A novel DPP IV-resistant C-terminally extended glucagon analogue exhibits weight-lowering and diabetes-protective effects in high-fat-fed mice mediated through glucagon and GLP-1 receptor activation

Abstract

This study emphasises the potential of (D-Ser(2))glucagon-exe for the treatment of obesity-related diabetes.

Running on mixed fuel‐dual agonistic approach of GLP‐1 and GCG receptors leads to beneficial impact on body weight and blood glucose control: A comparative study between mice and non‐human primates

“…We performed indirect calorimetry studies, illustrating a switch of substrate preference during chronic treatment with dual GLP‐1R/GCGR agonists, starting with preferred fat oxidation and gradually increasing carbohydrate oxidation. The incidence of increased oxygen consumption and energy expenditure during chronic treatment of DIO mice with dual GLP‐1R/GCGR agonists is not novel and has been shown in previous studies . While Day and colleagues observed a tendency toward a decreased respiratory exchange ratio (RER or RQ, respiratory quotient), Lynch et al claimed that RER remained unchanged .…”

“…The incidence of increased oxygen consumption and energy expenditure during chronic treatment of DIO mice with dual GLP‐1R/GCGR agonists is not novel and has been shown in previous studies . While Day and colleagues observed a tendency toward a decreased respiratory exchange ratio (RER or RQ, respiratory quotient), Lynch et al claimed that RER remained unchanged . Our results confirmed the latter observations during chronic treatment.…”

“…Subsequent clinical studies of oxyntomodulin demonstrated significant efficacy concerning weight loss, resulting from the combined reduction of energy intake and increase of energy expenditure . As natural gastrointestinal hormones such as GLP‐1, glucagon or oxyntomodulin are rapidly degraded by serum proteases and are renally cleared, a number of stabilized oxyntomodulin analogs, as well as GLP‐1R/GCGR dual agonists based on glucagon, have been described as therapeutic agents for the management of obesity and associated metabolic disorders such as type 2 diabetes. However, the apparent challenge associated with translating the beneficial weight loss associated with a dual GLP‐1R/GCGR agonist is to curb the potential glucose‐elevating effects associated with excess glucagon pharmacology.…”

“…However, as the elevated fat oxidation should decrease RER further, the increased carbohydrate oxidation apparently compensates for the expected decrease in the case of a dual mouse‐specific agonist. The increased energy expenditure could be linked, only in part, to increased locomotor activity, but others did not report an elevation in spontaneous physical activity . However, our results can provide further clarification by matching the increased energy expenditure to the additional carbohydrate oxidation obtained from GCGR‐stimulated carbohydrate release from hepatic storage.…”

“…*P < .01 dual agonist vs vehicle control. #P < .01 dual agonist vs liraglutide (days −7 to 0, days 1 to 3, days 4 to 6, days 7 to 9, days 10 to 45) cleared, a number of stabilized oxyntomodulin analogs,10,28,34 as well as GLP-1R/GCGR dual agonists based on glucagon,8,12,14,[35][36][37] have been described as therapeutic agents for the management of obesity and associated metabolic disorders such as type 2 diabetes. However, the apparent challenge associated with translating the beneficial weight loss associated with a dual GLP-1R/GCGR agonist is to curb the potential glucose-elevating effects associated with excess glucagon pharmacology.…”