Long-acting Glucagon-like Peptide-1 Analogue Research Articles

Efficacy and safety of GLP-1 analog ecnoglutide in adults with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 2 trial

Glucagon-like peptide-1 (GLP-1) analogs are important therapeutics for type 2 diabetes and obesity. Ecnoglutide (XW003) is a novel, long-acting GLP-1 analog. We conducted a Phase 2, randomized, double-blind, placebo-controlled study enrolling 145 adults with T2DM. Participants were randomized to 0.4, 0.8, or 1.2 mg ecnoglutide or placebo as once-weekly injections for 20 weeks. The primary objective was to evaluate the efficacy of ecnoglutide, as measured by HbA1c change from baseline at Week 20. Secondary endpoints included body weight, glucose and lipid parameters, as well as safety. We show that, at end of treatment, the 0.4, 0.8, and 1.2 mg groups had statistically significant HbA1c reductions from baseline of −1.81%, −1.90%, and −2.39%, respectively, compared to −0.55% for placebo (P < 0.0001). At end of treatment, 71.9% of the 1.2 mg group had HbA1c ≤ 6.5% versus 9.1% on placebo, and 33.3% had body weight reductions ≥5% versus 3.0% for placebo. Ecnoglutide was generally safe and well tolerated. China Drug Trials Registry CTR20211014.

Liraglutide enhances the effect of checkpoint blockade in lung and liver cancers through the inhibition of neutrophil extracellular traps.

Glucagon-like peptide-1 (GLP-1) regulates glycemic excursions by augmenting insulin production and inhibiting glucagon secretion. Liraglutide, a long-acting GLP-1 analog, can improve glycemic control for treating type 2 diabetes and prevent neutrophil extravasation in inflammation. Here, we explored the role of liraglutide in the development and therapy of murine lung and liver cancers. In this study, liraglutide substantially decreased circulating neutrophil extracellular trap (NET) markers myeloperoxidase, elastase, and dsDNA in Lewis lung cancer (LLC) and Hepa1-6 tumor-bearing mice. Furthermore, liraglutide downregulated NETs and reactive oxygen species (ROS) of neutrophils in the tumor microenvironment. Functionally, in vitro experiments showed that liraglutide reduced NET formation by inhibiting ROS. In addition, we showed that liraglutide enhanced the anti-tumoral efficiency of programmed cell death-1 (PD-1) inhibition in LLC and Hepa1-6 tumor-bearing C57BL/6 mice. However, the removal of NETs significantly weakened the antitumor efficiency of liraglutide. We further demonstrated that the long-term antitumor CD8+ T cell responses induced by the combination therapy rejected rechallenges by respective tumor cell lines. Taken together, our findings suggest that liraglutide may promote the anti-tumoral efficiency of PD-1 inhibition by reducing NETs in lung and liver cancers.

The glucagon-like peptide-1 (GLP-1) analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission.

Growing evidence indicates that the glucagon-like peptide-1 (GLP-1) system is involved in the neurobiology of addictive behaviors, and GLP-1 analogues may be used for the treatment of alcohol use disorder (AUD). Here, we examined the effects of semaglutide, a long-acting GLP-1 analogue, on biobehavioral correlates of alcohol use in rodents. A drinking-in-the-dark procedure was used to test the effects of semaglutide on binge-like drinking in male and female mice. We also tested the effects of semaglutide on binge-like and dependence-induced alcohol drinking in male and female rats, as well as acute effects of semaglutide on spontaneous inhibitory postsynaptic currents (sIPSCs) from central amygdala (CeA) and infralimbic cortex (ILC) neurons. Semaglutide dose-dependently reduced binge-like alcohol drinking in mice; a similar effect was observed on the intake of other caloric/noncaloric solutions. Semaglutide also reduced binge-like and dependence-induced alcohol drinking in rats. Semaglutide increased sIPSC frequency in CeA and ILC neurons from alcohol-naive rats, suggesting enhanced GABA release, but had no overall effect on GABA transmission in alcohol-dependent rats. In conclusion, the GLP-1 analogue semaglutide decreased alcohol intake across different drinking models and species and modulated central GABA neurotransmission, providing support for clinical testing of semaglutide as a potentially novel pharmacotherapy for AUD.

Metabolomics Provides Insights into Renoprotective Effects of Semaglutide in Obese Mice.

Semaglutide, a new long-acting glucagon-like peptide-1 analogue, has shown benefits for renal diseases, but its direct role on kidney metabolism under obesity remains unclear. The study aims to elucidate the protective effect and metabolic modulation mechanism of semaglutide on obesity-related kidney injury. Male C57BL/6J mice were divided into control and obesity groups. Mice in the obesity group had a high-fat diet and were treated with or without semaglutide (30nmol/kg/day). The study assayed blood biochemistry and then evaluated renal pathological injury through Periodic Acid-Schiff staining and electron microscopy. Metabolomics was utilized to analyze obesity-related metabolites in kidney samples. Semaglutide significantly improved glucose homeostasis, insulin resistance, and kidney injury in obese mice. We successfully identified 377 altered metabolites (P<0.05). It was suggested that semaglutide directly improved oxidative stress and inflammation-related metabolites such as nicotinamide adenine dinucleotide (NAD+) and adenosine in the kidney of obese mice, which have not been documented in obesity-related kidney injury. Relevant enriched pathways were included phospholipids and lysophospholipids metabolism, purine metabolism, NAD+ metabolism, and insulin resistance-related metabolism. They could serve as potential targets for intervention of obesity-related kidney injury. Our study revealed the metabolomics-based renoprotective mechanism of semaglutide in obese mice for the first time. The innovation lied in the identified metabolites such as NAD+ and adenosine targeted by semaglutide, which have not been documented in obesity-related kidney injury. Semaglutide may be a promising therapy for obesity-related kidney diseases.

Population pharmacokinetic of paracetamol and atorvastatin with co-administration of semaglutide.

Semaglutide is a glucagon‐like‐peptide‐1 (GLP‐1) analogue marketed for once‐weekly subcutaneous administration for type 2 diabetes mellitus. Like other long‐acting GLP‐1 analogues, semaglutide reduces gastric emptying and, potentially, alters the rate of absorption of orally co‐administered drugs. The objective of the current analysis was to evaluate the effects on the gastric emptying rate caused by semaglutide on pharmacokinetic model parameters of paracetamol and atorvastatin in healthy subjects. Non‐linear mixed effect modeling was used to estimate population pharmacokinetic model parameters of paracetamol and atorvastatin after single doses with or without semaglutide. The absorption rate (ka) of paracetamol decreased by 53% when co‐administered with semaglutide. For atorvastatin, ka and transit compartment rate (ktr) decreased by 72% and 91%, respectively. Thus, gastric emptying, measured as T50, i.e., drug disappearance from the absorption compartments, showed an additional 5‐min delay for paracetamol and a 67‐min delay for atorvastatin when co‐administered with semaglutide. Semaglutide affected pharmacokinetic model parameters of paracetamol and atorvastatin, and minor quantitative differences in gastric emptying between placebo vs. semaglutide administration were observed. However, these effects of semaglutide were considered not to be of clinical relevance.

GZR18, a novel long-acting GLP-1 analog, demonstrated positive in vitro and in vivo pharmacokinetic and pharmacodynamic characteristics in animal models

GZR18 is a novel analog of glucagon-like peptide-1 (GLP-1). This study evaluates the pharmacology, pharmacokinetics, and efficacy of GZR18, and its potential for the treatment of Type 2 diabetes mellitus (T2DM). In vitro pharmacology and activity of GZR18 were characterized by a binding assay of GZR18 using human serum albumin (HSA), an activation assay in human GLP-1 receptor-expressing cell lines, and its effect on glucose-stimulated insulin secretion (GSIS) in primary mice islets. Pharmacokinetic profiling was performed in Sprague Dawley rats and cynomolgus monkeys, and efficacy evaluated using GZR18 single or repeated doses in db/db mice. GZR18 showed similar binding affinity for HSA and GLP-1 receptor compared with semaglutide and liraglutide. GZR18 increased GSIS, which was confirmed by dynamic islet perifusion and fluorescence imaging using PKZnR-5 for real-time detection. In cynomolgus monkeys, the average GZR18 maximal concentration was 527 nmol L−1, the terminal half-life (T1/2) was 61.3 h, and the time to maximum concentration was 14 h. Single-dose GZR18 lowered blood glucose levels and reduced body weight over 72 h in db/db mice. GZR18 successive administration (every three days for 33 days, i.e. 11 doses) lowered nonfasting and fasting blood glucose levels (p < 0.05 versus control) and glycated hemoglobin, following the 11th dose. Food and water consumption in db/db mice was lowered following repeated doses of GZR18 (p < 0.05 versus control), without a reduction in body weight. These results demonstrate the potential of GZR18 as a long-acting GLP-1 analog for the treatment of T2DM.

S1368 The Pharmacokinetics of Long-Acting GLP-1 Analogue (NM-002) in Patients With Short Bowel Syndrome

Introduction: Glucagon-like peptide-1 (GLP-1) analogues are known to slow down gastric and intestinal motility. NM-002 is a long-acting GLP-1 analogue designed to be used in patients with short bowel syndrome (SBS). The aim of this study was to explore the pharmacokinetic profile of NM-002 in patients with SBS. Methods: Adult patients with SBS were randomized to receive either 50 mg, 100 mg, or 150 mg of NM-002 on Day 1 and Day 15 of the study. Levels of NM-002 were measured with an electrochemiluminescence (ECL) immunoassay, where human anti-Exendin-4 antibody and anti-XTEN biotinylated antibody were used to capture NM-002 molecules and SULFO-TAG Streptavidin bound to the biotinylated NM-002 that was used to generate an electrochemiluminescence signal. This signal was compared to signals generated with known standards of NM-002; the concentration of the NM-002 was back-calculated from the 4-parameter 1/y2 non-linear regression of the standards. The accuracy and precision of this method was validated to be within -3.80% to 12.18%. Results: Nine SBS patients (5m/4f) were recruited to the study; the average age was 51.8 years and an average BMI was 22.1 kg.m-2. Three subjects received 50 mg dose, 4 subjects received 100 mg dose and 2 subjects received 150 mg dose. One of the 50 mg patients did not receive a second dose due to a protocol violation. The mean half-life ranged between 300 and 750 hours and was independent of the dose administered. The pharmacokinetic profile of NM-002 are shown in the table and graph below (Mean + SD). Conclusion: The pharmacokinetic profile of NM-002, a long-acting GLP-1 analogue, shows dose dependent effect with accumulation at Day 15 supporting its extended half-life time. These pharmacokinetic data support twice monthly fixed dosing regimen (or better).Table 1.: The pharmacokinetic profile of NM-002.

An extended release GLP-1 analogue increases α-synuclein accumulation in a mouse model of prodromal Parkinson's disease

The repurposing of drugs developed to treat type 2 diabetes for the treatment of Parkinson's disease (PD) was encouraged by the beneficial effect exerted by the glucagon-like peptide 1 (GLP-1) analogue exenatide in a phase 2 clinical trial. The effects of GLP-1 analogues have been investigated extensively using rodent toxin models of PD. However, many of the toxin-based models used lack robust α-synuclein (α-syn) pathology, akin to the Lewy bodies and neurites seen in PD. One prior study has reported a protective effect of a GLP-1 analogue on midbrain dopamine neurons following injection of α-syn preformed fibrils (PFF) into the striatum. Here, we used olfactory bulb injections of PFF as a model of prodromal PD and monitored the effect of a long-acting GLP-1 analogue on the propagation of α-syn pathology in the olfactory system. Thirteen weeks after PFF injection, mice treated with long-acting the GLP-1 analogue had a significant increase in pathological α-syn in brain regions connected to the olfactory bulb, accompanied by signs of microglia activation. Our results suggest that the nature of the neuronal insult and intrinsic properties of the targeted neuronal population markedly influence the effect of GLP-1 analogues.

Long-Acting Glucagon-Like Peptide-1 Receptor Agonists Suppress Voluntary Alcohol Intake in Male Wistar Rats.

Alcohol use disorder (AUD) is a chronic relapsing condition characterized by compulsive alcohol-seeking behaviors, with serious detrimental health consequences. Despite high prevalence and societal burden, available approved medications to treat AUD are limited in number and efficacy, highlighting a critical need for more and novel pharmacotherapies. Glucagon-like peptide-1 (GLP-1) is a gut hormone and neuropeptide involved in the regulation of food intake and glucose metabolism via GLP-1 receptors (GLP-1Rs). GLP-1 analogs are approved for clinical use for diabetes and obesity. Recently, the GLP-1 system has been shown to play a role in the neurobiology of addictive behaviors, including alcohol seeking and consumption. Here we investigated the effects of different pharmacological manipulations of the GLP-1 system on escalated alcohol intake and preference in male Wistar rats exposed to intermittent access 2-bottle choice of 10% ethanol or water. Administration of AR231453 and APD668, two different agonists of G-protein receptor 119, whose activation increases GLP-1 release from intestinal L-cells, did not affect voluntary ethanol intake. By contrast, injections of either liraglutide or semaglutide, two long-acting GLP-1 analogs, potently decreased ethanol intake. These effects, however, were transient, lasting no longer than 48 h. Semaglutide, but not liraglutide, also reduced ethanol preference on the day of injection. As expected, both analogs induced a reduction in body weight. Co-administration of exendin 9-39, a GLP-1R antagonist, did not prevent liraglutide- or semaglutide-induced effects in this study. Injection of exendin 9-39 alone, or blockade of dipeptidyl peptidase-4, an enzyme responsible for GLP-1 degradation, via injection of sitagliptin, did not affect ethanol intake or preference. Our findings suggest that among medications targeting the GLP-1 system, GLP-1 analogs may represent novel and promising pharmacological tools for AUD treatment.

Liraglutide ameliorates non-alcoholic steatohepatitis by inhibiting NLRP3 inflammasome and pyroptosis activation via mitophagy

Non-alcoholic steatohepatitis (NASH) is a key step in the progression of non-alcoholic fatty liver disease (NAFLD), which causes serious health problems worldwide. The nucleotide-binding oligomerization domain, leucine-rich repeat-containing receptor-containing pyrin domain 3 (NLRP3) inflammasome and pyroptosis play crucial roles in the progression of NASH. Our team has provided clinical evidence of the effects of glucagon-like peptide-1 (GLP-1) on the improvement in liver function and histological resolution of NAFLD. Preliminary work has demonstrated that GLP-1 inhibited NLRP3 inflammasome activation in a mouse model of NAFLD. We further explored the potential molecular mechanisms underlying the anti-inflammatory effect of liraglutide, a long-acting GLP-1 analog, in the treatment of NASH. We established a HepG2 cell model of NASH using double stimulation with palmitic acid and lipopolysaccharide to assess NLRP3 inflammasome and pyroptotic cell activity and to evaluate mitochondrial function and mitophagy. Liraglutide reduced lipid accumulation, inhibited NLRP3 inflammasome and pyroptosis activation, attenuated mitochondrial dysfunction and reactive oxygen species generation, augmented mitophagy in hepatocytes. Mitophagy inhibition with 3-methyladenine/PINK1-directed siRNA weakened the liraglutide-mediated suppression of inflammatory injury. We propose that liraglutide suppresses NLRP3 inflammasome-induced hepatocyte pyroptosis via mitophagy to slow the progression of NASH.

The Discovery and Development of Liraglutide and Semaglutide.

The discovery of glucagon-like peptide-1 (GLP-1), an incretin hormone with important effects on glycemic control and body weight regulation, led to efforts to extend its half-life and make it therapeutically effective in people with type 2 diabetes (T2D). The development of short- and then long-acting GLP-1 receptor agonists (GLP-1RAs) followed. Our article charts the discovery and development of the long-acting GLP-1 analogs liraglutide and, subsequently, semaglutide. We examine the chemistry employed in designing liraglutide and semaglutide, the human and non-human studies used to investigate their cellular targets and pharmacological effects, and ongoing investigations into new applications and formulations of these drugs. Reversible binding to albumin was used for the systemic protraction of liraglutide and semaglutide, with optimal fatty acid and linker combinations identified to maximize albumin binding while maintaining GLP-1 receptor (GLP-1R) potency. GLP-1RAs mediate their effects via this receptor, which is expressed in the pancreas, gastrointestinal tract, heart, lungs, kidneys, and brain. GLP-1Rs in the pancreas and brain have been shown to account for the respective improvements in glycemic control and body weight that are evident with liraglutide and semaglutide. Both liraglutide and semaglutide also positively affect cardiovascular (CV) outcomes in individuals with T2D, although the precise mechanism is still being explored. Significant weight loss, through an effect to reduce energy intake, led to the approval of liraglutide (3.0 mg) for the treatment of obesity, an indication currently under investigation with semaglutide. Other ongoing investigations with semaglutide include the treatment of non-alcoholic fatty liver disease (NASH) and its use in an oral formulation for the treatment of T2D. In summary, rational design has led to the development of two long-acting GLP-1 analogs, liraglutide and semaglutide, that have made a vast contribution to the management of T2D in terms of improvements in glycemic control, body weight, blood pressure, lipids, beta-cell function, and CV outcomes. Furthermore, the development of an oral formulation for semaglutide may provide individuals with additional benefits in relation to treatment adherence. In addition to T2D, liraglutide is used in the treatment of obesity, while semaglutide is currently under investigation for use in obesity and NASH.

Lipidation and conformational constraining for prolonging the effects of peptides: Xenopus glucagon-like peptide 1 analogues with potent and long-acting hypoglycemic activity

The main disadvantages of glucagon-like peptide 1 (GLP-1) are its rapid degradation and excretion. These bottlenecks can be overcome by lipidation or other structural modification. The aim of this study was to design a series of long-acting GLP-1 analogues based on our previously discovered Xenopus GLP-1 analogs (1–3). The structure-activity relationship around lipidated 1–3 derivatives (1a–3l) with respect to in vitro potency as well as protraction was firstly explored. Compound 3g was selected for further modification. The Gly2 of 3g was replaced with Aib2, and a lactam constraint between Glu16 and Lys20 (i to i + 4) was introduced to further improve the in vivo activity and stability, affording compound 4. The receptor activation capability and in vitro stability of 4 were better than 3g and liraglutide. In addition, the hypoglycemic and insulinotropic activity of 4 was significantly better than liraglutide in db/db mice. Moreover, the enhanced in vitro stability of 4 translated into improved in vivo pharmacokinetic profiles and a prolonged antidiabetic duration. Administration of 4 twice daily for one week in diet-induced obese mice caused a significant decrease in food intake, body fat and body weight. The five-week treatment study on db/db mice of 4 further demonstrated the therapeutic effects of 4 on body weight, HbA1c and glucose tolerance. These preclinical studies demonstrate the therapeutic potential of 4 for type 2 diabetes and obesity. The present study also suggests that combined lipidation and conformational constraint strategy has potential to be used for improving the therapeutic properties of peptides.

Neuroprotective effects of the novel GLP-1 long acting analogue semaglutide in the MPTP Parkinson's disease mouse model

Parkinson's disease (PD) is the second most common neurodegenerative disease, and there is no recognised therapy to cure it. Recently, it has been shown that treatments to improve insulin resistance in type 2 diabetes (T2DM) may be useful for PD patients. In previous studies, the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide showed good neuroprotective effects in animal models of PD. In addition, the GLP-1 mimetic exendin-4 has shown good protective effects in PD patients in a phase II clinical trial. Here, we report the protective effects of semaglutide (25 nmol/kg ip. once-daily for 7 days), a new long-acting GLP-1 analogue, in the MPTP mouse model of PD. Moreover, we compared the neuroprotective effect of semaglutide with liraglutide given at the same dose. Our work shows that both semaglutide and liraglutide improved 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor impairments. In addition, both GLP-1 analogues rescued the decrease of tyrosine hydroxylase (TH) levels, alleviated the inflammation response, reduced lipid peroxidation, inhibited the apoptosis pathway, and also increased autophagy- related protein expression, to protect dopaminergic neurons in the substantia nigra and striatum. Moreover, the long-acting GLP-1 analogue semaglutide was superior to liraglutide in most parameters measured in this study. Our results demonstrate that the new long- acting GLP-1 analogue semaglutide may be a promising treatment for PD.

Augmentation of glucagon-like peptide-1 receptor signalling by neprilysin inhibition: potential implications for patients with heart failure.

Augmentation of glucagon-like peptide-1 (GLP-1) receptor signalling is an established approach to the treatment of type 2 diabetes. However, endogenous GLP-1 and long-acting GLP-1 receptor analogues are degraded not only by dipeptidyl peptidase-4, but also by neprilysin. This observation raises the possibilities that endogenous GLP-1 contributes to the clinical effects of neprilysin inhibition and that patients concurrently treated with sacubitril/valsartan and incretin-based drugs may experience important drug-drug interactions. Specifically, potentiation of GLP-1 receptor signalling may underlie the antihyperglycaemic actions of sacubitril/valsartan. Neprilysin inhibitors may also be able to augment the effects of long-acting GLP-1 analogues to increase heart rate and myocardial cyclic AMP, and thus, potentiate these deleterious actions; if so, concomitant treatment with GLP-1 receptor agonists may limit the efficacy of neprilysin inhibitors in patients with both heart failure and diabetes. For patients not concurrently treated with GLP-1 analogues, the action of neprilysin to enhance the effects of GLP-1 may be particularly relevant in the brain, where augmentation of GLP-1 and other endogenous peptides may act to inhibit amyloid-induced neuroinflammation and cytotoxicity and improve memory formation and executive functioning. Experimentally, neprilysin inhibitors may also potentiate the effects of endogenous GLP-1 and GLP-1 receptor agonists on blood vessels and the kidney. The role of neprilysin in the metabolism of endogenous GLP-1 and long-acting GLP-1 analogues points to a range of potential pathophysiological effects that may be clinically relevant to patients with heart failure, with or without diabetes.

Glycation of human serum albumin impairs binding to the glucagon-like peptide-1 analogue liraglutide

The long-acting glucagon-like peptide-1 analogue liraglutide has proven efficiency in the management of type 2 diabetes and also has beneficial effects on cardiovascular diseases. Liraglutide's protracted action highly depends on its capacity to bind to albumin via its palmitic acid part. However, in diabetes, albumin can undergo glycation, resulting in impaired drug binding. Our objective in this study was to assess the impact of human serum albumin (HSA) glycation on liraglutide affinity. Using fluorine labeling of the drug and 19F NMR, we determined HSA affinity for liraglutide in two glycated albumin models. We either glycated HSA in vitro by incubation with glucose (G25- or G100-HSA) or methylglyoxal (MGO-HSA) or purified in vivo glycated HSA from the plasma of diabetic patients with poor glycemic control. Nonglycated commercial HSA (G0-HSA) and HSA purified from plasma of healthy individuals served as controls. We found that glycation decreases affinity for liraglutide by 7-fold for G100-HSA and by 5-fold for MGO-HSA compared with G0-HSA. A similarly reduced affinity was observed for HSA purified from diabetic individuals compared with HSA from healthy individuals. Our results reveal that glycation significantly impairs HSA affinity to liraglutide and confirm that glycation contributes to liraglutide's variable therapeutic efficiency, depending on diabetes stage. Because diabetes is a progressive disease, the effect of glycated albumin on liraglutide affinity found here is important to consider when diabetes is managed with this drug.

Discovery of a long-acting glucagon-like peptide-1 analog with enhanced aggregation propensity

In the course of our search for new GLP-1 analogs, we screened a number of [Ser8]-GLP-1 analogs using the C-terminal helix 3 of the albumin binding domain 3 of protein G from bacterial Streptococcal G strain 148 (G148-ABD3) as appendage. Our efforts led to the discovery of [Ser8]-GLP-1 (7-35)-GVKALIDEILAA-NH2, peptide 6, as a long-acting GLP-1 analog with enhanced self-associated aggregation. Peptide 6 showed enhanced stability in rat and human plasma and an extended half-life of 5.4 h with good bioavailability in rats and subsequently prolonged therapeutic effects in diabetic mice. Analytical ultracentrifugation and TLC suggest that 6 remains oligomeric in the circulation, which accounts for its extended in vivo half-life. The present work shows the possible enhancement of medium-sized oligopeptides aggregation propensity and highlights the potential advantages of peptide aggregates for long-acting peptide drugs.

PGLP-1, a novel long-acting dual-function GLP-1 analog, ameliorates streptozotocin-induced hyperglycemia and inhibits body weight loss.

It is well known that glucagon-like peptide 1 (GLP-1) has antidiabetic action. It has 2 distinct functions, an insulinotropic effect dependent on GLP-1 receptor (GLP-1R) and an insulinomimetic effect independent of GLP-1R. However, use of GLP-1 in vivo is limited by its short half-life. Therefore, our lab designed PGLP-1, a novel 2-function candidate peptide as a potential substitute. Using a streptozotocin-induced hyperglycemic mouse model, we demonstrated in vitro and in vivo that PGLP-1 had insulinotropic actions dependent on GLP-1R and insulinomimetic functions independent of GLP-1R. PGLP-1 treatment increased islet β-cell mass, plasma insulin, and C-peptide levels and Ki-67-immunoreactive β-cell numbers, verifying that PGLP-1 can work as a short GLP-1R agonist, similar to commercially available exendin-4. Additionally, PGLP-1 improved insulin sensitivity, inhibited gluconeogenesis by increasing expression of AMPK and receptor subfamily 0, group B, member 2 (SHP), and inhibited body weight loss by inhibiting β-oxidation, suggesting that PGLP-1 had insulinomimetic action. Taken together, these data indicated that PGLP-1, as a dual-function peptide, improved glycemic control and inhibited body weight loss, suggesting it could be useful for type 1 diabetes mellitus patients as an adjunctive therapy to insulin.-Gao, H., Zhao, Q., Song, Z., Yang, Z., Wu, Y., Tang, S., Alahdal, M., Zhang, Y., Jin, L. PGLP-1, a novel long-acting dual-function GLP-1 analog, ameliorates streptozotocin-induced hyperglycemia and inhibits body weight loss.

BPI-3016, a novel long-acting hGLP-1 analogue for the treatment of Type 2 diabetes mellitus

Glucagon-like peptide-1 (GLP-1) analogues have been commonly used as add-on medications for patients with Type 2 diabetes mellitus (T2DM). Currently, the development of long-acting GLP-1 analogues which allow the freedom and flexibility of once-weekly injections while maintaining their potency for a relatively long period has become the mainstream. Here, we successfully developed a long-acting human GLP-1(7–37) analogue (BPI-3016) with significantly extended half-life and increased resistance to dipeptidyl peptidase IV (DPP-IV) cleavage by structural modifications of human GLP-1. In vitro activity of BPI-3016 including GLP-1 receptor affinity and stimulation of cyclic adenosine monophosphate (cAMP) production was measured. In vivo activity of BPI-3016 such as its effects on glycemic control, β-cell mass and body weight was evaluated in ob/ob mice, db/db mice, and spontaneous diabetic cynomolgus monkeys. The results indicated that BPI-3016 preserved receptor affinity to GLP receptors, and was capable of stimulating cAMP production. In in vivo pharmacokinetic study, the half-life of BPI-3016 was more than 95h after single dosing in diabetic cynomolgus monkeys. Also, BPI-3016 reduced fasting and post-prandial plasma glucose levels for up to a week after a single dose; It reduced body mass index (BMI), body fat, improved glucose tolerance and showed insulinotropic effects after once-weekly injection for 7 weeks. In conclusion, BPI-3016 retains the effects of GLP-1 with significantly prolonged half-life, making it a promising therapy for type 2 diabetes with once-weekly treatment in the clinic.

Lack of effect of prolonged treatment with liraglutide on cardiac remodeling in rats after acute myocardial infarction

Following the acute phase of a myocardial infarction, a set of structural and functional changes evolves in the myocardium, collectively referred to as cardiac remodeling. This complex set of processes, including interstitial fibrosis, inflammation, myocyte hypertrophy and apoptosis may progress to heart failure. Analogs of the incretin hormone glucagon-like peptide 1 (GLP-1) have shown some promise as cardioprotective agents. We hypothesized that a long-acting GLP-1 analog liraglutide would ameliorate cardiac remodeling over the course of 4 weeks in a rat model of non-reperfused myocardial infarction. In 134 male Sprague Dawley rats myocardial infarctions were induced by ligation of the left anterior descending coronary artery. Rats were randomized to either subcutaneous injection of placebo or 0.3mg liraglutide once daily. Cardiac magnetic resonance imaging was performed after 4 weeks. Histology of the infarcted and remote non-infarcted myocardium, selected molecular remodeling markers and mitochondrial respiration in fibers of remote non-infarcted myocardium were analyzed. Left ventricular end diastolic volume increased in the infarcted hearts by 62% (from 0.58±0.03mL to 0.95±0.07mL, P<0.05) compared to sham operated hearts and left ventricle ejection fraction decreased by 37% (63±1%–40±3%, P<0.05). Increased interstitial fibrosis and phosphorylation of p38 Mitogen Activated Protein Kinase were observed in the non-infarct regions. Mitochondrial fatty acid oxidation was impaired. Liraglutide did not affect any of these alterations. Four-week treatment with liraglutide did not affect cardiac remodeling following a non-reperfused myocardial infarction, as assessed by cardiac magnetic resonance imaging, histological and molecular analysis and measurements of mitochondrial respiration.

New Medications for the Treatment of Diabetes.

New Medications for the Treatment of Diabetes.