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In the assessment of potential new treatments for Type 2 diabetes, robust pharmacological methods are helpful in assessing efficacy, defining dose response, duration of effect and ultimately in deciding whether to progress compounds to the next phase of drug development. Hepatic glucose handling is abnormal in Type 2 diabetes. We evaluated glucagon challenge as a way of assessing effects on the glycogenolytic pathway.In each of 2 studies healthy subjects received glucagon as an IV bolus of 0.5 mg studied after an overnight fast and plasma glucose was monitored before and for 180 min after glucagon challenge. Study 1 was a double-blind placebo controlled study comparing glucagon administered twice with saline placebo. In study 2, subjects were studied on a single occasion and the glucagon challenge was carried out in the morning and then repeated 7 h later. In study 2, insulin concentrations were also monitored before and after the glucagon challenge.In study 1, glucose rose in a reproducible manner with a peak glucose 20 min after challenge falling to baseline values by 120 min and then fell below values for saline challenge between 120 and 180 min. Analysis of the data showed that the corrected AUC(0-20) min was the most robust variable and could be expected to detect clinically relevant changes in small numbers (10) of subjects. In study 2, we demonstrated that when glucagon challenge was repeated 7 h after the first challenge, the glucose excursion was highly variable. The plasma insulin response was robust following the initial challenge but variable following the second challenge.We have demonstrated that an IV bolus glucagon challenge (0.5 mg) results in a reproducible rise in glucose in healthy volunteers and can be repeated within a week but when repeated on the same day gave a poorly reproducible rise in glucose. Glucagon challenge may be useful in studying novel drugs that affect glycogen handling in the liver. |
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