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Diabetes Care 24:788-789, 2001
© 2001 by the American Diabetes Association, Inc.

Letters: Observations
Letter

Administration of Troglitazone, but Not Pioglitazone, Reduces Insulin Resistance Caused by Short-Term Dexamethasone (DXM) Treatment by Accelerating the Metabolism of DXM

Hiroshi Morita, MD, Yutaka Oki, MD, Takeshi Ito, MD, Hiroko Ohishi, MD, Sadako Suzuki, MD and Hirotoshi Nakamura, MD

Second Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan

Thiazolidine derivatives are newly developed insulin sensitizer agents that act to lower plasma glucose and reduce hyperinsulinemia (1), and they are being used to treat patients with type 2 diabetes accompanying insulin resistance. However, the precise molecular mechanism by which thiazolidines counteract general insulin resistance has yet to be clarified. Glucocorticoid induces gluconeogenesis and insulin resistance, resulting in the development of diabetes (2), but the precise molecular mechanisms remain to be elucidated. Recent studies showed that troglitazone, which was the first clinically applied drug of thiazolidine derivatives, improved dexamethasone (DXM)-induced insulin resistance in rats in a glucose clamp study (3) and that it had a good effect on patients with glucocorticoid-induced diabetes (4). In the present study, we examined the effects of troglitazone and pioglitazone, another insulin sensitizer, on insulin resistance induced by short-term DXM treatment, and compared their effects with those of metformin. Furthermore, troglitazone has been reported to reduce the plasma concentration of the oral contraceptives ethinylestradiol and norethindrone, which are metabolized by the liver enzyme CYP3A4 (5). Troglitazone is also believed to be an inducer of CYP3A4 like rifampicin and phenytoin, and it has been speculated that troglitazone may reduce the effects of glucocorticoid, which is metabolized by CYP3A4, by enhancing the activity of CYP3A4. In this study, we investigated the effects of troglitazone and pioglitazone on serum DXM concentrations.

A 75-g oral glucose tolerance test (OGTT) was administered to five healthy men in the following regimens: 1) no pretreatment; 2) after oral administration of 4 mg DXM daily for 3 days; and 3) after oral administration of 400 mg troglitazone, 500 mg metformin, or 30 mg pioglitazone daily for 14 days, together with oral administration of 4 mg DXM daily for the last 3 days. Troglitazone administration reduced the DXM-induced increase of the mean area under the plasma and serum concentration time curve from 0 to 3 h [AUC(0–3)] for both the plasma glucose concentration and the serum insulin concentration during a 75-g OGTT (350.0 ± 24.7 vs. 433.9 ± 24.3 mg · dl–1 · h–1 and 127.9 ± 15.0 vs. 241.2 ± 16.8 µU · ml–1 · h–1, respectively, P < 0.05), but metformin and pioglitazone administrations had no effects. Next, 2 mg DXM was administered to six healthy men, and their serum DXM concentrations were measured using radioimmunoassay methods during 24 h after DXM administration with and without preadministration of 400 mg troglitazone or 30 mg pioglitazone daily for 14 days. All serum concentrations of DXM, except that at 0.5 h, were significantly decreased (P < 0.05), and the AUC(0–24) of DXM was remarkably reduced by 49% after pretreatment with troglitazone (76.2 ± 10.2 vs. 150.1 ± 17.0 ng · ml–1 · h–1, P < 0.05), but not after pretreatment with pioglitazone (Fig. 1).



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  		Figure 1 — Serum DXM concentrations before and after the oral administration of 2 mg DXM with and without pretreatment with 400 mg daily troglitazone or 30 mg daily pioglitazone for 14 days; {circ}, without pretreatment; •, with pretreatment of 400 mg troglitazone daily for 14 days; {blacktriangleup}, with pretreatment of 30 mg pioglitazone daily for 14 days. Data are means ± SEM, n = 6. *P < 0.05 vs. without pretreatment.

 
In the present study, we found that troglitazone preadministration decreased DXM-induced hyperglycemia and hyperinsulinemia and that pioglitazone and metformin did not. These findings suggest that the preadministration of troglitazone reverses glucose tolerance in healthy men receiving DXM. We speculated that these properties of troglitazone were independent of peroxisome proliferator–activated receptor-{gamma} (PPAR{gamma}), because another PPAR{gamma} ligand, pioglitazone, induced no effects. There are two possible mechanisms for these troglitazone-induced effects. Troglitazone may have a direct beneficial effect on glucocorticoid-induced insulin resistance, and troglitazone may induce the rapid metabolism of DXM, resulting in a reduction of the general effect of glucocorticoid, including the induction of insulin resistance.

The precise molecular mechanism of glucocorticoid-induced insulin resistance remains unclear. Glucocorticoid reduces the translocation of GLUT4 from the cytosol into the membrane, while it increases the amount of GLUT4 protein itself (6,7). In vitro studies showed that troglitazone improved the impairment of 2-deoxyglucose uptake in 3T3-l1 adipocytes treated with DXM and in soleus muscle from DXM-treated rats (3,8). Therefore, it is possible that troglitazone may recover the glucocorticoid-impaired translocation of GLUT4. Alternatively, the reversal effect of troglitazone on DXM-induced insulin resistance may be attributable to inducement of the rapid metabolism of DXM. Troglitazone has recently been reported to reduce plasma concentrations of ethinylestradiol and norethindrone, oral contraceptives, which are metabolized by CYP3A4 (5); thus, using a higher dose of oral contraceptives or alternative methods of contraception during troglitazone therapy is recommended to prevent unplanned pregnancies. Troglitazone has also been reported to increase the urinary excretion of 6ß-hydroxycortisol of CYP3A4 metabolites of cortisol in normal control subjects (9). The ratio of 24-h urinary 6ß-hydroxycortisol to cortisol excretion can be evaluated as a noninvasive clinical test to detect enzyme activity of CYP3A4 substrates. Ramachandran et al. (10) showed that troglitazone increased the protein level and enzyme activity of CYP3A in primary cultures of human hepatocytes. These data suggest that troglitazone enhances the activity of CYP3A4 like rifampicin, phenytoin, phenobarbiturates, and carbamazepine. It is possible to improve diabetic control in nonoperable patients with Cushing’s syndrome by the administration of troglitazone, and it has been reported that diabetic control was improved in diabetic patients who were given predonisolone by troglitazone administration (4). Because pioglitazone induced fewer effects on the pharmacokinetics of DXM in this study, it may also have fewer effects on the activity of CYP3A4. The reason for the difference between troglitazone and pioglitazone in the activity against CYP3A4 remains to be elucidated, but CYP3A4 inducers, such as rifampicin and phenobarbiturates, have recently been reported to be the ligands for an orphan nuclear receptor, pregnane X receptor (PXR), which is expressed in the liver and intestine (11). Thus, it would be interesting to assess whether troglitazone, but not pioglitazone, is a ligand for PXR.

In conclusion, the present study showed that DXM-induced insulin resistance was improved by troglitazone, but not by metformin or pioglitazone. Troglitazone administration reduced the serum concentration of orally administered DXM, indicating that the reversal effects of troglitazone on DXM-induced insulin resistance might have been mainly attributable to the rapid metabolism of DXM through the enhancement of the activity of CYP3A4 in vivo. In contrast, pioglitazone had fewer effects on the pharmacokinetics of DXM, and it was not an inducer of CYP3A4.

FOOTNOTES

Address correspondence to Hiroshi Morita, MD, Second Department of Medicine, Hamamatsu University School of Medicine, 3600 Handa-cho, Hamamatsu 431-3192, Japan. E-mail: moritahr{at}hama-med.ac.jp.

References

  1. Fujiwara T, Yoshioka S, Yoshioka T, Ushiyama I, Horikoshi H: Characterization of new oral anti diabetic agent CS-045: studies in KK and ob/ob mice and Zucker fatty rats. Diabetes 37:1549–1558, 1988[Abstract]
  2. Carter-Su C, Okamoto K: Effects of insulin and glucocorticoids on glucose transporters in rat adipocytes. Am J Physiol 252:E441–E453, 1987[Abstract/Free Full Text]
  3. Okumura S, Takeda N, Takami K, Yoshino K, Hattori J, Nakashima K, Sugimoto M, Ishimori M, Takami R, Yasuda K: Effects of troglitazone on dexamethasone-induced insulin resistance in rats. Metabolism 47:351–354, 1998[Medline]
  4. Fujibayashi K, Nagasaka S, Saito T: Troglitazone efficacy in a subject with glucocorticoid-induced diabetes. Diabetes Care 22:2088–2089, 1999[Free Full Text]
  5. Loi CM, Knowlton PW, Stern R, Randinitis EJ, Vassos AB, Koup JR, Sedman AJ: Effect of troglitazone on the pharmacokinetics of an oral contraceptives. J Clin Pharmacol 39:410–417, 1999[Abstract]
  6. Giorgino F, Almahfouz A, Goodyear LJ, Smith RJ: Glucocorticoid regulation of insulin receptor and substrate IRS-1 tyrosine phosphorylation in rat skeletal muscle in vivo. J Clin Invest 91:2020–2030, 1992
  7. Haber RS, Weinstein SP: Role of glucose transporters in glucocorticoid-induced insulin resistance. Diabetes 41:728–735, 1992[Abstract]
  8. Weinstein SP, Holand A, O’Boyle E, Harber RS: Effects of thiazolidinediones on glucocorticoid-induced insulin resistance and GLUT4 glucose transporter expression in rat skeletal muscle. Metabolism 42:1365–1369, 1993[Medline]
  9. Koup JR, Anderson GD, Loi C: Effect of troglitazone on urinary excretion of 6ß-hydroxycortisol. J Clin Phamacol 38:815–818, 1998
  10. Ramachandran V: Troglitazone increases cytochrome p 450 3A protein and activity in primary cultures of human hepatocytes. Drug Metab Dispos 10:1194–1199, 1999
  11. Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA: The human orphan receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Invest 102:1016–1023, 1998[Medline]

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Home page
 J. Clin. Endocrinol. Metab.Home page
E. V. Dimaraki and C. A. Jaffe
Troglitazone Induces CYP3A4 Activity Leading to Falsely Abnormal Dexamethasone Suppression Test
J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3113 - 3116.
[Abstract] [Full Text] [PDF]

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