The evolution of diabetes in the male leptin receptor؊deficient (fa/fa) Zucker diabetic fatty (ZDF) rat is associated with disruption of normal islet architecture, ␤-cell degranulation, and increased ␤-cell death. It is unknown whether these changes precede or develop as a result of the increasing plasma glucose, or whether the increased ␤-cell death can be prevented. Early intervention with thiazolidinediones prevents disruption of the islet architecture. To determine the specific effects of rosiglitazone (RSG) on ␤-cell mass dynamics, male fa/fa (obese) and ؉/fa or ؉/؉ (lean) rats age 6 weeks were fed either chow (control group [CN]) or chow mixed with rosiglitazone (RSG group) at a dosage of 10 mol ⅐ kg ؊1 body wt ⅐ day ؊1 . Rats were killed after 0, 2, 4, 6, or 10 weeks of treatment (at age 6, 8, 10, 12, or 16 weeks). Plasma glucose increased from 8.9 ؎ 0.4 mmol/l at 0 weeks to 34.2 ؎ 1.8 mmol/l (P ‫؍‬ 0.0001) at 6 weeks of treatment in obese CN rats and fell from 8.0 ؎ 0.3 to 6.3 ؎ 0.4 mmol/l in obese RSG rats (P ‫؍‬ 0.02). ␤-cell mass fell by 51% from 2 to 6 weeks of treatment (ages 8 -12 weeks) in obese CN rats (6.9 ؎ 0.9 to 3.4 ؎ 0.5 mg; P < 0.05), whereas ␤-cell mass was unchanged in obese RSG rats. At 10 weeks of treatment (age 16 weeks), ␤-cell mass in obese CN rats was only 56% of that of obese RSG rats (4.4 ؎ 0.4 vs. 7.8 ؎ 0.3 mg, respectively; P ‫؍‬ 0.0001). The ␤-cell replication rate fell from a baseline value of 0.95 ؎ 0.12% in lean rats and 0.94 ؎ 0.07% in obese rats (at 0 weeks) to ϳ0.3-0.5% in all groups by 6 weeks of treatment (age 12 weeks). After 10 weeks of treatment, ␤-cell replication was higher in obese RSG rats than in CN rats (0.59 ؎ 0.14 vs. 0.28 ؎ 0.05%, respectively; P < 0.02). Application of our mass balance model of ␤-cell turnover indicated that net ␤-cell death was fivefold higher in obese CN rats as compared with RSG rats after 6 weeks of treatment (age 12 weeks). The increase in ␤-cell death in obese CN rats during the 6-week observation period was well correlated with the increase in plasma glucose (r 2 ‫؍‬ 0.90, P < 0.0001). These results suggest that the development of hyperglycemia in ZDF rats is concomitant with increasing net ␤-cell death. ␤-cell proliferation compensates for the increased ␤-cell loss at a time when plasma glucose is moderately elevated, but compensation ultimately fails and the plasma glucose levels increase beyond ϳ20 mmol/l. Treatment with rosiglitazone, previously shown to reduce insulin resistance, prevents the loss of ␤-cell mass in obese ZDF rats by maintaining ␤-cell proliferation and preventing increased net ␤-cell death.

The cysteinyl leukotrienes (CysLTs) mimic many of the features of asthma and are implicated in its pathophysiology. Little, however, is known about the effects of the CysLTs on airways remodeling. In this study the effects of leukotriene D4 (LTD4) on human airway smooth muscle (HASM) cell proliferation and expression of extracellular matrix proteins were investigated. LTD4 (0.1-10 microM) alone had no effect on DNA synthesis in HASM. LTD4, however, markedly augmented proliferation induced by the mitogen, epidermal growth factor (EGF, 1 ng/ml). The potentiating effect of LTD4 (1 microM) on EGF-induced DNA synthesis was abolished by pranlukast (1 microM) or pobilukast (30 microM), but unaffected by zafirlukast (1 microM). In contrast, pranlukast (pKB = 6.9), pobilukast (pKB = 7.0), and zafirlukast (pKB = 6.5) had equivalent potencies for inhibition of LTD4-induced contraction in human bronchus. LTD4 (0.1 or 10 microM) did not increase the total messenger RNA expression of the extracellular matrix proteins (pro-alpha[I] type I or alpha1[IV] type IV collagen), elastin, biglycan, decorin, and fibronectin, and did not influence tumor growth factor-beta (10 ng/ml)-induced effects on the expression of these proteins in HASM cells. These data indicate that LTD4 augments growth factor-induced HASM proliferation but does not alter the expression of various extracellular matrix components. The observed differences in sensitivity to the antagonists suggests that the former phenomenon may be mediated by a CysLT receptor distinct from that which mediates LTD4-induced HASM contraction. Collectively, these results provide preliminary evidence that CysLTs may play a role in airways remodeling in asthma.

These data propose a role for modification of nucleosomal structure in inflammatory cytokine gene transcription in response to smoking. The imbalance between histone deacetylation and acetylation in favor of acetylation may contribute to the enhanced inflammation in smokers susceptible to the development of COPD.