Background/Aims: Pimagedine inhibits the formation of advanced glycation end products and slows the progression of diabetic complications in experimental models. This study was undertaken to determine if pimagedine ameliorates nephropathy in type 1 (insulin-dependent) diabetes mellitus. Methods: This was a randomized, double-masked, placebo-controlled study performed in 690 patients with type 1 diabetes mellitus, nephropathy, and retinopathy. The patients received twice daily dosing with placebo, pimagedine 150 mg, or pimagedine 300 mg for 2–4 years. The primary end point was the time to doubling of serum creatinine; the secondary end points included evaluations of proteinuria, kidney function, and retinopathy. Results: Serum creatinine doubled in 26% (61/236) of the placebo-treated patients and in 20% (91/454) of those who received pimagedine (p = 0.099). The estimated glomerular filtration rate decreased more slowly in the pimagedine-treated patients with a 36-month decrease from baseline of 6.26 ml/min/1.73 m2 as compared with 9.80 ml/min/1.73 m2 in the placebo-treated patients (p = 0.05), and pimagedine reduced the 24-hour total urinary proteinuria. (The mean reduction from baseline at month 36 was 732 mg/24 h at the low dose and 329 mg/24 h at the high dose as compared with 35 mg/24 h in the placebo group; p ≤ 0.001.) Fewer pimagedine-treated patients with baseline and end point evaluations (31/324; 10%) as compared with those receiving placebo (16%; 28/179) experienced a three-step or greater progression of the retinopathy (Early Treatment of Diabetic Retinopathy Study) score (p = 0.030). Three patients receiving high-dose pimagedine but none receiving low-dose treatment developed glomerulonephritis. Conclusions: While this study did not demonstrate a statistically significant beneficial effect of pimagedine on the progression of overt nephropathy resulting from type 1 diabetes, it is noteworthy in providing the first clinical proof of the concept that inhibiting advanced glycation end product formation can result in a clinically important attenuation of the serious complications of type 1 diabetes mellitus.
Syndromes of resistance to thyroid hormones are caused by mutations in the T3-binding domain of the c-erbA beta thyroid hormone receptor gene. The S receptor (deletion of THR332) is a potent dominant negative protein cloned from a kindred with generalized resistance to thyroid hormones. The G-H receptor (ARG311HIS) has compromised dominant negative function and was found in both normal individuals and in a patient with severe pituitary resistance to thyroid hormones. We have investigated the mechanism responsible for the difference in receptor phenotypes by analyzing the binding of S and G-H receptors to thyroid hormone response elements with electrophoretic mobility shift analysis. Wild-type human c-erbA beta 1 (WT), S, and G-H receptors were synthesized in reticulocyte lysate, reacted with a thyroid hormone response element consisting of a direct repeat with 4 base pairs (DR+4; AGGTCA CAGG AGGTCA), and the products analyzed by gel shift. G-H receptor homodimerization was greatly impaired; G-H formed predominantly monomeric complex compared with monomeric and homodimeric WT complexes. The G-H receptor was able to form heterodimeric complexes with cellular thyroid hormone receptor auxiliary protein (TRAP) factors including the human retinoid X receptor-alpha. When TRAP was limiting, the levels of G-H heterodimeric complex were 2- to 3-fold reduced compared with WT receptor. In contrast to the WT and G-H receptors, the S receptor formed almost exclusively homodimeric complex with DR+4; the approximate ratio of S:WT:G-H homodimeric complexes at equivalent concentrations of receptors was 60:20:1. A measurable increase (1.2- to 2.6-fold) in heterodimeric complex formation was observed with the S receptor relative to WT when TRAP was at limiting concentration. As reported previously by others, thyroid hormone significantly reduced the WT homodimeric complex with DR+4. There was no effect on the S homodimeric complex. Finally, the WT, S, and G-H receptors formed different complexes with the element consisting of an inverted repeat with 5 base pairs (IR+5; AGGTCA ACAGT TGACCT) and the IR element (AGGTCA TGACCT), which were differently regulated by thyroid hormone. The S receptor bound as a homodimer with IR+5, whereas the WT receptor bound as a homodimer only with thyroid hormone. No homodimeric complex formed with IR+5 and the G-H receptor. Qualitatively similar results were observed with the IR element. We conclude that the ARG311HIS mutation severely perturbs the homodimerization and, to a much less degree, heterodimerization functions of the c-erbA beta 1 receptor. Furthermore, the THR332 deletion mutation augments homodimerization of the c-erbA beta 1 receptor. These results indicate that different mutations in the c-erbA beta 1 thyroid hormone receptor have divergently affected dimerization activities which seem to influence the level of dominant negative activity in man.
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