Insulin is a vital part of diabetes treatment, whereas glucagon is primarily used to treat insulin-induced hypoglycemia. However, glucagon is suggested to have a central role in the regulation of body weight, which would be beneficial for diabetic patients. Since the glucagon effect on blood glucose is known to be transient, it is relevant to investigate the pharmacodynamics of glucagon after repeated dosing. In the present study, we used telemetry to continuously measure blood glucose in streptozotocin induced diabetic Sprague-Dawley rats. This allowed for a more detailed analysis of glucose regulation compared to intermittent blood sampling. In particular, we evaluated the blood glucose-lowering effect of different insulin doses alone, and in combination with a long acting glucagon analog (LAG). We showed how the effect of the LAG accumulated and persisted over time. Furthermore, we found that addition of the LAG decreased body weight without affecting food intake.In a subsequent study, we focused on the glucagon effect on body weight and food intake during equal glycemic control. In order to obtain comparable maximum blood glucose lowering effect to insulin alone, the insulin dose had to be increased four times in combination with 1 nmol/kg of the LAG. In this set-up the LAG prevented further increase in body weight despite the four times higher insulin-dose. However, the body composition was changed. The insulin group increased both lean and fat mass, whereas the group receiving four times insulin in combination with the LAG only significantly increased the fat mass. No differences were observed in food intake, suggesting a direct effect on energy expenditure by glucagon. Surprisingly, we observed decreased levels of FGF21 in plasma compared to insulin treatment alone. With the combination of insulin and the LAG the blood glucose-lowering effect of insulin was prolonged, which could potentially be beneficial in diabetes treatment.
The current available insulin therapies decrease blood glucose but are associated with the risk of developing hypoglycemia. Glucagon is a counter regulatory hormone and we hypothesize that a fixed ratio of insulin and a long‐acting glucagon‐analogue can reduce the risk of hypoglycemia. To define an appropriate ratio we tested two fixed glucagon doses (3.5 and 10 nmol/kg) in combination with increasing doses of insulin in diabetic rats. We observed a plateau in blood glucose at 15.2 mmol/L with 10 nmol/kg of the glucagon‐analogue. The mechanism behind this plateau, protecting against hypoglycemia, was investigated by measuring the glucose output, cAMP production, and hormone binding in primary rat hepatocytes. While glucose output could contribute to the observed plateau in blood glucose, cAMP response or hormone binding did not explain the observation. Though such plateau indicated decreased risk of hypoglycemia a full normalization of blood glucose was still needed. Based on the data obtained with 3.5 nmol/kg of the glucagon‐analogue, a 1:23 (glucagon‐analogue:insulin) ratio was chosen and a dose‐response was performed in diabetic rats. At low doses (≤20 nmol/kg), insulin and the 1:23 ratio showed similar efficacy of lowering blood glucose. Interestingly, the insulin‐dose resulting in hypoglycemia was increased from 40 nmol/kg insulin alone to 160 nmol/kg insulin in the 1:23 ratio. Analysis of the liver glycogen content at the end of the experiment showed that the highest dose in the 1:23 ratio almost emptied the liver from glycogen. Thus, liver glycogen is essential for the protective effect of glucagon in hypoglycemia.
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