Combination Of Glucagon-like Peptide-1 Research Articles

The importance of glucose-dependent insulinotropic polypeptide receptor activation for the effects of tirzepatide.

Tirzepatide is a unimolecular co-agonist of the glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors recently approved for the treatment of type 2 diabetes by the US Food and Drug Administration and the European Medicine Agency. Tirzepatide treatment results in an unprecedented improvement of glycaemic control and lowering of body weight, but the contribution of the GIP receptor-activating component of tirzepatide to these effects is uncertain. In this review, we present the current knowledge about the physiological roles of the incretin hormones GLP-1 and GIP, their receptors, and previous results of co-targeting the two incretin hormone receptors in humans. We also analyse the molecular pharmacological, preclinical and clinical effects of tirzepatide to discuss the role of GIP receptor activation for the clinical effects of tirzepatide. Based on the available literature on the combination of GLP-1 and GIP receptor activation, tirzepatide does not seem to have a classical co-activating mode of action in humans. Rather, in vitro studies of the human GLP-1 and GIP receptors reveal a biased GLP-1 receptor activation profile and GIP receptor downregulation. Therefore, we propose three hypotheses for the mode of action of tirzepatide, which can be addressed in future, elaborate clinical trials.

Efficacy and Safety of Tirzepatide in Type 2 Diabetes and Obesity Management.

The combination of glucagon-like peptide-1 (GLP-1) with other gut hormones including the glucose-dependent insulinotropic polypeptide (GIP) has been explored to complement and enhance further the GLP-1 effects on glycemia and weight loss. Tirzepatide is the first dual GLP-1/GIP receptor co-agonist which has been approved for treatment of type 2 diabetes mellitus (T2DM) based on the findings from the SURPASS program. The SURPASS trials assessed the safety and efficacy of tirzepatide in people with T2DM, from monotherapy through to insulin add-on in global populations, with another two trials dedicated to Japanese population. Over periods of treatment up to 104 weeks, once weekly tirzepatide 5 to 15 mg reduced glycosylated hemoglobin (1.87% to 3.02%), body weight (5.4 to 12.9 kg) and improved multiple cardiometabolic risk factors (including reduction in liver fat, new-onset macroalbuminuria, blood pressure, and lipids) across the T2DM spectrum. Tirzepatide provided better efficacy than placebo and other commonly used glucose-lowering medications such as semaglutide 1 mg, dulaglutide, insulin degludec, and glargine. All tirzepatide doses were well tolerated with similar side-effect profile to the GLP-1 receptor analogues. In people without diabetes, tirzepatide 5 to 15 mg once weekly for the treatment for obesity (SURMOUNT-1) resulted in substantial reductions in body weight (16.5% to 22.4%) over 72 weeks. Overall, the SURPASS program and SURMOUNT-1 study suggest that tirzepatide is marking a new era in T2DM and/or obesity management through dual agonism of gut hormones.

The Cardiovascular Effect of Tirzepatide: A Glucagon-Like Peptide-1 and Glucose-Dependent Insulinotropic Polypeptide Dual Agonist.

Glucagon-like peptide-1 (GLP-1) receptor agonists have been used extensively in the clinic and have an established safety profile in cardiovascular disease settings. For the treatment of peptide-secreting enteroendocrine cells, most research has focused on developing peptide multi-agonists as most of these cells are multihormonal. Among the various peptides secreted by enteroendocrine cells, the combination of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) is an attractive strategy for treating type 2 diabetes mellitus (T2DM) because both of these hormones have glucose-lowering actions. Tirzepatide, a synthetic peptide composed of 39 amino acids, functions as a dual receptor agonist of both the GIP and GLP-1 receptors. This unique mechanism of action has earned tirzepatide the nickname "twincretin." Tirzepatide's dual agonist activity may be the mechanism by which tirzepatide significantly reduces glycated hemoglobin levels and body weight in patients with T2DM as observed in phase 3 clinical trials. Besides its glucose-lowering and anti-obesity effects, tirzepatide has been reported to have potential cardiovascular benefits. In this review, we discuss the cardiovascular effects of tirzepatide based on the available preclinical and clinical data.

Dapiglutide, a novel dual GLP-1 and GLP-2 receptor agonist, attenuates intestinal insufficiency in a murine model of short bowel.

Extensive intestinal resection may lead to short bowel (SB) syndrome, resulting in intestinal insufficiency or intestinal failure (IF). Intestinal insufficiency and IF involve deficiency of the proglucagon-derived hormones glucagon-like peptide-1 (GLP-1) and GLP-2. Two major problems of SB are epithelial surface loss and accelerated transit. Standard treatment now targets intestinal adaptation with a GLP-2 analogue to enlarge absorptive surface area. It is possible that additional benefit can be gained from a combination of GLP-1 and GLP-2 activity, with the aim to enlarge intestinal surface area and slow intestinal transit. The GLP-1- and GLP-2-specific effects of the novel dual GLP-1 receptor (GLP-1R) and GLP-2 receptor (GLP-2R) agonist dapiglutide (rINN) were characterized in rodents. Furthermore, in a murine SB model of intestinal insufficiency with 40% ileocecal resection, the influence of dapiglutide on intestinal growth, body weight, food intake, volume status, and stool water content was tested against vehicle and sham-operated male mice. Dapiglutide significantly improves oral glucose tolerance, reduces intestinal transit time, and promotes intestinal growth. In the SB mouse model, dapiglutide promotes body weight recovery, despite unchanged intake of liquid diet. Dapiglutide promotes significant intestinal growth, as indicated by significantly increased villus height as well as intestinal length. Furthermore, dapiglutide reduces stool water losses, resulting in reduced plasma aldosterone. Dapiglutide possesses specific and potent GLP-1R and GLP-2R agonist effects in rodents. In the murine SB model, combined unimolecular GLP-1R and GLP-2R stimulation with dapiglutide potently attenuates intestinal insufficiency and potentially also IF.

Combination Therapies for Obesity

The objective of this review is to examine advances in the development of combination therapies for the treatment of obesity beyond diet or lifestyle interventions. Experimental combination pharmacotherapies include combinations of pramlintide and phentermine as well as amylin and bupropion-naltrexone. Incretin and pancreatic hormones generally inhibit upper gastrointestinal motor functions, and combinations showing efficacy in obesity are coadministration of glucagon-like peptide-1 (GLP-1) with glucagon, a unimolecular dual incretin of PEGylated GLP-1/GIP coagonist, the combination of GLP-1 and PYY3-36, and, in proof of concept studies, combined infusions of GLP-1, peptide YY, and oxyntomodulin. Among bariatric procedures, repeat intragastric balloon (IGB) treatments are more efficacious than IGB plus diet, and endoscopic intervention can enhance the effects of Roux-en-Y gastric bypass when weight regain occurs. A first trial has provided promising results with combination of IGB plus the GLP-1 analog, liraglutide, compared to the balloon alone. Thus, combination therapies for the treatment of obesity hold promise for introduction into clinical practice.

Novel GLP-1/GLP-2 co-agonists display marked effects on gut volume and improves glycemic control in mice.

Analogues of several gastrointestinal peptide hormones have been developed into effective medicines for treatment of diseases such as type 2 diabetes mellitus (T2DM), obesity and short bowel syndrome (SBS). In this study, we aimed to explore whether the combination of glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) into a potent co-agonist could provide additional benefits compared to existing monotherapies. A short-acting (GUB09-123) and a half-life extended (GUB09-145) GLP-1/GLP-2 co-agonist were generated using solid-phase peptide synthesis and tested for effects on food intake, body weight, glucose homeostasis, and gut proliferation in lean mice and in diabetic db/db mice. Sub-chronic administration of GUB09-123 to lean mice significantly reduced food intake, improved glucose tolerance, and increased gut volume, superior to monotherapy with the GLP-2 analogue teduglutide. Chronic administration of GUB09-123 to diabetic mice significantly improved glycemic control and showed persistent effects on gastric emptying, superior to monotherapy with the GLP-1 analogue liraglutide. Due to the short-acting nature of the molecule, no effects on body weight were observed, whereas a marked and robust intestinotrophic effect on mainly the small intestine volume and surface area was obtained. In contrast to GUB09-123, sub-chronic administration of a half-life extended GUB09-145 to lean mice caused marked dose-dependent effects on body weight while maintaining its potent intestinotrophic effect. Our data demonstrate that the GLP-1/GLP-2 co-agonists have effects on gut morphometry, showing a marked increase in intestinal volume and mucosal surface area. Furthermore, effects on glucose tolerance and long-term glycemic control are evident. Effects on body weight and gastric emptying are also observed depending on the pharmacokinetic properties of the molecule. We suggest that this novel co-agonistic approach could exemplify a novel concept for treatment of T2DM or SBS.

A novel GLP-1/GIP dual agonist is more effective than liraglutide in reducing inflammation and enhancing GDNF release in the MPTP mouse model of Parkinson's disease

Type 2 diabetes mellitus (T2DM) is one of the risk factors for Parkinson's disease (PD). Insulin desensitisation has been observed in the brains of patients, which may promote neurodegeneration. Incretins are a family of growth factors that can re-sensitise insulin signalling. We have previously shown that mimetics of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropypridine (MPTP) mouse model of PD. Recently, dual GLP-1/GIP receptor agonists have been developed. We therefore tested the novel dual agonist DA3-CH in comparison with the best GLP-1 analogue currently on the market, liraglutide (both drugs 25nmol/kg ip once-daily for 7 days) in the MPTP mouse model of PD (25mg/kg ip once-daily for 7 days). In the Rotarod and grip strength assessment, DA3-CH was superior to liraglutide in reversing the MPTP–induced motor impairment. Dopamine synthesis as indicated by levels of tyrosine hydroxylase was much reduced by MPTP in the substantia nigra and striatum, and DA3-CH reversed this while liragutide only partially reversed this. The chronic inflammation response as shown in increased levels of activated microglia and astrocytes was reduced by both drugs. Importantly, expression levels of the neuroprotective growth factor Glial Derived Neurotrophic Factor (GDNF) was much enhanced by both DA3-CH and liragutide. The results demonstrate that the combination of GLP-1 and GIP receptor activation is superior to single GLP-1 receptor activation alone. Therefore, new dual agonists may be a promising treatment for PD. The GLP-1 receptor agonist exendin-4 has already shown disease modifying effects in clinical trials in PD patients.

Combination therapy with GLP-1 analogues and SGLT-2 inhibitors in the management of diabesity: the real world experience

Diabesity-obesity resulting in diabetes-is a major health problem globally because of the obesity epidemic. Several anti-diabetic medications cause weight gain and may worsen obesity, and possibly diabeisty. Two recent small retrospective cohort studies showed weight loss and diabetes improvement with combination of glucagon-like peptide-1 (GLP-1) agonists and sodium-glucose co-transporter type-2 (SGLT-2) inhibitors in obese subjects. We assessed the effect of combination therapy with GLP-1 agonists and SGLT-2 inhibitors in the management of diabesity in a retrospective study at the Wolverhampton Diabetes Centre. Out of 79 patients on this combination regimen with other anti-diabetic medications, 37 cases who had follow up at 3-6 months were studied. Mean age and duration of follow up were 57.4 (+/-7.8) and 139 (+/-32.6) days, respectively. Twenty-two patients (59.5 %) were Asians. Statistically significant improvements in clinical parameters such as body weight reduction (3.07 kg), glycated haemoglobin (HbA1c) reduction (1.05 %), lower BMI (-1.13 kg/M2) and insulin dose reduction (6.8 units) were observed (p < 0.05 for all) in patients on combination regimen. Linear regression analysis showed that baseline HbA1c and baseline insulin dose were independent predictors of HbA1c reduction and insulin dose reduction, respectively. Our results suggest that combination therapy with GLP-1 agonists and SGLT-2 inhibitors is a promising option for patients with diabesity.

Glucagon and GLP-1 exhibit no synergistic enhancement of glucose-stimulated insulin secretion in mice

The combination of glucagon and glucagon-like peptide-1 (GLP-1) has been suggested as an approach to target obesity, since the two hormones have complementary action on body weight. We examined whether complementary action of the two hormones also exist on insulin secretion. Female C57BL/6 mice were injected intravenously with glucose with or without GLP-1, glucagon or the combination of GLP-1 and glucagon at three different dose levels. Furthermore, freshly isolated mouse islets were incubated for 30min in the presence of 2.8, 11.1 or 16.7mmol/l glucose or with 11.1mmol/l glucose in the presence of 100nmol/l glucagon and/or GLP-1. It was found that at 1min after glucose injection alone, insulin rose to a peak level and this peak, as well as the 50min area under the insulin curve (AUC insulin) were dose-dependently augmented by GLP-1 and glucagon. However, peak insulin with the two hormones together (with glucose) was not higher than after either single administration at any of the tested doses, i.e., no additive of synergistic action was observed by the combination on glucose-stimulated insulin secretion. Similar results were observed when calculating insulin for the whole test period. Also in vitro, both glucagon and GLP-1 augmented insulin secretion; however, there was no difference between the combined stimulation of insulin secretion by GLP-1 and glucagon together compared with either hormone alone. Insulin sensitivity did not exhibit significant changes from the glucose only condition.We conclude that the acute combined administration of the strongly insulinotropic GLP-1 and glucagon, both in vivo and in vitro, did not induce any additive or synergistic action on glucose-stimulated insulin secretion. This shows that the risk of a marked insulinotropic action when the two compounds are given together most likely does not result in increased risk of hypoglycemia.

GLP-1 receptor agonists and basal insulin in type 2 diabetes

Drug development is a slow process, and understanding how best to deploy new treatments even slower. In The Lancet, Conrad Eng and colleagues1 report the findings from their systematic review and meta-analysis of evidence about the combination of glucagon-like peptide-1 (GLP-1) receptor agonists and basal insulin in type 2 diabetes.

The Future of Combination Therapies of Insulin with a Glucagon-like Peptide-1 Receptor Agonists in Type 2 Diabetes – Is it Advantageous?

Safe and effective therapies for type 2 diabetes are needed to reduce the burden of late complications and costs associated with this chronic disease. Hypoglycaemia and body weight gain are side effects and limitations of the therapy with insulin and/or sulphonylureas. Recently, the combination of glucagon-like peptide-1 (GLP-1) receptor agonists and insulin has become available, which is associated with good efficacy and less risk for hypoglycaemia and weight gain. This editorial discusses the strategies to escalate treatment in type 2 diabetes in view of this novel combination and discusses its placement within the therapeutic algorithm of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Recent developments to simplify this combination therapy are also dealt with.

The effect of glucagon-like peptide-1 on the secretion of cholecystokinin and gastrin in patients with type-1 diabetes and healthy subjects

Objective: Ingestion of a meal is known to trigger a rise in plasma concentrations of glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK) and gastrin. These hormones are known to have important roles in the regulation of gastrointestinal motility and secretion, appetite and food intake. There is limited information relating to any possible interaction between these three hormones. However, it has been suggested that the combination of GLP-1, CCK and gastrin provides beneficial effects in the treatment of diabetes.

CCk8 Enhances Anti‐diabetic Efficacy of GLP1

The objective of the study is to investigate potential synergistic or additive effects of combining GLP1 with CCK8 in diet induced obese (DIO) mice. Glucagon‐like peptide‐1 (GLP1) is a peptide hormone secreted by the intestinal L cells in response to food ingestion. It augments glucose‐mediated insulin secretion, inhibits glucagon secretion, reduces appetite and food intake, and delays gastric emptying. Another gastrointestinal peptide released upon food ingestion is cholecystokinin (CCK). CCK is secreted from the duodenal I cells in response to fat and protein. CCK can stimulate pancreatic enzyme secretion, increase gall bladder contractions and delay gastric emptying. CCK also triggers a gut‐brain‐liver neuronal network to control glucose production. The major form of biologically active CCK is CCK‐8. When DIO mice were infused with low doses of a GLP1 analog or a CCK8 analog for two weeks, no effects on food intake or body weight were observed. However, the group received both peptides (GLP1+CCK8) showed significant reductions in food intake and body weight. At the completion of two‐week treatments, both GLP1‐ and CCK8‐treated groups decreased glucose excursion in response to an oral glucose challenge. The GLP1+CCK8 group demonstrated additive effects on glucose lowering. In conclusion, combination of GLP1 with CCK8 has the potential to be a more efficacious therapy for type II diabetes.

Reversible immortalization of Nestin-positive precursor cells from pancreas and differentiation into insulin-secreting cells

Pancreatic stem cells or progenitor cells posses the ability of directed differentiation into pancreatic β cells. However, these cells usually have limited proliferative capacity and finite lifespan in vitro. In the present study, Nestin-positive progenitor cells (NPPCs) from mouse pancreas that expressed the pancreatic stem cells or progenitor cell marker Nestin were isolated to obtain a sufficient number of differentiated pancreatic β cells. Tet-on system for SV40 large T-antigen expression in NPPCs was used to achieve reversible immortalization. The reversible immortal Nestin-positive progenitor cells (RINPPCs) can undergo at least 80 population doublings without senescence in vitro while maintaining their biological and genetic characteristics. RINPPCs can be efficiently induced to differentiate into insulin-producing cells that contain a combination of glucagon-like peptide-1 (GLP-1) and sodium butyrate. The results of the present study can be used to explore transplantation therapy of type I diabetes mellitus.

Stromal cell-derived factor-1 (SDF-1)/chemokine (C-X-C motif) receptor 4 (CXCR4) axis activation induces intra-islet glucagon-like peptide-1 (GLP-1) production and enhances beta cell survival

The endogenous production of stromal cell-derived factor-1 (SDF-1) in beta cells in transgenic mice attenuates the development of diabetes in response to streptozotocin. Here we propose that beta cell injury induces SDF-1 production, and the SDF-1/chemokine (C-X-C motif) receptor 4 (CXCR4) interaction auto-activates Sdf1 expression, resulting in the autocrine production of SDF-1 by beta cells and the paracrine activation of glucagon-like peptide-1 (GLP-1) production by alpha cells. SDF-1 production in adult mouse and human islets and rat INS-1 cells was measured in models of beta cell injury. The paracrine actions of SDF-1 on GLP-1 production in alpha cells were explored. The potential synergism between the growth-promoting actions of GLP-1 and the pro-survival actions of SDF-1 on the preservation of cell mass was evaluated by cell viability assays. In adult islets and INS-1 cells, Sdf1 expression was re-induced in response to injury. The interaction of SDF-1 with its receptor on alphaTC1 cells activated protein kinase Akt, stimulated cell proliferation and induced the expression of prohormone convertase 1/3 and the consequent production of GLP-1 in alpha cells. The combination of GLP-1 and SDF-1 additively enhanced both the growth and longevity of INS-1 beta cells. The results of these studies suggest that in response to beta cell injury and the ensuing induction of SDF-1, the biological function of alpha cells switches from the production of glucagon to the provision of the local growth factor GLP-1 which, in combination with SDF-1, promotes the growth, survival and viability of the beta cells.

Dreams for Type 1 Diabetes: Shutting Off Autoimmunity and Stimulating β-Cell Regeneration

Although not the first study to show that inhibitors of dipeptidyl peptidase IV (DPP-IV) can reverse newly diagnosed diabetes in nonobese diabetic (NOD) mice (1), a study by Tian et al. (2) in this issue of Endocrinology confirms this finding with a different DPP-IV inhibitor (NVP-DPP728) and provides explanations for the reversal by finding reduced islet inflammation, increases in CD4 CD25 FoxP3 regulatory T cells, and -cell regeneration. Impressively, 6 wk of treatment with this agent reversed diabetes in 73% of the mice. DPP-IV inhibitors are usedclinically to treatdiabetesbecause they slow the breakdown of the incretin hormone glucagon-like peptide 1 (GLP-1), which can stimulate insulin secretion, inhibit -cell apoptosis, and promote -cell replication (3). However, these inhibitors have long been known to have effects on the immune system, which presumably contributed to the marked reduction in islet inflammation. In particular, lymphocytes have a membrane-associated protein with DPP-IV activity, CD26, which has been shown to have important effects upon T-cell development, migration, and cytokine production (4). It has been previously shown that inhibition of DPP-IV can slow the progression of experimental allergic encephalitis and increase the production of TGF, which is known to suppress autoimmunity (5). In the present study, the reversal of diabetes was accompanied by a reduction of insulitis, an increase in CD4 CD25 FoxP3 regulatory T cells, and an increase in circulating TGF. Interestingly, the regulatory T cells were particularly plentiful in the thymus and pancreatic lymph nodes. It is possible that the therapeutic benefit of the present study is not completely due to the effects of DPP-IV inhibition on the immune system but in part a result of increased circulating levels of GLP-1. Inhibition of CD26 is an attractive mechanism, but the actual contribution from this specific mechanism remains to be defined. It is even possible that GLP-1 can somehow ameliorate immune killing of -cells independently of DPP-IV. We certainly have much more to learn about the effects of GLP-1 on the immune system (3). It is noteworthy that the combination of GLP-1 and gastrin has been shown to reverse diabetes in NOD mice, and this reversal was even seen in some mice with just GLP-1 treatment alone (6). The effect of GLP-1 on the target of the immune attack, the -cell, may be very important. GLP-1 is known to have an antiapoptotic effect upon -cells, probably by bolstering the insulin receptor substrate 2 signaling pathway (7, 8). Therefore, it is possible that a reduction of -cell death and less release of antigen could somehow influence the balance of T-cell regulation and slow the rate of immune destruction. Clearly, more work is needed to sort out the relative contributions of DPP-IV inhibition and GLP-1 agonism. Another addition to the equation is gastrin, the circulating levels of which can be increased with either injections of the peptide or the use of proton pump inhibitors. We know that gastrin given in combination with either epidermal growth factor or GLP-1 agonism can stimulate -cell regeneration (6, 9). Now we must ask how gastrin might contribute to reduced autoimmune destruction. The demonstration of -cell regeneration, accompanied by increased -cell replication, is similar to what has been found with some other but not all interventions that reverse diabetes in NOD mice. It seems likely that increases in -cell mass result from replication of residual -cells, although there is a provocative recent report sug-

Combination of GLP-1 and sodium butyrate promote differentiation of pancreatic progenitor cells into insulin-producing cells

We identified that nestin-EGFP-positive cells isolated by fluorescent-activated cell sorting (FACS) were downstream progenitor cells from colony-initiating pancreatic precursor cells. Under differentiation condition, these nestin-EGFP-positive cells could generate islet and neural cells. To investigate the conditions that allowed nestin-EGFP-positive progenitor cells (NPPCs) to efficaciously differentiate into insulin-producing cells in vitro, protocols were designed with glucagon-like peptide-1 (GLP-1) and the histone deacetylase inhibitor, sodium butyrate. We demonstrated that the combination of GLP-1 and sodium butyrate resulted in the increasing of levels of transcripts encoding pancreatic developmental factors and insulin. As a consequence, the amount of insulin-producing cells and insulin secretion were enhanced. These results indicated that NPPCs which were cultured in the presence of GLP-1 and sodium butyrate could specially differentiate into insulin-producing cells.

GLP-1 and GLP-2 act in concert to inhibit fasted, but not fed, small bowel motility in the rat.

Small bowel motility was studied in rats at increasing (1-20 pmol/kg/min) intravenous doses of either glucagon-like peptide-1 (GLP-1) or glucagon-like peptide-2 (GLP-2) alone, or in combination in the fasted and fed state. There was a dose-dependent inhibitory action of GLP-1 on the migrating myoelectric complex (MMC), where the dose of 5 pmol/kg/min induced an increased MMC cycle length. No effect was seen with GLP-2 alone, but the combination of GLP-1 and GLP-2 induced a more pronounced inhibitory effect, with significant increase of the MMC cycle length from a dose of 2 pmol/kg/min. During fed motility, infusion of GLP-1 resulted in an inhibition of spiking activity compared to control. In contrast, infusion of GLP-2 only numerically increased spiking activity compared to control, while the combination of GLP-1 and GLP-2 resulted in no change compared to control. In summary, this study demonstrates an additive effect of peripheral administration of GLP-1 and GLP-2 on fasted small bowel motility. In the fed state, GLP-1 and GLP-2 seem to display counter-balancing effects on motility of the small intestine.