252 research outputs found
GLP-1/GIP analogs: potential impact in the landscape of obesity pharmacotherapy:potential impact in the landscape of obesity pharmacotherapy
Introduction: Obesity is recognized as a major healthcare challenge. Following years of slow progress in discovery of safe, effective therapies for weight management, recent approval of the glucagon-like peptide 1 receptor (GLP-1R) mimetics, liraglutide and semaglutide, for obesity has generated considerable excitement. It is anticipated these agents will pave the way for application of tirzepatide, a highly effective glucose-dependent insulinotropic polypeptide receptor (GIPR), GLP-1R co-agonist, recently approved for management of type 2 diabetes mellitus. Areas covered: Following promising weight loss in obese individuals in Phase III clinical trials, liraglutide and semaglutide were approved for weight management without diabetes. Tirzepatide has attained Fast Track designation for obesity management by the US Food and Drug Association. This narrative review summarizes experimental, preclinical, and clinical data for these agents and related GLP-1R/GIPR co-agonists, prioritizing clinical research published within the last 10Ā years where possible. Expert Opinion: GLP-1R mimetics are often discontinued within 24 months meaning long-term application of these agents in obesity is questioned. Combined GIPR/GLP-1R agonism appears to induce fewer side effects, indicating GLP-1R/GIPR co-agonists may be more suitable for enduring obesity management. After years of debate, this GIPR-biased GLP-1R/GIPR co-agonist highlights the therapeutic promise of including GIPR modulation for diabetes and obesity therapy.</p
An update on peptide-based therapies for type 2 diabetes and obesity
Long-acting analogues of the naturally occurring incretin, glucagon-like peptide-1 (GLP-1) and those modified to interact also with receptors for glucose-dependent insulinotropic polypeptide (GIP) have shown high glucose-lowering and weight-lowering efficacy when administered by once-weekly subcutaneous injection. These analogues herald an exciting new era in peptide-based therapy for type 2 diabetes (T2D) and obesity. Of note is the GLP-1R agonist semaglutide, available in oral and injectable formulations and in clinical trials combined with the long-acting amylin analogue, cagrilintide. Particularly high efficacy in both glucose- and weight lowering capacities has also been observed with the GLP-1R/GIP-R unimolecular dual agonist, tirzepatide. In addition, a number of long-acting unimolecular GLP-1R/GCGR dual agonist peptides and GLP-1R/GCGR/GIPR triagonist peptides have entered clinical trials. Other pharmacological approaches to chronic weight management include the human monoclonal antibody, bimagrumab which blocks activin type II receptors and is associated with growth of skeletal muscle, an antibody blocking activation of GIPR to which are conjugated GLP-1R peptide agonists (AMG-133), and the melanocortin-4 receptor agonist, setmelanotide for use in certain inherited obesity conditions. The high global demand for the GLP-1R agonists liraglutide and semaglutide as anti-obesity agents has led to shortage so that their use in T2D therapy is currently being prioritized. [Abstract copyright: Copyright Ā© 2023 The Authors. Published by Elsevier Inc. All rights reserved.
Differential Acute and Long Term Actions of Succinic Acid Monomethyl Ester Exposure on Insulin-Secreting BRIN-BD11 Cells
Esters of succinic acid are potent insulin secretagogues,
and have been proposed as novel antidiabetic
agents for type 2 diabetes. This study
examines the effects of acute and chronic exposure
to succinic acid monomethyl ester (SAM) on insulin
secretion, glucose metabolism and pancreatic beta
cell function using the BRIN-BD11 cell line. SAM
stimulated insulin release in a dose-dependent
manner at both non-stimulatory (1.1mM) and stimulatory
(16.7mM) glucose. The depolarizing actions
of arginine also stimulated a significant increase
in SAM-induced insulin release but 2-ketoisocaproic
acid (KIC) inhibited SAM induced insulin
secretion indicating a possible competition between
the preferential oxidative metabolism of these two
agents. Prolonged (18hour) exposure to SAM revealed
decreases in the insulin-secretory responses
to glucose, KIC, glyceraldehyde and alanine.
Furthermore, SAM diminished the effects of nonmetabolized
secretagogues arginine and 3-isobutyl-1-methylxanthine (IBMX). While the ability of
BRIN-BD11 cells to oxidise glucose was unaffected
by SAM culture, glucose utilization was substantially
reduced. Collectively, these data suggest that
while SAM may enhance the secretory potential of
non-metabolized secretagogues, it may also serve as
a preferential metabolic fuel in preference to other
important physiological nutrients and compromise
pancreatic beta cell function following prolonged
exposure
Does glucose-dependent insulinotropic polypeptide receptor blockade as well as agonism have a role to play in management of obesity and diabetes?
Recent approval of the dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, tirzepatide, for the management of type 2 diabetes mellitus (T2DM) has reinvigorated interest in exploitation of GIP receptor (GIPR) pathways as a means of metabolic disease management. However, debate has long surrounded the use of the GIPR as a therapeutic target and whether agonism or antagonism is of most benefit in management of obesity/diabetes. This controversy appears to be partly resolved by the success of tirzepatide. However, emerging studies indicate that prolonged GIPR agonism may desensitise the GIPR to essentially induce receptor antagonism, with this phenomenon suggested to be more pronounced in the human than rodent setting. Thus, deliberation continues to rage in relation to benefits of GIPR agonism vs. antagonism. That said, as with GIPR agonism, it is clear that the metabolic advantages of sustained GIPR antagonism in obesity and obesity-driven forms of diabetes can be enhanced by concurrent GLP-1 receptor (GLP-1R) activation. This narrative review discusses various approaches of pharmacological GIPR antagonism including small molecule, peptide, monoclonal antibody and peptide-antibody conjugates, indicating stage of development and significance to the field. Taken together, there is little doubt that interesting times lie ahead for GIPR agonism and antagonism, either alone or when combined with GLP-1R agonists, as a therapeutic intervention for the management of obesity and associated metabolic disease
Novel enzymeāresistant pancreatic polypeptide analogs evoke pancreatic betaācell rest, enhance islet cell turnover, and inhibit food intake in mice
Pancreatic polypeptide (PP) is a postprandial hormone secreted from pancreatic islets that activates neuropeptide Y4 receptors (NPY4Rs). PP is known to induce satiety but effects at the level of the endocrine pancreas are less well characterized. In addition, rapid metabolism of PP by dipeptidyl peptidaseā4 (DPPā4) limits the investigation of the effects of the native peptide. Therefore, in the present study, five novel amino acid substituted and/or fatty acid derivatized PP analogs were synthesized, namely [P3]PP, [K13Pal]PP, [P3,K13Pal]PP, [NāPal]PP, and [NāPal,P3]PP, and their impact on pancreatic betaācell function, as well as appetite regulation and glucose homeostasis investigated. All PP analogs displayed increased resistance to DPPā4 degradation. In addition, all peptides inhibited alanineāinduced insulin secretion from BRINāBD11 beta cells. Native PP and related analogs (10ā8 and 10ā6 M), and especially [P3]PP and [K13Pal]PP, significantly protected against cytokineāinduced betaācell apoptosis and promoted cellular proliferation, with effects dependent on the NPY4R for all peptides barring [NāPal,P3]PP. In mice, all peptides, except [NāPal]PP and [NāPal,P3]PP, evoked a doseādependent (25, 75, and 200 nmol/kg) suppression of appetite, with native PP and [P3]PP further augmenting glucagonālike peptideā1 (GLPā1) and cholecystokinin (CCK) induced reductions of food intake. The PP peptides had no obvious detrimental effect on glucose tolerance and they did not noticeably impair the glucoseāregulatory actions of GLPā1 or CCK. In conclusion, Pro3 amino acid substitution of PP, either alone or together with midāchain acylation, creates PP analogs with benefits on betaācell rest, islet cell turnover, and energy regulation that may be applicable to the treatment of diabetes and obesity
[ P<sup>3</sup> ] PP, a stable, longāacting pancreatic polypeptide analogue, evokes weight lowering and pancreatic betaācellāprotective effects in obesityāassociated diabetes
Aim: To thoroughly investigate the impact of sustained neuropeptide Y4 receptor (NPY4R) activation in obesityāassociated diabetes. Methods: Initially, the prolonged pharmacodynamic profile of the enzymatically stable pancreatic polypeptide (PP) analogue, [P3]PP, was confirmed in normal mice up to 24 h after injection. Subsequent to this, [P3]PP was administered twice daily (25 nmol/kg) for 28 days to highāfatāfed mice with streptozotocināinduced insulin deficiency, known as HFF/STZ mice. Results: Treatment with [P3]PP for 28 days reduced energy intake and was associated with notable weight loss. In addition, circulating glucose was returned to values of approximately 8 mmol/L in [P3]PPātreated mice, with significantly increased plasma insulin and decreased glucagon concentrations. Glucose tolerance and glucoseāstimulated insulin secretion were improved in [P3]PPātreated HFF/STZ mice, with no obvious effect on peripheral insulin sensitivity. Benefits on insulin secretion were associated with elevated pancreatic insulin content as well as islet and betaācell areas. Positive effects on islet architecture were linked to increased betaācell proliferation and decreased apoptosis. Treatment intervention also decreased islet alphaācell area, but pancreatic glucagon content remained unaffected. In addition, [P3]PPātreated HFF/STZ mice presented with reduced plasma alanine transaminase and aspartate transaminase levels, with no change in circulating amylase concentrations. In terms of plasma lipid profile, triglyceride and cholesterol levels were significantly decreased by [P3]PP treatment, when compared to saline controls. Conclusion: Collectively, these data highlight for the first time the potential of enzymatically stable PP analogues for the treatment of obesity and related diabetes
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