Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial.

Importance: The effect of continued treatment with tirzepatide on maintaining initial weight reduction is unknown. Objective: To assess the effect of tirzepatide, with diet and physical activity, on the maintenance of weight reduction. Design, Setting, and Participants: This phase 3, randomized withdrawal clinical trial conducted at 70 sites in 4 countries with a 36-week, open-label tirzepatide lead-in period followed by a 52-week, double-blind, placebo-controlled period included adults with a body mass index greater than or equal to 30 or greater than or equal to 27 and a weight-related complication, excluding diabetes. Interventions: Participants (n = 783) enrolled in an open-label lead-in period received once-weekly subcutaneous maximum tolerated dose (10 or 15 mg) of tirzepatide for 36 weeks. At week 36, a total of 670 participants were randomized (1:1) to continue receiving tirzepatide (n = 335) or switch to placebo (n = 335) for 52 weeks. Main Outcomes and Measures: The primary end point was the mean percent change in weight from week 36 (randomization) to week 88. Key secondary end points included the proportion of participants at week 88 who maintained at least 80% of the weight loss during the lead-in period. Results: Participants (n = 670; mean age, 48 years; 473 [71%] women; mean weight, 107.3 kg) who completed the 36-week lead-in period experienced a mean weight reduction of 20.9%. The mean percent weight change from week 36 to week 88 was -5.5% with tirzepatide vs 14.0% with placebo (difference, -19.4% [95% CI, -21.2% to -17.7%]; P < .001). Overall, 300 participants (89.5%) receiving tirzepatide at 88 weeks maintained at least 80% of the weight loss during the lead-in period compared with 16.6% receiving placebo (P < .001). The overall mean weight reduction from week 0 to 88 was 25.3% for tirzepatide and 9.9% for placebo. The most common adverse events were mostly mild to moderate gastrointestinal events, which occurred more commonly with tirzepatide vs placebo. Conclusions and Relevance: In participants with obesity or overweight, withdrawing tirzepatide led to substantial regain of lost weight, whereas continued treatment maintained and augmented initial weight reduction. Trial Registration: ClinicalTrials.gov Identifier: NCT04660643.

Insulin clearance and incretin hormones following oral and "isoglycemic" intravenous glucose in type 2 diabetes patients under different antidiabetic treatments.

It has not been elucidated whether incretins affect insulin clearance in type 2 diabetes (T2D). We aimed exploring possible associations between insulin clearance and endogenously secreted or exogenously administered incretins in T2D patients. Twenty T2D patients were studied (16 males/4 females, 59 ± 2 years (mean ± standard error), BMI = 31 ± 1 kg/m2, HbA1c = 7.0 ± 0.1%). Patients were treated with metformin, sitagliptin, metformin/sitagliptin combination, and placebo (randomized order). On each treatment period, oral and isoglycemic intravenous glucose infusion tests were performed (OGTT, IIGI, respectively). We also studied twelve T2D patients (9 males/3 females, 61 ± 3 years, BMI = 30 ± 1 kg/m2, HbA1c = 7.3 ± 0.4%) that underwent infusion of GLP-1(7-36)-amide, GIP, GLP-1/GIP combination, and placebo. Plasma glucose, insulin, C-peptide, and incretins were measured. Insulin clearance was assessed as insulin secretion to insulin concentration ratio. In the first study, we found OGTT/IIGI insulin clearance ratio weakly inversely related to OGTT/IIGI total GIP and intact GLP-1 (R2 = 0.13, p < 0.02). However, insulin clearance showed some differences between sitagliptin and metformin treatment (p < 0.02). In the second study we found no difference in insulin clearance following GLP-1 and/or GIP infusion (p > 0.5). Thus, our data suggest that in T2D there are no relevant incretin effects on insulin clearance. Conversely, different antidiabetic treatments may determine insulin clearance variations.

Cardiovascular Effects of Incretin-Based Therapies: Integrating Mechanisms With Cardiovascular Outcome Trials.

As the worldwide prevalence of diabetes and obesity continues to rise, so does the risk of debilitating cardiovascular complications. Given the significant association between diabetes and cardiovascular risk, the actions of glucose-lowering therapies within the cardiovascular system must be clearly defined. Incretin hormones, including GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic polypeptide), are gut hormones secreted in response to nutrient intake that maintain glycemic control by regulating insulin and glucagon release. GLP-1 receptor agonists (GLP-1Ras) and dipeptidyl peptidase 4 inhibitors (DPP-4is) represent two drug classes used for the treatment of type 2 diabetes mellitus (T2DM) that improve glucose regulation through stimulating the actions of gut-derived incretin hormones or inhibiting their degradation, respectively. Despite both classes acting to potentiate the incretin response, the potential cardioprotective benefits afforded by GLP-1Ras have not been recapitulated in cardiovascular outcome trials (CVOTs) evaluating DPP-4is. This review provides insights through discussion of clinical and preclinical studies to illuminate the physiological mechanisms that may underlie and reconcile observations from GLP-1Ra and DPP-4i CVOTs. Furthermore, critical knowledge gaps and areas for further investigation will be emphasized to guide future studies and, ultimately, facilitate improved clinical management of cardiovascular disease in T2DM.

Oral GLP-1 analogue: perspectives and impact on atherosclerosis in type 2 diabetic patients.

Cardiovascular events related to atherosclerosis are responsible for high morbidity and mortality among patients with type 2 diabetes. Improvement in care, especially in early stages, is crucial. Oral semaglutide, a glucagon-like peptide 1 analogue, controls blood glucose and results in significant body weight loss in patients with type 2 diabetes. Beyond these well-known effects, an interesting aspect of this drug is its antiatherogenic activity, which should be further explored in clinical practice. This paper reviews the evidence related to oral semaglutide decreasing cardiovascular risk in patients with type 2 diabetes, focusing on the drug's antiatherosclerotic properties. The glucagon-like peptide 1 analogue restores endothelial dysfunction, induces vasodilatation, and reduces plasma lipids. Oral semaglutide showed cardiovascular safety profile, with significant reduced risk of death from cardiovascular events. Based on current data, clinicians should consider oral semaglutide for type 2 diabetes management.

Efficacy and safety of once-weekly dulaglutide in adult Chinese patients with type 2 diabetes and lower baseline body mass index.

Highlights In Chinese patients with type 2 diabetes (T2D) and body mass index (BMI) <25 kg/m2 , dulaglutide demonstrated great improvements in glycemic control with mild body weight reduction and low hypoglycemia risk. The results indicate that dulaglutide is effective and safe in patients with T2D and lower BMI; therefore, BMI should not be a consideration when dulaglutide is prescribed to Chinese patients with T2D.

Glucagon-like peptide-1 analog improves neuronal and behavioral impairment and promotes neuroprotection in a rat model of aluminum-induced dementia.

BACKGROUND: Alzheimer's disease (AD) is a worldwide severe medical and social burden. Liraglutide (LIR) has neuroprotective effects in preclinical animal models. AIM: To explore the probable neuroprotective impact of Glucagon-like peptide-1 (GLP-1) on rats' behavior and to elucidate its underlying mechanisms. METHODS: A total of 24 male albino rats were assigned to control, LIR (300 µg/kg subcutaneously (s.c.)), AD only (100 mg/kg aluminum chloride (AlCl3 ) orally) and LIR + AD treated groups. Eight radial arm maze was performed. Serum blood glucose, proinflammatory cytokines, oxidative stress markers were measured and hippocampal tissue homogenate neurotransmitters were evaluated. Histopathological and immunofluorescent examinations were performed. RESULTS: LIR prevents the impairment of learning and improves both working memory and reference memory through significant reduction of serum tumor necrosis factor (TNF-α), interleukin 6 (IL-6) and interferon-γ (INF-γ) and malondialdehyde (MDA) and through the increase of superoxide dismutase (SOD), dopamine, adrenaline, and noradrenaline. LIR also improves hippocampal histological features of ALCL3 administrated rats and decreases the percentage of neuronal loss. CONCLUSION: LIR normalizes ALCL3 -induced dementia. It improves cognitive dysfunction and ameliorates cerebral damage.

Display of quintuple glucagon-like peptide 1 (28-36) nonapeptide on Bacillus subtilis spore for oral administration in the treatment of type 2 diabetes.

AIMS: To develop an oral delivery system of glucagon-like peptide 1 (GLP-1) (28-36) for treating type-2 diabetes, B.S-GLP-1(28-36), a recombinant Bacillus subtilis spores transformed with a plasmid vector encoding five consecutive GLP-1 (28-36) nonapeptides with an enterokinase site was constructed. METHODS AND RESULTS: GLP-1(28-36) nonapeptide was successfully expressed on the surface of B. subtilis spores and validated by Western blot and immunofluorescence. The therapeutic effect of oral administration of B.S-GLP-1(28-36) spores was evaluated in type 2 diabetic model mice. The efficacy of recombinant spores was examined for a period of 13 weeks after oral administration in diabetic mice. At the end of the sixth week, diabetic mice with oral administration of BS-GLP-1(28-36) spores showed decreased blood glucose levels from 2·4 × 10- 2  mol l-1 to 1·7 × 10- 2  mol l-1 . By the ninth week, the mean fasting blood glucose level in the experimental group was significantly lower than that in the control group 30 min after injection of pyruvate. At the end of the 10th week of oral administration, the blood glucose of the experimental group was significantly lower than that of the control group after intraperitoneal injection of glucose. By the 12th week, fasting blood glucose level and fasting insulin level were measured in all mice, the results showed that the recombinant spores increased the insulin sensitivity of mice. CONCLUSIONS: The results of pathological observation showed that the recombinant spores also had a certain protective effect on the liver and islets of mice, and the content of GLP-1(28-36) in the pancreas of the experimental group was increased. SIGNIFICANCE AND IMPACT OF THE STUDY: The results of this study revealed that GLP-1(28-36) nonapeptides can reduce blood glucose and play an important role in the treatment of type 2 diabetes.

Different mechanisms of GIP and GLP-1 action explain their different therapeutic efficacy in type 2 diabetes.

BACKGROUND AND AIMS: The reduced action of incretin hormones in type 2 diabetes (T2D) is mainly attributed to GIP insensitivity, but efficacy estimates of GIP and GLP-1 differ among studies, and the negligible effects of pharmacological GIP doses remain unexplained. We aimed to characterize incretin action in vivo in subjects with normal glucose tolerance (NGT) or T2D and provide an explanation for the different insulinotropic activity of GIP and GLP-1 in T2D subjects. METHODS: We used in vivo data from ten studies employing hormone infusion or an oral glucose test (OGTT). To homogeneously interpret and compare the results of the studies we performed the analysis using a mathematical model of the ß-cell incorporating the effects of incretins on the triggering and amplifying pathways. The effect on the amplifying pathway was quantified by a time-dependent factor that is greater than one when insulin secretion (ISR) is amplified by incretins. To validate the model results for GIP in NGT subjects, we performed an extensive literature search of the available data. RESULTS: a) the stimulatory effects of GIP and GLP-1 differ markedly: ISR potentiation increases linearly with GLP-1 over the whole dose range, while with GIP infusion it reaches a plateau at ~100 pmol/L GIP, with ISR potentiation of ~2 fold; b) ISR potentiation in T2D is reduced by ~50% for GIP and by ~40% for GLP-1; c) the literature search of GIP in NGT subjects confirmed the saturative effect on insulin secretion. CONCLUSION: We show that incretin potentiation of ISR is reduced in T2D, but not abolished, and that the lack of effects of pharmacological GIP doses is due to saturation of the GIP effect more than insensitivity to GIP in T2D.

Anticipatory guidance and systematic review of prescribing combination incretin therapy in the treatment of type 2 diabetes.

WHAT IS KNOWN AND OBJECTIVE: Few studies have evaluated the efficacy and safety of combining a glucagon-like peptide-1 receptor agonist and dipeptidyl peptidase-4 inhibitor in patients with type 2 diabetes mellitus. Clinicians may frequently encounter this drug therapy combination in practice and should be aware of clinical evidence and risks associated with its use. METHODS: A literature search was conducted in Embase (1947-April 20, 2020), Medline - Ovid (1946-April 21, 2020), Medline - PubMed (1946-April 21, 2020), Cochrane Library CENTRAL Register of Controlled Trials (1991-April 20, 2020) and Web of Science (1900-April 17, 2020). Databases were searched using keywords and subject headings to identify studies assessing efficacy and safety of combination incretin therapy. The search identified 1255 studies. Of these, 383 were excluded for duplicate citations. Articles were then excluded based on title and abstract screen. RESULTS AND DISCUSSION: Six studies were included. A small reduction in haemoglobin A1c and weight loss was found by combining incretin therapy. Adverse effects such as hypoglycaemia, gastrointestinal upset and pancreatitis were infrequent. WHAT IS NEW AND CONCLUSION: On current evidence, the small benefit in glycaemic control that may be realized by using combination incretin therapy is unlikely to be offset by the potential increased risk of pancreatitis or additional cost. Additional long-term prospectively designed studies are needed to better understand the efficacy and safety of combination incretin therapy.

Glucose effectiveness: Lessons from studies on insulin-independent glucose clearance in mice.

Besides insulin-mediated transport of glucose into the cells, an important role is also played by the non-insulin-mediated transport. This latter process is called glucose effectiveness (acronym SG ), which is estimated by modeling of glucose and insulin data after an intravenous glucose administration, and accounts for ≈70% of glucose disposal. This review summarizes studies on SG , mainly in humans and rodents with focus on results achieved in model experiments in mice. In humans, SG is reduced in type 2 diabetes, in obesity, in liver cirrhosis and in some elderly populations. In model experiments in mice, SG is independent from glucose levels, but increases when insulin secretion is stimulated, such as after administration of the incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. SG is reduced in insulin resistance induced by high-fat feeding and by exogenous administration of glucagon. Glucose-dependent (insulin-independent) glucose disposal is therefore important for glucose elimination, and it is also well regulated. It might be of pathophysiological relevance for the development of type 2 diabetes, in particular during insulin resistance, and might also be a target for glucose-reducing therapy. Measuring SG is essentially important when carrying out metabolic studies to understand glucose homeostasis.

GLP-1 Receptor Signaling Differentially Modifies the Outcomes of Sterile vs Viral Pulmonary Inflammation in Male Mice.

A number of disease states, including type 2 diabetes (T2D), are associated with an increased risk of pulmonary infection. Glucagon-like peptide-1 (GLP-1) receptor agonists are used to treat T2D and exert anti-inflammatory actions through a single, well-defined GLP-1 receptor (GLP-1R). Although highly expressed in the lung, little is known about the role of the GLP-1R in the context of pulmonary inflammation. Here we examined the consequences of gain or loss of GLP-1R activity in infectious and noninfectious lung inflammation. We studied wild-type mice treated with a GLP-1R agonist, and Glp1r-/- mice, in the setting of bleomycin-induced noninfectious lung injury and influenza virus infection. Loss of the GLP-1R attenuated the severity of bleomycin-induced lung injury, whereas activation of GLP-1R signaling increased pulmonary inflammation via the sympathetic nervous system. In contrast, GLP-1R agonism reduced the pathogen load in mice with experimental influenza virus infection in association with increased expression of intracellular interferon-inducible GTPases. Notably, the GLP-1 receptor agonist liraglutide improved the survival rate after influenza virus infection. Our results reveal context-dependent roles for the GLP-1 system in the response to lung injury. Notably, the therapeutic response of GLP-1R agonism in the setting of experimental influenza virus infection may have relevance for ongoing studies of GLP-1R agonism in people with T2D susceptible to viral lung injury.

Treating type 2 diabetes in COVID-19 patients: the potential benefits of injective therapies.

The coronavirus disease 2019 (COVID-19) has been declared as pandemic by the World Health Organization and is causing substantial morbidity and mortality all over the world. Type 2 diabetes, hypertension, and cardiovascular disease significantly increase the risk for hospitalization and death in COVID-19 patients. Hypoglycemia and hyperglycemia are both predictors for adverse outcomes in hospitalized patients. An optimized glycemic control should be pursued in patients with diabetes and SARS-CoV-2 infection in order to reduce the risk of severe COVID-19 course. Both insulin and GLP-1RAs have shown optimal glucose-lowering and anti-inflammatory effects in type 2 diabetic patients and may represent a valid therapeutic option to treat asymptomatic and non-critically ill COVID-19 diabetic patients.

Comparison of the effects of twice-daily exenatide and insulin on carotid intima-media thickness in type 2 diabetes mellitus patients: a 52-week randomized, open-label, controlled trial.

BACKGROUND: Exenatide, a glucagon like peptide 1 analog, has been suggested to reduce the cardiovascular disease risk factors, such as body weight, blood pressure and subclinical atherosclerosis in patients with type 2 diabetes mellitus (T2DM). This was the first randomized, open-label, controlled trial to compare the effects of exenatide versus insulin on subclinical atherosclerosis, as assessed by carotid-intima media thickness (CIMT), in patients with T2DM. METHODS: A total of 66 patients with T2DM admitted from March 10, 2015 to June 20, 2017 in the Department of Endocrinology, Beijing Hospital were randomized to receive twice-daily exenatide or aspartate 70/30 insulin for 52 weeks. The primary endpoint was change from baseline in CIMT, and secondary endpoints included changes at week 52 from baseline in body weight, glycemic markers, lipid metabolism markers, blood pressure, C-reactive protein, fibrinogen, 8-hydroxydeoxyguanosine, irisin, and brain natriuretic peptide. RESULTS: Exenatide more significantly reduced the CIMT from baseline compared with insulin after 52 weeks, with a mean difference of - 0.14 mm (95% interval confidence: - 0.25, - 0.02; P = 0.016). Weight and body mass index were both significantly reduced in the exenatide group over 52 weeks. Exenatide reduced total lipoprotein and low-density lipoprotein cholesterol levels more significantly than insulin at weeks 16 and 40. Correlation analyses showed that CIMT was positively correlated with low-density lipoprotein cholesterol. CONCLUSIONS: Twice-daily exenatide could prevent atherosclerosis progression in patients with T2DM over a 52-week treatment period compared with insulin therapy. Trial registration Chinese Clinical Trial Registry ChiCTR-1800015658.

Risk of acute pancreatitis with incretin-based therapy: a systematic review and updated meta-analysis of cardiovascular outcomes trials.

BACKGROUND: The link of acute pancreatitis (AP) with Incretin based therapies (IBTs) in type 2 diabetes has existed since United States Food and Drug Administration alert in 2010. This issue still remains unresolved due to conflicting results among studies. RESEARCH DESIGN AND METHODS: We performed a systematic search of the PubMed, Embase, and Cochrane Library databases until 31 July 2019, and retrieved all cardiovascular outcome trials (CVOTs) of IBTs conducted for ≥12 months that reported the pre-specified and or pre-adjudicated pancreatitis outcomes. Subsequently, we conducted a meta-analysis to study the risk of AP observed with IBT in CVOTs. RESULTS: A meta-analysis of seven CVOTs of GLP-1 receptor agonists (GLP-1RAs) compared with placebo (N = 55,932) found no significant increase in AP (odds ratio [OR], 1.05; 95% confidence interval [CI], 0.77-1.42; p = 0.77). In contrast, meta-analysis of five CVOTs comparing DPP-4 inhibitors with placebo (N = 47,714) and six CVOTs comparing DPP-4 inhibitors with placebo or active comparator (N = 53,747), found a significant increase (OR, 1.81; 95% CI, 1.21-2.70; p = 0.04 and OR, 1.54; 95% CI, 1.08-2.18; p = 0.02, respectively) in AP without any significant heterogeneity. CONCLUSIONS: This meta-analysis revealed a significant association between pancreatitis and DPP-4 inhibitors; however, no such association was observed for GLP-1RAs.

Pharmacological antagonism of the incretin system protects against diet-induced obesity.

OBJECTIVE: Glucose-dependent insulinotropic polypeptide is an intestinally derived hormone that is essential for normal metabolic regulation. Loss of the GIP receptor (GIPR) through genetic elimination or pharmacological antagonism reduces body weight and adiposity in the context of nutrient excess. Interrupting GIPR signaling also enhances the sensitivity of the receptor for the other incretin peptide, glucagon-like peptide 1 (GLP-1). The role of GLP-1 compensation in loss of GIPR signaling to protect against obesity has not been directly tested. METHODS: We blocked the GIPR and GLP-1R with specific antibodies, alone and in combination, in healthy and diet-induced obese (DIO) mice. The primary outcome measure of these interventions was the effect on body weight and composition. RESULTS: Antagonism of either the GIPR or GLP-1R system reduced food intake and weight gain during high-fat feeding and enhanced sensitivity to the alternative incretin signaling system. Combined antagonism of both GIPR and GLP-1R produced additive effects to mitigate DIO. Acute pharmacological studies using GIPR and GLP-1R agonists demonstrated both peptides reduced food intake, which was prevented by co-administration of the respective antagonists. CONCLUSIONS: Disruption of either axis of the incretin system protects against diet-induced obesity in mice. However, combined antagonism of both GIPR and GLP-1R produced additional protection against diet-induced obesity, suggesting additional factors beyond compensation by the complementary incretin axis. While antagonizing the GLP-1 system decreases weight gain, GLP-1R agonists are used clinically to target obesity. Hence, the phenotype arising from loss of function of GLP-1R does not implicate GLP-1 as an obesogenic hormone. By extension, caution is warranted in labeling GIP as an obesogenic hormone based on loss-of-function studies.

Chronic apelin analogue administration is more effective than established incretin therapies for alleviating metabolic dysfunction in diabetic db/db mice.

Stable apelin-13 peptide analogues have shown promising acute antidiabetic effects in mice with diet-induced obesity diabetes. Here the efficacy of (pGlu)apelin-13 amide (apelin amide) and the acylated analogue (pGlu)(Lys8GluPAL)apelin-13 amide (apelin FA), were examined following chronic administration in db/db mice, a genetic model of degenerative diabetes. Groups of 9-week old male db/db mice (n = 8) received twice daily injections (09:00 and 17:00 h; i.p.) or saline vehicle, apelin amide, apelin FA, or the established incretin therapies, exendin-4(1-39) or liraglutide, all at 25 nmol/kg body weight for 21 days. Control C57BL/6J mice were given saline twice daily. No changes in body weight or food intake were observed with either apelin or liraglutide treatments, but exendin-4 showed a reduction in cumulative food intake (p < 0.01) compared with saline-treated db/db mice. Apelin analogues and incretin mimetics induced sustained improvements of glycaemia (p < 0.05 to p < 0.001, from day 9-21), lowered HbA1c at 21 days (p < 0.05) and raised plasma insulin concentrations. The treatments also improved OGTT and ipGTT with enhanced insulin responses compared with saline-treated control db/db mice (p < 0.05 to p < 0.001). Apelin amide was superior to incretin mimetics in lowering plasma triglycerides by 34% (p < 0.05). Apelin analogues unlike both incretin mimetics reduced pancreatic α-cell area (p < 0.05 to p < 0.01) and all peptide treatments enhanced pancreatic insulin content (p < 0.05 to p < 0.01). In conclusion, longer-term administration of apelin-13 analogues, induced similar and in some respects more effective metabolic improvements than incretin mimetics in db/db mice, providing a viable alternative approach for counteracting metabolic dysfunction for mild and more degenerative forms of the disease.

A long-acting, dual-agonist analogue of lamprey GLP-1 shows potent insulinotropic, ß-cell protective, and anorexic activities and improves glucose homeostasis in high fat-fed mice.

Peptidase-resistant analogues of GLP-1 peptides from sea lamprey and paddlefish ([D-Ala2]palmitoyl-lamprey GLP-1 and [D-Ala2]palmitoyl-paddlefish GLP-1) produced significant (P ≤ 0.05) and concentration-dependent increases in insulin release from BRIN-BD11 clonal ß-cells and from isolated mouse islets. Both analogues retained the ability of the native peptides to activate both the GLP-1 receptor (GLP1R) and the glucagon receptor (GCGR). [D-Ala2]palmitoyl-lamprey GLP-1 significantly (P < 0.001) stimulated proliferation of BRIN-BD11 cells and protected against cytokine-induced apoptosis. Administration of the lamprey analogue (25 nmol/kg body weight) to lean mice up to 4 h before a glucose load improved glucose tolerance and increased plasma insulin concentrations. Twice daily administration of the lamprey GLP-1 analogue to high fat-fed mice for 21 days decreased body weight, food intake, and circulating glucose and insulin concentrations. The analogue significantly improved glucose tolerance and insulin sensitivity with beneficial effects on islet ß-cell area and insulin secretory responsiveness. Islet gene expression of Glp1r, Gcgr and Gipr significantly increased. The lamprey GLP-1 analogue shows therapeutic promise for treatment of patients with obesity-related Type 2 diabetes.

Novel strategy for oral peptide delivery in incretin-based diabetes treatment.

OBJECTIVE: To fulfil an unmet therapeutic need for treating type 2 diabetes by developing an innovative oral drug delivery nanosystem increasing the production of glucagon-like peptide-1 (GLP-1) and the absorption of peptides into the circulation. DESIGN: We developed a nanocarrier for the oral delivery of peptides using lipid-based nanocapsules. We encapsulated the GLP-1 analogue exenatide within nanocapsules and investigated in vitro in human L-cells (NCl-H716) and murine L-cells (GLUTag cells) the ability of the nanosystem to trigger GLP-1 secretion. The therapeutic relevance of the nanosystem in vivo was tested in high-fat diet (HFD)-induced diabetic mice following acute (one administration) or chronic treatment (5 weeks) in obese and diabetic mice. RESULTS: We demonstrated that this innovative nanosystem triggers GLP-1 secretion in both human and murine cells as well as in vivo in mice. This strategy increases the endogenous secretion of GLP-1 and the oral bioavailability of the GLP-1 analogue exenatide (4% bioavailability with our nanosystem).The nanosystem synergizes its own biological effect with the encapsulated GLP-1 analogue leading to a marked improvement of glucose tolerance and insulin resistance (acute and chronic). The chronic treatment decreased diet-induced obesity, fat mass, hepatic steatosis, together with lower infiltration and recruitment of immune cell populations and inflammation. CONCLUSION: We developed a novel nanosystem compatible with human use that synergizes its own biological effect with the effects of increasing the bioavailability of a GLP-1 analogue. The effects of the formulation were comparable to the results observed for the marketed subcutaneous formulation. This nanocarrier-based strategy represents a novel promising approach for oral peptide delivery in incretin-based diabetes treatment.

Conservation of glucagon like peptide-1 level with liraglutide and linagilptin protects the kidney against angiotensin II-induced tissue fibrosis in rats.

This study tested the hypothesis that the enhancement of glucagon-like peptide-1 (GLP-1) level through either exogenous supply of GLP-1 agonist, liraglutide or prevention of endogenous GLP-1 degradation with dipeptidyl peptidease-4 inhibitor, lingaliptin ameliorates angiotensin II (Ang II)-induced renal fibrosis. Sprague-Dawley rats were randomly divided into four groups: 0.9% saline or Ang II (500 ng/kg/min) was infused with osmotic minipumps for 4 weeks, defined as sham and Ang II groups. In drug treated groups, liraglutide (0.3 mg/kg) was injected subcutaneously twice daily or linagliptin (8 mg/kg) was administered daily via oral gavage during Ang II infusion. Compared with Ang II stimulation, liraglutide or linagliptin comparatively down-regulated the protein level of the AT1 receptor, and up-regulated the AT2 receptor, as identified by a reduced AT1/AT2 ratio (all p < 0.05), consistent with less locally-expressed AT1 receptor and enhanced AT2 receptor in the glomerular capillaries and proximal tubules of the renal cortex. Furthermore, both drugs significantly increased the expression of GLP-1 receptor and attenuated the protein levels of TLR4, NOX4 and IL-6. The populations of macrophages and α-SMA expressing myofibroblasts decreased with treatment of liraglutide and linagliptin, in coincidence with the reduced expression of phosphor-Smad2/3, Smad4, TGFß1, and up-regulated Smad7. Along with these modulations, renal morphology was preserved and synthesis of fibronectin/collagen I was down-regulated, as identified by small collagen-rich area in the renal cortex. These results suggest that the preservation of GLP-1 level using liraglutide or linagliptin might be considered as an add-on therapeutic option for inhibiting Ang II induced renal fibrosis and failure.

Effect of the Incretin Hormones on the Endocrine Pancreas in End-Stage Renal Disease.

CONTEXT: The insulin-stimulating and glucagon-regulating effects of the 2 incretin hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), contribute to maintain normal glucose homeostasis. Impaired glucose tolerance occurs with high prevalence among patients with end-stage renal disease (ESRD). OBJECTIVE: To evaluate the effect of the incretin hormones on endocrine pancreatic function in patients with ESRD. DESIGN AND SETTING: Twelve ESRD patients on chronic hemodialysis and 12 matched healthy controls, all with normal oral glucose tolerance test, were included. On 3 separate days, a 2-hour euglycemic clamp followed by a 2-hour hyperglycemic clamp (3 mM above fasting level) was performed with concomitant infusion of GLP-1 (1 pmol/kg/min), GIP (2 pmol/kg/min), or saline administered in a randomized, double-blinded fashion. A 30% lower infusion rate was used in the ESRD group to obtain comparable incretin hormone plasma levels. RESULTS: During clamps, comparable plasma glucose and intact incretin hormone concentrations were achieved. The effect of GLP-1 to increase insulin concentrations relative to placebo levels tended to be lower during euglycemia in ESRD and was significantly reduced during hyperglycemia (50 [8-72]%, P = 0.03). Similarly, the effect of GIP relative to placebo levels tended to be lower during euglycemia in ESRD and was significantly reduced during hyperglycemia (34 [13-50]%, P = 0.005). Glucagon was suppressed in both groups, with controls reaching lower concentrations than ESRD patients. CONCLUSIONS: The effect of incretin hormones to increase insulin release is reduced in ESRD, which, together with elevated glucagon levels, could contribute to the high prevalence of impaired glucose tolerance among ESRD patients.