Novel GLP-1 Analog Supaglutide Stimulates Insulin Secretion in Mouse and Human Islet Beta-Cells and Improves Glucose Homeostasis in Diabetic Mice

Abstract

Glucagon-like peptide-1 (GLP-1), an incretin hormone plays an important role in regulating glucose homeostasis. The therapeutic use of native GLP-1 is inadequate due to its short in vivo half-life. We recently developed a novel GLP-1 mimetics supaglutide, and demonstrated that this formulation retained native GLP-1 biological activities and possessed long-lasting GLP-1 actions. In this study, we further examined its abilities in regulating blood glucose in diabetic mice. We found that supaglutide stimulated insulin secretion in both mouse and human islets in a dose-dependent fashion. Oral glucose tolerance test conducted in normal ICR mice showed that supaglutide significantly decreased postprandial glucose excursions in a dose-dependent fashion. In type 2 diabetic db/db mice, a single-dose injection of supaglutide significantly decreased blood glucose levels, and this efficacy was lasted for at least 72 h in a dose-dependent fashion. During a 4-weeks intervention course supaglutide (twice injections per week) dose-dependently and significantly decreased fasting and random blood glucose levels in hyperglycemic db/db mice. Supaglutide, at a dose of 1.2 mg/kg, significantly reduced serum fructosamine levels. This was associated with significant enlargement of beta-cell mass, increased pancreatic insulin content, and increased plasma insulin level. Notably, during the intervention course supaglutide significantly reduced body-weight gain in these obese diabetic mice, associated with reduced fat mass (but not the lean mass), improved lipid profile, i.e., declined serum triglyceride, and free fatty acid levels compared to the placebo control. These finding reveals that supaglutide exerts beneficial effects in regulating blood glucose and lipid homeostasis in diabetic db/db mice.

Novel GLP-1 analog supaglutide improves glucose homeostasis in diabetic monkeys

“…This is consistent with other's observations that in diet-induced obese mice and non-human primates, GLP-1 based therapy significantly reduced blood glucose, and reduced body weight mainly due to the increased lipid and carbohydrate oxidation and energy consumption (Elvert et al 2018). Supaglutide treatment improved glucose tolerance associated with improved β-cell function, exemplified by enhanced insulin secretion, particularly in the first phase during IVGTT in diabetic monkeys, consistent with our recent data showing that long-term treatment with supaglutide stimulates insulin secretion and enlarges β-cell mass in diabetic db/db mice (Ren et al 2019).…”

“…During the intervention period of 4 weeks, although HbA1c was not obviously changed, the plasma FRA, a validated-biomarker that reflects the average levels of glucose control over the past 2-3 weeks (Ren et al 2019, Calderon et al 2020, was significantly decreased, in a dose-dependent fashion. The metabolic cycle of erythrocytes in rhesus monkeys is about 90 days (Pasini et al 2010).…”

OXM-104, a potential candidate for the treatment of obesity, NASH and type 2 diabetes

“…In accordance with these findings, dual GLP-1 and GCG receptor agonist SAR425899 was recently shown to improve β-cell function 37 . In addition, it has previously been shown that GLP-1 receptor agonist supaglutide increases β-cell mass in severely diabetic mice 32 .…”

“…Despite being great weight loss candidates, GLP-1 and dual GLP-1 and GCG receptor agonists also improve overall glucose homeostasis in diabetic subjects [31][32][33] . Therefore, we assessed the effects of OXM-104, cotadutide, and semaglutide on glucose control in severely diabetic mice.…”

The Regulation Role of the Gut-Islets Axis in Diabetes

“…As a consequence of this treatment, there was an enlargement in the mass of the islets, a promotion of β-cell proliferation, and enhancements in glucose tolerance and insulin secretion. 21 …”