Reduction of postprandial hyperglycemia in subjects with IDDM by intravenous infusion of AC137, a human amylin analogue

Abstract

Objective: To demonstrate that intravenous administration of AC137 (25,28,29 tripro-human amylin), a human amylin analogue, modulates the rate of appearance of glucose derived from a standard oral meal in the peripheral circulation of patients with insulin-dependent diabetes mellitus (IDDM).

Research design and methods: After the observation that a 2-h infusion of AC137 at a rate of 150 micrograms/h, in conjunction with the subjects' usual morning insulin dose, decreased postprandial hyperglycemia in 6 subjects with IDDM, a double-blind placebo-controlled two-period crossover design in an additional 18 IDDM patients was undertaken to confirm and extend the observation. Based on reasoning that an effect to modulate the appearance of orally administered glucose would have no impact on the disposition of an intravenous glucose load, nine patients were challenged with an intravenous glucose loads (300 mg/kg), while another nine patients were challenged with a standardized Sustacal meal (350 kcal) during a 5-h infusion of AC137 (50 micrograms/h). On each occasion, the subjects received their usual morning doses of insulin subcutaneously. The impact of the AC137 infusion on the plasma glucose responses to these different challenges was assessed.

Results: Intravenous infusion of AC137 yielding steady state plasma concentrations of 225 +/- 15 pmol/l (mean +/- SE) reduced postprandial plasma glucose concentrations after the standardized Sustacal meal challenge. The mean area under the glucose curve, corrected for baseline, was reduced from -1,869 +/- 5,562 mg.dl-1.min during placebo infusion to -28,872 +/- 4,812 mg.dl-1.min during AC137 infusion, P = 0.0015. In contrast, an AC137 infusion producing steady-state concentrations of 234 +/- 16 pmol/l had no effect on the plasma glucose profile after administration of an intravenous glucose load.

Conclusions: AC137 administration, in these patients with IDDM, reduced postprandial hyperglycemia apparently by affecting the delivery rate of glucose from the gastrointestinal tract. AC137 may prove to be a clinically useful addition to insulin regimens to facilitate the achievement of glycemic control.