty acids in obese patients has been associated with a decline in insulin secretion during progression to overt type 2 diabetes (34, 35). High levels of free fatty acids have also been shown to interfere with the regulation of PI biosynthesis and PI processing in the ß-cell (36, 37). It has been previously reported from one of the studies presented here (22), as well as others (38, 39, 40), that rosiglitazone significantly reduces plasma free fatty acid levels (by approximately 20–24% from baseline). To assess whether there was any association of plasma free fatty acid and plasma insulin parameters, we have performed multiple correlation analyses. However, in neither study was there any significant correlation between changes in plasma free fatty acid concentrations and PI levels or PI:IRI ratio (data not shown). The nuclear receptor with which thiazolidinediones interact, peroxisome proliferator-activated receptor-{gamma}, is expressed in human islets (including ß-cells), suggesting that the effects of these agents may be mediated, at least in part, by a direct action on the ß-cell. In support of this, it has been recently demonstrated that rosiglitazone can significantly ameliorate the impairment of ß-cell function induced by fatty acids in isolated human islets in vitro (41).

It is recognized that changes in PI:IRI ratios and HOMA estimates do not provide direct evidence of changes in ß-cell secretory dynamics. Short-term intervention studies have, however, suggested that thiazolidinedione therapy may influence insulin secretion. In obese subjects with impaired glucose tolerance, troglitazone (400 mg/d; 12 wk) improved both the reduced ß-cell response to glucose and oral glucose tolerance (42). Recently, in a 12-wk study, rosiglitazone has been shown to enhance the insulinogenic index to glucose in type 2 diabetic patients (43). In a study of similar duration, the drug also improved insulin secretion pulsatility to an iv glucose infusion, suggesting an enhanced ability of the ß-cell to sense and respond to glucose (44). The ability of rosiglitazone to sustain and/or improve ß-cell function and provide durable glycemic control during long-term administration (4 yr) in type 2 diabetes is under investigation in a prospective comparative study with both sulfonylurea and metformin (45).

An elevation of the PI:IRI ratio in healthy individuals is predictive of the subsequent development of type 2 diabetes (5, 6, 7). Thus it is possible that if the elevated PI:IRI ratio can be reduced, then the development of type 2 diabetes in susceptible individuals might be delayed or even prevented. The recent report that 0.9 yr of troglitazone therapy produced a 75% reduction in the incidence of type 2 diabetes in the Diabetes Prevention Program study supports this view (46). Similarly, Durbin (47) has shown that thiazolidinedione therapy for 3 yr reduced the incidence of type 2 diabetes in a cohort of insulin-resistant subjects with impaired glucose tolerance by 88.9% compared with a nonmedicated control group.

Elevated PI is an independent risk factor for coronary heart disease in the nondiabetic population (13). Absolute circulating concentrations of PI are significantly higher in type 2 diabetic compared with nondiabetic subjects, and this may contribute to the excess cardiovascular risk. This study shows that rosiglitazone significantly lowers PI concentration, whereas the sulfonylurea glyburide significantly raises plasma PI. Whether the PI-lowering effect of rosiglitazone will translate through to long-term cardiovascular benefits will be revealed from ongoing outcomes studies (48).

Conclusions

Treatment of people with type 2 diabetes with rosiglitazone for up to 52 wk was associated with significant decreases in the plasma PI:IRI ratio, an indirect marker of improved ß-cell function. These results suggest that rosiglitazone, in addition to reducing insulin resistance, may be able to reduce ß-cell dysfunction, a principal underlying cause of type 2 diabetes. Rosiglitazone, but not the sulfonylurea glyburide, produced dose-dependent significant reductions in the absolute concentration of plasma PI, an independent risk factor for coronary heart disease in nondiabetic humans.


   Footnotes
 
Abbreviations: HbA1c, Glycosylated hemoglobin; HOMA, homeostasis model of assessment; IRI, immunoreactive insulin; PI, proinsulin.

Received April 23, 2004.

Accepted July 30, 2004.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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