Unimolecular Dual Incretins Maximize Metabolic Benefits in Rodents, Monkeys, and Humans (original) (raw)
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GIP as a Therapeutic Target in Diabetes and Obesity: Insight From Incretin Co-agonists
The Journal of Clinical Endocrinology & Metabolism, 2020
The 2 hormones responsible for the amplification of insulin secretion after oral as opposed to intravenous nutrient administration are the gut peptides, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). However, whereas GLP-1 also inhibits appetite and food intake and improves glucose regulation in patients with type 2 diabetes (T2DM), GIP seems to be devoid of these activities, although the 2 hormones as well as their receptors are highly related. In fact, numerous studies have suggested that GIP may promote obesity. However, chimeric peptides, combining elements of both peptides and capable of activating both receptors, have recently been demonstrated to have remarkable weight-losing and glucose-lowering efficacy in obese individuals with T2DM. At the same time, antagonists of the GIP receptor have been reported to reduce weight gain/cause weight loss in experimental animals including nonhuman primates. This suggests that both agonists and ant...
The American Journal of Medicine, 2011
The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagonlike peptide-1 (GLP-1), which are secreted by cells of the gastrointestinal tract in response to meal ingestion, exercise important glucoregulatory effects, including the glucose-dependent potentiation of insulin secretion by pancreatic -cells. Research on the defective incretin action in type 2 diabetes mellitus suggests that the observed loss of insulinotropic activity may be due primarily to a decreased responsiveness of -cells to GIP. GLP-1 does retain efficacy, albeit not at physiologic levels. Accordingly, augmentation of GLP-1 is a logical therapeutic strategy to ameliorate this deficiency, although the short metabolic half-life of the native hormone renders direct infusion impractical. GLP-1 receptor agonists that resist degradation by the enzyme dipeptidyl peptidase-4 (DPP-4) and have protracted-action kinetics have been developed, and DPP-4 inhibitors that slow the enzymatic cleavage of native GLP-1 provide alternative approaches to enhancing incretin-mediated glucose control. However, GLP-1 receptor agonists and DPP-4 inhibitors are premised on highly divergent mechanisms of action. DPP-4 is ubiquitously expressed in many tissues and is involved in a wide range of physiologic processes in addition to its physiologic influence on incretin hormone biological activity. GLP-1 receptor agonists provide a pharmacologic level of GLP-1 receptor stimulation, whereas DPP-4 inhibitors appear to increase levels of circulating GLP-1 to within the physiologic range. This article examines the physiology of the incretin system, mechanistic differences between GLP-1 receptor agonists and DPP-4 inhibitors used as glucose-lowering agents in the treatment of type 2 diabetes, and the implications of these differences for treatment. The results of recent head-tohead trials are reviewed, comparing the effects of incretin-based therapies on a range of clinical parameters, including glycemia, -cell function, weight, and cardiovascular function.
The Incretin Approach for Diabetes Treatment: Modulation of Islet Hormone Release by GLP-1 Agonism
Diabetes, 2004
Glucagon-like peptide (GLP)-1 is a gut hormone that stimulates insulin secretion, gene expression, and -cell growth. Together with the related hormone glucosedependent insulinotropic polypeptide (GIP), it is responsible for the incretin effect, the augmentation of insulin secretion after oral as opposed to intravenous administration of glucose. Type 2 diabetic patients typically have little or no incretin-mediated augmentation of insulin secretion. This is due to decreased secretion of GLP-1 and loss of the insulinotropic effects of GIP. GLP-1, however, retains insulinotropic effects, and the hormone effectively improves metabolism in patients with type 2 diabetes. Continuous subcutaneous administration greatly improved glucose profiles and lowered body weight and HbA 1c levels. Further, free fatty acid levels were lowered, insulin resistance was improved, and -cell performance was greatly improved. The natural peptide is rapidly degraded by the enzyme dipeptidyl peptidase IV (DPP IV), but resistant analogs as well as inhibitors of DPP IV are now under development, and both approaches have shown remarkable efficacy in experimental and clinical studies. Diabetes 53 (Suppl. 3):
European Journal of Endocrinology, 2008
Type 2 diabetes mellitus is associated with progressive decreases in pancreatic b-cell function. Most patients thus require increasingly intensive treatment, including oral combination therapies followed by insulin. Fear of hypoglycemia is a potential barrier to treatment adherence and glycemic control, while weight gain can exacerbate hyperglycemia or insulin resistance. Administration of insulin can roughly mimic physiologic insulin secretion but does not address underlying pathophysiology. Glucagon-like peptide 1 (GLP-1) is an incretin hormone released by the gut in response to meal intake that helps to maintain glucose homeostasis through coordinated effects on islet aand b-cells, inhibiting glucagon output, and stimulating insulin secretion in a glucose-dependent manner. Biological effects of GLP-1 include slowing gastric emptying and decreasing appetite. Incretin mimetics (GLP-1 receptor agonists with more suitable pharmacokinetic properties versus GLP-1) significantly lower hemoglobin A1c, body weight, and postprandial glucose excursions in humans and significantly improve b-cell function in vivo (animal data). These novel incretin-based therapies offer the potential to reduce body weight or prevent weight gain, although the durability of these effects and their potential long-term benefits need to be studied further. This article reviews recent clinical trials comparing therapy with the incretin mimetic exenatide to insulin in patients with oral treatment failure, identifies factors consistent with the use of each treatment, and delineates areas for future research.
Next Step in Incretin-Based Therapy: From Single to Dual Agonism
EMJ Diabetes
The twin epidemics of Type 2 diabetes (T2D) and obesity will continue to bring significant health challenges in the coming decades. Randomised controlled trials of glucagon-like peptide 1 (GLP-1)-based therapies showed high glycaemic efficacy with clinically meaningful weight loss, and have been considered as game-changers in the diabesity population. Emerging evidence has demonstrated that co-administration of glucose-dependent insulinotropic peptide (GIP) and GLP-1 results in enhanced insulinotropic effect in an additive way with significant glucagonostatic response, compared with the administration of each hormone separately. These findings have driven the choice to pursue incretin-based dual agonist therapies, known as ‘twincretin’. Observations from the global registration Phase III trials suggest that tirzepatide (a novel dual GIP/GLP-1 receptor agonist) represent advancement over current GLP-1 analogues, providing enhanced glycaemic and weight benefits with similar gastrointe...
Incretin-based therapies: can we achieve glycemic control and cardioprotection?
Journal of Endocrinology, 2013
Glucagon-like (GLP-1) is a peptide hormone secreted from the small intestine in response to nutrient ingestion. GLP-1 stimulates insulin secretion in a glucose-dependent manner, inhibits glucagon secretion and gastric emptying, and reduces appetite. Because of the short circulating half-life of the native GLP-1, novel GLP-1 receptor (GLP-1R) agonists and analogs and dipeptidyl peptidase 4 (DPP-4) inhibitors have been developed to facilitate clinical use. Emerging evidence indicates that GLP-1-based therapies are safe and may provide cardiovascular (CV) benefits beyond glycemic control. Preclinical and clinical studies are providing increasing evidence that GLP-1 therapies may positively affect CV function and metabolism by salutary effects on CV risk factors as well as via direct cardioprotective actions. However, the mechanisms whereby the various classes of incretin-based therapies exert CV effects may be mechanistically distinct and may not necessarily lead to similar CV outcomes...
Incretin-based therapies: focus on effects beyond glycemic control alone
Diabetes therapy : research, treatment and education of diabetes and related disorders, 2013
Type 2 diabetes is associated with a high prevalence of comorbidities resulting from hypertension, dyslipidemia, and hyperglycemia. Inadequate management of these risk factors will eventually result in detrimental health consequences. Thus, the effect of a drug on factors such as weight, cardiovascular (CV) risk factors, and adherence is important to consider. A review was undertaken of the recent medical literature describing the extraglycemic characteristics of the two classes of incretin-based therapies-glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 (DPP-4) inhibitors. PubMed searches were performed to identify published data on incretin therapies that describe their effects on CV risk factors, CV events, and factors related to medication adherence. The maintenance or loss of weight associated with the use of GLP-1RAs and DPP-4 inhibitors is well described in the medical literature. These agents also appear to be associated with a modest decrease i...
An Overview of Incretin-Based Therapies: Pharmacology and Future Perspectives
Bulletin of Pharmaceutical Sciences. Assiut
Glucagon-like peptide-1 (GLP-1) is a gut-derived incretin hormone that is released upon nutrient ingestion stimulating insulin secretion, suppressing glucagon secretion, and suppressing appetite and food intake which contribute to glucose homeostasis. The incretin system is impaired during type 2 diabetes mellitus (T2DM). Incretin-based therapies are gaining popularity in the clinical field nowadays. Current treatment guidelines for T2DM incorporate glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase 4 inhibitors (DPP-4i) as second-line agents with the advantages of low risk of hypoglycemia with good control of postprandial hyperglycemia (with short-acting GLP-1 RAs and DPP-4i) and weight loss (with GLP-1 RAs). GLP-1 RAs have more efficacy and are preferred with patients with preexisting cardiovascular disease. Growing evidence suggests that incretin-based therapies have beneficial effects on cardiovascular, liver, kidney, and nervous system disorders. The current review includes the biology of the incretin system, the pharmacology of incretinbased therapies, and their applications in experimental and clinical work.
Molecular Pharmacology of the Incretin Receptors
Medical Principles and Practice, 2015
The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are important regulators of insulin and glucagon secretion as well as lipid metabolism and appetite. These biological functions make their respective receptors (GIPR and GLP-1R) attractive targets in the treatment of both type 2 diabetes mellitus (T2DM) and obesity. The use of these native peptides in the treatment of these conditions is limited by their short half-lives. However, long-acting GLP-1R agonists and inhibitors of the enzyme that rapidly inactivates GIP and GLP-1 (dipeptidyl peptidase IV) are in clinical use. Although there is a loss of response to both hormones in T2DM, this effect appears to be more pronounced for GIP. This has made targeting GIPR less successful than GLP-1R. Furthermore, results demonstrating that GIPR knockout mice were resistant to diet-induced obesity suggested that GIPR antagonists may prove to be useful therapeutics. More recently, molecules that activate both receptors have shown promise in terms of glycemic and body weight control. This review focused on recent advances in the understanding of the signaling mechanisms and regulation of these two clinically important receptors.
2021
We report the discovery of a novel unimolecular glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor dual agonist that exhibits potent glycemic control and weight loss in diet-induced obese mice. The dual agonism of GLP-1 and GIP receptor was achieved by replacing the tryptophan cage of exendin-4 with the C- terminal undecapeptide sequence of oxyntomodulin along with a single amino acid substitution from histidine to tyrosine at the amino terminus of the peptide. The structural modification places lysine 30 of the novel incretin agonist in frame with the corresponding lysine residue in the native GIP sequence. The novel incretin receptor dual agonist, named I-M-150847, induces rapid redistribution of GLP-1R at the plasma membrane following activation ensuring the maintenance of the receptor in a sensitized state. I-M-150847 promotes glucose-stimulated insulin exocytosis in cultured pancreatic beta cells and augments insulin-stimulated gluco...