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Activins and inhibins, structurally related members of the TGF-beta superfamily of growth and differentiation factors, are mutually antagonistic regulators of reproductive and other functions. Activins bind specific type II receptor serine kinases (ActRII or IIB) to promote the recruitment and phosphorylation of the type I receptor serine kinase, ALK4 (refs 7-9), which then regulates gene expression by activating Smad proteins. Inhibins also bind type II activin receptors but do not recruit ALK4, providing a competitive model for the antagonism of activin by inhibin. Inhibins fail to antagonize activin in some tissues and cells, however, suggesting that additional components are required for inhibin action. Here we show that the type III TGF-beta receptor, betaglycan, can function as an inhibin co-receptor with ActRII. Betaglycan binds inhibin with high affinity and enhances binding in cells co-expressing ActRII and betaglycan. Inhibin also forms crosslinked complexes with both recombinant and endogenously expressed betaglycan and ActRII. Finally, betaglycan confers inhibin sensitivity to cell lines that otherwise respond poorly to this hormone. The ability of betaglycan to facilitate inhibin antagonism of activin provides a variation on the emerging roles of proteoglycans as co-receptors modulating ligand-receptor sensitivity, selectivity and function.

OBJECTIVE -In patients with type 2 diabetes, exenatide reduces A1C, postprandial and fasting glucose, and weight. In this study we investigated the effects of continuous exenatide administration from a long-acting release (LAR) formulation.RESEARCH DESIGN AND METHODS -In this randomized, placebo-controlled phase 2 study, exenatide LAR (0.8 or 2.0 mg) was administered subcutaneously once weekly for 15 weeks to subjects with type 2 diabetes (n ϭ 45) suboptimally controlled with metformin (60%) and/or diet and exercise (40%): 40% female, A1C (mean Ϯ SD) 8.5 Ϯ 1.2%, fasting plasma glucose 9.9 Ϯ 2.3 mmol/l, weight 106 Ϯ 20 kg, and diabetes duration 5 Ϯ 4 years.RESULTS -From baseline to week 15, exenatide LAR reduced mean Ϯ SE A1C by Ϫ1.4 Ϯ 0.3% (0.8 mg) and Ϫ1.7 Ϯ 0.3% (2.0 mg), compared with ϩ0.4 Ϯ 0.3% with placebo LAR (P Ͻ 0.0001 for both). A1C of Յ7% was achieved by 36 and 86% of subjects receiving 0.8 and 2.0 mg exenatide LAR, respectively, compared with 0% of subjects receiving placebo LAR. Fasting plasma glucose was reduced by Ϫ2.4 Ϯ 0.9 mmol/l (0.8 mg) and Ϫ2.2 Ϯ 0.5 mmol/l (2.0 mg) compared with ϩ1.0 Ϯ 0.7 mmol/l with placebo LAR (P Ͻ 0.001 for both). Exenatide LAR reduced self-monitored postprandial hyperglycemia. Subjects receiving 2.0 mg exenatide LAR had body weight reductions (Ϫ3.8 Ϯ 1.4 kg) (P Ͻ 0.05), whereas body weight was unchanged with both placebo LAR and the 0.8-mg dose. Mild nausea was the most frequent adverse event.No subjects treated with exenatide LAR withdrew from the study.CONCLUSIONS -Exenatide LAR offers the potential of 24-h glycemic control and weight reduction with a novel once-weekly treatment for type 2 diabetes.

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