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Introduction Glucagon-like peptide-1 (GLP-1) is an endogenous peptide that stimulates insulin secretion and decreases glucagon secretion. The use of GLP-1 receptor agonists (GLP-1RA) showed efficacy reducing the weight and glucose levels in patients with and without type 2 diabetes. This effect was also associated with a decreased risk of major cardiovascular events. Objectives Our aim is to review the role of GLP-1RA in psychiatric patients at cardio-metabolic risk due to antipsychotics treatment. Methods We reviewed articles published in PubMed using the keywords: “GLP-1” “glucagon like peptide” “antipsychotics” and “psychiatry”. Results The number need to treat (NNT) to achieve clinical meaningful weight loss was 3.8. GLP-1RA treatment was also associated with greater reductions in body mass index, fasting glucose, HbA1c and visceral fat. This effect is true for antipsychotic treatment in general and for those on clozapine and olanzapine in particular. Overall, the GLP-1RA are well tolerated with nausea being the most common related adverse effect. Other variables such as age, sex, psychosis severity, nausea or any adverse drug reaction did not affect the weight loss. Conclusions Studies showed a promising role in the management of antipsychotics induced weight gain, particularly in clozapine and olanzapine treated patients. Although these promising results, the route of administration, with a daily or weekly subcutaneous injection, and the GLP-1RA associated financial costs, can be viewed as important factors which can limit the wide use of this type of treatment in psychiatric patients. Disclosure No significant relationships.

Dulaglutide (glucagon like peptide-1/IgG-Fc fusion protein, GLP-1-Fc) is a long lasting GLP-1 agonist, which consists of two arms of GLP-1 moieties fused to IgG Fc fragment. Dulaglutide is a safe and effective medication for type 2 diabetes. In an attempt to develop a biosimilar version of dulaglutide, we found that up to 75% of GLP-1-Fc displayed N-terminal truncations in one or both GLP-1 arms. We proposed that the N-terminal heterogeneity was caused by mis-cleavage of signal peptide and solved this problem through signal peptide optimization. Murine immunoglobulin kappa light chain signal peptide (KASP) significantly improves GLP-1-Fc N-terminal integrity and homogeneity. 92.8–95.7% of GLP-1-Fc molecules directed by KASP contain intact N-terminus. The productivity of GLP-1-Fc could reach 2.2 g/L in shaking flask fed batch culture. KASP is an optimal signal peptide for GLP-1-Fc expression in Chinese hamster ovary (CHO) cells. [ABSTRACT FROM AUTHOR]

Drugs that augment the incretin system [glucagon like peptide (GLP) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors] represent a novel class of anti-hyperglycemic agents that have shown to improve the health and survival of beta-cells (improvement in postprandial hyperglycemia) and suppress glucagon (improvement in fasting hyperglycemia). The incretins represent a large family of molecules referred to as the "glucagon superfamily of peptide hormones" of which more than 90% of the physiological effects of incretins are accomplished by GLP-1 7-37 and GLP1 7-36 amide and gastric insulinotropic peptide (GIP). GLP-1 mediates its effects via the GLP-1 receptor, which has a wide tissue distribution [pancreas, lung, heart, vascular smooth muscle cells, endothelial cells, macrophages and monocytes, kidney, gastrointestinal tract (stomach and intestine), central nervous system (neoortex, cerebellum, hypothalamus, hippocampus, brainstem nucleus tractus solitarius) and peripheral nervous system]. This would imply that the incretin system has effects outside the pancreas. Over time data has accumulated to suggest that therapies that augment the incretin system has beneficial pleiotrophic effects. The incretins have shown to possess a cardiac-friendly profile, preserve neuronal cells and safeguard from neuronal degeneration, improve hepatic inflammation and hepatosteatosis, improve insulin resistance, promote weight loss and induce satiety. There is growing evidence that they may also be renoprotective promoting wound healing and bone health.

For decades, parenteral nutrition (PN) has been a successful method for intravenous delivery of nutrition and remains an essential therapy for individuals with intolerance of enteral feedings or impaired gut function. Although the benefits of PN are evident, its use does not come without a significant risk of complications. For instance, parenteral nutrition-associated liver disease (PNALD)—a well-described cholestatic liver injury—and atrophic changes in the gut have both been described in patients receiving PN. Although several mechanisms for these changes have been postulated, data have revealed that the introduction of enteral nutrition may mitigate this injury. This observation has led to the hypothesis that gut-derived signals, originating in response to the presence of luminal contents, may contribute to a decrease in damage to the liver and gut. This review seeks to present the current knowledge regarding the modulation of what is known as the “gut–liver axis” and the gut-derived signals which play a role in PN-associated injury.

[Display omitted] With the target to develop small molecules based anti-diabetic agents, we, herein, report the design, synthesis and biological studies on Lys-Pro and Gly-Pro esters, and a Phe-Pro-Phe tripeptide inhibiting the activity of glycoprotein dipeptidyl peptidase-4 (DPP-4). Since DPP-4 cleaves the glucagon like peptide (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) hormones which are responsible for inducing insulin secretion, the results of present studies could be significant in making control over glycemia. The structural analysis of DPP-4 and its binding mode with the substrate as well as the reported inhibitors provided the background for the design of new molecules. Among the 17 compounds screened against DPP-4, 14 compounds displayed IC 50 better than the known drug Sitagliptin. Collectively, a highly encouraging set of molecules was identified that may prove as the clinical candidates for the treatment of diabetes. [ABSTRACT FROM AUTHOR]

This study has investigated the patterns of colocalisation of the conventional K cell marker, glucagon-like insulinotropic peptide (GIP), and the L cell markers, glucagon like peptide-1 (GLP-1) and peptide YY (PYY), in enteroendocrine cells (EEC) of the small intestine and colon of mouse and pig. All combinations of the hormones, 3 in a cell, 2 in a cell and 1 at a time, were encountered. In both species, the three most common EEC types contained (1) both GLP-1 and PYY but not GIP, (2) GLP-1 alone or (3) GIP plus GLP-1 without PYY. Few GIP plus PYY cells and rare cells containing all 3 hormones were encountered. Gradients of cell types occurred along the intestine. For example, in mouse, there were no PYY cells in the duodenum and few in the jejunum, but >50 % of labelled EEC in the distal ileum and colon were PYY immunoreactive. By contrast, over 40 % of EEC in the pig duodenum contained PYY, and most also contained either GLP-1 or GIP. The gradient in pig was less pronounced. It is concluded that the traditional classification of K and L cells requires revision, and that there are major inter-species differences in the patterns of colocalisation of hormones that have been used to characterise K and L cells. [ABSTRACT FROM AUTHOR]

Background: To study the effects of pro-kinetic agents on post-prandial glycaemia in type 2 diabetes mellitus. Methods :In this comparative study one hundred and eighty patients with Type 2 diabetes mellitus and features of gastroparesis were randomly recruited. They were divided randomly into two groups of ninety each.Group I was given oral antidiabetic agents and placebo. Group II was given oral anti-diabetic agents along with domperidone. Mean levels of glycaemic difference. Difference between Premeal and two hours postmeal and glycaemic levels were determined and compared in the two groups. Results :Mean fasting blood sugar of Group I was 168.57 mg/dl and 2 hours postprandial was 296.73 mg/dl. In Group II mean fasting blood sugar was 201.24 mg/dl and mean 2 hours postprandial blood sugar was 296.42 mg/dl. Mean difference in fasting and 2 hours post prandial was 156.38 mg/dl and 114.15 mg/dl, respectively in Group I and II. Conclusion: Mean difference between fasting and 2 hours postprandial blood sugar is significantly low in patients taking prokinetic drugs, as compared to the diabetics not taking pro-kinetic drugs.

Diabetes resulting from both genetic and lifestyle factors causes high insulin deficiency or its resistance. As hyperglycemia and decreased insulin secretion and/or its sensitivity appear to be the primary defects associated with diabetes, available treatments focus on reducing those defects. A novel approach of treatment is to target the incretin mimetic hormones, which are secreted by intestinal cells in response to food intake, provoking glucose-dependent insulin secretion from the pancreas. Efficacy and safety studies of dipetidyl peptidase inhibitors (DPP-IV), sitagliptin, vildagliptin and linagliptin provide similar improvements in HbA1c levels when compared with metformin, sulfonylureas or glitazones without contributing to weight gain and hypoglycemia. Caution is required when choosing the gliptin in people with renal or hepatic impairment and with a risk of pancreatitis. The glucagon like peptide (GLP-1) analogues Exenatide and Liraglutide also have positive impact on glycemic control especially when used as a combination therapy. Another upcoming approach is using sodium-glucose co transporter two inhibitors in kidney, by exploring pathophysiology of renal glucose re absorption in the proximal tubule. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that has been shown to have hemodynamic and cardioprotective capacity in addition to its better characterized glucoregulatory actions. Because of this, emerging research has focused on the ability of GLP-1 based therapies to drive myocardial substrate selection, enhance cardiac performance and regulate heart rate, blood pressure and vascular tone. These studies have produced consistent and reproducible results amongst numerous laboratories. However, there are obvious disparities in findings obtained in small animal models versus those of higher mammals. This species dependent discrepancy calls to question, the translational value of individual findings. Moreover, few studies of GLP-1 mediated cardiovascular action have been performed in the presence of a pre-existing comorbidities (e.g. obesity/diabetes) which limits interpretation of the effectiveness of incretin-based therapies in the setting of disease. This review addresses cardiovascular and hemodynamic potential of GLP-1 based therapies with attention to species specific effects as well as the interaction between therapies and disease. [ABSTRACT FROM AUTHOR]

A sub-group of enteroendocrine cells (L cells) release gastrointestinal hormones, GLP-1 and PYY, which have different but overlapping physiological effects, in response to intraluminal nutrients. Whilst their release profiles are not identical, how the plasma levels of these two hormones are differentially regulated is not well understood. We investigate the possibility that GLP-1 and PYY are in separate storage vesicles. In this study, the subcellular location of GLP-1 and PYY storage organelles is investigated using double-labelling immunohistochemistry, super resolution microscopy and high-resolution confocal microscopy. In all species tested, human, pig, rat and mouse, most cytoplasmic stores that exhibited GLP-1 or PYY immunofluorescence were distinct from each other. The volume occupancy, determined by 3D analysis, overlapped by only about 10∼20 %. At the lower resolution achieved by conventional confocal microscopy, there was also evidence of GLP-1 and PYY being in separate storage compartments but, in subcellular regions where there were many storage vesicles, separate storage could not be resolved. The results indicate that different storage vesicles in L cells contain predominantly GLP-1 or predominantly PYY. Whether GLP-1 and PYY storage vesicles are selectively mobilised and their products are selectively released needs to be determined. [ABSTRACT FROM AUTHOR]

Drugs that augment the incretin system [glucagon like peptide (GLP) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors] represent a novel class of anti-hyperglycemic agents that have shown to improve the health and survival of beta-cells (improvement in postprandial hyperglycemia) and suppress glucagon (improvement in fasting hyperglycemia). The incretins represent a large family of molecules referred to as the "glucagon superfamily of peptide hormones" of which more than 90% of the physiological effects of incretins are accomplished by GLP-17-37 and GLP17-36 amide and gastric insulinotropic peptide (GIP). GLP-1 mediates its effects via the GLP-1 receptor, which has a wide tissue distribution [pancreas, lung, heart, vascular smooth muscle cells, endothelial cells, macrophages and monocytes, kidney, gastrointestinal tract (stomach and intestine), central nervous system (neoortex, cerebellum, hypothalamus, hippocampus, brainstem nucleus tractus solitarius) and peripheral nervous system]. This would imply that the incretin system has effects outside the pancreas. Over time data has accumulated to suggest that therapies that augment the incretin system has beneficial pleiotrophic effects. The incretins have shown to possess a cardiac-friendly profile, preserve neuronal cells and safeguard from neuronal degeneration, improve hepatic inflammation and hepatosteatosis, improve insulin resistance, promote weight loss and induce satiety. There is growing evidence that they may also be renoprotective promoting wound healing and bone health. [ABSTRACT FROM AUTHOR]

Purpose: To determine whether a Protected Graft Copolymer (PGC) containing fatty acid can be used as a stabilizing excipient for GLP-1 and whether PGC/GLP-1 given once a week can be an effective treatment for diabetes. Methods: To create a PGC excipient, polylysine was grafted with methoxypolyethyleneglycol and fatty acid at the epsilon amino groups. We performed evaluation of the binding of excipient to GLP-1, the DPP IV sensitivity of GLP-1 formulated with PGC as the excipient, the in vitro bio-activity of excipient-formulated GLP-1, the in vivo pharmacokinetics of excipient-formulated GLP-1, and the efficacy of the excipient-formulated GLP-1 in diabetic rats. Results: We showed reproducible synthesis of PGC excipient, high affinity binding of PGC to GLP-1, slowed protease degradation of excipient-formulated GLP-1, and that excipient-formulated GLP-1 induced calcium influx in INS cells. Excipient-formulated GLP-1 stays in the blood for at least 4 days. When excipient-formulated GLP-1 was given subcutaneously once a week to diabetic ZDF rats, a significant reduction of HbA1c compared to control was observed. The reduction is similar to diabetic ZDF rats given exendin twice a day. Conclusions: PGC can be an ideal in vivo stabilizing excipient for biologically labile peptides. [ABSTRACT FROM AUTHOR]

Drug delivery strategies for diabetes have included a wide range of scientific and engineering approaches, including molecular design, formulation and device design. Molecular engineering has resulted in modified pharmacokinetics, such as rapid-acting or slow-release analogs of insulin. Long-acting insulin formulations are designed to meet the body's basal needs, whereas rapid-acting insulin formulations are designed to cover mealtime glucose spikes. Furthermore, the discovery of new therapeutic biomolecules, which like insulin need to be injected, will drive the need for more flexible and universally applicable delivery systems. Formulation design, such as particle engineering, can be used to modify pharmacokinetic profiles. In general, suspension formulations of insulin commonly demonstrate reduced solubility and result in sustained release. Similarly, depot injections can result in precipitation of insulin at the site of injection, again resulting in lower solubility and sustained release. Particle engineering also has been applied to pulmonary formulations for delivery to the deep lung. The creation of novel drug delivery methods for the treatment of diabetes should remove barriers to insulin therapy and increase patient acceptance and compliance. Eliminating routine injections with needle-free injectors, insulin pumps, inhalation, buccal sprays, intra-nasal delivery, and transdermal patches may offer increasingly attractive alternatives. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96:1925–1954, 2007 [ABSTRACT FROM AUTHOR]

Introduction: Glucagon-like peptide-1 (GLP-1) is an endogenous peptide that stimulates insulin secretion and decreases glucagon secretion. The use of GLP-1 receptor agonists (GLP-1RA) showed efficacy reducing the weight and glucose levels in patients with and without type 2 diabetes. This effect was also associated with a decreased risk of major cardiovascular events. Objectives: Our aim is to review the role of GLP-1RA in psychiatric patients at cardio-metabolic risk due to antipsychotics treatment. Methods: We reviewed articles published in PubMed using the keywords: "GLP-1" "glucagon like peptide" "antipsychotics" and "psychiatry". Results: The number need to treat (NNT) to achieve clinical meaningful weight loss was 3.8. GLP-1RA treatment was also associated with greater reductions in body mass index, fasting glucose, HbA1c and visceral fat. This effect is true for antipsychotic treatment in general and for those on clozapine and olanzapine in particular. Overall, the GLP-1RA are well tolerated with nausea being the most common related adverse effect. Other variables such as age, sex, psychosis severity, nausea or any adverse drug reaction did not affect the weight loss. Conclusions: Studies showed a promising role in the management of antipsychotics induced weight gain, particularly in clozapine and olanzapine treated patients. Although these promising results, the route of administration, with a daily or weekly subcutaneous injection, and the GLP-1RA associated financial costs, can be viewed as important factors which can limit the wide use of this type of treatment in psychiatric patients. [ABSTRACT FROM AUTHOR]

For decades, parenteral nutrition (PN) has been a successful method for intravenous delivery of nutrition and remains an essential therapy for individuals with intolerance of enteral feedings or impaired gut function. Although the benefits of PN are evident, its use does not come without a significant risk of complications. For instance, parenteral nutrition-associated liver disease (PNALD)-a well-described cholestatic liver injury-and atrophic changes in the gut have both been described in patients receiving PN. Although several mechanisms for these changes have been postulated, data have revealed that the introduction of enteral nutrition may mitigate this injury. This observation has led to the hypothesis that gut-derived signals, originating in response to the presence of luminal contents, may contribute to a decrease in damage to the liver and gut. This review seeks to present the current knowledge regarding the modulation of what is known as the "gut⁻liver axis" and the gut-derived signals which play a role in PN-associated injury.

The increasing prevalence of diabetes especially type 2 diabetes worldwide is indisputable. Diabetics suffer increased morbidity and mortality, compared to their non-diabetic counterparts, not only because of vascular complications, but also because of an increased fracture incidence. Both types 1 and 2 diabetes and some medications used to treat it are associated with osteoporotic fractures. The responsible mechanisms remain incompletely elucidated. In this review, we evaluate the role of glycemic control in bone health, and the effect of anti-diabetic medications such as thiazolidinediones, sulfonylureas, DPP-4 inhibitors, and GLP-1 agonists. In addition, we examine the possible role of insulin and metformin as anabolic agents for bone. Lastly, we identify the current and future screening tools that help evaluate bone health in diabetics and their limitations. In this way we can offer individualized treatment, to the at-risk diabetic population., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)