We quantified the contribution of GLP-1 as a mediator of the therapeutic effects of dipeptidyl peptidase 4 (DPP-4) inhibition (vildagliptin) by using the GLP-1 receptor antagonist exendin in patients with type 2 diabetes and in healthy subjects. Thirty-two patients with type 2 diabetes and 29 age-and weight-matched healthy control subjects were treated in randomized order with 100 mg once daily vildagliptin or placebo for 10 days. Meal tests were performed (days 9 and 10) without and with a high-dose intravenous infusion of exendin . The main end point was the ratio of the areas under the curve (AUCs) of integrated insulin secretion rates (total AUC ISR ) and glucose (total AUC glucose ) over 4 h after the meal. Vildagliptin treatment more than doubled responses of intact GLP-1 and glucose-dependent insulinotropic polypeptide and lowered glucose responses without changing AUC ISR /AUC glucose in healthy subjects. Vildagliptin significantly increased this ratio by 10.5% in patients with type 2 diabetes, and exendin [9-39] reduced it (both P < 0.0001). The percentage reduction in the AUC ISR / AUC glucose ratio achieved with exendin [9-39] was significantly smaller after vildagliptin treatment than after placebo treatment (P = 0.026) and was equivalent to 47 6 5% of the increments due to vildagliptin. Thus, other mediators appear to contribute significantly to the therapeutic effects of DPP-4 inhibition.

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The reaction of 4,6‐dinitrobenzofuroxan 1 with pyridinium ylides 2 affords σ‐CC bonded Meisenheimer complexes 3. The structure of these adducts is studied by n. m. r. spectroscopy and X‐ray structure analysis.

Upon treatment with KF in acetonitrile the zwitterionic Meisenheimer complexes 3 undergo β‐elimination leading to potassium 7‐(2‐aryl‐2‐oxo‐ethylidene)‐4,6‐dinitro‐7,x‐dihydrobenzofurazanide 1‐oxides 4 in 72–87% yield. Compounds 4 give 7‐(2‐aryl‐2‐oxo‐ethyl)‐4,6‐dinitrobenzofuroxans 6 when treated with hydrochloric acid. 4‐(2‐Aryl‐1‐dimethylsulfonio‐2‐oxo‐ethylidene)‐5,7‐dinitro‐4,x‐dihydrobenzofurazanides 5 are obtained by reaction of 3 with sodium methoxide. The structure of 5e is confirmed by X‐ray structure analysis. The reaction of complexes 8 with acetic acid/potassium acetate at 80°C affords 4‐(2‐aryl‐2‐oxo‐1‐pyridinio‐ethylidene)‐5,7‐dinitro‐4,x‐dihydrobenzofurazanides 9 in moderate yields.

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