A novel, long-acting agonist of glucose-dependent insulinotropic polypeptide suitable for once-daily administration in type 2 diabetes

Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone with a potentially therapeutic role in type 2 diabetes. Rapid degradation by dipeptidylpeptidase IV has prompted the development of enzyme-resistant N-terminally modified analogs, but renal clearance still limits in vivo bioactivity. In this study, we report long-term antidiabetic effects of a novel, N-terminally protected, fatty acid-derivatized analog of GIP, N-AcGIP(LysPAL(37)), in obese diabetic (ob/ob) mice. Once-daily injections of N-AcGIP(LysPAL(37)) over a 14-day period significantly decreased plasma glucose, glycated hemoglobin, and improved glucose tolerance compared with ob/ob mice treated with saline or native GIP. Plasma insulin and pancreatic insulin content were significantly increased by N-AcGIP(LysPAL(37)). This was accompanied by a significant enhancement in the insulin response to glucose together with a notable improvement of insulin sensitivity. No evidence was found for GIP receptor desensitization and the metabolic effects of NAcGIP(LysPAL(37)) were independent of any change in feeding or body weight. Similar daily injections of native GIP did not affect any of the parameters measured. These data demonstrate the ability of once-daily injections of N-terminally modified, fatty acid-derivatized analogs of GIP, such as N-AcGIP(LysPAL(37)), to improve diabetes control and to offer a new class of agents for the treatment of type 2 diabetes.

The Equalization of Effective Communicative Freedom: Democratic Justice in the Constitutional State and Beyond

Jurgen Habermas takes the realization of rights through the democratic self-organization of legal communities to be the normative core of emancipatory politics. In this article I explore the implications of this claim in relation to the requirements of justice. I argue that Habermas's discourse theory of democratic legitimacy presupposes a substantive principle of justice that demands the equalization of effective communicative freedom for all structurally constituted social groups in any constitutional state. This involves the elimination of a range of structural injustices rooted in the complex interrelationships between political, economic and cultural orders. In the final section I sketch briefly the implications of this analysis in the context of ongoing globalization processes. It is suggested that the most effective way to establish a just system of global governance is to equalize effective communicative freedom among nation-states.