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Another Potential Use of Troglitazone in Noninsulin-Dependent Diabetes Mellitus

Hyogo Prefectural Amagasaki Hospital Hyogo 660, Japan

We read with interest the article by Izumino et al. (1), which suggests a therapeutic use of troglitazone, an insulin sensitizer, in Werner’s syndrome as well as in noninsulin-dependent diabetes mellitus (NIDDM). We here report another possible benefit of troglitazone treatment: prevention of atherosclerosis. We measured the intimal and medial complex thickness (IMT) of common carotid artery using B-mode ultrasound technique to evaluate early atherosclerotic lesions (2). First we investigated the relationship between IMT and urinary C-peptide levels (u-CPR) or insulin dosage in 106 Japanese subjects with NIDDM [52 males and 54 females, age 62.5 yr (SE 0.9) yr]. Eighty-one of them were receiving insulin treatment, and the others were taking sulfonylureas. u-CPR of 24-hr urine samples were measured with a radioimmunoassay kit and were expressed as a mean value in three consecutive days. IMT values showed a positive correlation with both u-CPR (r = 0.655, P < 0.0001) and insulin dosage, calculated as an average dose per day (r = 0.399, P < 0.005). The correlation remained significant after adjusting for HbA_Ic, body mass index, age, serum total cholesterol, and triglyceride levels. Second, we examined the effect of short-term treatment with troglitazone (400 mg daily for 3 months) on IMT in 33 patients with NIDDM. Before troglitazone treatment they had been treated with sulfonylureas (32 glibenclamide and 1 gliclazide), which were continued in the same doses during the troglitazone treatment. Thirty-two diabetic subjects (29 receiving sulfonylureas and 3 diet alone) were examined as control group. The group given troglitazone showed a significant decrease in IMT after 3 months [IMT change: -0.196 mm (SE 0.082) vs. control 0.034 mm (SE 0.010), P < 0.01]. There was no relation between a decrease in IMT and a decline in HbA_Ic.

Our finding indicated an association of IMT with both endogenous and exogenous insulin in NIDDM. It is in contrast with a previous study, which failed to demonstrate an association of serum C-peptide with IMT in NIDDM (3), but is compatible with another report indicating an association of fasting insulin and IMT in normal subjects (4). It is also intriguing that we found an analogous association between lumbar bone mineral density and endogenous or exogenous insulin in NIDDM (5). It is possible that the association of IMT with insulin may reflect a direct or indirect atherogenic action of insulin on the vascular wall. However, troglitazone markedly decreased IMT, suggesting that the correlation of IMT and insulin represents a relationship between atherosclerosis and insulin resistance rather than the actions of insulin. Negative association has recently been reported between IMT and insulin sensitivity (6). Alternatively, it is possible that insulin has both atherogenic and antiatherogenic actions, but insulin resistance may selectively inhibit the antiatherogenic action (7), which can be reversed by troglitazone treatment. However, actions of troglitazone other than those as an insulin-sensitizer, such as antioxidant activity (8), cannot be totally excluded. Whatever the mechanisms, the present preliminary result suggests a potent inhibitory action of troglitazone on atherosclerosis, which is compatible with a study in the rat (9). Since Werner’s syndrome is characterized with progeria (1), it is of interest to investigate whether IMT is increased and whether troglitazone may decrease IMT in this disorder. It is also to be elucidated whether troglitazone may prevent restenosis after coronary angioplasty in NIDDM.

The authors are grateful to Dr. Hougaku for his technical advice.

Footnotes

Address correspondence to: Dr. Hiroyuki Koshiyama, Division of Endocrinology and Metabolism, Department of Internal Medicine, Hyogo Prefectural Amagasaki Hospital, 1-1-1 Higashi-Daimotsu-cho, Amagasaki, Hyogo 660, Japan.

Received October 27, 1997.

References

1. Izumino K, Sakamaki H, Ishibashi M, et al. 1997 Troglitazone ameliorates insulin resistance in patients with Werner’s syndrome. J Clin Endocrinol Metab. 82:2391–2395.[Abstract/Free Full Text]
2. Fukunaga Y, Minamikawa J, Inoue D, Koshiyama H., Fujisawa I. 1997 Pseudoacromegaly and hyperinsulinemia: a possibility of premature atherosclerosis? (Letter). J Clin Endocrinol Metab. 82:3515–3516.[Free Full Text]
3. Pujia A, Gnasso A, Irace C, Colonna A, Mattioli PL. 1994 Common carotid arterial wall thickness in NIDDM subjects. Diabetes Care. 17:1330–1336.[Abstract]
4. Folsom AR, Eckfeldt JH, Weitzman S, et al. 1994 Relation of carotid artery wall thickness to diabetes mellitus, fasting glucose and insulin, body size, and physical activity. Stroke. 25:66–73.[Abstract]
5. Fukunaga Y, Minamikawa J, Inoue D, Koshiyama H. 1997 Does insulin use increase bone mineral density in patients with non-insulin-dependent diabetes mellitus? Arch Intern Med. 157:2668–2669.
6. Howard G, O’Leary DH, Zaccaro D, et al. 1996 Insulin sensitivity and atherosclerosis. Circulation. 93:1809–1817.[Abstract/Free Full Text]
7. Feener EP, King GL. 1997 Vascular dysfunction in diabetes mellitus. Lancet. 350:SI9–13.
8. Cominacini L, Garbin U, Pastorino AM, et al. 1997 Effects of troglitazone on in vitro of LDL and HDL induced by copper irons and endothelial cells. Diabetologia. 40:165–172.[CrossRef][Medline]
9. Law RE, Meehan WP, Xi X-P, et al. 1997 Troglitazone inhibits vascular smooth muscle cell growth and intimal hyperplasia. J Clin Invest. 98:1897–1905.[Medline]

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