No increased risk of hypoglycaemic episodes during 48 hours of continous GLP-1 administration in fasting healthy subjects

Background and Aims: During fasting the glycaemic level is orchestrated
by numerous biochemical processes. The insulinotropic and lucagonostatic effects of glucagon-like-peptide-1 (GLP-1) are glucose dependent. However it is speculative whether the ability to sufficiently compensate hypoglycaemia during fasting is preserved, when pharmacological GLP-1 levels are present. Furthermore, it is uncertain whether an oral glucose stimulus after a 60 hour fasting period would lead to reactive hypoglycaemia during high GLP-1 levels. To date the effect of GLP-1 administration on glycaemia and the counter regulatory response for more than 12 hours of fasting has never been explored. Thus the aim of the study was to assess the safety of a pharmacological relevant dose of native GLP-1 during long term fasting with regard to glycaemia and counter regulation. Our hypothesis was that there was no increased risk of hypoglycaemia with GLP-1 infusion due to glucose dependency and preserved counter regulation and only a minor risk of reactive hypoglycaemia exists in the wake of a subsequent glucose load.
Materials and Methods: We conducted a randomized placebo controlled
cross-over study in 8 healthy male subjects (age; 24±2 years (mean±SD), BMI 24.4±0.7kg/m2). After an overnight fast a subcutaneous infusion of GLP-1 (7–36amide) or placebo was started followed by a fasting period of 48 hours and finally a 3-hour oral glucose tolerance test (OGTT) was performed. Using a portable insulin pump GLP-1/placebo was infused continuously in a step wise manner for 6 hours following which 4.8pmol/kg/min was given for the rest of the study. Each subject completed two study periods. At a plasma glucose ” 2.8mM and/or neuroglycopenic symptoms the subjects were withdrawn from the study period. Results: 2 subjects in the GLP-1 group and 1 subject in the placebo group were withdrawn due to the above criteria (after 25, 29 and 25 hours of GLP-1 and placebo infusion, respectively). The average concentration of intact GLP-1 was 30.5±2.0 vs. 5.6±0.9 pmol/l (GLP-1 vs. placebo, mean±SEM), (P=0.004). During the fasting period plasma glucose (PG) declined in a comparable manner from 4.9±0.09 vs. 5.0±0.1 to 3.7±0.2 vs. 3.7±0.1 mmol/l (P=0.003). Levels of insulin (P=0.0006) and C-peptide (P=0.0001) decreased with fasting time, the glucagon level increased (P=0.0001) as did the levels of growth hormone (GH), (P=0.0001) and free fatty acids (FFA) (P=0.0001). No difference between GLP-1 and placebo was observed. Similarly, circulating insulin, C-peptide, FFA, glucagon, GH, cortisol and epinephrine did not differ. During the OGTT, PG was similar to GLP-1 and placebo (P=0.48) whereas circulating insulin (P=0.06) and C-peptide (P= 0.05) levels tended to be higher during GLP-1 infusion Conclusion: The counter regulatory response during 48 hours of subcutaneous GLP-1 infusion was preserved during fasting. There was no increased risk of major hypoglycaemic episodes. No reactive hypoglycaemia was observed after a glucose load following the fasting period. These observations may be of relevance utilizing potential future long acting GLP1 analogues.