Protective effect of glucagon‐like peptide‐2 in experimental corrosive esophagitis

Corrosive esophageal injuries are one of the life‐threatening morbidities leading to esophageal stricture and perforation affecting all age groups but especially children due to accidental ingestions in this age group. Glucagon‐like peptide‐2 (GLP‐2) is an intestinal polypeptide with potent anti‐inflammatory effects. Its effects are studied in various studies but not in corrosive esophagitis. We aimed to investigate whether it has protective effect in experimental corrosive esophagitis, in the absence of existing studies into possible links. Twenty‐four Wistar‐albino rats, weighing 220–240 g, were randomized into three groups (n = 8 in each). First group is control, second one is sham operated, and the third one is treatment group. Median laparotomy was made in all groups. In sham and treatment groups, esophagus was loosened and suspended from 1 cm proximal to the esophageal junction. The esophagus segment between suspenders was exposed to 0.1 mL 5% NaOH for 10 seconds. In the treatment group, rats were given GLP‐2 for 7 days intraperitoneally. After 7 days, all rats were sacrified and esophagi were totally removed. In the histopathologic examination, esophageal tissues were compared in terms of inflammation, muscularis mucosa injury, and collagen deposition of tunica muscularis. Histopathologic changes in the esophageal tissues of groups were compared. Histopathologic injury in the GLP‐2 treated group was significantly less than sham group (P < 0.05). There was statistically significant healing in the GLP‐2 treatment group. It is concluded that GLP‐2 has a preventive effect on inflammation and collagen accumulation in an experimental corrosive esophagitis. In the light of the information that initial lesions in the early phase are predictors of complications, GLP‐2 is a promising agent that has an anti‐inflammatory effect in caustic injuries.     

Glucose‐dependent insulinotropic polypeptide and glucagon‐like peptide‐1: Incretin actions beyond the pancreas

Glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) are the two primary incretin hormones secreted from the intestine on ingestion of various nutrients to stimulate insulin secretion from pancreatic β‐cells glucose‐dependently. GIP and GLP‐1 undergo degradation by dipeptidyl peptidase‐4 (DPP‐4), and rapidly lose their biological activities. The actions of GIP and GLP‐1 are mediated by their specific receptors, the GIP receptor (GIPR) and the GLP‐1 receptor (GLP‐1R), which are expressed in pancreatic β‐cells, as well as in various tissues and organs. A series of investigations using mice lacking GIPR and/or GLP‐1R, as well as mice lacking DPP‐4, showed involvement of GIP and GLP‐1 in divergent biological activities, some of which could have implications for preventing diabetes‐related microvascular complications (e.g., retinopathy, nephropathy and neuropathy) and macrovascular complications (e.g., coronary artery disease, peripheral artery disease and cerebrovascular disease), as well as diabetes‐related comorbidity (e.g., obesity, non‐alcoholic fatty liver disease, bone fracture and cognitive dysfunction). Furthermore, recent studies using incretin‐based drugs, such as GLP‐1 receptor agonists, which stably activate GLP‐1R signaling, and DPP‐4 inhibitors, which enhance both GLP‐1R and GIPR signaling, showed that GLP‐1 and GIP exert effects possibly linked to prevention or treatment of diabetes‐related complications and comorbidities independently of hyperglycemia. We review recent findings on the extrapancreatic effects of GIP and GLP‐1 on the heart, brain, kidney, eye and nerves, as well as in the liver, fat and several organs from the perspective of diabetes‐related complications and comorbidities.     

Augmentation of glucagon‐like peptide‐1 receptor signalling by neprilysin inhibition: potential implications for patients with heart failure

Augmentation of glucagon‐like peptide‐1 (GLP‐1) receptor signalling is an established approach to the treatment of type 2 diabetes. However, endogenous GLP‐1 and long‐acting GLP‐1 receptor analogues are degraded not only by dipeptidyl peptidase‐4, but also by neprilysin. This observation raises the possibilities that endogenous GLP‐1 contributes to the clinical effects of neprilysin inhibition and that patients concurrently treated with sacubitril/valsartan and incretin‐based drugs may experience important drug–drug interactions. Specifically, potentiation of GLP‐1 receptor signalling may underlie the antihyperglycaemic actions of sacubitril/valsartan. Neprilysin inhibitors may also be able to augment the effects of long‐acting GLP‐1 analogues to increase heart rate and myocardial cyclic AMP, and thus, potentiate these deleterious actions; if so, concomitant treatment with GLP‐1 receptor agonists may limit the efficacy of neprilysin inhibitors in patients with both heart failure and diabetes. For patients not concurrently treated with GLP‐1 analogues, the action of neprilysin to enhance the effects of GLP‐1 may be particularly relevant in the brain, where augmentation of GLP‐1 and other endogenous peptides may act to inhibit amyloid‐induced neuroinflammation and cytotoxicity and improve memory formation and executive functioning. Experimentally, neprilysin inhibitors may also potentiate the effects of endogenous GLP‐1 and GLP‐1 receptor agonists on blood vessels and the kidney. The role of neprilysin in the metabolism of endogenous GLP‐1 and long‐acting GLP‐1 analogues points to a range of potential pathophysiological effects that may be clinically relevant to patients with heart failure, with or without diabetes.     

Engineering and characterization of the long‐acting glucagon‐like peptide‐1 analogue LY2189265, an Fc fusion protein

Background

Glucagon‐like peptide‐1 (GLP‐1) receptor agonists are novel agents for type 2 diabetes treatment, offering glucose‐dependent insulinotropic effects, reduced glucagonemia and a neutral bodyweight or weight‐reducing profile. However, a short half‐life (minutes), secondary to rapid inactivation by dipeptidyl peptidase‐IV (DPP‐IV) and excretion, limits the therapeutic potential of the native GLP‐1 hormone. Recently, the GLP‐1 receptor agonist exenatide injected subcutaneously twice daily established a novel therapy class. Developing long‐acting and efficacious GLP‐1 analogues represents a pivotal research goal. We developed a GLP‐1 immunoglobulin G (IgG4) Fc fusion protein (LY2189265) with extended pharmacokinetics and activity.

Methods

In vitro and in vivo activity of LY2189265 was characterized in rodent and primate cell systems and animal models.

Results

LY2189265 retained full receptor activity in vitro and elicited insulinotropic activity in islets similar to native peptide. Half‐life in rats and cynomolgus monkeys was 1.5–2 days, and serum immunoreactivity representing active compound persisted > 6 days. In rats, LY2189265 enhanced insulin responses during graded glucose infusion 24 h after one dose. LY2189265 increased glucose tolerance in diabetic mice after one dose and lowered weight and delayed hyperglycaemia when administered twice weekly for 4 weeks. In monkeys, LY2189265 significantly increased glucose‐dependent insulin secretion for up to a week after one dose, retained efficacy when administered subchronically (once weekly for 4 weeks) and was well tolerated.

Conclusions

LY2189265 retains the effects of GLP‐1 with increased half‐life and efficacy, supporting further evaluation as a once‐weekly treatment of type 2 diabetes. Copyright © 2010 John Wiley & Sons, Ltd.     

The role of glucagon‐like peptide‐1 impairment in obesity and potential therapeutic implications

The hormone glucagon‐like peptide‐1 (GLP‐1) is released from the gut in response to food intake. It acts as a satiety signal, leading to reduced food intake, and also as a regulator of gastric emptying. Furthermore, GLP‐1 functions as an incretin hormone, stimulating insulin release and inhibiting glucagon secretion from the pancreas in response to food ingestion. Evidence suggests that the action or effect of GLP‐1 may be impaired in obese subjects, even in those with normal glucose tolerance. GLP‐1 impairment may help explain the increased gastric emptying and decreased satiety signalling seen in obesity. Incretin impairment, probably associated with reduced insulinotropic potency of GLP‐1, is also characteristic of type 2 diabetes (T2D). Therefore, it is possible that incretin impairment may contribute to the pathophysiological bridge between obesity and T2D. This review summarises current knowledge about the pathophysiology and consequences of GLP‐1 and incretin impairment in obesity, and examines the evidence for an incretin‐related link between obesity and T2D. It also considers the current literature surrounding the novel use of GLP‐1 receptor agonists as a treatment for obesity in patients with normoglycaemia, prediabetes and T2D.     

Involvement of glucagon‐like peptide‐1 in the glucose‐lowering effect of metformin

Metformin is an oral antihyperglycaemic drug used in the first‐line treatment of type 2 diabetes. Metformin's classic and most well‐known blood glucose‐lowering mechanisms include reduction of hepatic gluconeogenesis and increased peripheral insulin sensitivity. Interestingly, intravenously administered metformin is ineffective and recently, metformin was shown to increase plasma concentrations of the glucose‐lowering gut incretin hormone glucagon‐like peptide‐1 (GLP‐1), which may contribute to metformin's glucose‐lowering effect in patients with type 2 diabetes. The mechanisms behind metformin‐induced increments in GLP‐1 levels remain unknown, but it has been hypothesized that metformin stimulates GLP‐1 secretion directly and/or indirectly and that metformin prolongs the half‐life of GLP‐1. Also, it has been suggested that metformin may potentiate the glucose‐lowering effects of GLP‐1 by increasing target tissue sensitivity to GLP‐1. The present article critically reviews the possible mechanisms by which metformin may affect GLP‐1 levels and sensitivity and discusses whether such alterations may constitute important and clinically relevant glucose‐lowering actions of metformin.     

Incretin therapies: highlighting common features and differences in the modes of action of glucagon‐like peptide‐1 receptor agonists and dipeptidyl peptidase‐4 inhibitors

Over the last few years, incretin‐based therapies have emerged as important agents in the treatment of type 2 diabetes (T2D). These agents exert their effect via the incretin system, specifically targeting the receptor for the incretin hormone glucagon‐like peptide 1 (GLP‐1), which is partly responsible for augmenting glucose‐dependent insulin secretion in response to nutrient intake (the ‘incretin effect’). In patients with T2D, pharmacological doses/concentrations of GLP‐1 can compensate for the inability of diabetic β cells to respond to the main incretin hormone glucose‐dependent insulinotropic polypeptide, and this is therefore a suitable parent compound for incretin‐based glucose‐lowering medications. Two classes of incretin‐based therapies are available: GLP‐1 receptor agonists (GLP‐1RAs) and dipeptidyl peptidase‐4 (DPP‐4) inhibitors. GLP‐1RAs promote GLP‐1 receptor (GLP‐1R) signalling by providing GLP‐1R stimulation through ‘incretin mimetics’ circulating at pharmacological concentrations, whereas DPP‐4 inhibitors prevent the degradation of endogenously released GLP‐1. Both agents produce reductions in plasma glucose and, as a result of their glucose‐dependent mode of action, this is associated with low rates of hypoglycaemia; however, there are distinct modes of action resulting in differing efficacy and tolerability profiles. Furthermore, as their actions are not restricted to stimulating insulin secretion, these agents have also been associated with additional non‐glycaemic benefits such as weight loss, improvements in β‐cell function and cardiovascular risk markers. These attributes have made incretin therapies attractive treatments for the management of T2D and have presented physicians with an opportunity to tailor treatment plans. This review endeavours to outline the commonalities and differences among incretin‐based therapies and to provide guidance regarding agents most suitable for treating T2D in individual patients.     

Glucagon‐like peptide‐1 secretion by direct stimulation of L cells with luminal sugar vs non‐nutritive sweetener

Aims/Introduction: Oral ingestion of carbohydrate triggers secretion of glucagon‐like peptide (GLP)‐1, which inhibits the postprandial rise in blood glucose levels. However, the mechanism of carbohydrate‐induced GLP‐1 secretion from enteroendocrine L cells remains unclear. In the present study, GLP‐1 secretion was examined by meal tolerance tests of healthy Japanese volunteers. Materials and Methods: Twenty‐one healthy Japanese men participated in the study. The meal tolerance test was performed with modified nutrient compositions, with or without pretreatment with the α‐glucosidase inhibitor acarbose, or with substitution of sucrose with an equivalent dose of sweeteners in the meal. Blood concentrations of glucose, insulin, GLP‐1, and apolipoprotein (Apo) B‐48 were measured. Results: GLP‐1 secretion started concomitant with the increase in blood glucose levels 10 min after meal ingestion. Insulin secretion started at 5 min, before the increase in blood glucose levels, reflecting the contribution of direct nutrient stimulation on the former parameter and neural regulation in the latter. Carbohydrate retention in the gut lumen induced by acarbose pretreatment extended postprandial GLP‐1 secretion and negated the increase in serum ApoB‐48 levels. GLP‐1 secretion was markedly decreased by a reduction in the amount of sucrose in the meal and was not restored by an equivalent dose of sweeteners used to compensate for the sweet taste. Conclusions: The results indicate that direct stimulation of L cells with sugar, but not sweetener, is required for carbohydrate‐induced GLP‐1 secretion. In addition, inhibition of digestion of dietary carbohydrate by α‐glucosidase inhibitors may prevent postprandial hyperglycemia by increasing GLP‐1 secretion and by inhibiting glucose absorption. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00163.x, 2011)     

Ingestion of a moderate high‐sucrose diet results in glucose intolerance with reduced liver glucokinase activity and impaired glucagon‐like peptide‐1 secretion

Aims/Introduction: Excessive intake of sucrose can cause severe health issues, such as diabetes mellitus. In animal studies, consumption of a high‐sucrose diet (SUC) has been shown to cause obesity, insulin resistance and glucose intolerance. However, several in vivo experiments have been carried out using diets with much higher sucrose contents (50–70% of the total calories) than are typically ingested by humans. In the present study, we examined the effects of a moderate SUC on glucose metabolism and the underlying mechanism. Materials and Methods: C57BL/6J mice received a SUC (38.5% sucrose), a high‐starch diet (ST) or a control diet for 5 weeks. We assessed glucose tolerance, incretin secretion and liver glucose metabolism. Results: An oral glucose tolerance test (OGTT) showed that plasma glucose levels in the early phase were significantly higher in SUC‐fed mice than in ST‐fed or control mice, with no change in plasma insulin levels at any stage. SUC‐fed mice showed a significant improvement in insulin sensitivity. Glucagon‐like peptide‐1 (GLP‐1) secretion 15 min after oral glucose administration was significantly lower in SUC‐fed mice than in ST‐fed or control mice. Hepatic glucokinase (GCK) activity was significantly reduced in SUC‐fed mice. During the OGTT, the accumulation of glycogen in the liver was suppressed in SUC‐fed mice in a time‐dependent manner. Conclusions: These results indicate that mice that consume a moderate SUC show glucose intolerance with a reduction in hepatic GCK activity and impairment in GLP‐1 secretion. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00208.x , 2012)     

Plasma gastric inhibitory polypeptide and glucagon‐like peptide‐1 levels after glucose loading are associated with different factors in Japanese subjects

Aims/Introduction: Gastric inhibitory polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) are major incretins that potentiate insulin secretion from pancreatic β‐cells. The factors responsible for incretin secretion have been reported in Caucasian subjects, but have not been thoroughly evaluated in Japanese subjects. We evaluated the factors associated with incretin secretion during oral glucose tolerance test (OGTT) in Japanese subjects with normal glucose tolerance (NGT). Materials and Methods: We measured plasma GIP and GLP‐1 levels during OGTT in 17 Japanese NGT subjects and evaluated the factors associated with GIP and GLP‐1 secretion using simple and multiple regression analyses. Results: GIP secretion (AUC‐GIP) was positively associated with body mass index (P < 0.05), and area under the curve (AUC) of C‐peptide (P < 0.05) and glucagon (P < 0.01), whereas GLP‐1 secretion (AUC‐GLP‐1) was negatively associated with AUC of plasma glucose (P < 0.05). The insulinogenic index was most strongly associated with GIP secretion (P < 0.05); homeostasis model assessment β‐cell was the most the strongly associated factor in GLP‐1 secretion (P < 0.05) among the four indices of insulin secretion and insulin sensitivity. Conclusions: Several distinct factors might be associated with GIP and GLP‐1 secretion during OGTT in Japanese subjects. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00078.x, 2011)     

Diabetes and obesity treatment based on dual incretin receptor activation: ‘twincretins’

The gut incretin hormones glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) are secreted after meal ingestion and work in concert to promote postprandial insulin secretion and regulate glucagon secretion. GLP‐1 also slows gastric emptying and suppresses appetite, whereas GIP seems to affect lipid metabolism. The introduction of selective GLP‐1 receptor (GLP‐1R) agonists for the treatment of type 2 diabetes and obesity has increased the scientific and clinical interest in incretins. Combining the body weight‐lowering and glucose‐lowering effects of GLP‐1 with a more potent improvement of β cell function through additional GIP action could potentially offer a more effective treatment of diabetes and obesity, with fewer adverse effects than selective GLP‐1R agonists; therefore, new drugs designed to co‐activate both the GIP receptor (GIPR) and the GLP‐1R simultaneously are under development. In the present review, we address advances in the field of GIPR and GLP‐1R co‐agonism and review in vitro studies, animal studies and human trials involving co‐administration of the two incretins, as well as results from a recently developed GIPR/GLP‐1R co‐agonist, and highlight promising areas and challenges within the field of incretin dual agonists.     

Glucagon‐like peptide‐1 receptor agonists for type 2 diabetes: A rational drug development

Today, glucagon‐like peptide‐1 (GLP‐1) receptor agonists are established glucose‐lowering drugs used in the management of type 2 diabetes. Their development emerged from the understanding that a combined islet dysfunction comprising of impaired insulin secretion and exaggerated glucagon secretion is the key defect of hyperglycemia. GLP‐1 was shown to target these defects, and after the discovery that dipeptidyl peptidase‐4 inactivates native GLP‐1, several different dipeptidyl peptidase‐4‐resistant GLP‐1 receptor agonists have been developed. They are administered subcutaneously, but show differences in molecular structure, molecular size and pharmacokinetics, the latter allowing twice‐daily, once‐daily or once‐weekly administration. They have been shown to be efficient in reducing both glycated hemoglobin and bodyweight, and to be safe and highly tolerable. Cardiovascular outcomes trials have shown them to be neutral or beneficial. GLP‐1 receptor agonists are positioned as add‐ons to metformin alone or in combination with oral agents in the clinical paradigm. They are also efficient when combined with insulin, and fixed dose combinations with long‐acting insulin have been developed. Recent development includes a very long administration schedule and oral availability. The research from the first demonstration of the antidiabetic action of GLP‐1 in the early 1990s to the enormously accumulated data today represents a successful and rational development, which has been characterized by focused perseverance to establish this therapy in the management of type 2 diabetes.     

Short‐acting glucagon‐like peptide‐1 receptor agonists as add‐on to insulin therapy in type 1 diabetes: A review

A large proportion of patients with type 1 diabetes do not reach their glycaemic target of glycated hemoglobin (HbA1c) <7.0% (53 mmol/mol) and, furthermore, an increasing number of patients with type 1 diabetes are overweight and obese. Treatment of type 1 diabetes is based on insulin therapy, which is associated with well‐described and unfortunate adverse effects such as hypoglycaemia and increased body weight. Glucagon‐like peptide‐1 (GLP‐1) receptor agonists (RAs) are the focus of increasing interest as a possible adjunctive treatment to insulin in type 1 diabetes because of their glucagonostatic and extrapancreatic effects. So far, the focus has mainly been on the long‐acting GLP‐1RAs, but the risk–benefit ratio emerging from studies evaluating the effect of long‐acting GLP‐1RAs as adjunctive therapy to insulin therapy in patients with type 1 diabetes has been disappointing. This might be attributable to a lack of glucagonostatic effect of these long‐acting GLP‐1RAs in type 1 diabetes, alongside development of tachyphylaxis to GLP‐1‐induced retardation of gastric emptying. In contrast, the short‐acting GLP‐1RAs seem to have a preserved and sustained effect on glucagon secretion and gastric emptying in patients with type 1 diabetes, which could translate into effective lowering of postprandial glucose excursions; however, these observations regarding short‐acting GLP‐1RAs are all derived from small open‐label trials and should thus be interpreted with caution. In the present paper we review the potential role of GLP‐1RAs, in particular short‐acting GLP‐1RAs, as add‐on to insulin in the treatment of type 1 diabetes.     

Review of glucagon‐like peptide‐1 receptor agonists for the treatment of type 2 diabetes mellitus in patients with chronic kidney disease and their renal effects

Type 2 diabetes mellitus (T2DM) is the most common cause of chronic kidney disease (CKD), and when it causes CKD it is collectively referred to as diabetic kidney disease. One of the newer therapies for managing hyperglycemia is the glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) drug class. This review summarizes the effects of GLP‐1RAs in patients with T2DM with CKD and evidence for renoprotection with GLP‐1RAs using data from observational studies, prospective clinical trials, post hoc analyses, and meta‐analyses. Evidence from some preclinical studies was also reviewed. Taken together, subgroup analyses of patients with varying degrees of renal function demonstrated that glycemic control with GLP‐1RAs was not markedly less effective in patients with mild or moderate renal impairment vs that in patients with normal function. GLP‐1RAs were associated with improvements in some cardiorenal risk factors, including systolic blood pressure and body weight. Furthermore, several large cardiovascular outcome studies showed reduced risks of composite renal outcomes, mostly driven by a reduction in macroalbuminuria, suggesting potential renoprotective effects of GLP‐1RAs. In conclusion, GLP‐1RAs effectively reduced hyperglycemia in patients with mild or moderately impaired kidney function in the limited number of studies to date. GLP‐1RAs may be considered in combination with other glucose‐lowering medications because of their ability to lower glucose in a glucose‐dependent manner, lowering their risk for hypoglycemia, while improving some cardiorenal risk factors. Potential renoprotective effects of GLP‐1RAs, and their renal mechanisms of action, warrant further investigation.     

Gastrointestinal actions of glucagon‐like peptide‐1‐based therapies: glycaemic control beyond the pancreas

The gastrointestinal hormone glucagon‐like peptide‐1 (GLP‐1) lowers postprandial glucose concentrations by regulating pancreatic islet‐cell function, with stimulation of glucose‐dependent insulin and suppression of glucagon secretion. In addition to endocrine pancreatic effects, mounting evidence suggests that several gastrointestinal actions of GLP‐1 are at least as important for glucose‐lowering. GLP‐1 reduces gastric emptying rate and small bowel motility, thereby delaying glucose absorption and decreasing postprandial glucose excursions. Furthermore, it has been suggested that GLP‐1 directly stimulates hepatic glucose uptake, and suppresses hepatic glucose production, thereby adding to reduction of fasting and postprandial glucose levels. GLP‐1 receptor agonists, which mimic the effects of GLP‐1, have been developed for the treatment of type 2 diabetes. Based on their pharmacokinetic profile, GLP‐1 receptor agonists can be broadly categorized as short‐ or long‐acting, with each having unique islet‐cell and gastrointestinal effects that lower glucose levels. Short‐acting agonists predominantly lower postprandial glucose excursions, by inhibiting gastric emptying and intestinal glucose uptake, with little effect on insulin secretion. By contrast, long‐acting agonists mainly reduce fasting glucose levels, predominantly by increased insulin and reduced glucagon secretion, with potential additional direct inhibitory effects on hepatic glucose production. Understanding these pharmacokinetic and pharmacodynamic differences may allow personalized antihyperglycaemic therapy in type 2 diabetes. In addition, it may provide the rationale to explore treatment in patients with no or little residual β‐cell function.     

Combining GLP‐1 receptor agonists with insulin: therapeutic rationales and clinical findings

Due to the increasing prevalence of type 2 diabetes mellitus (T2DM), the emergent trend towards diagnosis in younger patients and the progressive nature of this disease, many more patients than before now require insulin to maintain glycaemic control. However, there is a degree of inertia among physicians and patients regarding the initiation and intensification of insulin therapy, in part due to concerns about the associated weight gain and increased risk of hypoglycaemia. Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) increase insulin release and suppress glucagon secretion in a glucose‐dependent manner, thus conferring glycaemic control with a low incidence of hypoglycaemia. GLP‐1RAs also promote weight loss, and have beneficial effects on markers of β cell function, lipid levels, blood pressure and cardiovascular risk markers. However, the durability of their effectiveness is unknown and, compared with insulin, the antihyperglycaemic efficacy of GLP‐1RAs is limited. The combination of a GLP‐1RA and insulin might thus be highly effective for optimal glucose control, ameliorating the adverse effects typically associated with insulin. Data from clinical studies support the therapeutic potential of GLP‐1RA–insulin combination therapy, typically showing beneficial effects on glycaemic control and body weight, with a low incidence of hypoglycaemia and, in established insulin therapy, facilitating reductions in insulin dose. In this review, the physiological and pharmacological rationale for using GLP‐1RA and insulin therapies in combination is discussed, and data from clinical studies that have assessed the efficacy and safety of this treatment strategy are outlined.     

Review of head‐to‐head comparisons of glucagon‐like peptide‐1 receptor agonists

Currently, six glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) are approved for treating type 2 diabetes. These fall into two classes based on their receptor activation: short‐acting exenatide twice daily and lixisenatide once daily; and longer‐acting liraglutide once daily, exenatide once weekly, albiglutide once weekly and dulaglutide once weekly. The phase III trial of a seventh GLP‐1RA, taspoglutide once weekly, was stopped because of unacceptable adverse events (AEs). Nine phase III head‐to‐head trials and one large phase II study have compared the efficacy and safety of these seven GLP‐1RAs. All trials were associated with notable reductions in glycated haemoglobin (HbA1c) levels, although liraglutide led to greater decreases than exenatide formulations and albiglutide, and HbA1c reductions did not differ between liraglutide and dulaglutide. As the short‐acting GLP‐1RAs delay gastric emptying, they have greater effects on postprandial glucose levels than the longer‐acting agents, whereas the longer‐acting compounds reduced plasma glucose throughout the 24‐h period studied. Liraglutide was associated with weight reductions similar to those with exenatide twice daily but greater than those with exenatide once weekly, albiglutide and dulaglutide. The most frequently observed AEs with GLP‐1RAs were gastrointestinal disorders, particularly nausea, vomiting and diarrhoea. Nauseaoccurred less frequently, however, with exenatide once weekly and albiglutide than exenatide twice daily and liraglutide. Both exenatide formulations and albiglutide may be associated with higher incidences of injection‐site reactions than liraglutide and dulaglutide. GLP‐1RA use in clinical practice should be customized for individual patients, based on clinical profile and patient preference. Ongoing assessments of novel GLP‐1RAs and delivery methods may further expand future treatment options.     

Improved glycaemic control with minimal hypoglycaemia and no weight change with the once‐daily human glucagon‐like peptide‐1 analogue liraglutide as add‐on to sulphonylurea in Japanese patients with type 2 diabetes

Aim: Sulphonylureas (SUs) are often used as first‐line treatments for type 2 diabetes in Japan, hence it is important to study new antidiabetic drugs in combination with SUs in Japanese patients. Methods: The efficacy and safety of the once‐daily human glucagon‐like peptide‐1 (GLP‐1) analogue liraglutide were compared in 264 Japanese subjects [mean body mass index (BMI) 24.9 kg/m²; mean glycated haemoglobin (HBA1c) 8.4%] randomized and exposed to receive liraglutide 0.6 mg/day (n = 88), 0.9 mg/day (n = 88) or placebo (n = 88) each added to SU monotherapy (glibenclamide, glicazide or glimeprimide) in a 24‐week, double‐blind, parallel‐group trial. Results: The mean change in HBA1c from baseline to week 24 (LOCF) was ?1.56 (s.d. 0.84) and ?1.46 (s.d. 0.95) with liraglutide 0.9 and 0.6 mg respectively, and ?0.40 (s.d. 0.93) with placebo. HBA1c decreased in the placebo group from 8.45 to 8.06%, while liraglutide reduced HBA1c from 8.60 to 7.14%, and from 8.23 to 6.67% at the 0.6 and 0.9 mg doses respectively. Mean HBA1c at week 24 of the two liraglutide groups were significantly lower than the placebo group (p < 0.0001 for both). More subjects reached HBA1c < 7.0% with liraglutide (0.6 mg: 46.5%; 0.9 mg: 71.3%) vs. placebo (14.8%). Fasting plasma glucose (FPG) levels were significantly improved with liraglutide (difference ?1.47 mmol/l and ?1.80 mmol/l with 0.6 and 0.9 mg vs. placebo; p < 0.0001). Overall safety was similar between treatments: no major hypoglycaemic episodes were reported, while 84/77/38 minor hypoglycaemic episodes occurred in the 0.6 mg/0.9 mg and placebo treatment groups (all in combination with SU), reflecting lower ambient glucose levels. No relevant change in mean body weight occurred in subjects receiving liraglutide (0.6 mg: 0.06 kg; 0.9 mg: ?0.37 kg), while mean body weight decreased in subjects receiving placebo (?1.12 kg). Conclusions: The addition of liraglutide to SU treatment for 24 weeks dose‐dependently improved glycaemic control vs. SU monotherapy, without causing major hypoglycaemia or weight gain or loss.     

Twelve weeks treatment with the DPP‐4 inhibitor,sitagliptin, prevents degradation of peptide YY and improves glucose and non‐glucose induced insulin secretion in patients with type 2 diabetes mellitus

Aim: To examine the effects of 12 weeks of treatment with the DPP‐4 inhibitor, sitagliptin, on gastrointestinal hormone responses to a standardized mixed meal and beta cell secretory capacity, measured as glucose and non‐glucose induced insulin secretion during a hyperglycaemic clamp, in patients with type 2 diabetes. Method: A double‐blinded, placebo‐controlled study over 12 weeks in which 24 patients with T2DM were randomized to receive either sitagliptin (Januvia) 100 mg qd or placebo as an add‐on therapy to metformin. In week 0, 1 and 12 patients underwent a meal test and a 90‐min 20 mM hyperglycaemic clamp with 5 g of l ‐arginine infusion. Main outcome measure was postprandial total glucagon‐like peptide 1 (GLP‐1) concentration. Additional measures were insulin and C‐peptide, glycaemic control, intact and total peptide YY (PYY) and glucose‐dependent insulinotropic polypeptide (GIP), and intact glucagon‐like peptide 2 (GLP‐2) and GLP‐1. Results: All patients [sitagliptin n = 12, age: 59.5 (39–64) years, HbA1c: 8.0 (7.3–10.0)%, BMI: 33.2 (29.3–39.4); placebo n = 12, age: 60 (31–72) years, HbA1c: 7.7 (7.1–9.8)%, BMI: 30.7 (25.7–40.5)] [median (range)] completed the trial. Sitagliptin treatment improved glycaemic control, had no effect on total GLP‐1, GIP or intact GLP‐2, but reduced total PYY and PYY_{3‐ 36}, and increased PYY_{1‐ 36} and intact incretin hormones. Sitagliptin improved first and second phases of beta cell secretion and maximal secretory capacity. All effects were achieved after 1 week. No significant changes occurred in the placebo group. Conclusion: The postprandial responses of total GLP‐1 and GIP and intact GLP‐2 were unaltered. PYY degradation was prevented. Glucose and non‐glucose induced beta cell secretion was improved. There was no difference in responses to sitagliptin between 1 and 12 weeks of treatment.     

Enteral supplementation with glutamine,fiber, and oligosaccharide modulates incretin and glucagon‐like peptide‐2 secretion

Aims/Introduction

A dietary supplementation product enriched with glutamine, dietary fiber and oligosaccharide (GFO) is widely applied for enteral nutrition support in Japan. The aim of the present study was to evaluate the effects of GFO ingestion on secretion of incretins, gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and glucagon-like peptide-2 (GLP-2).

Materials and Methods

We carried out a cross-over study involving 20 healthy Japanese volunteers. The participants received GFO or 17 g of glucose, the equivalent carbohydrate in GFO as the control. Plasma glucose, serum insulin, and plasma total GIP, total GLP-1 and total GLP-2 levels during GFO or glucose loading were determined.

Results

GFO loading produced significantly higher plasma GLP-1 levels at 30 min and 60 min, area under the curve-GLP-1 value, and area under the curve-GLP-2 value after administration compared with those by glucose loading. In contrast, plasma GIP levels at both 30 and 60 min, and area under the curve-GIP value after glucose loading were significantly higher than those after GFO loading.

Conclusions

These results show that GFO ingestion stimulates GLP-1 and GLP-2 secretion, and reduces GIP secretion compared with glucose ingestion. Therefore, GFO could have an intestinotrophic effect as well as an ameliorating effect on metabolic disorders through modification of release of gut hormones.