Sustained effect of glucagon on body weight and blood glucose: Assessed by continuous glucose monitoring in diabetic rats

PLoS One. 2018 Mar 20;13(3):e0194468. doi: 10.1371/journal.pone.0194468. eCollection 2018.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism*
  • Body Weight / drug effects*
  • Diabetes Mellitus, Experimental / blood
  • Diabetes Mellitus, Experimental / drug therapy*
  • Drug Therapy, Combination
  • Energy Metabolism / drug effects
  • Fibroblast Growth Factors / blood
  • Glucagon / administration & dosage
  • Glucagon / pharmacology*
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / pharmacology
  • Insulin / administration & dosage
  • Insulin / pharmacology
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Blood Glucose
  • Hypoglycemic Agents
  • Insulin
  • fibroblast growth factor 21
  • Fibroblast Growth Factors
  • Glucagon

Grant support

CP received funding from Novo Nordisk A/S (Innovation Fund Denmark - 4135-00003B and Novo Nordisk STAR Programme - 2014-03-DRU-03). The funder provided support in the form of salaries for authors (CP, TP, MT and NKR), but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.