Comparison of insulin sensitivity, glucose sensitivity, and first phase ...

Arch Pharm Res Vol 33, No 3, 411-416, 2010 DOI 10.1007/s12272-010-0310-6

Comparison of Insulin Sensitivity, Glucose Sensitivity, and First Phase Insulin Secretion in Patients Treated with Repaglinide or Gliclazide Chung-Ze Wu1, Dee Pei2, An-Tsz Hsieh1, Kun Wang2, Jiunn-Diann Lin3, Li-Hsiu Lee4, Yi-Min Chu4, Fone-Ching Hsiao5, Chun Pei6, and Te-Lin Hsia2 1

Division of Endocrinology and Metabolism, Department of Internal Medicine, Taipei Medical University - Shuang Ho Hospital, Taipei, Taiwan (ROC), 2Department of Internal Medicine, Cardinal Tien Hospital, Medical School, Fu Jen Catholic University, Taiwan (ROC), 3Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan (ROC), 4Department of Medical Technology, Cardinal Tien Hospital, Medical School, Fu Jen Catholic University, Taiwan (ROC), 5Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, Taipei, Taiwan (ROC), and 6Graduate School of Gerontic Technology and Service management, Nan Kai University of Technology, Nan Tou County, Taiwan (ROC) (Received August 2, 2009/Revised December 17, 2009/Accepted December 21, 2009)

The traditional sulfonylureas with long half-lives have sustained stimulatory effects on insulin secretion compared to the short-acting insulin secretagogue. In this study, we used the frequently sampled intravenous glucose tolerance test (FSIGT) to evaluate the insulin sensitivity (IS), glucose sensitivity (SG), and acute insulin response after glucose load (AIRg) after 4 months treatment with either gliclazide or repaglinide. The design of study was randomizedcrossover. We enrolled 20 patients with new-onset type 2 diabetes (mean age, 49.3 years). Totally three FSIGTs were performed, one before and one after each of the two treatment periods as aforementioned. No significant differences in fasting plasma glucose, insulin, body mass index, blood pressure, glycated hemoglobin, or lipids were noted between the two treatments. After the repaglinide treatment, higher AIRg, lower IS, and lower SG were noted, but they did not reach statistical significance. The disposal index (DI) was also not significantly different between the two treatments. In conclusion, since non-significantly higher DI, AIRg, lower IS and SG were noted after repaglinide treatment, it might be a better treatment for diabetes, relative to gliclazide. Key words: Insulin sensitivity, Frequently sampled intravenous glucose tolerance test, Repaglinide, Gliclazide, Disposal index

INTRODUCTION There are approximately one million known patients with type 2 diabetes in Taiwan. It is the fourth leading cause of death and results in a huge burden on society and individuals. Type 2 diabetes is characterized by defects in both insulin sensitivity (IS) and insulin secretion (DeFronzo et al., 1979; Kahn, 2003). Although not fully understood, type 2 diabetes Correspondence to: Te-Lin Hsia, Dept. of Internal Medicine, Cardinal Tien Hospital, No 362, Chung Cheng Rd., Xindian City, Taipei 231, Taiwan, ROC. Tel: 886-2-22193391, Fax: 886-2-22195821 e-mail: [email protected]

has a strong tendency for family segregation (O'Rahilly et al., 2005; Tusie, 2005), and it is generally believed that insulin resistance develops at an early stage of life (Meigs et al., 2000). Once insulin resistance appears, βcells adapt to the reduced IS in the hepatic and peripheral tissue by increasing insulin secretion and thus preventing the development of hyperglycemia. In type 2 diabetes, however, fasting hyperglycemia can occur when impaired β-cell function results in an underproduction of insulin. At present, the traditional insulin secretagogue, sulfonylurea, is one of the most widely used medications in Taiwan. It stimulates insulin secretion by combining with sulfonylurea receptors. However, the

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half-lives of these traditional medications are quite long, from 4 to 16 h for glipizide and gliclazide, respectively. In contrast, the half-life of repaglinide, a non-sulfonylurea secretagogue, is only one hour. It would be reasonable to postulate that sulfonylurea, with its longer half-life, might induce early β-cell exhaustion due to sustained insulin secretion when compare to repaglinide (Korytkowski et al., 2002). At present, there are several methods available for measuring IS and insulin secretion. For IS measurements, the hyperinsulinemic euglycemic clamp is recognized as the ‘gold standard’. However, the procedures involved in using the clamp are both time consuming and labor intensive (Galvin et al., 1992). Compared to the clamp, the frequently sampled intravenous glucose tolerance test (FSIGT) is easier to perform, and the estimation of IS using this method correlates well with clamp studies (Galvin et al., 1992; Mehring et al., 2002; Saad et al., 1994). Similarly, although the FSIGT is not the best test for measuring β-cell secretion, it does produce a relatively accurate estimation of first phase insulin secretion (Korytkowski et al., 1995). In this hospital-based cohort, randomized cross-over study, we enrolled 20 patients with type 2 diabetes who were then treated with either a long half-life sulfonylurea (gliclazide) or the short half-life repaglinide for 4 months. The patients were then switched to the other drug for another 4 months. We used FSIGT to compare the IS and first phase insulin secretion following the treatments with the two different drugs.

MATERIALS AND METHODS Subjects and study design In this study, we enrolled 20 patients with newonset type 2 diabetes diagnosed according to the 1997 ADA criteria (Anonymous, 1997). Their ages were between 40~60 years old and their body mass index (BMI) ranged between 22~27 kg/m2. Each patient had a complete routine workup to rule out the presence of significant cardiovascular, respiratory, renal, or endocrine disorders. No patient was taking any known medications that affected metabolism of glucose or lipids, except oral hypoglycemic agents. The study protocol was approved by the local Hospital Ethic Committee. The entire course of the study was divided into four stages. The period of the first stage was 3 weeks. During this ‘titration stage’ the patients were randomized to take either gliclazide or repaglinide. Adjustment of the medication dose was allowed, with alterations made according to the level of the patient’s

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fasting blood glucose. The maximum allowable dose for gliclazide and repaglinide was 160 mg and 6 mg per day, respectively. The goal at this stage was to maintain the blood glucose level below 7.7 mmol/L. If this goal was not reached and the patient required a second drug, the patient was excluded from the study. The second stage (baseline stage) lasted for 5 weeks. The doses of the medications were maintained throughout this stage. The purpose for this stage was to decrease the effect of glucose toxicity on β-cell function. The third stage (treatment stage one) was continued for 4 months. During this stage, the medications were maintained as in the previous stage. We then observed the effects on IS and insulin secretion after 4 months of treatment. Finally, during the fourth stage (treatment stage two), the medications taken in treatment stage one were switched and maintain for another 4 months. We then observed the effects on IS and insulin secretion after an additional 4 months of treatment.

Frequently sampled intravenous glucose tolerance test Follow-up was performed on two different days at the end of each treatment and included an FSIGT performed after a 10 to 12 h overnight fast. An indwelling catheter was inserted into the antecubital vein of one arm for blood sampling, while simultaneously on the contralateral arm an infusion of intravenous glucose (0.3 g/kg) was started. A 0.05-units/kg bolus of regular human insulin (Novo Nordisk Pharmaceutical) was injected 20 min after glucose loading. Blood samples for glucose and insulin assays were collected at 0, 2, 4, 8, 19, 22, 30, 40, 50, 70, 100, and 180 min after glucose loading. The plasma glucose and insulin levels during the FSIGT were input into Bergman’s Minimal Model (DeFronzo et al., 1979). The IS (ISFSIGT), glucose sensitivity (SG), and acute insulin response after the glucose load (AIRg) were obtained. Laboratory measurement Plasma samples were immediately separated and stored at -30oC until assayed. Insulin was measured by a commercial solid-phase radioimmunoassay kit (Coat-A-Count insulin kit, Diagnostic Products Corporation). The intra- and interassay coefficients of variance for insulin were 3.3% and 2.5%, respectively. Plasma glucose was measured using a glucose oxidase method (YSI 203 glucose analyzer, Yellow Spring Instrument Company Inc.). Total serum cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) were measured using the dry,

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Table I. Demographic data of subjects before each treatment Variables

Repaglinide

Male/female Age Fasting plasma glucose (mmol/L) Fasting plasma insulin (pmol/L) Body mass index (kg/m2) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Waist (cm) Glycated hemoglobin (%) Total cholesterol (mmol/L) Triglycerides (mmol/L) High density lipoprotein cholesterol (mmol/L)

Gliclazide

11/9 49.3 ± 2.2 007.5 ± 1.01 007.2 ± 00.48 040.9 ± 9.30 047.1 ± 11.60 025.4 ± 0.90 025.4 ± 00.9 120.7 ± 2.30 121.4 ±02.3 079.9 ± 1.60 079.2 ± 01.80 086.4 ± 2.20 085.9 ± 02.50 008.0 ± 0.80 007.8 ±0 0.60 004.7 ± 0.22 004.6 ±0 0.21 002.4 ± 0.26 002.1 ±00.23 001.2 ± 0.10 001.2 ± 00.10

Data are shown as mean ± S.E.M.

multilayer analytical-slide method in a Fuji Dri-Chem 3000 analyzer (Fuji Photo Film Corporation). Serum levels of high-density lipoprotein cholesterol (HDL-C) were determined by an enzymatic cholesterol assay after dextran sulfate precipitation. The level of glycated HgbA1C was evaluated using ion-exchange high-pressure liquid chromatography (HPLC) (BioRad Variant II).

Statistical analyses All data were expressed as the mean ± S.E.M., and analyses were performed using the SPSS version 10.0 statistical package for Windows (SPSS). The fasting plasma glucose, insulin, and lipids levels were compared by paired t test. The IS, SG, and AIRg derived from the FSIGT were also compared with the paired t test. The disposal index (DI) was also compared in this study. DI is the product of IS and AIRg. When discussing glucose metabolism, it is important to consider the insulin action (IS) as well as insulin secretion (AIRg); thus, subjects with higher IS and AIRg would have better glucose metabolism and a lower incidence of diabetes. All statistical tests were two-sided and p values less than 0.05 were considered significant.

RESULTS Table I shows the demographic data at the end of each treatment period. Using the paired t-test, there were no significant differences between fasting plasma glucose, insulin, BMI, blood pressure, glycated hemoglobin, or lipids. Changes in plasma glucose and insulin during the FSIGT are shown in Fig. 1. The two ISFSIGT (panel A),

Fig. 1. Plasma glucose (panel A) and insulin (panel B) levels during the frequently sampled intravenous glucose tolerance test (FSIGT)

SG (panel B), and AIRg (panel C) data points derived from the FISGT after each treatment were compared, and the results are shown in Fig. 2. After the paired ttest, no significant differences were noted among these parameters. There was also no difference in the DI after the treatments.

DISCUSSION Although newer medications with different mechanisms have been emerging, insulin secretagogues are still the most widely used drugs to treat type 2 diabetes. However, it is generally accepted that in type 2 diabetes, the first phase of insulin secretion is lost and the second phase is blunted (Davies et al., 1994). Due to the sustained stimulation of â-cells from treatment with long-acting insulin secretagogues, it is reasonable to postulate that compared to the short-acting forms the sulfonylurea with a long half-life will further

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Fig. 2. The insulin sensitivity (panel A), glucose sensitivity (panel B), acute insulin response after glucose load (panel C), and disposal index (panel D) derived from the FSIGT test

deteriorate the reserved capacity of insulin secretion. To investigate the differences between longer and shorter stimulation of β-cell function, Rizzo used a hyperglycemic clamp to measure insulin secretion in 14 subjects with type 2 diabetes after 3 months of treatments with either repaglinide or glimperide. He found that both the first and second phase insulin secretions were improved. Their results are similar to ours. In our study, the repaglinide treated group had higher (but not statically significant) AIRg after 3 months of treatment. This trend seen in our results is interesting and could possibly be explained by the different levels of glycated hemoglobin (8.4% and 7.9% for repaglinide and gliclazide, respectively). In contrast, in Rizzo’s study the glycated hemoglobin was only around 6.7%. It is well known that a higher plasma glucose level will further impair insulin action and secretion, and this phenomenon is called glucose toxicity (Yki-Jarvinen, 1998). The higher plasma glucose levels in our study indicated a more severe glucose toxicity that might have resulted in a decreased insulin secretion after the use of insulin secretagogues.

Secondly, ethnic differences might also play a role. Compared to Caucasians, patients with type 2 diabetics among the Chinese population tend to have a lower BMI (McFadzean et al., 1968; Tsu, 1976), similar to Japanese patients (Kosaka et al., 1996; Ohmura et al., 1994; Qiao et al., 2000; Sekikawa et al., 1993; Tripathy et al., 2000). Other than BMI, the insulin action and secretion might also be different between Asian and other ethnic groups. For instance, by using a homeostasis model assessment, Fukushima suggested that Japanese type 2 diabetic patients are characterized by a larger decrease in insulin secretion and show less attribution of insulin resistance compared to other ethnic groups (Fukushima et al., 2004). Although we cannot use the results of this study to explain our data, the background of ethnic Chinese are closer to those of Japanese than of Caucasians. If this is the case, then the stimulating effect on insulin secretion by the insulin secretagogues would be less apparent in Chinese relative to Caucasian patients. This might also contribute to the insignificant differences between the two treatments groups in our study. In this study, we were also interested in whether

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the two medications could improve IS. This same question has been investigated several times in the past. Early in 1984, Kolterman and Simonson demonstrated that after 3 months of sulfonylurea treatments IS could be improved 23% and 55%, respectively (Fukushima et al., 2004; Kolterman et al., 1984; Simonson et al., 1984). A recent study, however, presented the opposite finding. By using the euglycemic hyperinsulinemic clamp approach, Korytkowski found that there was no improvement in IS (Korytkowski et al., 1995). He also concluded that improvements in IS reported in prior studies may have been due to an amelioration of glucose toxicity. Interestingly enough, Rizzo designed a study similar to ours to explore this argument. After treatment for three months, the IS was improved more in the repaglinide treatment group than the glimperide group. He suggested that this improvement was due to the fact that repaglinide is given in multiple daily doses before meals. This might reproduce or mimic the daily pulsatile insulin secretion pattern. In our study, we used the FSIGT to evaluate IS. Contrary to Rizzo’s data, the IS trended to be lower in the repaglinide group compared to gliclazide. This difference in results could be explained by the use of different methods to measure insulin action. In Rizzo’s study, an euglycemic clamp was used for measuring insulin action. Although the ISFSIGT was shown to correlate well with the euglycemic clamp within the general population (Galvin et al., 1992; Mehring et al., 2002; Saad et al., 1994), in patients with type 2 diabetes the r-value was 0.41. In this study, only 20 subjects were enrolled, and this small number would further increase the possibility of under estimating IS. In our study, the SG was also measured and the repaglinide treatment group trended lower than the gliclazide group. It is noteworthy that the importance of SG is often overlooked when dealing with the pathophysiology of type 2 diabetes. Welch et al. (1990) showed that in normal subjects, at a plasma glucose level of 11.1 mmol/L, 50.4% of glucose metabolism is from noninsulin-mediated glucose uptake (NIMGU) and 49.6% from insulin-mediated glucose uptake (IMGU). Interestingly, in diabetic subjects NIMGU contributes 67% and IMGU contributes 33% to glucose metabolism. These results show that NIMGU might be an important contributor during the pathophysiology of diabetes. Our finding further suggests that treatment with gliclazide might have a beneficial effect on SG. To have clinically apparent diabetes, a patient must demonstrate deterioration of both IS and insulin secretion. To consider both of these defects, we used

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DI as a quantitative measurement. The lower the DI, the more impaired glucose metabolism is in that patient. In our study, the repaglinide group had a DI that trended higher than the other group. Not surprisingly, this was mainly due to the better AIRg in the repaglinide group. In conclusion, a trend toward a higher AIRg, but lower SI and SG, could be noted after 4 months of repaglinide treatment compared with the gliclazide treatment. However, since the DI also trended higher in the repaglinide group, repaglinide might prove to be a superior treatment for type 2 diabetes.

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