Excessive loss of islet beta cells is a major cause for the development of type 2 diabetes (T2D) , and seeking an effective method to enhance beta cell proliferation is a promising therapeutic strategy for T2D. In this study, we examined whether combined therapy of GABA and sitagliptin is effective in promoting beta cell proliferation and ameliorating the impairment of beta-cell function caused by high-fat diet (HFD) feeding in mice. Male C57BL/6J mice were fed with normal chow diet, HFD, or HFD combined with GABA, sitagliptin, or both drugs. Daily oral drug administration was initiated one week before HFD and maintained for two weeks. After two weeks of intervention, we found that GABA or sitagliptin administration ameliorated the impairment of glucose tolerance induced by HFD. This was associated with improved insulin secretion in vivo. Notably, combined administration of GABA and sitagliptin significantly enhanced these effects as compared to each of the monotherapies. Combined GABA and sitagliptin was superior at increasing beta-cell mass, and associated Ki67+ and PDX-1+ beta-cell counts. In addition, we found that HFD-induced compensatory beta-cell proliferation was associated with increased activation of unfolded protein response (UPR) , as indicated by BiP expression. This could be an important mechanism of compensatory beta-cell proliferation, and beta cells treated with GABA and sitagliptin showed greater UPR activation. Our results suggest that the combined use of these agents produces superior therapeutic outcomes. Disclosure Z. Wang: None. Q. Wang: None. L. Fan: None. Y. Ni: None. A. Ma: None. D. Wu: None. Q. Cui: None. Y. Zhou: None. Y. Lou: None. G. J. Prud'homme: None. Funding The National Natural Science Foundation of China (No.81630020, 81570518, and 81800751) , the Ministry of Science and Technology (No. 2017ZX09303001) , Shanghai Science and Technology Department (No. 2017ZX09303001) , and Juvenile Diabetes Research Foundation (JDRF, 2-SRA-2017-64-G-R to G P, QW, and T J; and 2-SRA-2015-64 to Q W, G P and T J) .

Supaglutide (Supa) is a novel once-weekly, human-derived long-acting GLP-1 analogue developed for patients with type 2 diabetes. In this study, we investigated the safety, pharmacokinetics (PK) , pharmacodynamics (PD) and potential immunogenicity of single-dose subcutaneous injections of Supa in healthy subjects. In this double-blind, single dose-escalation, 14-week trial, 48 healthy subjects were randomized to subcutaneous Supa treatment (ranging from 0.375 to 9 mg) or placebo arms for 2 weeks. PK profile and safety parameters were assessed. PD parameters (glucose and insulin concentrations) were measured following an oral glucose tolerance test (OGTT) (Day 3) . The half-life of Supa was approximately 120 h with a median Tmax ranging from 48 to 72 h (Table 1) . Supa treatment significantly reduced body weight compared to placebo in a dose-dependent and time-dependent fashion. OGTT results showed that Supa at all doses investigated significantly decreased glucose levels during the test, suggesting increased glucose tolerance. Supa was safe and well-tolerated in healthy subjects with some increase in mild to moderate gastrointestinal symptoms with escalating doses. No subjects developed anti-Supa antibodies. The safety, PK and PD profiles supported Supa as a long-acting injectable medication for glycemic control and weight loss, as an alternative GLP-1 therapy. Disclosure A. Ma: None. J. Li: None. G. J. Prud’homme: None. D. Zhu: n/a. Q. Wang: None. Y. Zhou: None. Y. Lou: None. Y. Liao: None. A. Shao: None. Z. Wang: None. Y. Jiang: None. Q. Cui: None. Y. Zhao: None. Funding Ministry of Science and Technology (No. 2011ZX09102, No. 2017ZX09303001) , Shanghai Science and Technology Department (No. 2017ZX09303001)

Supaglutide, a novel GLP-1-IgG Fc fusion protein, exerts hypoglycemic effects in type 2 diabetic db/db mice and spontaneous diabetic monkeys. In this study, we investigated the pharmacokinetics and pharmacodynamics of supaglutide by single or repeated subcutaneous and intravenous injection (s) in rats and rhesus monkeys. We found that the half-life of supaglutide at 0.1 mg/kg in rhesus monkeys was 39.7 hours and 35.8 hours upon subcutaneous or intravenous administration, respectively. The plasma supaglutide peaked at 8-10 hours, while the plasma drug exposure levels increased with the increase of dose, showing approximately a linear pharmacokinetic characteristic. The elimination kinetics was similar between subcutaneous (∼0.025 in rats and ∼0.018 in monkeys) and intravenous administration (0.021 in rats and 0.020 in monkeys) , whereas the bioavailability was found to be 31.1% in rats and 63.9% in monkeys. In monkeys, the marked glucose-lowering effect of a single dose injection of supaglutide peaked at 14-16 hours and lasted for 72 hours. 125I-supaglutide distributed mainly in the serum and organs rich in blood supply. Urine was found to be the primary excretion route of supaglutide, following by feces, but the least by bile. Our results demonstrate that supaglutide has an excellent pharmacokinetic profile with prolonged hypoglycemic effects and is a potential weekly dosing therapeutic agent for the treatment of type 2 diabetes. Disclosure Y. Liao: None. A. Ma: None. Z. Wang: None. Y. Zhou: None. L. Zhang: None. L. Liu: None. N. Zhang: None. G. J. Prud’homme: None. Q. Wang: None.

Supaglutide (Supa) is a weekly dosing GLP-1 analog. We conducted a randomized, double-blind, placebo-controlled, multiple dose-escalation study to investigate the safety, PK/PD and efficacy of Supa in patients with T2D. 40 subjects were randomized in a 4:1 ratio to receive Supa (sc., 1, 2, 3 and 4mg) or placebo. We performed intensive PK blood sampling for two weeks after the first dose, followed by weekly repeated dosing for 4 consecutive weeks. The 4mg group received an adaptive dose of 1mg to reduce gastrointestinal reactions. The PK results revealed that the T1/2 of Supa was ∼207 h with median Tmax of 60∼84 h. The PD results showed that after 7 weeks of therapy, Supa significantly reduced fasting blood glucose, and HbA1c decreased by 1.3%. Supa increased fasting insulin/C-peptide while decreasing body weight. OGTT results showed significantly reduced glucose excursion, and the glucose-stimulated insulin secretion assay demonstrated significantly increased insulin secretion, suggesting improved glucose tolerance and enhanced β-cell function. AEs identified during the study were mainly mild to moderate gastrointestinal symptoms. None of the subjects developed anti-drug antibodies. Safety assessments including AEs, vital signs, ECGs and laboratory parameters, revealed that Supa was safe and well-tolerated. These data suggest Supa is a novel alternative therapy for T2D and metabolic disorders. Disclosure Y. Zhou: None. X. Jiang: None. Y. Lou: None. A. Ma: None. J. Li: None. Y. Zhao: None. G. J. Prud'homme: None. Q. Wang: None.