glucagon-like-peptide-1 and Hypoglycemia

The objective of the review led to the pursuit of adopting dipeptidyl peptidase-4 inhibitors (DPP4i) as a novel pharmacotherapy in diabetes mellitus (DM) and cardiorenal syndrome (CRS). The CRS is defined as the co-existence of myocardial ischemia with renal failure. At present, the commercially available drugs enhance insulin secretion or action. However, most of the drugs are associated with adverse effects, such as weight gain or hypoglycemia. As a result, newer therapies with better safety and efficacy profiles are being explored. The DPP4 protease enzyme is involved in cardiovascular and renal diseases in association with over-expressed cytokines. The novel characteristic of DPP4i is to control the elevated blood glucose levels in response to nutrient ingestion without causing hypoglycemia. Also, DPP4i are indirectly involved in reducing myocardial ischemia by promoting cardioprotective peptides. They protect the glucagon-like peptide 1 (GLP-1) from the deteriorating effect of the DPP4 enzyme. The GLP-1 receptors (GLP-1R) are abundantly expressed in renal and cardiovascular tissue. The overexpression of GLP-1R will confer protection of the heart and kidney during CRS. DPP4i were found to significantly clear plasma glucose by the simultaneously activating natural thrombolytic system and increasing insulin levels. They can be used in the early stages of the disease, including pre-diabetes or obesity combined with impaired incretin response, while the combination of DPP4i with metformin or thiazolidinediones as insulin sensitizers offers an additional improvement in the treatment of DM. With its positive attributes in a host of associated parameters of interest, DPP4i are studied extensively in the present review.

Topics: Cardio-Renal Syndrome; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucose; Homeostasis; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Myocardial Ischemia

2022 corresponds to the 100th anniversary of the discovery of glucagon. This TimeCapsule aims to recall the main steps leading to the discovery, characterisation, and clinical importance of the so-called second pancreatic hormone. We describe the early historical findings in basic research (ie, discovery, purification, structure, α-cell origin, radioimmunoassay, glucagon gene [GCG], and glucagon receptor [GLR]), in which three future Nobel Prize laureates were actively involved. Considered as an anti-insulin hormone, glucagon was rapidly used to treat insulin-induced hypoglycaemic coma episodes in people with type 1 diabetes. A key step in the story of glucagon was the discovery of its role and the role of α cells in the physiology and pathophysiology (ie, paracrinopathy) of type 2 diabetes. This concept led to the design of different strategies targeting glucagon, among which GLP-1 receptor (GLP1R) agonists were a major breakthrough, and combination of inhibition of glucagon secretion with stimulation of insulin secretion (both in a glucose-dependent manner). Taking advantage of the glucagon-induced increase in energy metabolism, biased coagonists were developed. Besides the GLP-1 receptor, these coagonists also target the glucagon receptor to further promote weight loss. Thus, the 100-year story of glucagon has most probably not come to an end.

Topics: Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Receptors, Glucagon

Tirzepatide is a novel dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 receptor agonist (GLP-1 RA). At present, there is no controversy over its effectiveness, but its safety. We conducted a systematic review to assess the safety of tirzepatide.. We searched PubMed, Embase and Cochrane databases for randomized controlled trials (RCTs) of tirzepatide from databases inception to August 28, 2022 and used the Cochrane Systematic Assessment Manual Risk of Bias Assessment Tool (version 5.1) and modified Jadad scale to assess risk of bias. The systematic review was conducted. Nine RCTs with a total of 9818 patients were included. The overall safety profile of tirzepatide is similar to GLP-1RAs, except for the hypoglycemia (tirzepatide 15mg, pooled RR=3.83, 95% CI [1.19- 12.30],. The safety profile of tirzepatide is generally acceptable, similar to GLP-1 RAs. It is necessary to pay attention to its specific adverse events (hypoglycemia and discontinuation) at high doses (10mg or higher). Nausea, vomiting, diarrhea, discontinuation and injection-site reaction were dose-dependence among specific dose ranges.As the heterogeneity in different studies by interventions, the results may be with biases and the further confirmation is needed. Meanwhile, more well-designed trials are needed to control the confounding factors and ensure adequate sample size.

Topics: Diabetes Mellitus, Type 2; Diarrhea; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Nausea; Vomiting

Fasting during Ramadan is obligatory for adult Muslims, except those who have a medical illness. Many Muslims with type 2 diabetes (T2DM) choose to fast, which may increase their risks of hypoglycaemia and dehydration.. To assess the effects of interventions for people with type 2 diabetes fasting during Ramadan.. We searched CENTRAL, MEDLINE, PsycINFO, CINAHL, WHO ICTRP and ClinicalTrials.gov (29 June 2022) without language restrictions.. Randomised controlled trials (RCTs) conducted during Ramadan that evaluated all pharmacological or behavioural interventions in Muslims with T2DM.. Two authors screened and selected records, assessed risk of bias and extracted data independently. Discrepancies were resolved by a third author. For meta-analyses we used a random-effects model, with risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes with their associated 95% confidence intervals (CIs). We assessed the certainty of evidence using the GRADE approach.. We included 17 RCTs with 5359 participants, with a four-week study duration and at least four weeks of follow-up. All studies had at least one high-risk domain in the risk of bias assessment. Four trials compared dipeptidyl-peptidase-4 (DPP-4) inhibitors with sulphonylurea. DPP-4 inhibitors may reduce hypoglycaemia compared to sulphonylureas (85/1237 versus 165/1258, RR 0.53, 95% CI 0.41 to 0.68; low-certainty evidence). Serious hypoglycaemia was similar between groups (no events were reported in two trials; 6/279 in the DPP-4 versus 4/278 in the sulphonylurea group was reported in one trial, RR 1.49, 95% CI 0.43 to 5.24; very low-certainty evidence). The evidence was very uncertain about the effects of DPP-4 inhibitors on adverse events other than hypoglycaemia (141/1207 versus 157/1219, RR 0.90, 95% CI 0.52 to 1.54) and HbA1c changes (MD -0.11%, 95% CI -0.57 to 0.36) (very low-certainty evidence for both outcomes). No deaths were reported (moderate-certainty evidence). Health-related quality of life (HRQoL) and treatment satisfaction were not evaluated. Two trials compared meglitinides with sulphonylurea. The evidence is very uncertain about the effect on hypoglycaemia (14/133 versus 21/140, RR 0.72, 95% CI 0.40 to 1.28) and HbA1c changes (MD 0.38%, 95% CI 0.35% to 0.41%) (very low-certainty evidence for both outcomes). Death, serious hypoglycaemic events, adverse events, treatment satisfaction and HRQoL were not evaluated. One trial compared sodium-glucose co-transporter-2 (SGLT-2) inhibitors with sulphonylurea. SGLT-2 may reduce hypoglycaemia compared to sulphonylurea (4/58 versus 13/52, RR 0.28, 95% CI 0.10 to 0.79; low-certainty evidence). The evidence was very uncertain for serious hypoglycaemia (one event reported in both groups, RR 0.90, 95% CI 0.06 to 13.97) and adverse events other than hypoglycaemia (20/58 versus 18/52, RR 1.00, 95% CI 0.60 to 1.67) (very low-certainty evidence for both outcomes). SGLT-2 inhibitors result in little or no difference in HbA1c (MD 0.27%, 95% CI -0.04 to 0.58; 1 trial, 110 participants; low-certainty evidence). Death, treatment satisfaction and HRQoL were not evaluated. Three trials compared glucagon-like peptide 1 (GLP-1) analogues with sulphonylurea. GLP-1 analogues may reduce hypoglycaemia compared to sulphonylurea (20/291 versus 48/305, RR 0.45, 95% CI 0.28 to 0.74; low-certainty evidence). The evidence was very uncertain for serious hypoglycaemia (0/91 versus 1/91, RR 0.33, 95% CI 0.01 to 7.99; very low-certa. There is no clear evidence of the benefits or harms of interventions for individuals with T2DM who fast during Ramadan. All results should be interpreted with caution due to concerns about risk of bias, imprecision and inconsistency between studies, which give rise to low- to very low-certainty evidence. Major outcomes, such as mortality, health-related quality of life and severe hypoglycaemia, were rarely evaluated. Sufficiently powered studies that examine the effects of various interventions on these outcomes are needed.

Topics: Adult; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Fasting; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Insulin

Bariatric surgery is the most effective treatment in individuals with obesity to achieve remission of type 2 diabetes. Post-bariatric surgery hypoglycaemia occurs frequently, and management remains suboptimal, because of a poor understanding of the underlying pathophysiology. The glucoregulatory hormone responses to nutrients in individuals with and without post-bariatric surgery hypoglycaemia have not been systematically examined.. The study protocol was prospectively registered with PROSPERO. PubMed, EMBASE, Web of Science and the Cochrane databases were searched for publications between January 1990 and November 2021 using MeSH terms related to post-bariatric surgery hypoglycaemia. Studies were included if they evaluated individuals with post-bariatric surgery hypoglycaemia and included measurements of plasma glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), insulin, C-peptide and/or glucagon concentrations following an ingested nutrient load. Glycated haemoglobin (HbA. From 377 identified publications, 12 were included in the analysis. In all 12 studies, the type of bariatric surgery was Roux-en-Y gastric bypass (RYGB). Comparing individuals with and without post-bariatric surgery hypoglycaemia following an ingested nutrient load, the standardised mean difference in peak GLP-1 was 0.57 (95% CI, 0.32, 0.82), peak GIP 0.05 (-0.26, 0.36), peak insulin 0.84 (0.44, 1.23), peak C-peptide 0.69 (0.28, 1.1) and peak glucagon 0.05 (-0.26, 0.36). HbA. Following RYGB, postprandial peak plasma GLP-1, insulin and C-peptide concentrations are greater in individuals with post-bariatric surgery hypoglycaemia, while HbA

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Insulin

With a rise in obesity and more patients opting for bariatric surgery, it becomes crucial to understand associated complications like postprandial hypoglycemia (PPH). After bariatric surgery, significant changes are seen in insulin sensitivity, beta cell function, glucagon-like peptide 1 (GLP-1) levels, the gut microbiome, and bile acid metabolism. And in a small subset of patients, exaggerated imbalances in these functional and metabolic processes lead to insulin-glucose mismatch and hypoglycemia. The main treatment for PPH involves dietary modifications. For those that do not respond, medications or surgical interventions are considered to reverse some of the imbalances. We present a few case reports of patients that safely tolerated GLP-1 agonists. However, larger randomized control trials are needed to further characterize PPH and understand its treatment.

Topics: Bariatric Surgery; Blood Glucose; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Insulin; Obesity, Morbid

The study aims to evaluate tirzepatide's efficacy and safety in treating type 2 diabetes by meta-analysis and trial-sequential-analysis (TSA).. Eight databases were searched for clinical trials on tirzepatide for type 2 diabetes with a time limit of November 2022. Revman5.3 and TSA 0.9.5.10 Beta were selected for meta-analysis and TSA.. Compared with placebo, the meta-analysis demonstrated that tirzepatide 15 mg reduced hemoglobin-type-A1C (HbA1c) (p<0.00001), fasting-serum-glucose (FSG) (p<0.00001), and weight (p<0.00001). Compared with insulin, tirzepatide 15 mg reduced HbA1c (p<0.00001), FSG (p<0.00007), and weight (p<0.00001). Compared with glucagon-like-peptide-1 receptor-agonist (GLP-1 RA), tirzepatide 15 mg reduced HbA1c (p=0.00004), FSG (p=0.001), and weight (p<0.00001). In safety endpoints, the meta-analysis revealed that adverse events (AEs) of placebo, insulin and GLP-1 RA were comparable to tirzepatide 15 mg. The total AEs (p=0.02) and gastrointestinal (GI) AEs (p=0.03) were higher in tirzepatide 15 mg than in the placebo, while hypoglycemia (<54 mg/dl) was comparable. The major adverse cardiovascular events-4 (MACE-4) (p=0.03) and hypoglycemia (<54 mg/dl) (p<0.00001) of tirzepatide 15 mg were lower when compared to insulin, while total AEs (p=0.03) were increased. Compared with GLP-1 RA, tirzepatide 15 mg was comparable in safety endpoints in total AEs and GI AEs, while hypoglycemia (<54 mg/dl) (p=0.04) was higher. TSA indicated that HgA1c, FSG, and weight benefits were conclusive. In safety endpoints, only MACE-4 and hypoglycemia (<54 mg/dl) of Tirzepatide 15 mg vs. Insulin were conclusive. Harbord regression of AEs suggested no evident publication bias (p=0.618).. Tirzepatide 15 mg reduced HbA1c and weight more effectively than placebo, insulin, and GLP-1 RA. Total AEs were higher than placebo and insulin but comparable to GLP-1 RA. Tirzepatide 15 mg is a kind of optimal strategy to treat type 2 diabetes. However, there is a need to focus on GI AEs.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Insulin

Tirzepatide is a novel dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 receptor agonist (GLP-1 RA) currently under review for marketing approval. Individual trials have assessed the clinical profile of tirzepatide vs different comparators. We conducted a systematic review and meta-analysis to assess the efficacy and safety of tirzepatide for type 2 diabetes.. A dose-dependent superiority on glycaemic efficacy and body weight reduction was evident with tirzepatide vs placebo, GLP-1 RAs and basal insulin. Tirzepatide did not increase the odds of hypoglycaemia but was associated with increased incidence of gastrointestinal adverse events. Study limitations include presence of statistical heterogeneity in the meta-analyses for change in HbA

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Diarrhea; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulins; Treatment Outcome

Safety of sulfonylurea drugs in the treatment of Type 2 Diabetes is still under debate. The aim of this study was to compare the all-cause mortality and cardiovascular adverse events of sulfonylureas and drugs with a low risk for hypoglycaemia in adults with type 2 diabetes.. Systematic review and meta-analysis of randomised controlled trials.. MEDLINE (PubMed, OVID), Embase, Cochrane Central Register of Controlled Trials, CINAHL, WOS and Lilacs.. Randomised controlled head-to-head trials that compared sulfonylureas with active control with low hypoglycaemic potential in adults (≥ 18 years old) with type 2 diabetes published up to August 2015. The drug classes involved in the analysis were metformin, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose co-transporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists.. The primary endpoint was all-cause mortality. The secondary endpoints were MACE, cardiovascular events and severe hypoglycaemia.. Two reviewers checked study eligibility, independently extracted data and assessed quality with disagreements resolved through discussion. We assessed the risk of bias of the included studies using the Cochrane risk of bias tool for randomized trials v2. Pooled odds ratios (ORs) were estimated by using fixed effects model. The study is registered on PROSPERO (26/05/2016 CRD42016038780).. Our final analysis comprised 31 studies (26,204 patients, 11,711 patients given sulfonylureas and 14,493 given comparator drugs). In comparison to drugs with low hypoglycaemic potential, sulfonylureas had higher odds for all-cause mortality (OR 1.32, 95% CI 1.00-1.75), MACE (OR 1.32, 95% CI 1.07-1.61), myocardial infarction (fatal and non-fatal) (OR 1.67, 95% CI 1.17-2.38) and hypoglycaemia (OR 5.24, 95% CI 4.20-6.55). Subsequent sensitivity analysis revealed differences in the effect of sulfonylureas, with an increased risk of all-cause mortality with glipizide but not the other molecules.. Our meta-analysis raises concern about the safety of SUs compared to alternative drugs involved in current analysis. Important differences may exist within the drug class, and glimepiride seems to have best safety profile.

Topics: Adolescent; Adult; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Glipizide; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemia; Hypoglycemic Agents; Metformin; Sodium; Sodium-Glucose Transporter 2 Inhibitors; Symporters

To assess the available literature evaluating the efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) with multiple daily insulin injections (MDII).. A literature search of MEDLINE and Embase was performed (2004 to May 2020) using the following search terms: glucagon-like 1 receptor agonist, liraglutide, albiglutide, dulaglutide, exenatide, semaglutide, diabetes mellitus, and prandial insulin or bolus insulin. Additional references were obtained from cross-referencing the bibliographies of selected articles.. All information obtained from the searches were reviewed. All relevant trials are included in this review.. Eight studies met criteria for inclusion. The addition of a GLP-1 RA to multiple daily insulin injections was associated with a reduction in A1c in 7 out of 8 studies, and weight loss in 5 studies. In studies that allowed insulin adjustment after the addition of GLP-1 RA, the average total daily insulin dose was reduced in 3 studies. When evaluated, hypoglycemia frequency or other adverse events were not increased when GLP-1 RAs were added to MDII.. Guidelines do not offer recommendations regarding the use of GLP-1 RAs in combination with MDII regimens. This review evaluates current studies demonstrating efficacy and safety considerations of this combination.. While some studies did demonstrate an improvement in A1c and reduction in insulin doses without increased hypoglycemia, larger randomized controlled trials are needed to adequately assess the benefit and safety of GLP-1 RAs in combination with MDII.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin

GLP-1 receptor agonists (GLP-1 RAs) with exenatide b.i.d. first approved to treat type 2 diabetes in 2005 have been further developed to yield effective compounds/preparations that have overcome the original problem of rapid elimination (short half-life), initially necessitating short intervals between injections (twice daily for exenatide b.i.d.).. To summarize current knowledge about GLP-1 receptor agonist.

Topics: Animals; Blood Glucose; Body Weight; Cardiovascular System; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemia; Immunoglobulin Fc Fragments; Insulin; Liraglutide; Neurodegenerative Diseases; Peptides; Psoriasis; Recombinant Fusion Proteins

Pancreatic α-cells are the major source of glucagon, a hormone that counteracts the hypoglycemic action of insulin and strongly contributes to the correction of acute hypoglycemia. The mechanisms by which glucose controls glucagon secretion are hotly debated, and it is still unclear to what extent this control results from a direct action of glucose on α-cells or is indirectly mediated by β- and/or δ-cells. Besides its hyperglycemic action, glucagon has many other effects, in particular on lipid and amino acid metabolism. Counterintuitively, glucagon seems also required for an optimal insulin secretion in response to glucose by acting on its cognate receptor and, even more importantly, on GLP-1 receptors. Patients with diabetes mellitus display two main alterations of glucagon secretion: a relative hyperglucagonemia that aggravates hyperglycemia, and an impaired glucagon response to hypoglycemia. Under metabolic stress states, such as diabetes, pancreatic α-cells also secrete GLP-1, a glucose-lowering hormone, whereas the gut can produce glucagon. The contribution of extrapancreatic glucagon to the abnormal glucose homeostasis is unclear. Here, I review the possible mechanisms of control of glucagon secretion and the role of α-cells on islet function in healthy state. I discuss the possible causes of the abnormal glucagonemia in diabetes, with particular emphasis on type 2 diabetes, and I briefly comment the current antidiabetic therapies affecting α-cells.

Topics: Animals; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Secreting Cells; Glucose; Humans; Hypoglycemia; Insulin

The latest recommendations from the American Diabetes Association and the European Association for the Study of Diabetes prioritize the use of drugs with proven cardiovascular (CV) benefit in patients with established CV disease. Especially among the glucagon-like peptide (GLP)-1 receptor agonists (GLP-1RA) class, results of cardiovascular outcomes trials (CVOT) have been heterogeneous. Baseline characteristics of the population, study design, drugs in the control arm, modifications of CV risk factors, including glycemic control, reduction of hypoglycemia, and the GLP-1RA direct effects on CV cells and tissues, were considered. Ultimately, the time of exposure to the GLP-1RA appears to be the factor most prominently explaining trial heterogeneity. Thus, the CV benefit should be regarded as a class effect of GLP-1RA, as largely similar results are seen for drugs sharing a common mechanism of action.

Topics: Animals; Cardiovascular Diseases; Cardiovascular System; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia

Recent literature suggests dietary glutamine supplementation may lower blood glucose in patients with type 1 diabetes (T1D), who have no residual insulin secretion. The mechanisms and potential relevance to the care of T1D remain unclear.. Glutamine is involved in multiple pathways including gluconeogenesis, lipolysis, antioxidant defense, the production of nitric oxide, the secretion of peptides (e.g., glucagon-like peptide 1, GLP-1), or neuromediators (e.g., [Latin Small Letter Gamma]-aminobutyric acid), all processes that may impact insulin sensitivity and/or glucose homeostasis. The article reviews potential mechanisms and literature evidence suggesting a role in improving glucose tolerance in patients with illness associated with insulin resistance, as well as the preliminary evidence for the increased incidence of postexercise hypoglycemia in T1D after oral glutamine.. Further studies are warranted to determine whether the lowering effect of glutamine on blood glucose is sustained over time. If so, long-term randomized trials would be warranted to determine whether there is a role for glutamine as an adjunct dietary supplement to improve glucose control in patients with T1D.

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Glucagon-Like Peptide 1; Gluconeogenesis; Glutamine; Glutathione; Homeostasis; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Secretion; Randomized Controlled Trials as Topic

Diabetes mellitus affects over 20% of people aged > 65 years. With the population of older people living with diabetes growing, the condition may be only one of a number of significant comorbidities that increases the complexity of their care, reduces functional status and inhibits their ability to self-care. Coexisting comorbidities may compete for the attention of the patient and their healthcare team, and therapies to manage comorbidities may adversely affect a person's diabetes. The presence of renal or liver disease reduces the types of antihyperglycemic therapies available for use. As a result, insulin and sulfonylurea-based therapies may have to be used, but with caution. There may be a growing role for sodium-glucose co-transporter 2 (SGLT-2) inhibitors in diabetic renal disease and for glucagon-like peptide (GLP)-1 therapy in renal and liver disease (nonalcoholic steatohepatitis). Cancer treatments pose considerable challenges in glucose therapy, especially the use of cyclical chemotherapy or glucocorticoids, and cyclical antihyperglycemic regimens may be required. Clinical trials of glucose lowering show reductions in microvascular and, to a lesser extent, cardiovascular complications of diabetes, but these benefits take many years to accrue, and evidence specifically in older people is lacking. Guidelines recognize that clinicians managing patients with type 2 diabetes mellitus need to be mindful of comorbidity, particularly the risks of hypoglycemia, and ensure that patient-centered therapeutic management of diabetes is offered. Targets for glucose control need to be carefully considered in the context of comorbidity, life expectancy, quality of life, and patient wishes and expectations. This review discusses the role of chronic kidney disease, chronic liver disease, cancer, severe mental illness, ischemic heart disease, and frailty as comorbidities in the therapeutic management of hyperglycemia in patients with type 2 diabetes mellitus.

Topics: Comorbidity; Diabetes Mellitus, Type 2; Drug Therapy, Combination; End Stage Liver Disease; Frailty; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Insulin; Mental Disorders; Myocardial Ischemia; Neoplasms; Quality of Life; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors

Once-weekly (OW) glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated improved glycemic control in patients with type 2 diabetes (T2D), and some have a number of other benefits, including weight loss, improvements in blood pressure and lipid profiles, and cardiovascular protection. They also provide a therapy option with a low risk of hypoglycemia, an attractive choice for many patients. Molecular structure and pharmacokinetic properties vary among GLP-1 RAs, with some more closely related than others to native glucagon-like peptide-1 (GLP-1). OW GLP-1 RAs have various modifications to their molecular structure that make the molecules resistant to degradation by dipeptidyl peptidase-4 (DPP-4), increasing the half-life of these drugs and making them suitable for OW administration. These differences in the molecular structures and pharmacokinetic properties between the various OW GLP-1 RAs help to explain the differences in efficacy, mechanisms, and safety profiles among the drugs, and these considerations can help primary care physicians to optimize prescribing practices.

Topics: Delayed-Action Preparations; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Monitoring; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Randomized Controlled Trials as Topic

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are indicated for restoring normoglycemia in patients with type 2 diabetes (T2D). This review analyzed and compared the efficacy results from 30 trials with the once-weekly (OW) GLP-1 RAs albiglutide, dulaglutide, exenatide extended-release (ER) and semaglutide. The 4 OW GLP-1 RAs showed a higher reduction in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG) and body weight, when compared to placebo. Semaglutide significantly reduced the HbA1c level (estimated treatment difference [ETD]: -0.62%; 95% confidence interval [CI], -0.79 to -0.44; P<0.0001), FPG (ETD: -15 mmol/L; 95% CI, -22 to -8.3; P<0.0001) and body weight (ETD: -3.73 kg; 95% CI, -4.53 to -2.93; P<0.0001) compared with exenatide ER. A direct comparison between OW, once-daily (OD), and twice-daily (BD) GLP-1 RAs indicated some trends in efficacy, for example, with OD liraglutide, providing a significant reduction in body weight vs albiglutide (ETD: 1.55 kg; 95% CI, 1.05-2.06; P<0.0001 for albiglutide), dulaglutide (ETD: 0.71 kg; 95% CI, 0.17 -1.26; P=0.011 for dulaglutide), and exenatide ER (ETD: 0.90 kg; 95% CI, 0.39- 1.40; P=0.0005 for exenatide ER). OW GLP-1 RAs also offered improved glycemic control when compared with the dipeptidyl peptidase-4 inhibitor sitagliptin. In conclusion, OW GLP-1 RAs offer a valid therapeutic option for T2D.

Topics: Blood Glucose; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Monitoring; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Treatment Outcome

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been found efficacious in the treatment of type 2 diabetes (T2D), demonstrating the ability to lower HbA1c, and having the potential for inducing weight loss and reducing the risk of hypoglycemia, compared with other antihyperglycemic agents. Currently, 4 once-weekly (OW) GLP-1 RAs are approved: albiglutide, dulaglutide, exenatide ER, and recently, semaglutide. This review compares the relative safety of OW GLP-1 RAs, as well as their safety in comparison to other antihyperglycemic agents, using safety data reported in key sponsor-led phase 3 studies of the 4 OW GLP-1 RAs. The favorable safety profiles of OW GLP-1 RAs, added to their efficacy and the favorable weekly dosing regimen, make these agents appropriate options for patients with T2D. However, there are key differences within this class of drugs in macrovascular, microvascular, gastrointestinal and injection-site reaction adverse events, and these should be considered when healthcare providers are prescribing therapy.

Topics: Blood Glucose; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Monitoring; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Treatment Outcome

Roux-en-Y gastric bypass (RYGB) is an efficient treatment for morbid obesity and reduces obesity-related co-morbidities. With the growing number of patients undergoing gastric bypass, complications now demand further attention. Postprandial hyperinsulinemic hypoglycemia (PHH) after Roux-en-Y gastric bypass is a complex condition, characterized by increased glucose variability including both hyperglycemic and hypoglycemic values. PHH seems to be more prevalent than previously suggested and is highly dependent on the choice of diagnostic tool, which has not yet been standardized. Questionnaires, an oral glucose tolerance test, a mixed meal tolerance test, and continuous glucose monitoring have been used, each with their own advantages. The condition is further complicated by a large group of asymptomatic cases. Patients with symptoms of PHH after gastric bypass are characterized by exaggerated insulin and glucagon-like peptide-1 responses compared to asymptomatic operated patients. The counter-regulatory mechanisms responsible for preventing hypoglycemia appear to be altered. The cause of these changes is not entirely understood, and it remains difficult to identify patients at risk of developing hypoglycemia. Known risk factors are female sex, longer time since surgery, and lack of prior diabetes. Management of the hypoglycemic episodes is difficult, and only dietary modifications consisting of frequent and less carbohydrate-rich meals seem to be efficient. Medical treatments and surgical procedures have been attempted in few studies and still warrant further examination.

Topics: Biomarkers; Blood Glucose; Female; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Male; Monitoring, Ambulatory; Obesity, Morbid; Postoperative Complications; Postprandial Period; Risk Factors; Sex Factors

To compare efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in people with type 2 diabetes.. We electronically searched, up to June 3, 2016, published randomized clinical trials lasting between 24 and 32 weeks that compared a GLP-1RA (albiglutide, dulaglutide, twice-daily exenatide and once-weekly exenatide, liraglutide, lixisenatide, semaglutide and taspoglutide) with placebo or another GLP-1RA. Data on cardiometabolic and safety outcomes were analysed using a mixed-treatment comparison meta-analysis.. A total of 34 trials (14 464 participants) met the inclusion criteria; no published data for semaglutide were available. Compared with placebo, all GLP-1RAs reduced glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG) levels (reductions ranged from -0.55% and -0.73 mmol/L, respectively, for lixisenatide to -1.21% and -1.97 mmol/L, respectively, for dulaglutide). There were no differences within short-acting (twice-daily exenatide and lixisenatide) or long-acting (albiglutide, dulaglutide, once-weekly exenatide, liraglutide and taspoglutide) groups. Compared with twice-daily exenatide, dulaglutide treatment was associated with the greatest HbA1c and FPG reduction (0.51% and 1.04 mmol/L, respectively), followed by liraglutide (0.45% and 0.93 mmol/L, respectively) and once-weekly exenatide (0.38% and 0.85 mmol/L, respectively); similar reductions were found when these 3 agents were compared with lixisenatide. Compared with placebo, all GLP-1RAs except albiglutide reduced weight and increased the risk of hypoglycaemia and gastrointestinal side effects, and all agents except dulaglutide and taspoglutide reduced systolic blood pressure. When all GLP-1RAs were compared with each other, no clinically meaningful differences were observed in weight loss, blood pressure reduction or hypoglycaemia risk. Albiglutide had the lowest risk of nausea and diarrhoea and once-weekly exenatide the lowest risk of vomiting.. The RCTs in the present analysis show that all GLP-1RAs improve glycaemic control, reduce body weight and increase the risk of adverse gastrointestinal symptoms compared with placebo. Although there were no differences when short-acting agents were compared with each other or when long-acting agents were compared with each other, dulaglutide, liraglutide and once-weekly exenatide were superior to twice-daily exenatide and lixisenatide at lowering HbA1c and FPG levels. There were no differences in hypoglycaemia between these 3 agents, whilst once-weekly exenatide had the lowest risk of vomiting. These results, along with patient's preferences and individualized targets, should be considered when selecting a GLP-1RA.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Incretins; Liraglutide; Male; Middle Aged; Peptides; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Treatment Outcome; Venoms

Incretin-based agents, including dipeptidyl peptidase-4 inhibitors (DPP-4Is) and glucagon-like peptide-1 agonists (GLP-1As), work via GLP-1 receptor for hyperglycemic control directly or indirectly, but have different effect on cardiovascular (CV) outcomes. The present study is to evaluate and compare effects of incretin-based agents on CV and pancreatic outcomes in patients with type 2 diabetes mellitus (T2DM) and high CV risk.. Six prospective randomized controlled trials (EXMAINE, SAVOR-TIMI53, TECOS, ELIXA, LEADER and SUSTAIN-6), which included three trials for DPP-4Is and three trials for GLP-1As, with 55,248 participants were selected to assess the effect of different categories of incretin-based agents on death, CV outcomes (CV mortality, major adverse CV events, nonfatal myocardial infarction, nonfatal stroke, heart failure hospitalization), pancreatic events (acute pancreatitis and pancreatic cancer) as well as on hypoglycemia.. When we evaluated the combined effect of six trials, the results suggested that incretin-based treatment had no significant effect on overall risks of CV and pancreatic outcomes compared with placebo. However, GLP-1As reduced all-cause death (RR = 0.90, 95% CI 0.82-0.98) and CV mortality (RR = 0.84, 95% CI 0.73-0.97), whereas DPP-4Is had no significant effect on CV outcomes but elevated the risk for acute pancreatitis (OR = 1.76, 95% CI 1.14-2.72) and hypoglycemia (both any and severe hypoglycemia), while GLP-1As lowered the risk of severe hypoglycemia.. GLP-1As decreased risks of all-cause and CV mortality and severe hypoglycemia, whereas DPP-4Is had no effect on CV outcomes but increased risks in acute pancreatitis and hypoglycemia.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Pancreatitis; Randomized Controlled Trials as Topic; Risk Factors; Treatment Outcome

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are injectable agents used for the treatment of hyperglycemia in type 2 diabetes. The interest for this pharmacological class is rising with the development of once weekly compounds and the demonstration of a potential reduction in cardiorenal outcomes. Areas covered: The paper describes the main pharmacokinetic/pharmacodynamic characteristics of dulaglutide, a new once-weekly GLP-1 RA. Dulaglutide was extensively investigated in the phase-3 AWARD program, which demonstrated its safety and efficacy when compared to placebo or active glucose-lowering agents in patients treated with diet alone, metformin or sulfonylurea monotherapy, oral dual therapies and basal insulin. In both Caucasian and Japanese patients, comparative trials showed better glucose control with dulaglutide, with a minimal risk of hypoglycemia and weight loss, but at the expense of an increased dropout rate due to side effects, mostly transient gastrointestinal disturbances. Dulaglutide proved its non-inferiority versus liraglutide and the safety and tolerance profile is similar to that of other GLP-1 RAs. Expert opinion: The once-weekly formulation and the combined positive effects on both glucose control and weight improves patient satisfaction despite nausea. Dulaglutide must prove its capacity to reduce cardiovascular and diabetic complications in the ongoing prospective REWIND trial.

Topics: Animals; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Insulin; Prospective Studies; Recombinant Fusion Proteins; Treatment Outcome

Bile acids are amphipathic water-soluble steroid-based molecules best known for their important lipid-solubilizing role in the assimilation of fat. Recently, bile acids have emerged as metabolic integrators with glucose-lowering potential. Among a variety of gluco-metabolic effects, bile acids have been demonstrated to modulate the secretion of the gut-derived incretin hormone glucagon-like peptide-1 (GLP-1), possibly via the transmembrane receptor Takeda G-protein-coupled receptor 5 and the nuclear farnesoid X receptor, in intestinal L cells. The present article critically reviews current evidence connecting established glucose-lowering drugs to bile acid-induced GLP-1 secretion, and discusses whether bile acid-induced GLP-1 secretion may constitute a new basis for understanding how metformin, inhibitors of the apical sodium-dependent bile acids transporter, and bile acid sequestrants - old, new and neglected glucose-lowering drugs - improve glucose metabolism.

Topics: Animals; Bile Acids and Salts; Diabetes Mellitus, Type 2; Enteroendocrine Cells; Evidence-Based Medicine; Gastrointestinal Agents; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Models, Biological

Hypoglycaemia after gastric bypass can be severe, but is uncommon, and is sometimes only revealed through monitoring glucose concentrations. The published literature is limited by the heterogeneity of the criteria used for diagnosis, arguing in favour of the Whipple triad with a glycaemia threshold of 55 mg/dl as the diagnostic reference. Women who lost most of their excess weight after gastric bypass, long after the surgery was performed, and who did not have diabetes before surgery are at the greatest risk. In this context, hypoglycaemia results from hyperinsulinism, which is either generated by pancreas anomalies (nesidioblastosis) and/or caused by an overstimulation of β cells by incretins, mainly glucagon-like peptide-1 (GLP-1). Glucose absorption is both accelerated and increased because of the direct communication between the gastric pouch and the jejunum. This is a post-surgical exaggeration of a natural adaptation that is seen in patients who have not undergone surgery in whom glucose is infused directly into the jejunum. There is not always a correspondence between symptoms and biological traits; however, hyperinsulinism is constant if hypoglycaemia is severe and there are neuroglucopenic symptoms. The treatment relies firstly on changes in eating habits, splitting food intake into five to six daily meals, slowing gastric emptying, reducing the glycaemic load and glycaemic index of foods, using fructose and avoiding stress at meals. Pharmacological treatment with acarbose is efficient, but other drugs still need to be validated in a greater number of subjects (insulin, glucagon, calcium channel blockers, somatostatin analogues and GLP-1 analogues). Lastly, if the surgical option has to be used, the benefits (efficient symptom relief) and the risks (weight regain, diabetes) should be weighed carefully.

Topics: Acarbose; Adaptation, Physiological; Adult; Blood Glucose; Diet Therapy; Female; Gastric Bypass; Glucagon-Like Peptide 1; Glycoside Hydrolase Inhibitors; Humans; Hyperinsulinism; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin-Secreting Cells; Jejunum; Male

Pancreatic islet α-cell tumours that overexpress proglucagon are typically associated with the glucagonoma syndrome, a rare disease entity characterised by necrolytic migratory erythema, impaired glucose tolerance, thromboembolic complications and psychiatric disturbances. Paraneoplastic phenomena associated with enteric overexpression of proglucagon-derived peptides are less well recognized and include gastrointestinal dysfunction and hyperinsulinaemic hypoglycaemia. The diverse clinical manifestations associated with glucagon-expressing tumours can be explained, in part, by the repertoire of tumorally secreted peptides liberated through differential post-translational processing of tumour-derived proglucagon. Proglucagon-expressing tumours may be divided into two broad biochemical subtypes defined by either secretion of glucagon or GLP-1, GLP-2 and the glucagon-containing peptides, glicentin and oxyntomodulin, due to an islet α-cell or enteroendocrine L-cell pattern of proglucagon processing, respectively. In the current review we provide an updated overview of the clinical presentation of proglucagon-expressing tumours in relation to known physiological actions of proglucagon-derived peptides and suggest that detailed biochemical characterisation of the peptide repertoire secreted from these tumours may provide new opportunities for diagnosis and clinical management.

Topics: Animals; Gastrointestinal Diseases; Gene Expression Regulation; Glicentin; Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Glucagonoma; Humans; Hypoglycemia; Islets of Langerhans; Oxyntomodulin; Pancreas; Pancreatic Neoplasms; Peptide Fragments; Peptides; Phenotype; Proglucagon; Protein Domains

Bariatric surgery is a highly effective treatment for severe obesity, resulting in substantial weight loss and normalizing obesity-related comorbidities. However, long-term consequences can occur, such as postbariatric surgery hypoglycaemia. This is a challenging medical problem, and the number of patients presenting with it has been increasing. Roux-en-Y gastric bypass (RYGB) is the most popular bariatric procedure, and it is the surgery most commonly associated with the development of postbariatric surgery hypoglycaemia. To date, the pathogenesis of this condition has not been completely established. However, various factors - particularly increased postprandial glucagon-like peptide (GLP)-1 secretion - have been considered as crucial mediator. The mechanisms responsible for diabetic remission after bariatric surgery may be responsible for the development of hypoglycaemia, which typically occurs 1-3 h after a meal and is concurrent with inappropriate hyperinsulinaemia. Carbohydrate-rich foods usually provoke hypoglycaemic symptoms, which can typically be alleviated by strict dietary modifications, including carbohydrate restriction and avoidance of high glycaemic index foods and simple sugars. Few patients require further medical intervention, such as medications, but some patients have required a pancreatectomy. Because this option is not always successful, it is no longer routinely recommended. Clinical trials are needed to further determine the pathophysiology of this condition as well as the best diagnostic and treatment approaches for these patients.

Topics: Diet Therapy; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Postprandial Period

Obesity is a major public health problem worldwide. Obesity-related illnesses, such as coronary heart disease, type 2 diabetes, hypertension, dyslipidemia, stroke, sleep apnea, and several forms of cancer (endometrial, breast, and colon), contribute to a significant number of deaths in the USA. Bariatric surgery, including the Roux-en-Y gastric bypass (RYGB) procedure, has demonstrated significant improvements in obesity and obesity-related co-morbidities and is becoming more popular as the number of obese individuals rises. Despite the reported benefits of bariatric surgery, there are potential complications that physicians need to be aware of as the number of patients undergoing these procedures continues to increase. One challenging and potentially life-threatening complication that to date is not well understood is post-RYGB surgery hypoglycemia (PGBH). In this review, we will present the definition, historical perspective, diagnostic approach, currently available treatment options, and anecdotal assessment and treatment algorithm for this disorder.

Topics: Gastric Bypass; Glucagon-Like Peptide 1; Humans; Hypertension; Hypoglycemia; Incretins; Obesity

The hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted by enteroendocrine cells in the intestinal mucosa in response to nutrient ingestion. They are called incretin hormones because of their ability to enhance insulin secretion. However, in recent years it has become clear that the incretin hormones also affect glucagon secretion. While GLP-1 decreases glucagon levels, the effect of GIP on glucagon levels has been unclear. The regulation of glucagon secretion is interesting, as the combination of inadequate insulin secretion and excessive glucagon secretion are essential contributors to the hyperglycaemia that characterise patients with type 2 diabetes. Moreover, the near absence of a well-timed glucagon response contributes to an increased risk of hypoglycaemia in patients with type 1 diabetes. The overall aim of this PhD thesis was to investigate how the blood glucose level affects the glucagon and insulin responses to GIP in healthy subjects (Study 1) and patients with Type 2 diabetes (Study 2), and more specifically to investigate the effects of GIP and GLP-1 at low blood glucose in patients with Type 1 diabetes without endogenous insulin secretion (Study 3). The investigations in the three mentioned study populations have been described in three original articles. The employed study designs were in randomised, placebo-controlled, crossover set-up, in which the same research subject is subjected to several study days thereby acting as his own control. Interventions were intravenous administration of hormones GIP, GLP-1 and placebo (saline) during different blood glucose levels maintained (clamped) at a certain level. The end-points were plasma concentrations of glucagon and insulin as well as the amount of glucose used to clamp the blood glucose levels. In Study 3, we also used stable glucose isotopes to estimate the endogenous glucose production and assessed symptoms and cognitive function during hypoglycaemia. The results from the three studies indicate that GIP has effects on insulin and glucagon responses highly dependent upon the blood glucose levels. At fasting glycaemia and lower levels of glycaemia, GIP acts to increase glucagon with little effect on insulin release. At hyperglycaemia the insulin releasing effect of GIP prevail, which lead to an increase in glucose disposal by approximately 75% in healthy subjects (Study 1) and 25% in patients with Type 2 diabetes (Study 2) relative to

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemia; Insulin; Insulin Secretion; Male; Randomized Controlled Trials as Topic

Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel, potent oral antihyperglycemic agents that reduce degradation of endogenous glucagon-like peptide 1 (GLP-1) to increase insulin secretion and satiety and decrease glucagon. DPP-4 inhibitors enhance insulin secretion in a glucose-dependent manner, which potentially reduces hypoglycemia risks during monotherapy or combination therapy with other antidiabetic agents. Evogliptin (Suganon(TM)) is a new oral DPP-4 inhibitor developed for the treatment of patients with type 2 diabetes inadequately controlled by diet and exercise.. This review summarizes the collected data concerning mechanism of action, clinical efficacy, and safety of evogliptin in improving glycemic control in patients with type 2 diabetes. Additional non-glycemic benefits and safety profiles of evogliptin are also discussed.. Evogliptin is effective in improving glycosylated hemoglobin (HbA1c) and fasting plasma glucose without inducing hypoglycemia events, which potentially can improve adherence and prevent complications. It is also found that evogliptin has benefits on insulin secretory and β-cell functions. Based on the current clinical data, evogliptin has a neutral effect on body weight. These attributes contribute to the clinical practice in monotherapy or in combination with other antidiabetic agents.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glucose; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Piperazines

To review the use of GLP-1 agonists in patients with type 1 diabetes mellitus (T1DM).. A search using the MEDLINE database, EMBASE, and Cochrane Database was performed through March 2016 using the search terms glucagon-like peptide 1 (GLP-1) agonists, incretin, liraglutide, exenatide, albiglutide, dulaglutide, type 1 diabetes mellitus. All English-language trials that examined glycemic end points using GLP-1 agonists in humans with T1DM were included.. A total of 9 clinical trials examining the use of GLP-1 agonists in T1DM were identified. On average, hemoglobin A1C (A1C) was lower than baseline, with a maximal lowering of 0.6%. This effect was not significant when tested against a control group, with a relative decrease in A1C of 0.1% to 0.2%. In all trials examined, reported hypoglycemia was low, demonstrating no difference when compared with insulin monotherapy. Weight loss was seen in all trials, with a maximum weight loss of 6.4 kg over 24 weeks. Gastrointestinal adverse effects are potentially limiting, with a significant number of patients in trials reporting nausea.. The use of GLP-1 agonists should be considered in T1DM patients who are overweight or obese and not at glycemic goals despite aggressive insulin therapy; however, tolerability of these agents is a potential concern. Liraglutide has the strongest evidence for use and would be the agent of choice for use in overweight or obese adult patients with uncontrolled T1DM.

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Incretins; Liraglutide; Peptides; Recombinant Fusion Proteins; Venoms

The treatment of patients with type 2 diabetes mellitus remains challenging, as it goes beyond adequate glycemic control, in particular addressing weight, blood pressure and other contributors to cardiovascular disease. In addition, the progressive nature of type 2 diabetes mellitus demands the intensification and combination of glucose lowering therapies. In many patients, there is a clinical inertia for the initiation of insulin therapy, leading to failure in reaching glycemic targets in many patients.. Recently a fixed-ratio combination therapy of the basal insulin degludec and the glucagon-like peptide-1 analogue liraglutide has been developed and approved by the EMA. The rationale for this combination, as well as an overview of the published phase III clinical trials (DUAL I,II,V), are covered, highlighting the most important conclusions.. The combination therapy of insulin degludec and liraglutide is an attractive therapeutic strategy in patients with type 2 diabetes mellitus as it gives a robust glycemic control with a low risk for hypoglycemia and less weight gain or even weight loss. The fixed-ratio combination of insulin degludec and liraglutide offers a smart therapeutic strategy in patients with type 2 diabetes mellitus where basal insulin needs to be initiated or intensified.

Topics: Animals; Blood Glucose; Blood Pressure; Body Weight; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Combinations; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin, Long-Acting; Liraglutide; Weight Gain

Bariatric surgery is the most effective treatment for obesity and diabetes. The 2 most commonly performed weight-loss procedures, Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy, improve glycemic control in patients with type 2 diabetes independent of weight loss. One of the early hypotheses raised to explain the immediate antidiabetic effect of RYGB was that rapid delivery of nutrients from the stomach pouch into the distal small intestine enhances enteroinsular signaling to promote insulin signaling. Given the tenfold increase in postmeal glucagon-like peptide-1 (GLP-1) response compared to unchanged integrated levels of postprandial glucose-dependent insulinotropic peptide after RYGB, enhanced meal-induced insulin secretion after this procedure was thought to be the result of elevated glucose and GLP-1 levels. In this contribution to the larger point-counterpoint debate about the role of GLP-1 after bariatric surgery, most of the focus will be on RYGB.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Gastrectomy; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Secretion; Peptide Fragments; Postprandial Period; Weight Loss

Critical illness afflicts millions of people worldwide and is associated with a high risk of organ failure and death or an adverse outcome with persistent physical or cognitive deficits. Spontaneous hyperglycemia is common in critically ill patients and is associated with an adverse outcome compared to normoglycemia. Insulin is used for treating hyperglycemia in the critically ill patients but may be complicated by hypoglycemia, which is difficult to detect in these patients and which may lead to serious neurological sequelae and death. The incretin hormone, glucagon-like peptide (GLP) 1, stimulates insulin secretion and inhibits glucagon release both in healthy individuals and in patients with type 2 diabetes (T2DM). Compared to insulin, GLP-1 appears to be associated with a lower risk of severe hypoglycemia, probably because the magnitude of its insulinotropic action is dependent on blood glucose (BG). This is taken advantage of in the treatment of patients with T2DM, for whom GLP-1 analogs have been introduced during the recent years. Infusion of GLP-1 also lowers the BG level in critically ill patients without causing severe hypoglycemia. The T2DM and critical illness share similar characteristics and are, among other things, both characterized by different grades of systemic inflammation and insulin resistance. The GLP-1 might be a potential new treatment target in critically ill patients with stress-induced hyperglycemia.

Topics: Blood Glucose; Critical Illness; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion

The goal of this article was to review the safety, efficacy, and potential for utilization of the newly approved once-weekly glucagon-like peptide-1 (GLP-1) receptor agonists in the treatment of type 2 diabetes.. Published articles for Phase III trials were found by performing a MEDLINE search using the search terms exenatide, exenatide once weekly, DURATION, albiglutide, and HARMONY as key terms. Search results were restricted by using filters to include clinical trials in humans. A search of relevant diabetes journals (including Diabetes Care and Diabetologia) was also performed to find abstracts for studies that did not have complete published articles at the time of this review.. Exenatide once weekly reduced glycosylated hemoglobin (HbA1c) by -1.0% to -2.0% when used as monotherapy and add-on therapy; it also provided significant weight loss ranging from 2 to 4 kg and maintained a relatively low risk of hypoglycemia. Albiglutide was able to reduce glycosylated hemoglobin levels between -0.5% and -0.84% when used as monotherapy and in combination with other antidiabetic medications. The newest once-weekly GLP-1 receptor agonist, dulaglutide, reduced glycosylated hemoglobin levels between -0.78% and -1.51% and demonstrated noninferiority to once-daily liraglutide.. The GLP-1 receptor agonists have proven efficacy in the treatment of type 2 diabetes and may provide patients with additional nonglycemic benefits, including significant weight loss and decreased systolic blood pressure. The newer once-weekly formulations are more convenient than the BID and once-daily medications, which could improve adherence and may be more attractive to providers and patients.

Topics: Adult; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Liraglutide; Middle Aged; Peptides; Randomized Controlled Trials as Topic; Receptors, Glucagon; Recombinant Fusion Proteins; Venoms

The objective of this review was to assess glucagon-like peptide-1 receptor agonists (GLP-1 RAs), basal insulin, and premixed insulin among participants with type 2 diabetes inadequately controlled with metformin and/or a sulfonylurea.. We searched PubMed, EmBase, and the Cochrane Library to identify eligible randomized controlled trials (RCTs) for a network meta-analysis.. A total of 17 RCTs involving 5874 adult individuals were included. Compared with placebo, all three therapies showed a significant effect on achieving target glycated hemoglobin (HbA1c) (GLP-1 RAs: 31.7%, 95% CI, 24.7-38.6%; premixed insulin: 31.1%, 95% CI, 20.4-41.8%; basal insulin: 26.0%, 95% CI, 16.4-35.7%). However, there was no significant difference between the three therapies. A similar result was found in HbA1c reduction. The use of GLP-1 RAs resulted in significant body weight loss (-3.73 kg, 95% CI, -4.52 to -2.95 kg vs. basal insulin and -5.27 kg, 95% CI, -6.17 to -4.36 kg vs. premixed insulin) but there was a higher drop-out rate of participants. Premixed insulin seemed associated with more severe hypoglycemic episodes.. The three injectables had similar impact on glycemic control but other differentiating features relevant to the management of type 2 diabetes with GLP-1 RAs having the most favorable profile.

Topics: Adult; Blood Glucose; Community Networks; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Injections; Insulin; Male; Metformin; Randomized Controlled Trials as Topic; Sulfonylurea Compounds; Treatment Failure

Type 2 diabetes mellitus (T2DM) is a complex disease in which multiple organs and hormones contribute to the pathogenesis of disease. The intestinal hormone, glucagon-like peptide-1 (GLP-1), secreted in response to nutrient ingestion, increases insulin secretion from pancreatic β-cells and reduces glucagon secretion from pancreatic α-cells. GLP-1 is inactivated by the dipeptidyl peptidase-4 (DPP-4) enzyme. Saxagliptin is a DPP-4 inhibitor that prevents the degradation of endogenous GLP-1 and prolongs its actions on insulin and glucagon secretion. This article reviews the efficacy and safety of saxagliptin in patients with T2DM.. A PubMed literature search was conducted to identify relevant, peer-reviewed saxagliptin clinical trial articles published between January 2008 and June 2015. Search terms included "saxagliptin" and "DPP-4 inhibitors".. In clinical trials, saxagliptin significantly improved glycemic control when used as monotherapy or as add-on therapy to other antidiabetes agents and was associated with a low risk of hypoglycemia. In a large cardiovascular (CV) outcomes trial (SAVOR) in patients with T2DM and with established CV disease or multiple CV risk factors, saxagliptin neither increased nor decreased CV risk compared with placebo as assessed by the composite end point of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke. Unexpectedly, more patients in the saxagliptin (3.5%) than in the placebo group (2.8%) were hospitalized for heart failure.. Saxagliptin demonstrated statistically significant and clinically meaningful improvements in glycemic control and a low risk of hypoglycemia in patients with T2DM. However, this positive profile needs to be tempered by the observation of an increased risk of hospitalization for heart failure in the SAVOR trial. Results from ongoing CV outcome trials with other DPP-4 inhibitors may provide additional data on how best to manage patients with T2DM who are at risk for heart failure.. AstraZeneca LP.

Topics: Adamantane; Blood Glucose; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents

Integrating patient-centered diabetes care and algorithmic medicine poses particular challenges when optimized basal insulin fails to maintain glycaemic control in patients with type 2 diabetes. Multiple entwined physiological, psychosocial and systems barriers to insulin adherence are not easily studied and are not adequately considered in most treatment algorithms. Moreover, the limited number of alternatives to add-on prandial insulin therapy has hindered shared decision-making, a central feature of patient-centered care. This article considers how the addition of a glucagon-like peptide 1 (GLP-1) analogue to basal insulin may provide new opportunities at this stage of treatment, especially for patients concerned about weight gain and risk of hypoglycaemia. A flexible framework for patient-clinician discussions is presented to encourage development of decision-support tools applicable to both specialty and primary care practice.

Topics: Blood Glucose; Decision Support Systems, Clinical; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Exenatide; Fasting; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Detemir; Insulin, Long-Acting; Male; Meals; Patient Preference; Patient-Centered Care; Peptides; Venoms; Weight Gain

Tumor-induced hypoglycemia (TIH) is a rare clinical entity that may occur in patients with diverse kinds of tumor lineages and that may be caused by different mechanisms. These pathogenic mechanisms include the eutopic insulin secretion by a pancreatic islet β-cell tumor, and also the ectopic tumor insulin secretion by non-islet-cell tumor, such as bronchial carcinoids and gastrointestinal stromal tumors. Insulinoma is, by far, the most common tumor associated with clinical and biochemical hypoglycemia. Insulinomas are usually single, small, sporadic, and intrapancreatic benign tumors. Only 5-10% of insulinomas are malignant. Insulinoma may be associated with the multiple endocrine neoplasia type 1 in 4-6% of patients. Medical therapy with diazoxide or somatostatin analogs has been used to control hypoglycemic symptoms in patients with insulinoma, but only surgical excision by enucleation or partial pancreatectomy is curative. Other mechanisms that may, more uncommonly, account for tumor-associated hypoglycemia without excess insulin secretion are the tumor secretion of peptides capable of causing glucose consumption by different mechanisms. These are the cases of tumors producing IGF2 precursors, IGF1, somatostatin, and glucagon-like peptide 1. Tumor autoimmune hypoglycemia occurs due to the production of insulin by tumor cells or insulin receptor autoantibodies. Lastly, massive tumor burden with glucose consumption, massive tumor liver infiltration, and pituitary or adrenal glands destruction by tumor are other mechanisms for TIH in cases of large and aggressive neoplasias.

Topics: Autoantibodies; Bronchial Neoplasms; Carcinoid Tumor; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Insulinoma; Neoplasms; Pancreatic Neoplasms; Paraneoplastic Syndromes; Receptor, Insulin; Somatostatin

Suboptimal blood glucose control among patients with type 2 diabetes continues to support the need for new pharmacologic approaches.. The purpose of this commentary was to highlight newly available and soon-to-be available agents that are promising tools for targeting specific pathophysiologic pathways in the management of diabetes.. Published evidence to support the application of novel incretin-based therapies, dipeptidyl peptidase (DPP)-4 inhibitors, sodium-glucose cotransporter (SGLT)-2 inhibitors, other oral agents and insulins for managing specific aspects of type 2 diabetes, as well as disadvantages associated with those novel medications, are discussed.. Several new glucagon-like peptide (GLP)-1 receptor agonists with different time frames of action, although each has unique advantages and disadvantages, have been through clinical trials. Examples of these are lixisenatide and albiglutide. Currently available DPP-4 inhibitor agents, important for inhibiting the breakdown of endogenous GLP-1, have not been associated with weight gain or hypoglycemia. SGLT-2 inhibitors, which do not depend on insulin secretion or insulin action, may be advantageous in that they appear to be broadly efficacious at all stages of diabetes. New insulin analogues, such as degludec and U-500, improve glycemic control without contributing to hypoglycemia.. Advances in pharmacologic options offer the promise of improving glycemic control for longer periods, with limited glycemic fluctuations, hypoglycemia, and weight gain. However, the effectiveness of these agents ultimately depends on their availability to providers managing the health care of patients at high risk for poor diabetes outcomes and patients' use of them as directed. Long-term effectiveness and safety trials are ongoing.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin, Long-Acting; Male; Peptides

The relative effectiveness and tolerability of treatments for type 2 diabetes mellitus (T2DM) is not well understood because few randomized, controlled trials (RCTs) have compared these treatments directly. The purpose of the present study was to evaluate the relative effectiveness and tolerability of treatments of T2DM.. We performed a network meta-analysis of available RCTs with pharmacologic interventions in T2DM and compared antidiabetic drugs and combination regimens with metformin (the reference drug). Glycemic control (proportion achieving HbA1c goal) and tolerability (risk of hypoglycemia) were the primary outcomes of interest. Direct and indirect relative effects (unadjusted) were expressed as odds ratios and 95% CIs.. Eight treatments (glucagon-like peptide-1 [GLP-1] agonists plus metformin, sulfonylureas plus metformin, dipeptidyl peptidase-4 [DPP-4] inhibitors] plus metformin, colesevelan plus metformin, thiazolidinediones plus metformin, meglitinides plus metformin, α-glucosidase inhibitor plus metformin, and rosiglitazone monotherapy) outperformed metformin (direct effects). Triple combinations of GLP-1, thiazolinedione, insulin, metiglinide, or sulfonylureas added to a metformin backbone improved glycemic control (indirect effects). Higher risk of hypoglycemia was noted for sulfonylureas, α-glycosidases, and metiglinides when added to metformin (direct effects). Across indirect effects, only 17% of comparisons yielded less risk of hypoglycemia (70% were worse and 13% were comparable).. Our results point out the relative superiority of 2- and 3-drug combination regimens over metformin and summarize treatment effects and tolerability in a comprehensive manner, which adds to our knowledge regarding T2DM treatment options.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Metformin; Randomized Controlled Trials as Topic; Sulfonylurea Compounds; Thiazolidinediones; Treatment Outcome

Treatment of severe obesity by Roux-en-Y gastric bypass (RYGB) causes sustained weight losses and improves health complica-tions. RYGB is, however, also associated with adverse effects. Dumping is a well-known complication causing invalidating symptoms, and lately there have been mounting concerns about post-RYGB hypoglycaemia. This condition is characterized by neuroglycopenia and inappropriately elevated insulin concentration. The mechanism behind this hypoglycaemia is not completely elucidated. Diagnostic procedures and treatment possibilities are discussed in this article.

Topics: Blood Glucose; Dumping Syndrome; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Insulin; Obesity

Subcutaneous liraglutide (Victoza(®)), a glucagon-like peptide 1 receptor agonist, is approved for the treatment of adult patients with type 2 diabetes mellitus. Once-daily liraglutide, as monotherapy or add-on therapy to other antidiabetic agents (including basal insulin), was an effective and generally well tolerated treatment in adult patients with type 2 diabetes in several well-designed phase III trials and in the real world clinical practice setting. In addition to improving glycaemic control, liraglutide had beneficial effects on bodyweight, systolic blood pressure and surrogate measures of β-cell function in clinical trials, with these benefits maintained during long-term treatment (≤2 years). Liraglutide has a convenient once-daily administration regimen, a low potential for drug-drug interactions and low propensity to cause hypoglycaemia. Thus, liraglutide continues to be a useful option for the management of type 2 diabetes. This article reviews the therapeutic use of liraglutide in adult patients with type 2 diabetes and summarizes its pharmacological properties.

Topics: Adult; Biological Availability; Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Hypoglycemic Agents; Liraglutide; Receptors, Glucagon; Treatment Outcome

More than 26 million people in the United States have type 2 diabetes mellitus (T2D). Many treatment options exist, but achieving long-term glycemic control in patients with T2D remains challenging. The glucagon-like peptide-1 receptor agonists (GLP-1 RAs) offer a treatment option that improves glycemic control and reduces weight, with a low risk of hypoglycemia. They have emerged as attractive options for the treatment of T2D, and significant advances and developments continue to be published regarding these agents. To identify relevant literature on emerging issues related to GLP-1 RAs, a search of the MEDLINE database was performed. Studies published in English evaluating the safety and efficacy of GLP-1 RAs were analyzed. Because of their advantages and unique mechanism of action, GLP-1 RAs are currently being studied in new clinical areas, including in combination with basal insulin, as adjunctive therapy in type 1 diabetes, and for weight loss. In addition, there are several emerging agents in development. Lixisenatide is a once-daily GLP-1 RA that targets postprandial glucose and may be most useful when added to basal insulin as an alternative to rapid-acting insulin. Albiglutide and dulaglutide are once-weekly GLP-1 RAs that may offer more convenient dosing. The most common adverse effects of all GLP-1 RA agents are gastrointestinal (e.g., nausea, diarrhea, and vomiting), but the rates of occurrence vary among agents. Due to the differences in pharmacokinetics, efficacy, rates of adverse effects, and administration requirements within the GLP-1 RA class, each agent should be evaluated independently. The future of GLP-1 RAs offers broader treatment options for T2D as well as potential in other treatment areas.

Topics: Anti-Obesity Agents; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Drugs, Investigational; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Injections, Subcutaneous; Insulin; Peptides; Receptors, Glucagon; Recombinant Fusion Proteins; Weight Loss

GLP-1 receptors agonists have been a substantial change in treatment of type 2 diabetes mellitus, and its weekly administration has broken pre-established schemes. Daily exenatide is administered every 12 hours (BID) subcutaneously, while weekly exenatide is administered once a week. Both molecules share a common mechanism of action but have differential effects on basal and postprandial glucose. We review the major clinical trials with both exenatide BID and weekly exenatide. It can be concluded that exenatide BID shows a hypoglycemic effect similar to other treatments for type 2 DM but adding significant weight loss with low incidence of hypoglycemia. Weekly exenatide decreases HbA1c similar to liraglutide but larger than exenatide BID, both glargine and biphasic insulin, sitagliptin, and pioglitazone, maintaining weight loss and adding to gastrointestinal intolerance the induration at the injection site as a side effect.

Topics: Delayed-Action Preparations; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Administration Schedule; Exenatide; Female; Gastrointestinal Diseases; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Insulin; Insulin Glargine; Insulin, Long-Acting; Liraglutide; Male; Metformin; Peptides; Pioglitazone; Receptors, Glucagon; Thiazolidinediones; Venoms; Weight Loss

Glucagon-like peptide 1 receptor (GLP-1R) agonists provide good glycemic control combined with low hypoglycemia risk and weight loss. Here, we summarize the recently published data for this therapy class, focusing on sustainability of action, use in combination with basal insulin, and the efficacy of longer acting agents currently in development. The safety profile of GLP-1R agonists is also examined.. GLP-1R agonists provide sustained efficacy and their combination with basal insulin is well tolerated, providing additional glycemic control and weight benefits compared with basal insulin alone. Data suggest that the convenience of longer acting agents may be at the expense of efficacy. Despite the initial concerns, most evidence indicates that GLP-1R agonists do not increase the risk of pancreatitis or thyroid cancer. However, the extremely low incidence of these events means further investigations are required before a causal link can be eliminated. Large-scale clinical trials investigating the long-term cardiovascular safety of this therapy class are ongoing and may also provide important insights into pancreatic and thyroid safety.. GLP-1R agonists offer sustained glycemic efficacy, weight loss benefits, and a low risk of hypoglycemia. The results of ongoing trials should help to clarify the safety of this therapy class.

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Exenatide; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Insulin; Liraglutide; Male; Pancreatitis; Peptides; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Thyroid Neoplasms; Treatment Outcome; Venoms

Once lifestyle measures implemented, if hyperglycemia persists, above individual HbA1c targets, a medication should be started in type 2 diabetic patients (T2DM). First, unless exception, an oral antidiabetic drug. Except in case of intolerance, the initial monotherapy, metformin remains the strengthening treatment. Latter, combination of two oral drugs, now offers several options, mainly the choice to associate a "conventional insulin-secretor", sulfonylureas, glinide, or a "new one" belonging the class of "incretin", more readily a gliptine (DPP-4 inhibitors) rather than injectable GLP-1 analogue which can also be sometimes chosen at this stage. These options are mostly new and have the advantage a neutral or favourable (for GLP-1) effect on body weight in obese type 2 DM patient and the absence of any hypoglycaemic risk in both classes of incretins. But this risk varies depending on the patient profile, much higher if the target HbA1c is low (6 to 6.5 or 7%), or in the elderly, fragile and/or in case of renal insufficiency. These two different situations with a high risk of hypoglycaemia, define best indications of this new class. If dual oral therapy does not achieve the goals we are faced with three options: triple oral therapy: metformin-sulfonylurea-gliptine or one of two approaches with injections, insulin or GLP-1 analogues. The use of GLP-1 analogues is often delayed today and put wrongly in balance with the transition to insulin, a use already delayed in France and insufficient. The use of incretins is new and needs to be validated by studies of sustainability on glycemic control, prevention of microvascular and macrovascular complications and after years on the market security of use, primarily on the exocrine pancreas. In short, individualization of strategies and HbA1c targets are required, the new molecules can help us in this process. This individualization can easily be done through the handy guide proposed by the experts ADA EASD statement, endorsed by the SFD, abandoning the complex algorithm recently again proposed by HAS and ANSM in 2013. A recommendation that prioritizes the costs of the strategies. An absolutely critical issue, while admitting not to have the tools to measure them in all their dimensions. Finally, we must reconsider every treatment after a maximum of 6 months of use, if the results are deemed inadequate substitute rather than adding drugs.

Topics: Administration, Oral; Body Weight; Diabetes Complications; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Disease Management; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glycated Hemoglobin; Goals; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Kidney; Metformin; Obesity; Practice Guidelines as Topic; Risk; Societies, Medical; Sulfonylurea Compounds

GLP-1 agonists have been widely used in the therapy of type 2 diabetes due to their beneficial effects regarding weight loss and low risk of hypoglycemia. However, some safety concerns have been raised in view of possible detrimental effects to the pancreas. The future place of GLP-1 agonist in diabetes therapy will be determined by the current safety evaluation and data from studies investigating long-term effects.

Topics: Blood Pressure; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Pancreatic Diseases; Peptides; Venoms

Clinicians and patients are rapidly adapting GLP-1 receptor agonists as efficacious and safe therapeutic options for managing type 2 diabetes (T2DM). GLP-1 receptor agonists stimulate insulin production and secretion from the pancreatic β cells in a glucose-dependent manner, improve gastric emptying, favor weight reduction, and reduce postabsorptive glucagon secretion from pancreatic α cells. GLP-1 receptor activity is impaired in patients with T2DM. GLP-1 secretion and subsequent physiologic actions in patients with type 1 diabetes (T1DM) is ill-defined. Some researchers have suggested that the use of GLP-1 receptor agonists in T1DM may reduce excessive postprandial glucagon secretion allowing patients to reduce their total daily dose of exogenous insulin. Hypoglycemia risk may also be minimized in T1DM as glucagon counter-regulation can be preserved to some degree via the glucose-dependent action of the GLP-1 receptor agonists. This paper will consider the physiologic and pharmacologic benefits of adding GLP-1 receptor agonists to therapeutic regimens of patients with T1DM.

Topics: Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Off-Label Use; Receptors, Glucagon

Topics: Allylamine; Animals; Blood Glucose; Bromocriptine; Cardiovascular Diseases; Colesevelam Hydrochloride; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Gastrins; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Islet Amyloid Polypeptide; Leptin; Metformin; Sodium-Glucose Transporter 1; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Sulfonylurea Compounds; Thiazolidinediones; United States

The presence of cardiovascular disease (CVD) in Type 1 diabetes largely impairs life expectancy. Hyperglycemia leading to an increase in oxidative stress is considered to be the key pathophysiological factor of both micro- and macrovascular complications. In Type 1 diabetes, the presence of coronary calcifications is also related to coronary artery disease. Cardiac autonomic neuropathy, which significantly impairs myocardial function and blood flow, also enhances cardiac abnormalities. Also hypoglycemic episodes are considered to adversely influence cardiac performance. Intensive insulin therapy has been demonstrated to reduce the occurrence and progression of both micro- and macrovascular complications. This has been evidenced by the Diabetes Control and Complications Trial (DCCT) / Epidemiology of Diabetes Interventions and Complications (EDIC) study. The concept of a metabolic memory emerged based on the results of the study, which established that intensified insulin therapy is the standard of treatment of Type 1 diabetes. Future therapies may also include glucagon-like peptide (GLP)-based treatment therapies. Pilot studies with GLP-1-analogues have been shown to reduce insulin requirements.

Topics: Antihypertensive Agents; Autonomic Nervous System Diseases; Cardiovascular Diseases; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Neuropathies; Drug Therapy, Combination; Exenatide; Exercise Therapy; Glucagon-Like Peptide 1; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemia; Hypoglycemic Agents; Insulin; Oxidative Stress; Peptides; Pyrazines; Sitagliptin Phosphate; Triazoles; Venoms

It has been established that diabetes is an independent risk factor for microvascular and macrovascular complications, and many studies indicate that diabetic subjects are at greater risk of dementia, depression and fracture. Risk reductions for microvascular, macrovascular and death were observed by intensive therapy using insulin or oral diabetic agents. But a history of hypoglycemia was increased myocardial infarction, mortality, dementia and fracture. So it is important that optimum glycemic control has to be achieved without hypoglycemia. Treatment with a long-acting basal insulin analogue or glucagon-like peptide-1(GLP-1) receptor agonist, provide effective glycemic control without serious hypoglycemia in elderly patients. Self-monitoring of blood glucose might be effective in improving glycemic control in elderly patients, and it is useful for the diagnosis of hypoglycemia.

Topics: Administration, Oral; Aged; Aged, 80 and over; Blood Glucose Self-Monitoring; Diabetes Mellitus; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Liraglutide; Receptors, Glucagon

In this study, we review the efficacy and safety limitations of insulin-dependent oral antidiabetic agents. In terms of efficiency, the main drawback of metformin, sulfonylureas, gliptins and -to a lesser extent-glitazones is durability. No drug per se is able to maintain stable blood glucose control for years. Metformin, sulfonylureas and gliptins have demonstrated safety. Experience with the first two drug groups is more extensive. The main adverse effect of metformin is gastrointestinal discomfort. Major concerns related to the use of sulfonylureas are hypoglycemia and weight gain. The use of pioglitazone has been associated with an increased risk of bladder cancer, edema, heart failure, weight gain, and distal bone fractures in postmenopausal women. The most common adverse reactions associated with glucagon-like peptide-1 agonists are gastrointestinal discomfort that sometimes leads to treatment discontinuation.

Topics: Contraindications; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Drug Tolerance; Fractures, Spontaneous; Gastrointestinal Diseases; Glucagon-Like Peptide 1; Heart Failure; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Metformin; Pioglitazone; Sulfonylurea Compounds; Thiazolidinediones; Urinary Bladder Neoplasms; Weight Gain

Treatment algorithms for type 2 diabetes call for intensification of therapy over time as the disease progresses and glycaemic control worsens. If diet, exercise and oral antihyperglycaemic medications (OAMs) fail to maintain glycaemic control then basal insulin is added and ultimately prandial insulin may be required. However, such an intensification strategy carries risk of increased hypoglycaemia and weight gain, both of which are associated with worse long-term outcomes. An alternative strategy is to intensify therapy by the addition of a short-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA) rather than prandial insulin. Short-acting GLP-1 RAs such as exenatide twice daily are particularly effective at reducing postprandial glucose while basal insulin has a greater effect on fasting glucose, providing a physiological rationale for this complementary approach. This review analyzes the latest randomized controlled clinical trials of insulin/GLP-1 RA combination therapy and examines results from 'real-world' use of the combinations as reported through observational and clinical practice studies. The most common finding across all types of studies was that combination therapy improved glycaemic control without weight gain or an increased risk of hypoglycaemia. Many studies reported weight loss and a reduction in insulin use when a GLP-1 RA was added to existing insulin therapy. Overall, the relative degree of benefit to glycaemic control and weight was influenced by the insulin titration employed in conjunction with the GLP-1 RA. The greatest glycaemic benefits were observed in studies with structured titration of insulin to glycaemic targets while the greatest weight benefits were observed in studies with a protocol-specified focus on insulin sparing. The adverse event profile of GLP-1 RAs in the reviewed trials was similar to that reported with GLP-1 RAs as monotherapy or in combination with OAMs with gastrointestinal events being the most commonly reported.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Disease Progression; Drug Administration Schedule; Drug Therapy, Combination; Exenatide; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Peptides; Randomized Controlled Trials as Topic; Risk Reduction Behavior; Treatment Outcome; Venoms; Weight Gain

Hyperglycaemia frequently occurs in the critically ill, in patients with diabetes, as well as those who were previously glucose-tolerant. The terminology 'stress hyperglycaemia' reflects the pathogenesis of the latter group, which may comprise up to 40% of critically ill patients. For comparable glucose concentrations during acute illness outcomes in stress hyperglycaemia appear to be worse than those in patients with type 2 diabetes. While several studies have evaluated the optimum glycaemic range in the critically ill, their interpretation in relation to clinical recommendations is somewhat limited, at least in part because patients with stress hyperglycaemia and known diabetes were grouped together, and the optimum glycaemic range was regarded as static, rather than dynamic, phenomenon. In addition to hyperglycaemia, there is increasing evidence that hypoglycaemia and glycaemic variability influence outcomes in the critically ill adversely. These three categories of disordered glucose metabolism can be referred to as dysglycaemia. While stress hyperglycaemia is most frequently managed by administration of short-acting insulin, guided by simple algorithms, this does not treat all dysglycaemic categories; rather the use of insulin increases the risk of hypoglycaemia and may exacerbate variability. The pathogenesis of stress hyperglycaemia is complex, but hyperglucagonaemia, relative insulin deficiency and insulin resistance appear to be important. Accordingly, novel agents that have a pathophysiological rationale and treat hyperglycaemia, but do not cause hypoglycaemia and limit glycaemic variability, are appealing. The potential use of glucagon-like peptide-1 (or its agonists) and dipeptyl-peptidase-4 inhibitors is reviewed.

Topics: Analysis of Variance; Biomarkers; Blood Glucose; Critical Illness; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Risk Factors

Effective type 2 diabetes management requires a multifactorial approach extending beyond glycaemic control. Clinical practice guidelines suggest targets for HbA1c, blood pressure and lipids, and emphasize weight reduction and avoiding hypoglycaemia. The phase 3 clinical trial programme for liraglutide, a human glucagon-like peptide 1 analogue, showed significant improvements in HbA1c and weight with a low risk of hypoglycaemia compared to other diabetes therapies. In this context, we performed a meta-analysis of data from these trials evaluating the proportion of patients achieving a clinically relevant composite measure of diabetes control consisting of an HbA1c <7% without weight gain or hypoglycaemia.. A prespecified meta-analysis was performed on 26-week patient-level data from seven trials (N = 4625) evaluating liraglutide with commonly used therapies for type 2 diabetes: glimepiride, rosiglitazone, glargine, exenatide, sitagliptin or placebo, adjusting for baseline HbA1c and weight, for a composite outcome of HbA1c <7.0%, no weight gain and no hypoglycaemic events.. At 26 weeks, 40% of the liraglutide 1.8 mg group, 32% of the liraglutide 1.2 mg group and 6-25% of comparators (6% rosiglitazone, 8% glimepiride, 15% glargine, 25% exenatide, 11% sitagliptin, 8% placebo) achieved this composite outcome. Odds ratios favoured liraglutide 1.8 mg by 2.0- to 10.5-fold over comparators.. As assessed by the composite outcome of HbA1c <7%, no hypoglycaemia and no weight gain, liraglutide was clearly superior to the other commonly used therapies. However, the long-term clinical impact of this observation remains to be shown.

Topics: Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Weight Gain

Liraglutide, a once-daily glucagon-like peptide-1 receptor agonist, is approved for use as monotherapy in the USA and Japan (but not in Europe or Canada) and in combination with selected oral agents (all regions) for the treatment of patients with type 2 diabetes. Guidance from local advisory bodies is emerging on the most appropriate place for liraglutide in the treatment pathway. It is apparent from its phase 3 clinical trial programme that liraglutide provides superior glycaemic control compared with that achieved with other antidiabetic agents used early in the treatment pathway (e.g. glimepiride and sitagliptin). Key additional benefits include a low incidence of hypoglycaemia and clinically relevant weight loss, although these benefits may be ameliorated by concomitant sulphonylurea (SU) treatment and, in the case of hypoglycaemia, reduction of the SU dose may be necessary. Overall, the profile of liraglutide is similar and, in some aspects, superior to twice-daily exenatide. The implementation of liraglutide therapy is straightforward, with simple dose titration from the starting dose of 0.6 to 1.2 mg/day after 1 week; some patients may benefit from additional titration to 1.8 mg/day. Treatment is self-administered by subcutaneous injection. This contrasts with other agents used early in the treatment pathway, but clinical data suggest patients' overall treatment satisfaction with liraglutide is similar (1.2 mg) or better (1.8 mg) than that with sitagliptin despite differing administration methods. Some patients may experience nausea when initiating liraglutide treatment, but the titration regimen is designed to improve tolerability and clinical data indicate nausea is transient.

Topics: Administration, Oral; Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Injections, Subcutaneous; Liraglutide; Male; Metformin; Nausea; Sulfonylurea Compounds; Thiazolidinediones; Treatment Outcome; United States

To assess the efficacy and safety of dipeptidyl peptidase-4 (DPP-4) inhibitors compared with metformin as monotherapy, or with other commonly used hypoglycaemic drugs combined with metformin, in adults with type 2 diabetes mellitus.. Systematic review and meta-analysis of randomised controlled trials.. Medline, Embase, the Cochrane Library, conference proceedings, trial registers, and drug manufacturers' websites.. Randomised controlled trials of adults with type 2 diabetes mellitus that compared a DPP-4 with metformin as monotherapy or with a sulfonylurea, pioglitazone, a glucagon-like peptide-1 (GLP-1) agonist, or basal insulin combined with metformin on the change from baseline in glycated haemoglobin (HbA(1c)).. The primary outcome was the change in HbA(1c). Secondary outcomes included the proportion of patients achieving the goal of HbA(1c) <7%, the change in body weight, discontinuation rate because of any adverse event, occurrence of any serious adverse event, all cause mortality, and incidence of hypoglycaemia, nasopharyngitis, urinary tract infection, upper respiratory infection, nausea, vomiting, and diarrhoea.. 27 reports of 19 studies including 7136 patients randomised to a DPP-4 inhibitor and 6745 patients randomised to another hypoglycaemic drug were eligible for the systematic review and meta-analysis. Overall risk of bias for the primary outcome was low in three reports, unclear in nine, and high in 14. Compared with metformin as monotherapy, DPP-4 inhibitors were associated with a smaller decline in HbA(1c) (weighted mean difference 0.20, 95% confidence interval 0.08 to 0.32) and in body weight (1.5, 0.9 to 2.11). As a second line treatment, DPP-4 inhibitors were inferior to GLP-1 agonists (0.49, 0.31 to 0.67) and similar to pioglitazone (0.09, -0.07 to 0.24) in reducing HbA(1c) and had no advantage over sulfonylureas in the attainment of the HbA(1c) goal (risk ratio in favour of sulfonylureas 1.06, 0.98 to 1.14). DPP-4 inhibitors had a favourable weight profile compared with sulfonylureas (weighted mean difference -1.92, -2.34 to -1.49) or pioglitazone (-2.96, -4.13 to -1.78), but not compared with GLP-1 agonists (1.56, 0.94 to 2.18). Only a minimal number of hypoglycaemias were observed in any treatment arm in trials comparing a DPP-4 inhibitor with metformin as monotherapy or with pioglitazone or a GLP-1 agonist as second line treatment. In most trials comparing a DPP-4 inhibitor with sulfonylureas combined with metformin, the risk for hypoglycaemia was higher in the group treated with a sulfonylurea. Incidence of any serious adverse event was lower with DPP-4 inhibitors than with pioglitazone. Incidence of nausea, diarrhoea, and vomiting was higher in patients receiving metformin or a GLP-1 agonist than in those receiving a DPP-4 inhibitor. Risk for nasopharyngitis, upper respiratory tract infection, or urinary tract infection did not differ between DPP-4 inhibitors and any of the active comparators.. In patients with type 2 diabetes who do not achieve the glycaemic targets with metformin alone, DPP-4 inhibitors can lower HbA(1c), in a similar way to sulfonylureas or pioglitazone, with neutral effects on body weight. Increased unit cost, which largely exceeds that of the older drugs, and uncertainty about their long term safety, however, should also be considered.

Topics: Adult; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Disease Management; Drug Monitoring; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Metformin; Outcome Assessment, Health Care; Randomized Controlled Trials as Topic; Sulfonylurea Compounds; Treatment Outcome

Abstract Diet, lifestyle modification, and pharmacotherapy with metformin are appropriate initial treatments for many patients with type 2 diabetes (T2DM). However, most individuals do not maintain glycemic control with metformin alone. Addition of other oral antidiabetes drugs (OADs), including sulfonylurea, meglitinide, or thiazolidinedione, is often the next step. Newer options, including incretin-based glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, offer important benefits as monotherapies or in combination with OADs, with low risk for hypoglycemia. Reductions in glycated hemoglobin (A1C) have been reported among patients treated with GLP-1 RAs (exenatide, -0.8 to -1.1%; liraglutide, -0.8 to -1.6%), as has weight loss (exenatide, -1.6 to -3.1 kg; liraglutide, -1.6 to -3.2 kg). GLP-1 RAs also stimulate β-cell responses and have positive effects on cardiovascular risk factors often present in patients with T2DM. The most common adverse events associated with GLP-1 RAs are nausea, which diminishes over time, and hypoglycemia (when used in combination with a sulfonylurea). A large number of trials demonstrated benefits of GLP-1 RAs, suggesting they could provide suitable treatment options for patients with T2DM.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Liraglutide; Peptides; Receptors, Glucagon; Venoms

The role of glucagon-like peptide (GLP)-1-based treatment approaches for type 2 diabetes mellitus (T2DM) is increasing. Although self-monitoring of blood glucose (SMBG) has been performed in numerous studies on GLP-1 analogs and dipeptidyl peptidase-4 inhibitors, the potential role of SMBG in GLP-1-based treatment strategies has not been elaborated. The expert recommendation suggests individualized SMBG strategies in GLP-1-based treatment approaches and suggests simple and clinically applicable SMBG schemes. Potential benefits of SMBG in GLP-1-based treatment approaches are early assessment of treatment success or failure, timely modification of treatment, detection of hypoglycemic episodes, assessment of glucose excursions, and support of diabetes management and diabetes education. Its length and frequency should depend on the clinical setting and the quality of metabolic control. It is considered to play an important role for the optimization of diabetes management in T2DM patients treated with GLP-1-based approaches.

Topics: Biomarkers; Blood Glucose; Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Europe; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Practice Guidelines as Topic; Predictive Value of Tests; Time Factors; Treatment Outcome

Intravenous insulin therapy is the gold standard therapy for glycaemic control in hyperglycaemic critically ill adult patients. However, hypoglycaemia remains a major concern in critically ill patients, even in some populations who are not receiving infused insulin. Furthermore, the influence of factors such as glycaemic variability and nutritional support may conceal any benefit of strict glycaemic control on morbidity and mortality in these patients. The recently revised guidelines of the American Diabetic Association/American College of Clinical Endocrinologists no longer advocate very tight glycaemic control or normalization of glucose levels in all critically ill patients. In the light of various concerns over the optimal glucose level and means to achieve such control, the use of glucagon-like peptide-1 or its analogues administered intravenously may represent an interesting therapeutic option.

Topics: Blood Glucose; Critical Illness; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Infusions, Intravenous; Insulin; Male; Treatment Outcome; United States

Although several classes of pharmacotherapy are available for type 2 diabetes, glycaemic control is often hampered by medication-related adverse effects and contraindications such as renal impairment. Glucagon-like peptide-1 (GLP-1) receptor agonists provide a new pharmacotherapeutic option based on the multiple glucose-lowering effects of the human hormone GLP-1. This mechanism of action not only provides therapeutic efficacy but also suggests that GLP-1 receptor agonists have distinct safety and tolerability concerns compared with other diabetes therapies. Stimulation of pancreatic insulin secretion by GLP-1 receptor agonists is glucose dependent, conferring a lesser risk of hypoglycaemia than that seen with sulfonylureas. Individual GLP-1 receptor agonists differ in their metabolism and excretion profiles, affecting the choice of agent for patients with renal impairment. As with other protein-based therapies, GLP-1 receptor agonists may induce the formation of antibodies that may attenuate therapeutic efficacy and affect safety. Conclusions on cardiovascular safety must await outcomes studies, but at present no signal of harm has been reported, and preclinical data and effects on risk markers suggest a potential for benefit. Current data on thyroid medullary cancer in humans and pancreatic malignancy in rodents do not suggest that there is any reason to restrict the clinical use of GLP-1 analogues in most people with diabetes. It is currently difficult to ascertain the possible contributory role of GLP-1 receptor agonists in increasing the risk of pancreatitis, and vigilance for signs and symptoms is prudent. Primary tolerability issues include transient gastrointestinal symptoms, common with GLP-1 receptor agonists, which can be reduced through dose titration.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug-Related Side Effects and Adverse Reactions; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Incretins; Liraglutide; Nausea; Pancreatitis; Peptides; Randomized Controlled Trials as Topic; Receptors, Glucagon; Thyroid Gland; Venoms; Vomiting

Inhibition of dipeptidyl peptidase IV (DPP-4) augments glucose-dependent insulin release and is a new approach to the treatment of type 2 diabetes (T2DM). Vildagliptin is a new DPP-4 inhibitor approved in many countries for the treatment of T2DM. This review provides an overview of vildagliptin with emphasis on its pharmacology and clinical effectiveness.. Results of preclinical and several Phase II and III studies from 2004 - 2010 are discussed.. Vildagliptin acts to inhibit the breakdown of glucagon-like peptide (GLP)-1, which in turn enhances the beta-cell response to glucose and inhibits glucagon secretion. It is an effective agent alone or in combination in patients with T2DM, resulting in modest improvements in HbA1c usually in the 0.5 - 1% range. Advantages include weight neutrality and a lesser incidence of hypoglycemia. Concerns remain regarding its use in renal disease and potential complications seen in animal models.

Topics: Adamantane; Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Nitriles; Pyrrolidines; Vildagliptin

Basal insulin analogs are recognized as an effective method of achieving and maintaining glycemic control for patients with type 2 diabetes. However, the progressive nature of the disease means that some individuals may require additional ways to maintain their glycemic goals. Intensification in these circumstances has traditionally been achieved by the addition of short-acting insulin to cover postprandial glucose excursions that are not targeted by basal insulin. However, intensive insulin regimens are associated with a higher risk of hypoglycemia and weight gain, which can contribute to a greater burden on patients. The combination of basal insulin with a glucagon-like peptide-1 (GLP-1) mimetic is a potentially attractive solution to this problem for some patients with type 2 diabetes. GLP-1 mimetics target postprandial glucose and should complement the activity of basal insulins; they are also associated with a relatively low risk of associated hypoglycemia and moderate, but significant, weight loss. Although the combination has not been approved by regulatory authorities, preliminary evidence from mostly small-scale studies suggests that basal insulins in combination with GLP-1 mimetics do provide improvements in A1c and postprandial glucose with concomitant weight loss and no marked increase in the risk of hypoglycemia. These results are promising, but further studies are required, including comparisons with basal-bolus therapy, before the complex value of this association can be fully appreciated.

Topics: Diabetes Mellitus, Type 2; Disease Progression; Drug Therapy, Combination; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Insulin; Weight Gain

Although there is general agreement that metformin should be used as first-line pharmacotherapy in patients with type 2 diabetes, uncertainty remains regarding the choice of second-line therapy once metformin is no longer effective. We conducted a systematic review and meta-analysis to assess the comparative safety and efficacy of all available classes of antihyperglycemic therapies in patients with type 2 diabetes inadequately controlled on metformin monotherapy.. MEDLINE, EMBASE, BIOSIS Previews, PubMed and the Cochrane Central Register of Controlled Trials were searched for randomized controlled trials published in English from 1980 to October 2009. Additional citations were obtained from grey literature and conference proceedings and through stakeholder feedback. Two reviewers independently selected studies, extracted data and assessed risk of bias. Key outcomes of interest were hemoglobin A1c, body weight, hypoglycemia, quality of life, long-term diabetes-related complications, serious adverse drug events and mortality. Mixed-treatment comparison and pairwise meta-analyses were conducted to pool trial results, when appropriate.. We identified 49 active and non-active controlled randomized trials that compared 2 or more of the following classes of antihyperglycemic agents and weight-loss agents: sulfonylureas, meglitinides, thiazolidinediones (TZDs), dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) analogues, insulins, alpha-glucosidase inhibitors, sibutramine and orlistat. All classes of second-line antihyperglycemic therapies achieved clinically meaningful reductions in hemoglobin A1c (0.6% to 1.0%). No significant differences were found between classes. Insulins and insulin secretagogues were associated with significantly more events of overall hypoglycemia than the other agents, but severe hypoglycemia was rarely observed. An increase in body weight was observed with the majority of second-line therapies (1.8 to 3.0 kg), the exceptions being DPP-4 inhibitors, alpha-glucosidase inhibitors and GLP-1 analogues (0.6 to -1.8 kg). There were insufficient data available for diabetes complications, mortality or quality of life.. DPP-4 inhibitors and GLP-1 analogues achieved improvements in glycemic control similar to those of other second-line therapies, although they may have modest benefits in terms of weight gain and overall hypoglycemia. Further long-term trials of adequate power are required to determine whether newer drug classes differ from older agents in terms of clinically meaningful outcomes.

Topics: Bayes Theorem; Body Weight; Confidence Intervals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Metformin; Risk Factors; Time Factors; Treatment Failure

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Nitriles; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Triazoles; Vildagliptin

A systematic review of the literature, in combination with a meta-analysis of randomized controlled trials comparing treatments with placebo, was conducted to provide an update on the clinical efficacy and safety of incretin-based medications in adult patients with type 2 diabetes.. A literature search (2000-2009) identified 38 placebo-controlled trials (phase II or later - parallel design) comparing exenatide (n = 8), liraglutide (n = 7), vildagliptin (n = 11) and sitagliptin (n = 12) with placebo. Outcomes were change from baseline in HbA(1c) and in weight, and the number of patient-reported hypoglycemic episodes. HbA(1c) and weight outcomes were analyzed as weighted mean differences (WMD), and the number of hypoglycemic episodes as relative risks (RR).. Patients receiving liraglutide showed greater reduction in HbA(1c) in comparison to placebo (WMD = -1.03, 95% confidence interval, CI = -1.16 to -0.90, p < 0.001) than those on sitagliptin (WMD = -0.79, 95% CI = -0.93 to -0.65, p < 0.001), exenatide (WMD = -0.75, 95% CI = -0.83 to -0.67, p < 0.001) or vildagliptin (WMD = -0.67, 95% CI = -0.83 to -0.52, p < 0.001). Weight was statistically significantly negatively associated with exenatide (WMD = -1.10, 95% CI = -1.32 to -0.87, p < 0.001) and positively associated with sitagliptin (WMD = 0.60, 95% CI = 0.33-0.87, p < 0.001) and vildagliptin (WMD = 0.56, 95% CI = 0.27-0.84, p < 0.001). The number of patient-reported hypoglycemic episodes was statistically significantly associated with the use of sitagliptin (RR = 2.56, 95% CI = 1.23-5.33, p = 0.01) and exenatide (RR = 2.40, 95% CI = 1.30-4.11, p = 0.002).. Incretin-based therapies are effective in glycemic control and also offer other advantages such as weight loss (exenatide and liraglutide). This may have an important impact on patient adherence to medication.

Topics: Adamantane; Adult; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Liraglutide; Nitriles; Peptides; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Triazoles; Venoms; Vildagliptin; Weight Loss

Established therapies for type-2 diabetes effectively reduce blood glucose, but are often associated with adverse effects that pose risks to patient's health or diminish adherence to treatment. Weight gain, hypoglycaemia and gastrointestinal symptoms are commonly reported and some agents may not be safe for use in patients with renal impairment or elevated cardiovascular risk. New treatments based on the action of the endogenous human hormone glucagon-like peptide-1 (GLP-1), including exenatide and liraglutide, are available. These therapies provide a novel pharmacological approach to glycaemic control via multiple mechanisms of action, and accordingly exhibit different safety and tolerability profiles than conventional treatments. GLP-1 receptor agonists stimulate insulin release only in the presence of elevated blood glucose and are therefore associated with a fairly low risk of hypoglycaemia. Gastrointestinal symptoms are common but transient, and there appears to be little potential for interaction with other drugs. GLP-1 receptor agonists are associated with weight loss rather than weight gain. As protein-based therapies, these agents have the potential to induce antibody formation, but the impact on efficacy and safety is minor. GLP-1 receptor agonists thus offer a new and potentially useful option for clinicians concerned about some of the common adverse effects of type-2 diabetes therapies.

Topics: Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Type 2; Drug Interactions; Gastrointestinal Diseases; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart Diseases; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Kidney Diseases; Pancreatitis; Receptors, Glucagon; Sulfonylurea Compounds; Thiazolidinediones; Thyroid Diseases

To review the efficacy and safety of liraglutide from the phase 3 trials, focusing primarily on glycaemic control.. Liraglutide was shown to reduce glycated haemoglobin (HbA(1c) ) levels by up to 1.5% from baseline, significantly more than the comparators sitagliptin (-0.9%), glimepiride (-0.5%), rosiglitazone (-0.4%), insulin glargine (-1.1%) and exenatide (-0.8%). Both fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) levels were shown to be significantly reduced from baseline [up to -2.4 mmol/l (-43.2 mg/dl) and -2.7 mmol/l (-48.6 mg/dl) for FPG and PPG in the liraglutide 1.8 mg group, respectively]. Changes in HbA(1c) , FPG and PPG levels were sustained for the duration of the studies (up to 52 weeks). The glycaemic control offered by liraglutide was not associated with an increased rate of minor hypoglycaemic events compared with comparator treatments, with rates significantly lower than those of glimepiride and exenatide. Major hypoglycaemic events were rare and only occurred in combination with a sulfonylurea. Nausea was the most frequent adverse event, but subsided within the first few weeks.. Liraglutide has been shown to offer effective glycaemic control for patients with type 2 diabetes and is appropriate for use across the conventional continuum of care. Despite the sustained reductions in HbA(1c) , FPG and PPG levels achieved with liraglutide, rates of minor hypoglycaemia were generally low, although the risk increased when combined with a sulfonylurea. Liraglutide is therefore a promising new option for the treatment of type 2 diabetes.

Topics: Blood Glucose; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Liraglutide; Nausea

This article reviews practical issues that healthcare providers need to consider when implementing therapy with the once-daily glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide.. Liraglutide is administered once daily by subcutaneous injection, independent of meals and at any time of day. To improve gastro-intestinal tolerability, the starting dose is 0.6 mg liraglutide daily. After at least 1 week, the dose should be increased to 1.2 mg. Some patients may benefit from an additional increment to the maximum recommended daily dose of 1.8 mg. Daily blood glucose monitoring is not required, although may be necessary if liraglutide is used with a sulphonylurea (SU). Treatment is contraindicated in patients with known hypersensitivity to liraglutide or an excipient. Liraglutide slows gastric emptying, but does not interact with acetaminophen, oral contraceptives, atorvastatin, griseofulvin, lisinopril or digoxin in a way that necessitates dose adjustments of these agents. The efficacy and safety of liraglutide are not influenced by differences in gender, age or ethnicity and race. Overall, liraglutide is generally well tolerated. Patients can experience gastrointestinal side effects, such as nausea, which diminish over time. As liraglutide increases insulin production in a glucose-dependent manner, the incidence of hypoglycaemia largely depends on the hypoglycaemic risk profile of the selected oral antidiabetic with which it is used. The use of an SU may increase the risk of hypoglycaemia; this risk can be lowered by reducing the SU dose.. Liraglutide is a once-daily treatment option that can be used in adults with type 2 diabetes regardless of gender, age (although therapeutic experience in patients over 75 years of age is limited) and ethnicity or race.

Topics: Adult; Contraindications; Diabetes Mellitus, Type 2; Drug Dosage Calculations; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Hypoglycemic Agents; Injections, Subcutaneous; Liraglutide; Nausea; Receptors, Glucagon; Sulfonylurea Compounds; Treatment Outcome

Type 2 diabetes mellitus (DM) is a prevalent disorder that affects children, adolescents, and adults worldwide. In addition to risks of microvascular disease, patients with type 2 DM often have multiple risk factors of macrovascular disease; for example, approximately 90% of patients with type 2 DM are overweight/obese. Type 2 DM is a complex disease that involves a variety of pathophysiologic abnormalities, including insulin resistance, increased hepatic glucose production, and abnormalities in the secretion of hormones, such as insulin, glucagon, amylin, and incretins. Incretins are gut-derived peptides with a variety of glucoregulatory functions. Incretin dysfunction can be treated with glucagon-like peptide 1 (GLP-1) receptor agonists (eg, exenatide and liraglutide) or inhibitors of dipeptidyl peptidase 4 (DPP-4) (eg, sitagliptin and saxagliptin), the enzyme that degrades GLP-1. The GLP-1 receptor agonists and DPP-4 inhibitors both elevate GLP-1 activity and substantially improve glycemic control. The GLP-1 receptor agonists are more effective in lowering blood glucose and result in substantial weight loss, whereas therapy with DPP-4 inhibitors lowers blood glucose levels to a lesser degree, and they are weight neutral. Treatment with GLP-1 receptor agonists has demonstrated durable glycemic control and improvement in multiple cardiovascular disease risk factors. In addition, unlike insulin or sulfonylureas, treatment with a GLP-1 receptor agonist or a DPP-4 inhibitor has not been associated with substantial hypoglycemia. These factors should be considered when selecting monotherapy or elements of combination therapy for patients with type 2 DM who are overweight/obese, for patients who have experienced hypoglycemia with other agents, and when achieving glycemic targets is difficult.

Topics: Adolescent; Adult; Blood Glucose; Child; Diabetes Complications; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Male; Randomized Controlled Trials as Topic; Risk Assessment; Severity of Illness Index; Treatment Outcome; Young Adult

Bariatric surgery is currently the most effective method to promote major, sustained weight loss. Roux-en-Y gastric bypass (RYGB), the most commonly performed bariatric operation, ameliorates virtually all obesity-related comorbid conditions, the most impressive being a dramatic resolution of type 2 diabetes mellitus (T2DM). After RYGB, 84% of patients with T2DM experience complete remission of this disease, and virtually all have improved glycemic control. Increasing evidence indicates that the impact of RYGB on T2DM cannot be explained by the effects of weight loss and reduced energy intake alone. Weight-independent antidiabetic actions of RYGB are apparent because of the very rapid resolution of T2DM (before weight loss occurs), the greater improvement of glucose homeostasis after RYGB than after an equivalent weight loss from other means, and the occasional development of very late-onset, pancreatic beta-cell hyperfunction. Several mechanisms probably mediate the direct antidiabetic impact of RYGB, including enhanced nutrient stimulation of L-cell peptides (for example, GLP-1) from the lower intestine, intriguing but still uncharacterized phenomena related to exclusion of the upper intestine from contact with ingested nutrients, compromised ghrelin secretion, and very probably other effects that have yet to be discovered. Research designed to prioritize these mechanisms and identify potential additional mechanisms promises to help optimize surgical design and might also reveal novel pharmaceutical targets for diabetes treatment.

Topics: Animals; Blood Glucose; Caloric Restriction; Diabetes Mellitus, Type 2; Gastric Bypass; Ghrelin; Glucagon-Like Peptide 1; Glucose; Glycated Hemoglobin; Homeostasis; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Intestinal Absorption; Obesity; Rats; Remission Induction; Treatment Outcome; Weight Loss

Saxagliptin is a potent and selective reversible inhibitor of dipeptidyl peptidase-4, which is being developed for the treatment of type 2 diabetes. It is absorbed rapidly after oral administration and has a pharmacokinetic profile compatible with once daily dosing. Saxagliptin is metabolized in vivo to form an active metabolite, and both parent drug and metabolite are excreted primarily via the kidneys. Saxagliptin reduces the degradation of the incretin hormone glucagon-like peptide-1, thereby enhancing its actions, and is associated with improved beta-cell function and suppression of glucagon secretion. Clinical trials of up to 24 weeks duration have shown that saxagliptin improves glycemic control in monotherapy and provides additional efficacy when used in combination with other oral antidiabetic agents (metformin, sulfonylurea, thiazolidinedione). Both fasting and postprandial glucose concentrations are reduce leading to clinically meaningful reductions in glycated hemoglobin, and due to the glucose-dependency of its mechanism of action, there is a low risk of hypoglycemia. Saxagliptin is reported to be well tolerated with a side-effect profile similar to placebo. It has a neutral effect on body weight and dose adjustment because of age, gender, or hepatic impairment is not necessary. Saxagliptin is being co-developed by Bristol-Myers-Squibb (New York, NY, USA) and AstraZeneca (Cheshire, UK), and is currently undergoing regulatory review.

Topics: Adamantane; Administration, Oral; Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Drug Administration Schedule; Drug Evaluation, Preclinical; Drug Therapy, Combination; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Safety; Treatment Outcome

Type 2 diabetes mellitus (T2DM) is a chronic, progressive disorder that affects more than 230 million people worldwide and is expected to affect 366 million by 2030. Both the prevalence of T2DM and the cost of its long term complications has driven the focus and emphasis on treatments aimed at reducing hyperglycemia and controlling hypertension and dyslipidemia. In the last 5 years new glucose lowering drugs acting on novel pathways have been developed, licensed and launched. These drugs include the glucagon-like peptide (GLP-1) agonists, exenatide, and dipeptidyl peptidase (DPP-IV) inhibitors such as sitagliptin and saxagliptin. This review describes current approaches to T2DM treatment, focusing on newer agents which tend to be associated with less hypoglycemia and possible weight loss, and addresses the potential roles of novel oral pharmacologic agents in the late-stages of development that might provide new options for the management of this disease.

Topics: Animals; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents

Liraglutide (Victoza) is an acylated analogue of glucagon-like peptide-1 (GLP-1) indicated for the treatment of type 2 diabetes mellitus. In phase III studies, once-daily subcutaneous liraglutide improved glycaemic control compared with placebo or active comparator in adult patients with type 2 diabetes, both as monotherapy and in combination with one or two oral antidiabetic drugs such as metformin, sulfonylureas or thiazolidinediones. Liraglutide provided significantly better glycaemic control than rosiglitazone or insulin glargine in combination trials. At appropriate dosages, liraglutide was noninferior to glimepiride with respect to glycaemic control in a combination trial, but provided significantly better control than glimepiride or glibenclamide in monotherapy trials. Liraglutide improved pancreatic beta-cell function, generally led to weight loss, and was associated with a low risk of hypoglycaemia. Liraglutide was generally well tolerated, with the most common adverse events being gastrointestinal events, such as nausea, which decreased over time. Thus, liraglutide is an effective treatment option for use in patients with type 2 diabetes mellitus.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Liraglutide; Treatment Outcome

Topics: Animals; Diabetes Mellitus; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin-Secreting Cells; Receptors, Glucagon

Maintaining an adequate metabolic control is still a challenge in many patients with type 2 diabetes. Among the many factors advocated to explain the failure to achieve recommended goals, clinical inertia is increasingly recognised as a primary cause of poor glycaemic control. The existence of a "metabolic memory" strongly supports the adoption of a more aggressive treat-to-target approach, instead of waiting for treatment failure. This approach may be particularly important in the initial phases of the disease, to slow the progressive decline of beta-cell function and improve overall outcomes. The fear of hypoglycaemia and weight gain associated with most of the available treatments are among the main causes of clinical inertia, and strongly affect the attitudes of providers and patients toward therapy intensification. The incretin-based therapies represent a new potential goal-oriented treatment approach. Two classes of incretin-based drugs have been developed: GLP-1 mimetics (exenatide and liraglutide) and DPP-IV inhibitors (sitagliptin and vildagliptin). Incretino-mimetics have a peculiar mechanism of action that is associated with lack of hypoglycaemia and weight loss or neutrality; these characteristics may facilitate therapy intensification and help to attain established goals. Furthermore, they can induce benefits in terms of post-prandial hyperglicemia control and beta-cell function preservation. An early use of this class of drugs may show a positive impact on the disease progression and a delay in the need of insulin injections.

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Liraglutide; Nitriles; Peptides; Pyrazines; Pyrrolidines; Randomized Controlled Trials as Topic; Sitagliptin Phosphate; Triazoles; Venoms; Vildagliptin

Since Diabetes Control and Complications Trial (DCCT), intensive therapy has been directed at achieving glucose and glycosylated hemoglobin (HbA1c) values as close to normal as possible regarding safety issues. However, hyperglycemia (especially postprandial hyperglycemia) and hypoglicemia continue to be problematic in the management of type 1 diabetes. The objective of associating other drugs to insulin therapy is to achieve better metabolic control lowering postprandial blood glucose levels. Adjunctive therapies can be divided in four categories based on their mechanism of action: enhancement of insulin action (e.g. the biguanides and thiazolidinediones), alteration of gastrointestinal nutrient delivery (e.g. acarbose and amylin) and other targets of action (e.g. pirenzepine, insulin-like growth factor I and glucagon-like peptide-1). Many of these agents have been found to be effective in short-term studies with decreases in HbA1c of 0.5-1%, lowering postprandial blood glucose levels and decreasing daily insulin doses.

Topics: Acarbose; Amyloid; Blood Glucose; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Gastrointestinal Tract; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin-Like Growth Factor I; Islet Amyloid Polypeptide; Metformin; Muscarinic Antagonists; Pirenzepine; Postprandial Period; Thiazolidinediones

Exenatide is an incretin mimetic, while sitagliptin and vildagliptin are incretin enhancers used as adjunctive therapy in patients with type 2 diabetes failing oral agents. Sitagliptin and vildagliptin can also be used as monotherapy in patients with type 2 diabetes uncontrolled by diet.. To provide a critical review of clinical trials of exenatide, sitagliptin and vildagliptin.. Review of Phase III clinical trials based on Medline search published up to April 2008.. The use of exenatide is associated with reduction in average hemoglobin A1c (HbA1c) levels of approximately 0.8% compared with baseline. The corresponding reduction with either sitagliptin or vildagliptin is 0.7%. The actions of incretin-based drugs predominantly target postprandial hyperglycemia. Treatment-related hypoglycemia is generally mild, and mainly occurs when used with sulfonylureas (SUs). Exenatide treatment leads to a mild weight loss of around 2 kg after 30 weeks, whereas sitagliptin and vildagliptin have generally neutral effect on weight. Sitagliptin and vildagliptin are well tolerated in trials lasting up to 52 weeks. Meanwhile, 5 - 10% of patients cannot tolerate exenatide due to adverse effects, mainly nausea and vomiting. The three drugs are limited by the lack of long-term safety and efficacy data, as well as by their high cost.. Exenatide, sitagliptin and vildagliptin are useful add-on therapy for type 2 diabetes that is suboptimally controlled on oral agents, particularly when there is concern about weight gain and hypoglycemia, or when postprandial hyperglycemia is the major cause of inadequate glycemic control. Sitagliptin and vildagliptin may be used as monotherapy in patients who cannot tolerate metformin or SU, and sitagliptin may be used as alternative to metformin in renal insufficiency.

Topics: Adamantane; Body Weight; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Nausea; Nitriles; Peptides; Pyrazines; Pyrrolidines; Randomized Controlled Trials as Topic; Receptors, Glucagon; Sitagliptin Phosphate; Triazoles; Venoms; Vildagliptin; Vomiting

Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, the gene which is expressed in these cells. The current knowledge regarding regulation of proglucagon gene expression in the gut and in the brain and mechanisms responsible for the posttranslational processing are reviewed. GLP-1 is released in response to meal intake, and the stimuli and molecular mechanisms involved are discussed. GLP-1 is extremely rapidly metabolized and inactivated by the enzyme dipeptidyl peptidase IV even before the hormone has left the gut, raising the possibility that the actions of GLP-1 are transmitted via sensory neurons in the intestine and the liver expressing the GLP-1 receptor. Because of this, it is important to distinguish between measurements of the intact hormone (responsible for endocrine actions) or the sum of the intact hormone and its metabolites, reflecting the total L-cell secretion and therefore also the possible neural actions. The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin hormone) and to inhibit glucagon secretion, thereby contributing to limit postprandial glucose excursions. It also inhibits gastrointestinal motility and secretion and thus acts as an enterogastrone and part of the "ileal brake" mechanism. GLP-1 also appears to be a physiological regulator of appetite and food intake. Because of these actions, GLP-1 or GLP-1 receptor agonists are currently being evaluated for the therapy of type 2 diabetes. Decreased secretion of GLP-1 may contribute to the development of obesity, and exaggerated secretion may be responsible for postprandial reactive hypoglycemia.

Topics: Animals; Diabetes Mellitus; Gastrointestinal Tract; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Obesity; Proglucagon; Receptors, Glucagon

Inhibition of dipeptidyl peptidase 4 (DPP-4) is a novel treatment for type-2 diabetes. DPP-4 inhibition prevents the inactivation of glucagon-like peptide 1 (GLP-1), which increases levels of active GLP-1. This increases insulin secretion and reduces glucagon secretion, thereby lowering glucose levels. Several DPP-4 inhibitors are in clinical development. Most experience so far has been with sitagliptin (Merck; approved by the FDA) and vildagliptin (Novartis; filed). These are orally active compounds with a long duration, allowing once-daily administration. Both sitagliptin and vildagliptin improve metabolic control in type-2 diabetes, both in monotherapy and in combination with metformin and thiazolidinediones. A reduction in HbA(1c) of approximately 1% is seen in studies of DPP-4 inhibition of up to 52 weeks' duration. DPP-4 inhibition is safe and well tolerated, the risk of hypoglycaemia is minimal, and DPP-4 inhibition is body-weight neutral. DPP-4 inhibition is suggested to be a first-line treatment of type-2 diabetes, particularly in its early stages in combination with metformin. However, the durability and long-term safety of DPP-4 inhibition remain to be established.

Topics: Adamantane; Animals; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Lipid Metabolism; Metformin; Nitriles; Pioglitazone; Protease Inhibitors; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Substrate Specificity; Thiazolidinediones; Triazoles; Vildagliptin

Topics: Acarbose; Diet Therapy; Dumping Syndrome; Enzyme Inhibitors; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemia; Insulin; Insulin Secretion; Peptide Fragments; Protein Precursors

Topics: Amino Acid Sequence; Animals; Diabetes Mellitus; Gene Expression Regulation; Glicentin; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose; Homeostasis; Humans; Hypoglycemia; Islets of Langerhans; Molecular Sequence Data; Peptide Fragments; Protein Precursors

Hyperglycemia in acute ischemic stroke reduces the efficacy of stroke thrombolysis and thrombectomy, with worse clinical outcomes. Insulin-based therapies are difficult to implement and may cause hypoglycemia. We investigated whether exenatide, a GLP-1 (glucagon-like peptide-1) receptor agonist, would improve stroke outcomes, and control poststroke hyperglycemia with minimal hypoglycemia.. The TEXAIS trial (Treatment With Exenatide in Acute Ischemic Stroke) was an international, multicenter, phase 2 prospective randomized clinical trial (PROBE [Prospective Randomized Open Blinded End-Point] design) enrolling adult patients with acute ischemic stroke ≤9 hours of stroke onset to receive exenatide (5 µg BID subcutaneous injection) or standard care for 5 days, or until hospital discharge (whichever sooner). The primary outcome (intention to treat) was the proportion of patients with ≥8-point improvement in National Institutes of Health Stroke Scale score (or National Institutes of Health Stroke Scale scores 0-1) at 7 days poststroke. Safety outcomes included death, episodes of hyperglycemia, hypoglycemia, and adverse event.. From April 2016 to June 2021, 350 patients were randomized (exenatide, n=177, standard care, n=173). Median age, 71 years (interquartile range, 62-79), median National Institutes of Health Stroke Scale score, 4 (interquartile range, 2-8). Planned recruitment (n=528) was stopped early due to COVID-19 disruptions and funding constraints. The primary outcome was achieved in 97 of 171 (56.7%) in the standard care group versus 104 of 170 (61.2%) in the exenatide group (adjusted odds ratio, 1.22 [95% CI, 0.79-1.88];. Treatment with exenatide did not reduce neurological impairment at 7 days in patients with acute ischemic stroke. Exenatide did significantly reduce the frequency of hyperglycemic events, without hypoglycemia, and was safe to use. Larger acute stroke trials using GLP-1 agonists such as exenatide should be considered.. URL: www.australianclinicaltrials.gov.au; Unique identifier: ACTRN12617000409370. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03287076.

Topics: Adult; Aged; Exenatide; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemia; Ischemic Stroke; Prospective Studies; Stroke; Treatment Outcome

Oesophagectomy is associated with reduced appetite, weight loss and postprandial hypoglycaemia, the pathophysiological basis of which remains largely unexplored. This study aimed to investigate changes in enteroendocrine function after oesophagectomy.. In this prospective study, 12 consecutive patients undergoing oesophagectomy were studied before and 10 days, 6, 12 and 52 weeks after surgery. Serial plasma total fasting ghrelin, and glucagon-like peptide 1 (GLP-1), insulin and glucose release following a standard 400-kcal mixed-meal stimulus were determined. CT body composition and anthropometry were assessed, and symptom scores calculated using European Organisation for Research and Treatment of Cancer (EORTC) questionnaires.. At 1 year, two of the 12 patients exhibited postprandial hypoglycaemia, with reductions in bodyweight (mean(s.e.m.) 17·1(3·2) per cent, P < 0·001), fat mass (21.5(2.5) kg versus 25.5(2.4) kg before surgery; P = 0·014), lean body mass (51.5(2.2) versus 54.0(1.8) kg respectively; P = 0·003) and insulin resistance (HOMA-IR: 0.84(0.17) versus 1.16(0.20); P = 0·022). Mean(s.e.m.) fasting ghrelin levels decreased from postoperative day 10, but had recovered by 1 year (preoperative: 621·5(71·7) pg/ml; 10 days: 415·1(59·80) pg/ml; 6 weeks: 309·0(42·0) pg/ml; 12 weeks: 415·8(52·1) pg/ml; 52 weeks: 547·4(83·2) pg/ml; P < 0·001) and did not predict weight loss (P = 0·198). Postprandial insulin increased progressively at 10 days, 6, 12 and 52 weeks (mean(s.e.m.) insulin AUC. Altered enteroendocrine physiology is associated with early satiety, weight loss and postprandial hypoglycaemia after oesophagectomy.

Topics: Adult; Aged; Biomarkers; Blood Glucose; Body Composition; Esophagectomy; Female; Follow-Up Studies; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Insulin; Male; Middle Aged; Outcome Assessment, Health Care; Postoperative Complications; Postprandial Period; Prospective Studies; Satiety Response; Weight Loss

To investigate the effects of acarbose, sitagliptin, verapamil, liraglutide and pasireotide on post-bariatric hypoglycaemia (PBH) after Roux-en-Y gastric bypass.. In a randomized crossover study, 11 women who had undergone Roux-en-Y gastric bypass and had documented hypoglycaemia were each evaluated during a baseline period without treatment and during five treatment periods with the following interventions: acarbose 50 mg for 1 week, sitagliptin 100 mg for 1 week, verapamil 120 mg for 1 week, liraglutide 1.2 mg for 3 weeks and pasireotide 300 μg as a single dose. Treatment effects were evaluated by a mixed-meal tolerance test (MMTT) and, for all treatment periods except pasireotide, by 6 days of continuous glucose monitoring (CGM).. Treatment with acarbose and treatment with pasireotide both significantly lifted nadir glucose levels (mean ± SEM 3.9 ± 0.2 and 7.9 ± 0.4 vs 3.4 ± 0.2; P < .03) and reduced time in hypoglycaemia during the MMTTs. Acarbose reduced peak glucose levels and time in hyperglycaemia, whereas pasireotide greatly increased both variables. Acarbose and pasireotide reduced insulin and C-peptide levels, and pasireotide also diminished glucagon-like peptide-1 levels. Sitagliptin lowered nadir glucose values, while verapamil and liraglutide had no effect on hypoglycaemia. During the CGM periods, the treatments had no impact on hypoglycaemia, whereas acarbose and liraglutide reduced hyperglycaemia and glycaemic variability.. In an experimental setting, treatment with acarbose and pasireotide reduced PBH. Acarbose appears to have an overall glucose-stabilizing effect, whereas pasireotide leads to increased and sustained hyperglycaemia.

Topics: Acarbose; Adult; Blood Glucose; Blood Glucose Self-Monitoring; Cross-Over Studies; Female; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Obesity, Morbid; Postoperative Complications; Postprandial Period; Sitagliptin Phosphate; Somatostatin; Treatment Outcome; Verapamil

To compare the efficacy and safety of a glucagon-like peptide-1 receptor agonist (GLP1RA) plus basal insulin versus basal-bolus insulin treatment in patients with very uncontrolled type 2 diabetes.. The SIMPLE study was a 6-month pragmatic, randomized, open-label trial testing the effectiveness of two approaches to treat patients with type 2 diabetes and HbA1c ≥10%. We randomized patients to detemir plus liraglutide or detemir plus aspart (before each meal). The primary endpoint was change in HbA1c; changes in body weight, insulin dose, hypoglycaemia and diabetes-related quality-of-life were secondary outcomes.. In patients with HbA1c ≥10% treatment with GLP1RA plus basal insulin, compared with basal-bolus insulin, resulted in better glycaemic control and body weight, lower insulin dosage and hypoglycaemia, and improved quality of life. This treatment strategy is an effective and safe alternative to a basal-bolus insulin regimen.

Topics: Adult; Blood Glucose; Body Weight; Comparative Effectiveness Research; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Aspart; Insulin Detemir; Liraglutide; Male; Meals; Middle Aged; Treatment Outcome

The aim of the study was to explore the role of GLP-1 receptor activation on the counter-regulation and symptoms of hypoglycemia in subjects who have undergone gastric bypass surgery (GBP).. Experimental hyperinsulinemic-hypoglycemic clamp study.. Twelve post-GBP subjects participated in a randomized cross-over study with two hyperinsulinemic, hypoglycemic clamps (glucose nadir 2.7 mmol/L) performed on separate days with concomitant infusions of the GLP-1 analog exenatide or with saline, respectively. Continuous measurements of metabolites and counter-regulatory hormones as well as assessments of heart rate variability and symptoms of hypoglycemia were performed throughout the clamps.. No effect of GLP-1 receptor activation on counter-regulatory hormones (glucagon, catecholamines, cortisol, GH) or glucose infusion rate was seen, but we found indications of a downregulation of the sympathetic relative to the parasympathetic nerve activity, as reflected in heart rate variability. No significant differences in symptom of hypoglycemia were observed.. Short-term exposure to a GLP-1 receptor agonist does not seem to impact the counter-regulatory hormonal and metabolic responses in post-GBP subjects during hypoglycemic conditions, suggesting that the improvement in symptomatic hypoglycemia post-GBP seen following treatment with GLP-1 receptor agonists may be mediated by mechanism not directly involved in counter-regulation.

Topics: Adult; Blood Glucose; Catecholamines; Cross-Over Studies; Exenatide; Female; Gastric Bypass; Glucagon; Glucagon-Like Peptide 1; Glucose Clamp Technique; Heart Rate; Human Growth Hormone; Humans; Hydrocortisone; Hypoglycemia; Incretins; Male; Middle Aged; Parasympathetic Nervous System; Postoperative Period; Sympathetic Nervous System

Roux-en-Y gastric bypass (RYGB) augments postprandial secretion of glucagon-like peptide 1 (GLP-1), oxyntomodulin (OXM), and peptide YY (PYY). Subcutaneous infusion of these hormones ("GOP"), mimicking postprandial levels, reduces energy intake. Our objective was to study the effects of GOP on glycemia and body weight when given for 4 weeks to patients with diabetes and obesity.. In this single-blinded mechanistic study, obese patients with prediabetes/diabetes were randomized to GOP (. GOP infusion improves glycemia and reduces body weight. It achieves superior glucose tolerance and reduced glucose variability compared with RYGB and VLCD. GOP is a viable alternative for the treatment of diabetes with favorable effects on body weight.

Topics: Adult; Blood Glucose; Blood Glucose Self-Monitoring; Body Weight; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Infusions, Subcutaneous; Insulin; Male; Meals; Middle Aged; Obesity; Oxyntomodulin; Peptide YY; Postprandial Period; Prediabetic State; Single-Blind Method; Weight Loss

Gastric emptying is a critical regulator of postprandial glucose and delayed gastric emptying is an important mechanism of improved glycemic control achieved by short-acting glucagon-like peptide-1 (GLP-1) analogs in clinical practice. Here we report on a novel regulatory mechanism of gastric emptying in humans. We show that increasing interleukin (IL)-6 concentrations delays gastric emptying leading to reduced postprandial glycemia. IL-6 furthermore reduces insulin secretion in a GLP-1-dependent manner while effects on gastric emptying are GLP-1 independent. Inhibitory effects of IL-6 on gastric emptying were confirmed following exercise-induced increases in IL-6. Importantly, gastric- and insulin-reducing effects were maintained in individuals with type 2 diabetes. These data have clinical implications with respect to the use of IL-6 inhibition in autoimmune/inflammatory disease, and identify a novel target that could be exploited pharmacologically to delay gastric emptying and spare insulin, which may be beneficial for the beta cell in type 2 diabetes.

Topics: Aged; Blood Glucose; Case-Control Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Exercise; Gastric Emptying; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Insulin; Insulin Secretion; Insulin-Secreting Cells; Interleukin-6; Male; Recombinant Proteins; Young Adult

We have previously reported that once-weekly albiglutide was noninferior to thrice-daily lispro for glycemic lowering, with decreased weight and risk of hypoglycemia, in patients inadequately controlled on basal insulin over 26 weeks. Findings after 52 weeks reveal similar responses to albiglutide as an add-on to insulin glargine.

Topics: Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Monitoring; Drug Resistance; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incidence; Incretins; Insulin Glargine; Insulin Lispro; Meals; Risk; Weight Gain; Weight Loss

Post-bariatric hypoglycaemia (PBH) is a rare, but severe, metabolic disorder arising months to years after bariatric surgery. It is characterised by symptomatic postprandial hypoglycaemia, with inappropriately elevated insulin concentrations. The relative contribution of exaggerated incretin hormone signalling to dysregulated insulin secretion and symptomatic hypoglycaemia is a subject of ongoing inquiry. This study was designed to test the hypothesis that PBH and associated symptoms are primarily mediated by glucagon-like peptide-1 (GLP-1).. We conducted a double-blinded crossover study wherein eight participants with confirmed PBH were assigned in random order to intravenous infusion of the GLP-1 receptor (GLP-1r) antagonist. Exendin (9-39) (Ex-9), or placebo during an OGTT on two separate days at the Stanford University Clinical and Translational Research Unit. Metabolic, symptomatic and pharmacokinetic variables were evaluated. Results were compared with a cohort of BMI- and glucose-matched non-surgical controls (NSCs).. Infusion of Ex-9 decreased the time to peak glucose and rate of glucose decline during OGTT, and raised the postprandial nadir by over 70%, normalising it relative to NSCs and preventing hypoglycaemia in all PBH participants. Insulin AUC and secretion rate decreased by 57% and 71% respectively, and peak postprandial insulin was normalised relative to NSCs. Autonomic and neuroglycopenic symptoms were significantly reduced during Ex-9 infusion.. GLP-1r blockade prevented hypoglycaemia in 100% of individuals, normalised beta cell function and reversed neuroglycopenic symptoms, supporting the conclusion that GLP-1 plays a primary role in mediating hyperinsulinaemic hypoglycaemia in PBH. Competitive antagonism at the GLP-1r merits consideration as a therapeutic strategy.. ClinicalTrials.gov NCT02550145.

Topics: Adult; Cross-Over Studies; Double-Blind Method; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Glucose Tolerance Test; Humans; Hypoglycemia; Insulin; Male; Middle Aged; Peptide Fragments; Surveys and Questionnaires

The decline in insulin sensitivity (S. Thirteen adolescents with T1D (HbA1C 8.2 ± 0.1%) were admitted to perform afternoon exercise (four 15-min treadmill/5-min rest cycles of exercise) on two occasions within a 4-wk period. They were randomized to receive a drink containing either glutamine (0.25 g/kg) or placebo before exercise, at bedtime, and early morning in a double-blind, crossover design. Blood glucose was monitored overnight, and a hyperinsulinemic-euglycemic clamp was performed the following morning.. Oral glutamine supplementation decreases blood glucose in adolescents with T1D after exercise. Insulin sensitivity, however, was unaltered during the euglycemic clamp. Although the mechanisms involved remain to be elucidated, studies to explore the potential use of glutamine to improve blood glucose control are needed.

Topics: Adolescent; Blood Glucose; Body Mass Index; Cross-Over Studies; Diabetes Mellitus, Type 1; Dietary Supplements; Double-Blind Method; Exercise; Fatty Acids, Nonesterified; Female; Glucagon-Like Peptide 1; Glucose Clamp Technique; Glutamine; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Male

Sustained exogenous stimulation of a hormone-specific receptor can affect endogenous hormonal regulation. In this context, little is known about the impact of chronic treatment with glucagon-like peptide-1 (GLP-1) agonists on the endogenous GLP-1 response. We therefore evaluated the impact of chronic liraglutide therapy on endogenous GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) response to an oral glucose challenge. A total of 51 people with type 2 diabetes of 2.6 ± 1.9 years' duration were randomized to daily subcutaneous liraglutide or placebo injection and followed for 48 weeks, with an oral glucose tolerance test (OGTT) every 12 weeks. GLP-1 and GIP responses were assessed according to their respective area under the curve (AUC) from measurements taken at 0, 30, 60, 90 and 120 minutes during each OGTT. There were no differences in AUC

Topics: Adult; Diabetes Mellitus, Type 2; Double-Blind Method; Enteroendocrine Cells; Enzyme-Linked Immunosorbent Assay; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Insulin-Secreting Cells; Liraglutide; Time Factors

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) stimulate the incretin system and lower glycaemic parameters in type 2 diabetes mellitus (T2DM). This analysis of clinical studies of up to 3years evaluated the safety of albiglutide, a GLP-1 RA, in people with T2DM.. Integrated safety analysis included seven phase-3 T2DM studies of albiglutide compared with placebo and/or active comparators (a dipeptidyl peptidase-4 inhibitor, GLP-1 RA, insulin, sulphonylurea, and thiazolidinedione).. Studies of 32months (HARMONY 7), 1year (HARMONY 6), and 3years (HARMONY 1-5), reported similar rates of adverse events (AEs) (84.8%, 82.3%), and serious AEs (13.1%, 12.9%) between albiglutide and all comparators, respectively. AEs that did not differ between the groups included symptomatic or severe hypoglycaemia as well as nausea (12.0%, 11.3%) and vomiting (5.3%, 4.7%) for albiglutide and all comparators, respectively. According to the Medical Dictionary for Regulatory Activities preferred terms, only diarrhoea (13.7%, 9.9%), injection-site reaction (9.0%, 2.0%), and peripheral oedema (4.5%, 6.8%) had at least 2% difference between the albiglutide and all-comparator groups. In a similar integrated analysis, pancreatitis occurred more often with albiglutide (0.3%, 0.1%). Renal and cardiac function did not differ between the two groups.. In an integrated analysis of seven phase 3 clinical trials, albiglutide-treated patients experienced frequencies of AEs (including cardiovascular and renal) similar to the all-comparators group treated with other T2DM medications or placebo. Albiglutide treatment was associated with higher rates of diarrhoea and injection-site reactions, but not increased nausea and vomiting, versus all comparators.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Injections; Insulin; Male; Middle Aged; Sulfonylurea Compounds

Counterregulatory responses are critical to prevent hypoglycemia in subjects with type 2 diabetes. This is particularly important in insulin-treated patients. This study explored the effect of the glucagon-like peptide 1 receptor agonist lixisenatide on the hormonal counterregulatory responses to insulin-induced hypoglycemia when added to basal insulin therapy in subjects with type 2 diabetes.. The study was a single-center, double-blind, randomized, placebo-controlled crossover study involving 18 subjects with type 2 diabetes (11 males) with a mean age of 55 years, diabetes duration of 12 years, HbA1c level of 7.7%, fasting blood glucose (FBG) concentration of 9.7 mmol/L, and a BMI of 33 kg/m(2), who were treated with basal insulin (mean duration 7 years, daily dose 39 units/day) and metformin (mean daily dose 2.1 g). Subjects received treatment with lixisenatide or placebo for 6 weeks in random order, with a 4-week washout period in between. After 6 weeks of treatment, subjects underwent a two-step hyperinsulinemic hypoglycemic clamp at 3.5 and 2.8 mmol/L.. After 6 weeks of treatment, HbA1c and FBG levels were lower after lixisenatide therapy than after placebo therapy. At the hypoglycemic level of 3.5 mmol/L, glucagon and epinephrine levels were significantly lower during lixisenatide treatment than during placebo treatment, whereas at 2.8 mmol/L glucagon and epinephrine levels did not differ between the subjects. Cortisol, pancreatic polypeptide, and norepinephrine levels did not differ significantly between the treatments.. Glucagon and epinephrine levels are reduced by lixisenatide at a concentration of 3.5 mmol/L, but their counterregulatory responses to deep hypoglycemia at a concentration of 2.8 mmol/L are sustained during treatment with lixisenatide in combination with basal insulin.

Topics: Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hydrocortisone; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged; Peptides

Type 2 diabetes pathophysiology is characterized by dysregulated glucagon secretion. LY2409021, a potent, selective small-molecule glucagon receptor antagonist that lowers glucose was evaluated for efficacy and safety in patients with type 2 diabetes.. The efficacy (HbA1c and glucose) and safety (serum aminotransferase) of once-daily oral administration of LY2409021 was assessed in two double-blind studies. Phase 2a study patients were randomized to 10, 30, or 60 mg of LY2409021 or placebo for 12 weeks. Phase 2b study patients were randomized to 2.5, 10, or 20 mg LY2409021 or placebo for 24 weeks.. LY2409021 produced reductions in HbA1c that were significantly different from placebo over both 12 and 24 weeks. After 12 weeks, least squares (LS) mean change from baseline in HbA1c was -0.83% (10 mg), -0.65% (30 mg), and -0.66% (60 mg) (all P < 0.05) vs. placebo, 0.11%. After 24 weeks, LS mean change from baseline in HbA1c was -0.45% (2.5 mg), -0.78% (10 mg, P < 0.05), -0.92% (20 mg, P < 0.05), and -0.15% with placebo. Increases in serum aminotransferase, fasting glucagon, and total fasting glucagon-like peptide-1 (GLP-1) were observed; levels returned to baseline after drug washout. Fasting glucose was also lowered with LY2409021 at doses associated with only modest increases in aminotransferases (mean increase in alanine aminotransferase [ALT] ≤10 units/L). The incidence of hypoglycemia in the LY2409021 groups was not statistically different from placebo.. In patients with type 2 diabetes, glucagon receptor antagonist treatment significantly lowered HbA1c and glucose levels with good overall tolerability and a low risk for hypoglycemia. Modest, reversible increases in serum aminotransferases were observed.

Topics: Adult; Aged; Biphenyl Compounds; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Middle Aged; Receptors, Glucagon; Transaminases; Young Adult

Gastric bypass (GBP) surgery, one of the most common bariatric procedures, induces weight loss and metabolic effects. The mechanisms are not fully understood, but reduced food intake and effects on gastrointestinal hormones are thought to contribute. We recently observed that GBP patients have lowered glucose levels and frequent asymptomatic hypoglycemic episodes. Here, we subjected patients before and after undergoing GBP surgery to hypoglycemia and examined symptoms and hormonal and autonomic nerve responses. Twelve obese patients without diabetes (8 women, mean age 43.1 years [SD 10.8] and BMI 40.6 kg/m(2) [SD 3.1]) were examined before and 23 weeks (range 19-25) after GBP surgery with hyperinsulinemic-hypoglycemic clamp (stepwise to plasma glucose 2.7 mmol/L). The mean change in Edinburgh Hypoglycemia Score during clamp was attenuated from 10.7 (6.4) before surgery to 5.2 (4.9) after surgery. There were also marked postsurgery reductions in levels of glucagon, cortisol, and catecholamine and the sympathetic nerve responses to hypoglycemia. In addition, growth hormone displayed a delayed response but to a higher peak level. Levels of glucagon-like peptide 1 and gastric inhibitory polypeptide rose during hypoglycemia but rose less postsurgery compared with presurgery. Thus, GBP surgery causes a resetting of glucose homeostasis, which reduces symptoms and neurohormonal responses to hypoglycemia. Further studies should address the underlying mechanisms as well as their impact on the overall metabolic effects of GBP surgery.

Topics: Adult; Blood Glucose; Catecholamines; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Clamp Technique; Humans; Hydrocortisone; Hypoglycemia; Insulin; Male; Middle Aged; Obesity, Morbid

Glucose-dependent insulinotropic polypeptide (GIP) is glucagonotropic, and glucagon-like peptide-1 (GLP-1) is glucagonostatic. We studied the effects of GIP and GLP-1 on glucagon responses to insulin-induced hypoglycemia in patients with type 1 diabetes mellitus (T1DM). Ten male subjects with T1DM (C-peptide negative, age [mean ± SEM] 26 ± 1 years, BMI 24 ± 0.5 kg/m(2), HbA1c 7.3 ± 0.2%) were studied in a randomized, double-blinded, crossover study, with 2-h intravenous administration of saline, GIP, or GLP-1. The first hour, plasma glucose was lowered by insulin infusion, and the second hour constituted a "recovery phase." During the recovery phase, GIP infusions elicited larger glucagon responses (164 ± 50 [GIP] vs. 23 ± 25 [GLP-1] vs. 17 ± 46 [saline] min ⋅ pmol/L, P < 0.03) and endogenous glucose production was higher with GIP and lower with GLP-1 compared with saline (P < 0.02). On the GIP days, significantly less exogenous glucose was needed to keep plasma glucose above 2 mmol/L (155 ± 36 [GIP] vs. 232 ± 40 [GLP-1] vs. 212 ± 56 [saline] mg ⋅ kg(-1), P < 0.05). Levels of insulin, cortisol, growth hormone, and noradrenaline, as well as hypoglycemic symptoms and cognitive function, were similar on all days. Our results suggest that during hypoglycemia in patients with T1DM, exogenous GIP increases glucagon responses during the recovery phase after hypoglycemia and reduces the need for glucose administration.

Topics: Adult; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 1; Double-Blind Method; Drug Synergism; Fatty Acids, Nonesterified; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glycerol; Hormones; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Treatment Outcome

To determine if the glucagon-like peptide-1 (GLP-1) receptor agonist albiglutide, once weekly, impairs counter-regulatory responses during hypoglycaemia.. We conducted a randomized, double-blind, parallel, placebo-controlled study in subjects with type 2 diabetes mellitus. A single dose of albiglutide 50 mg (n = 22) or placebo (n = 22) was administered on day 1. Glucose was clamped on day 4 (to coincide with the approximate albiglutide maximum plasma concentration) at 9.0, 5.0, 4.0, 3.3 and 2.8 mmol/l (162, 90, 72, 59.4 and 50.4 mg/dl), with a post-clamp recovery period to 3.9 mmol/l (70 mg/dl). Hormone measurements were made at each plateau and adverse events (AEs) were recorded.. The counter-regulatory hormones glucagon, epinephrine, norepinephrine, growth hormone and cortisol were appropriately suppressed when plasma glucose levels were >4.0 mmol/l (>72 mg/dl), but increased in the albiglutide and placebo groups with glucose levels <3.3 mmol/l (<59.4 mg/dl) in response to hypoglycaemia. The area under the curve geometric mean ratios (albiglutide : placebo), calculated from the clamped plateau of 4.0 mmol/l (72 mg/dl) to the glucose recovery point, were not significantly different for any of the counter-regulatory hormones. When plasma glucose levels were >5.0 mmol/l (>90 mg/dl), albiglutide increased pancreatic β-cell secretion of C-peptide in a glucose-dependent manner to a greater extent than did placebo, and it was suppressed in each group when levels were <4.0 mmol/l (<72 mg/dl). No significant difference between groups was observed in the recovery time to glucose level ≥3.9 mmol/l (≥70 mg/dl). There were no clinically relevant differences in AEs or other safety variables.. A single 50-mg dose of albiglutide was well tolerated and did not impair the counter-regulatory response to hypoglycaemia. These data provide mechanistic evidence supporting the low intrinsic hypoglycaemic potential of albiglutide.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Down-Regulation; Female; Glucagon; Glucagon-Like Peptide 1; Glucose Clamp Technique; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Middle Aged; Pancreas; Recombinant Proteins; Up-Regulation

To assess whether the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin affects glucagon and other counter-regulatory hormone responses to hypoglycaemia in patients with type 1 diabetes.. We conducted a single-centre, randomized, double-blind, placebo-controlled, three-period crossover study. We studied 16 male patients with type 1 diabetes aged 18-52 years, with a diabetes duration of 5-20 years and intact hypoglycaemia awareness. Participants received sitagliptin (100 mg/day) or placebo for 6 weeks and attended the hospital for three acute hypoglycaemia studies (at baseline, after sitagliptin treatment and after placebo). The primary outcome was differences between the three hypoglycaemia study days with respect to plasma glucagon responses from the initialization phase of the hypoglycaemia intervention to 40 min after onset of the autonomic reaction.. Sitagliptin treatment significantly increased active levels of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1. No significant differences were observed for glucagon or adrenergic counter-regulatory responses during the three hypoglycaemia studies. Growth hormone concentration at 40 min after occurrence of autonomic reaction was significantly lower after sitagliptin treatment [median (IQR) 23 (0.2-211.0) mEq/l] compared with placebo [median (IQR) 90 (8.8-180) mEq/l; p = 0.008].. Sitagliptin does not affect glucagon or adrenergic counter-regulatory responses in patients with type 1 diabetes, but attenuates the growth hormone response during late hypoglycaemia.

Topics: Adolescent; Adult; Cross-Over Studies; Diabetes Mellitus, Type 1; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Growth Hormone; Humans; Hypoglycemia; Incretins; Male; Middle Aged; Sitagliptin Phosphate; Young Adult

Patients with type 1 diabetes face heightened risk of hypoglycemia after exercise. Subsequent overfeeding, as a preventative measure against hypoglycemia, negates the energy deficit after exercise. Patients are also required to reduce the insulin dose administered with postexercise foods to further combat hypoglycemia. However, the insulin dose is dictated solely by the carbohydrate content, even though postprandial glycemia is vastly influenced by glycemic index (GI). With a need to control the postexercise energy balance, appetite responses after meals differing in GI are of particular interest.. We assessed the appetite response to low-glycemic index (LGI) and high-glycemic index (HGI) postexercise meals in type 1 diabetes patients. This assessment also offered us the opportunity to evaluate the influence of GI on appetite responses independently of insulinemia, which confounds findings in individuals without diabetes.. Ten physically active men with type 1 diabetes completed 2 trials in a randomized crossover design. After 45 min of treadmill exercise at 70% of the peak oxygen uptake, participants consumed an LGI (GI ∼37) or HGI (GI ∼92) meal with a matched macronutrient composition, negligible fiber content, and standardized insulin-dose administration. The postprandial appetite response was determined for 180 min postmeal. During this time, circulating glucose, insulin, glucagon, and glucagon-like peptide-1 (GLP-1) concentrations and subjective appetite ratings were determined.. The HGI meal produced an ∼60% greater postprandial glucose area under the curve (AUC) than did the LGI meal (P = 0.008). Insulin, glucagon, and GLP-1 did not significantly differ between trials (P > 0.05). The fullness AUC was ∼25% greater after the HGI meal than after the LGI meal (P < 0.001), whereas hunger sensations were ∼9% lower after the HGI meal than after the LGI meal (P = 0.001).. Under conditions of matched insulinemia and fiber, an HGI postexercise meal suppresses feelings of hunger and augments postprandial fullness sensations more so than an otherwise equivalent LGI meal in type 1 diabetes patients.

Topics: Adult; Appetite Regulation; Combined Modality Therapy; Cross-Over Studies; Diabetes Mellitus, Type 1; Diet, Diabetic; Dietary Fiber; Drug Therapy, Combination; Exercise; Glucagon; Glucagon-Like Peptide 1; Glycemic Index; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Insulin Aspart; Insulin Glargine; Insulin, Long-Acting; Jogging; Male; Meals; Postprandial Period

To investigate the effect of glucagon-like peptide 1 receptor agonist liraglutide on the counter-regulatory hormone response to hypoglycaemia in type 1 diabetes.. We conducted a randomized, double-blind, placebo-controlled, single-centre trial, in which a total of 45 adults with type 1 diabetes [mean ± standard deviation age 34.5 ± 11.2 years, BMI 23.9 ± 2.4 kg/m(2) , glycated haemoglobin (HbA1c) 7.6 ± 0.8%, diabetes duration 16.6 ± 9.4 years] underwent a hypoglycaemic clamp after 4 weeks' crossover treatment with once-daily liraglutide/placebo added to insulin in one of three liraglutide dose groups: 0.6 mg (n = 15); 1.2 mg (n = 14); and 1.8 mg (n = 16). The main outcome measure was glucagon concentration at nadir plasma glucose (2.5 mmol/l). Clinical outcomes were also evaluated. Five participants were withdrawn from the trial; three because of adverse events. All participants were included in the analysis.. Glucagon concentration at nadir plasma glucose was modest, trending towards lower concentrations at increasing liraglutide dose versus placebo: 34.7 versus 38.1 pg/ml, p = 0.555 (0.6 mg); 28.8 versus 37.2 pg/ml, p = 0.126 (1.2 mg); and 28.4 versus 37.5 pg/ml, p = 0.092 (1.8 mg). There was no difference, however, between liraglutide and placebo in incremental change in glucagon during hypoglycaemia. Other counter-regulatory hormone levels increased during hypoglycaemia with no systematic differences between groups. Glucose infusion rates were significantly lower with liraglutide versus placebo during the clamp. After 4 weeks' treatment, HbA1c remained unchanged in the liraglutide and placebo groups. Greater reductions in insulin dose and body weight were seen with liraglutide versus placebo.. Liraglutide did not compromise hypoglycaemic responses in type 1 diabetes after 4 weeks' treatment.

Topics: Adult; Body Weight; Cross-Over Studies; Diabetes Mellitus, Type 1; Double-Blind Method; Drug Therapy, Combination; Female; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Liraglutide; Male; Middle Aged

To compare a sulphonylurea with the glucagon like peptide-1 (GLP-1) receptor agonist liraglutide in combination with metformin in patients on mono/dual oral therapy with established type 2 diabetes fasting during Ramadan.. Ninety-nine adults intending to fast during Ramadan [50% male, mean age 52 years, body mass index (BMI) 32 kg/m(2)] were randomized from two UK sites. Baseline data were collected ≥14 days prior to Ramadan and at 3 and 12 weeks after Ramadan.. At 12 weeks, more patients in the liraglutide compared with the sulphonylurea group achieved a composite endpoint of haemoglobin A1c (HbA1c) < 7%, no weight gain and no severe hypoglycaemia but this did not reach statistical significance [odds ratio (OR) 4.08, 95% confidence interval (CI) 0.97, 17.22, p = 0.06]. From a baseline of 7.7% there was no change in HbA1c at 12 weeks in the sulphonylurea (+0.02%) compared with a 0.3% reduction in the liraglutide group (adjusted coefficient -0.41, 95% CI -0.83, 0.01, p = 0.05). Significant reductions were also observed in weight and diastolic blood pressure (BP) in the liraglutide compared with the sulphonylurea group. Treatment satisfaction was comparable across the treatment groups. There were no episodes of severe hypoglycaemia in either group, however, self-recorded episodes of blood glucose ≤3.9 mmol/l were significantly lower with liraglutide (incidence rate ratio 0.29, 95% CI 0.19, 0.41, p < 0.0001).. Liraglutide compared with sulphonylurea is well tolerated and maybe an effective therapy in combination with metformin during Ramadan with more patients able to achieve target HbA1c, lose or maintain weight with no severe hypoglycaemia. This was achieved with a high level of treatment satisfaction.

Topics: Adult; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Fasting; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Islam; Liraglutide; Male; Metformin; Middle Aged; Patient Satisfaction; Receptors, Glucagon; Sulfonylurea Compounds; Treatment Outcome; United Kingdom

Glucagon-like peptide-1 (GLP-1) may provide beneficial cardiovascular effects, possibly due to enhanced myocardial energetic efficiency by increasing myocardial glucose uptake (MGU). We assessed the effects of GLP-1 on MGU in healthy subjects during normo- and hypoglycemia.. We included eighteen healthy men in two randomized, double-blinded, placebo-controlled cross-over studies. MGU was assessed with GLP-1 or saline infusion during pituitary-pancreatic normo- (plasma glucose (PG): 4.5 mM, n = 10) and hypoglycemic clamps (PG: 3.0 mM, n = 8) by positron emission tomography with (18)fluoro-deoxy-glucose ((18)F-FDG) as tracer.. In the normoglycemia study mean (± SD) age was 25±3 years, and BMI was 22.6±0.6 kg/m(2) and in the hypoglycemia study the mean age was 23±2 years with a mean body mass index of 23±2 kg/m(2). GLP-1 did not change MGU during normoglycemia (mean (+/- SD) 0.15+/-0.04 and 0.16+/-0.03 µmol/g/min, P = 0.46) or during hypoglycemia (0.16+/-0.03 and 0.13+/-0.04 µmol/g/min, P = 0.14). However, the effect of GLP-1 on MGU was negatively correlated to baseline MGU both during normo- and hypoglycemia, (P = 0.006, r(2) = 0.64 and P = 0.018, r(2) = 0.64, respectively) and changes in MGU correlated positively with the level of insulin resistance (HOMA 2IR) during hypoglycemia, P = 0.04, r(2) = 0.54. GLP-1 mediated an increase in circulating glucagon levels at PG levels below 3.5 mM and increased glucose infusion rates during the hypoglycemia study. No differences in other circulating hormones or metabolites were found.. While GLP-1 does not affect overall MGU, GLP-1 induces changes in MGU dependent on baseline MGU such that GLP-1 increases MGU in subjects with low baseline MGU and decreases MGU in subjects with high baseline MGU. GLP-1 preserves MGU during hypoglycemia in insulin resistant subjects. ClinicalTrials.gov registration numbers: NCT00418288: (hypoglycemia) and NCT00256256: (normoglycemia).

Topics: Adult; Blood Glucose; Cross-Over Studies; Fluorodeoxyglucose F18; Glucagon-Like Peptide 1; Glucose; Heart; Hormones; Humans; Hypoglycemia; Male; Metabolome; Myocardium; Positron-Emission Tomography; Young Adult

Exogenous GLP-1 slows gastric emptying in health and diabetes leading to diminished glycemic excursions. Gastric emptying is markedly accelerated by hypoglycemia. The primary objective was to determine whether GLP-1 attenuates the acceleration of gastric emptying induced by hypoglycemia.. Ten healthy volunteers were studied on four separate days in a randomized double-blind fashion. Blood glucose was stabilized using a glucose/insulin clamp at hypoglycemia (2.6 mmol/L on two occasions [hypo]) or euglycemia (6.0 mmol/L on two occasions [eu]) between T = -15 and 45 min before clamping at 6.0 mmol/L until 180 min. During hypoglycemia and euglycemia, subjects received intravenous GLP-1 (1.2 pmol/kg/min) or placebo. At T = 0 min, subjects ingested 100 g beef mince labeled with 20 MBq (99m)Tc-sulfur-colloid and 3 g of 3-O-methyl-glucose (3-OMG), a marker of glucose absorption. Gastric emptying was measured scintigraphically from T = 0 to 180 min and serum 3-OMG taken at 15-min intervals. The areas under the curve for gastric emptying and 3-OMG concentration were analyzed using one-way repeated-measures ANOVA with Bonferroni-Holm adjusted post hoc tests.. Gastric emptying was accelerated during hypoglycemia (hypo/placebo vs. eu/placebo; P < 0.001), as was glucose absorption (P < 0.03). GLP-1 slowed emptying during euglycemia (eu/placebo vs. eu/GLP-1; P < 0.001). However, hypoglycemia-induced acceleration of gastric emptying on placebo was markedly diminished by GLP-1 (hypo/placebo vs. hypo/GLP-1; P < 0.008), as was glucose absorption (P < 0.01).. Acute administration of exogenous GLP-1 attenuates, but does not abolish, the acceleration of gastric emptying by insulin-induced hypoglycemia in healthy subjects.

Topics: Aged; Blood Glucose; Double-Blind Method; Female; Gastric Emptying; Glucagon-Like Peptide 1; Glucose Clamp Technique; Healthy Volunteers; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Injections, Intravenous; Insulin; Male; Middle Aged

The most common form of maturity-onset diabetes of the young (MODY), hepatocyte nuclear factor 1α (HNF1A diabetes: MODY3) is often treated with sulfonylureas that confer a high risk of hypoglycemia. We evaluated treatment with GLP-1 receptor agonists (GLP-1RAs) in patients with HNF1A diabetes.. Sixteen patients with HNF1A diabetes (8 women; mean age 39 years [range 23-67 years]; BMI 24.9 ± 0.5 kg/m(2) [mean ± SEM]; fasting plasma glucose [FPG] 9.9 ± 0.9 mmol/L; HbA1c 6.4 ± 0.2% [47 ± 3 mmol/mol]) received 6 weeks of treatment with a GLP-1RA (liraglutide) and placebo (tablets), as well as a sulfonylurea (glimepiride) and placebo (injections), in randomized order, in a double-blind, crossover trial. Glimepiride was up-titrated once weekly in a treat-to-target manner; liraglutide was up-titrated once weekly to 1.8 mg once daily. At baseline and at the end of each treatment period a standardized liquid meal test was performed, including a 30-min light bicycle test.. FPG decreased during the treatment periods (-1.6 ± 0.5 mmol/L liraglutide [P = 0.012] and -2.8 ± 0.7 mmol/L glimepiride [P = 0.003]), with no difference between treatments (P = 0.624). Postprandial plasma glucose (PG) responses (total area under the curve) were lower with both glimepiride (2,136 ± 292 min × mmol/L) and liraglutide (2,624 ± 340 min × mmol/L) compared with baseline (3,127 ± 291 min × mmol/L; P < 0.001, glimepiride; P = 0.017, liraglutide), with no difference between treatments (P = 0.121). Eighteen episodes of hypoglycemia (PG ≤3.9 mmol/L) occurred during glimepiride treatment and one during liraglutide treatment.. Six weeks of treatment with glimepiride or liraglutide lowered FPG and postprandial glucose excursions in patients with HNF1A diabetes. The glucose-lowering effect was greater with glimepiride at the expense of a higher risk of exclusively mild hypoglycemia.

Topics: Adult; Aged; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Fasting; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Postprandial Period; Receptors, Glucagon; Sulfonylurea Compounds; Young Adult

Insulin degludec/liraglutide (IDegLira) is a novel combination of insulin degludec (IDeg) and liraglutide. This trial investigated the contribution of the liraglutide component of IDegLira versus IDeg alone on efficacy and safety in patients with type 2 diabetes.. In a 26-week, double-blind trial, patients with type 2 diabetes (A1C 7.5-10.0% [58-86 mmol/mol]) on basal insulin (20-40 units) and metformin with or without sulfonylurea/glinides were randomized (1:1) to once-daily IDegLira + metformin or IDeg + metformin with titration aiming for fasting plasma glucose between 4 and 5 mmol/L. Maximum allowed doses were 50 dose steps (equal to 50 units IDeg plus 1.8 mg liraglutide) and 50 units for IDeg. The primary end point was change in A1C from baseline.. A total of 413 patients were randomized (mean A1C 8.8% [73 mmol/mol]; BMI 33.7 kg/m2). IDeg dose, alone or as part of IDegLira, was equivalent (45 units). A1C decreased by 1.9% (21 mmol/mol) with IDegLira and by 0.9% (10 mmol/mol) with IDeg (estimated treatment difference -1.1% [95% CI -1.3, -0.8], -12 mmol/mol [95% CI -14, -9; P < 0.0001). Mean weight reduction with IDegLira was 2.7 kg vs. no weight change with IDeg, P < 0.0001. Hypoglycemia incidence was comparable (24% for IDegLira vs. 25% for IDeg). Overall adverse events were similar, and incidence of nausea was low in both groups (IDegLira 6.5% vs. IDeg 3.5%).. IDegLira achieved glycemic control superior to that of IDeg at equivalent insulin doses without higher risk of hypoglycemia and with the benefit of weight loss. These findings establish the efficacy and safety of IDegLira and the distinct contribution of the liraglutide component.

Topics: Aged; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin, Long-Acting; Liraglutide; Male; Metformin; Middle Aged; Sulfonylurea Compounds; Treatment Outcome; Weight Loss

To show that albiglutide, a glucagon-like peptide-1 receptor agonist, is an effective and generally safe treatment to improve glycaemic control in patients with type 2 diabetes mellitus whose hyperglycaemia is inadequately controlled with pioglitazone (with or without metformin).. In this 3-year, randomized, double-blind, placebo-controlled study, 310 adult patients on a regimen of pioglitazone (with or without metformin) were randomly assigned to receive additional treatment with albiglutide [30 mg subcutaneous (s.c.) once weekly, n = 155] or matching placebo (n = 155). The primary efficacy endpoint was change from baseline to week 52 (intention-to-treat) in glycated haemoglobin (HbA1c).. The model-adjusted change from baseline in HbA1c at week 52 was significantly better with albiglutide than with placebo (-0.8%, 95% confidence interval -1.0, -0.6; p < 0.0001). Change from baseline fasting plasma glucose was -1.3 mmol/l in the albiglutide group and +0.4 mmol/l in the placebo group (p < 0.0001); a significantly higher percentage of patients reached the HbA1c goals with albiglutide (p < 0.0001), and the rate of hyperglycaemia rescue up to week 52 for albiglutide was 24.4 versus 47.7% for placebo (p < 0.0001). Albiglutide plus pioglitazone had no impact on weight, and severe hypoglycaemia was observed rarely (n = 2). With few exceptions, the results of safety assessments were similar between the groups, and most adverse events (AEs) were mild or moderate. The 52-week incidence rates for gastrointestinal AEs for albiglutide and placebo were: 31.3 and 29.8%, respectively (diarrhoea: 11.3 and 8.6%; nausea: 10.7 and 11.3%; vomiting: 4.0 and 4.0%).. Albiglutide 30 mg administered once weekly as an add-on to pioglitazone (with or without metformin) provided effective and durable glucose lowering and was generally well tolerated.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Male; Metformin; Middle Aged; Pioglitazone; Thiazolidinediones; Treatment Outcome

Clinical studies evaluating the effects of medications on β-cell function in type 2 diabetes (T2DM) are compromised by an inability to determine the actual baseline degree of β-cell dysfunction independent of the reversible dysfunction induced by hyperglycemia (glucotoxicity). Short-term intensive insulin therapy (IIT) is a strategy for eliminating glucotoxicity before randomization. This study determined whether liraglutide can preserve β-cell function over 48 weeks in early T2DM following initial elimination of glucotoxicity with IIT.. In this double-blind, randomized, placebo-controlled trial, 51 patients with T2DM of 2.6 ± 1.9 years' duration and an A1C of 6.8 ± 0.8% (51 ± 8.7 mmol/mol) completed 4 weeks of IIT before randomization to daily subcutaneous liraglutide or placebo injection, with serial assessment of β-cell function by Insulin Secretion-Sensitivity Index-2 (ISSI-2) on oral glucose tolerance test performed every 12 weeks.. The primary outcome of baseline-adjusted ISSI-2 at 48 weeks was higher in the liraglutide group than in the placebo group (339.8 ± 27.8 vs. 229.3 ± 28.4, P = 0.008). Baseline-adjusted HbA1c at 48 weeks was lower in the liraglutide group (6.2 ± 0.1% vs. 6.6 ± 0.1%, P = 0.055) (44 ± 1.1 vs. 49 ± 1.1 mmol/mol). At each quarterly assessment, >50% of participants on liraglutide had an HbA1c ≤6.0% (42 mmol/mol) and glucose tolerance in the nondiabetic range. Despite this level of glycemic control, no difference was found in the incidence of hypoglycemia between the liraglutide and placebo groups (P = 0.61). Two weeks after stopping treatment, however, the beneficial effect on ISSI-2 of liraglutide versus placebo was entirely lost (191.9 ± 24.7 vs. 238.1 ± 25.2, P = 0.20).. Liraglutide provides robust enhancement of β-cell function that is sustained over 48 weeks in early T2DM but lost upon cessation of therapy.

Topics: Adult; Aged; Blood Glucose; Cytoprotection; Diabetes Mellitus, Type 2; Disease Progression; Double-Blind Method; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin-Secreting Cells; Liraglutide; Male; Middle Aged

Hyperglycemia and hypoglycemia currently are considered risk factors for cardiovascular disease in type 1 diabetes. Both acute hyperglycemia and hypoglycemia induce endothelial dysfunction and inflammation, raising the oxidative stress. Glucagon-like peptide 1 (GLP-1) has antioxidant properties, and evidence suggests that it protects endothelial function.. The effect of both acute hyperglycemia and acute hypoglycemia in type 1 diabetes, with or without the simultaneous infusion of GLP-1, on oxidative stress (plasma nitrotyrosine and plasma 8-iso prostaglandin F2alpha), inflammation (soluble intercellular adhesion molecule-1 and interleukin-6), and endothelial dysfunction has been evaluated.. Both hyperglycemia and hypoglycemia acutely induced oxidative stress, inflammation, and endothelial dysfunction. GLP-1 significantly counterbalanced these effects.. These results suggest a protective effect of GLP-1 during both hypoglycemia and hyperglycemia in type 1 diabetes.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 1; Endothelium, Vascular; Female; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemia; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-6; Male; Oxidative Stress

It has been reported that hyperglycemia following hypoglycemia produces an ischemia-reperfusion-like effect in type 1 diabetes. In this study the possibility that GLP-1 has a protective effect on this phenomenon has been tested.. 15 type 1 diabetic patients underwent to five experiments: a period of two hours of hypoglycemia followed by two hours of normo-glycemia or hyperglycemia with the concomitant infusion of GLP-1 or vitamin C or both. At baseline, after 2 and 4 hours, glycemia, plasma nitrotyrosine, plasma 8-iso prostaglandin F2alpha, sCAM-1a, IL-6 and flow mediated vasodilation were measured.. After 2 h of hypoglycemia, flow mediated vasodilation significantly decreased, while sICAM-1, 8-iso-PGF2a, nitrotyrosine and IL-6 significantly increased. While recovering with normoglycemia was accompanied by a significant improvement of endothelial dysfunction, oxidative stress and inflammation, a period of hyperglycemia after hypoglycemia worsens all these parameters. These effects were counterbalanced by GLP-1 and better by vitamin C, while the simultaneous infusion of both almost completely abolished the effect of hyperglycemia post hypoglycemia.. This study shows that GLP-1 infusion, during induced hyperglycemia post hypoglycemia, reduces the generation of oxidative stress and inflammation, improving the endothelial dysfunction, in type 1 diabetes. Furthermore, the data support that vitamin C and GLP-1 may have an additive protective effect in such condition.

Topics: Adult; Antioxidants; Ascorbic Acid; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 1; Dinoprost; Female; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Inflammation; Inflammation Mediators; Infusions, Parenteral; Intercellular Adhesion Molecule-1; Interleukin-6; Male; Oxidative Stress; Reperfusion Injury; Time Factors; Treatment Outcome; Tyrosine; Vasodilation; Young Adult

To test the hypothesis that acute hypoglycemia induces endothelial dysfunction and inflammation through the generation of an oxidative stress. Moreover, to test if the antioxidant vitamin C can further improve the protective effects of glucagon-like peptide 1 (GLP-1) on endothelial dysfunction and inflammation during hypoglycemia in type 1 diabetes.. A total of 20 type 1 diabetic patients underwent four experiments: a period of 2 h of acute hypoglycemia with or without infusion of GLP-1 or vitamin C or both. At baseline, after 1 and 2 h, glycemia, plasma nitrotyrosine, plasma 8-iso prostaglandin F2a (PGF2a), soluble intracellular adhesion molecule-1a (sICAM-1a), interleukin-6 (IL-6), and flow-mediated vasodilation were measured. At 2 h of hypoglycemia, flow-mediated vasodilation significantly decreased, while sICAM-1, 8-iso-PGF2a, nitrotyrosine, and IL-6 significantly increased. The simultaneous infusion of GLP-1 or vitamin C significantly attenuated all of these phenomena. Vitamin C was more effective. When GLP-1 and vitamin C were infused simultaneously, the deleterious effect of hypoglycemia was almost completely counterbalanced.. At 2 h of hypoglycemia, flow-mediated vasodilation significantly decreased, while sICAM-1, 8-iso-PGF2a, nitrotyrosine, and IL-6 significantly increased. The simultaneous infusion of GLP-1 or vitamin C significantly attenuated all of these phenomena. Vitamin C was more effective. When GLP-1 and vitamin C were infused simultaneously, the deleterious effect of hypoglycemia was almost completely counterbalanced.. This study shows that vitamin C infusion, during induced acute hypoglycemia, reduces the generation of oxidative stress and inflammation, improving endothelial dysfunction, in type 1 diabetes. Furthermore, the data support a protective effect of GLP-1 during acute hypoglycemia, but also suggest the presence of an endothelial resistance to the action of GLP-1, reasonably mediated by oxidative stress.

Topics: Acute Disease; Antioxidants; Ascorbic Acid; Blood Glucose; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Drug Therapy, Combination; Endothelium, Vascular; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Inflammation; Infusions, Intravenous; Insulin; Male; Oxidative Stress; Vasodilation; Young Adult

Oxyntomodulin (OXM), glucagon, glucagon-like peptide-1 (GLP-1), and exendin-4 (Ex-4) are peptide hormones that regulate glucose homeostasis in monogastric and ruminant animals. Recently, we reported that the insulin-releasing effects of OXM and glucagon in cattle are mediated through both GLP-1 and glucagon receptors. The purpose of this study was to examine the mechanisms of the glucoregulatory actions induced by Ex-4, GLP-1, OXM, and glucagon and the interrelationships among these hormones in cattle. Two experiments were performed in Holstein cattle. In Experiment 1, we initially assessed the effects of intravenous (iv) bolus injection of 0, 0.25, 1, and 2 μg/kg body weight (BW) of Ex-4, GLP-1, and OXM on insulin and glucose concentrations in 3-mo-old intact male Holstein calves. In Experiment 2, we studied insulin and glucose responses to iv coinjection of 0.25 μg of Ex-4 or GLP-1/kg BW with 2 μg of OXM or glucagon/kg BW in 4-mo-old Holstein steers. Administration of peptides and blood sampling were done via a jugular catheter. Plasma was separated and the concentrations of peptides and glucose in plasma were analyzed using radioimmunoassay and enzymatic methods, respectively. Results showed that the potent glucoregulatory action of Ex-4 in 4-mo-old steers was delayed and attenuated when Ex-4 was coinjected with OXM. The decline in plasma glucose concentrations began at 5 min in the Ex-4-injected group (P < 0.05) vs 15 min in the Ex-4 + OXM-injected group (P < 0.05). Plasma concentrations of glucose at 30 min were reduced 26% from basal concentrations in the Ex-4-injected group and 13% in the Ex-4 + OXM-injected group (P < 0.001). Results also showed that the glucose concentrations initially increased in the Ex-4 + glucagon-treated group, but declined to a relatively hypoglycemic condition by 90 to 120 min. In contrast, the glucose concentrations at specific time points between the GLP-1 + OXM-injected group and the OXM-injected group did not differ. Similarly, the glucose concentrations in the GLP-1 + glucagon-injected group did not differ from those in the glucagon-injected group. Because OXM and glucagon mediate glucose concentrations via the glucagon receptor, it is suggested that the potent glucose-lowering action of Ex-4 might include the glucagon receptor antagonistic action of Ex-4.

Topics: Animals; Blood Glucose; Cattle; Cattle Diseases; Dose-Response Relationship, Drug; Exenatide; Glucagon; Glucagon-Like Peptide 1; Hypoglycemia; Insulin; Male; Oxyntomodulin; Peptides; Radioimmunoassay; Venoms

Acarbose was administered at 300 mg/day to patients with type 2 diabetes mellitus (T2DM) who had been taking 25 mg/day of alogliptin, and levels of blood glucose were analyzed by continuous glucose monitoring (CGM) for 3 days. The mean blood glucose level with acarbose (136.4 ± 30.7 mg/dL) did not differ significantly from that without acarbose (141.7 ± 28.3 mg/dL). However, in the condition of the combination therapy, there were significant decreases in the standard deviation of the mean blood glucose levels for the 24-hour period (27.6 ± 9.1 vs. 16.2 ± 6.9 mg/dL, p<0.001) and mean amplitude of glycemic excursions (MAGE) (65.8 ± 26.1 vs. 38.8 ± 19.2 mg/dL, p=0.010). In addition, a meal tolerance test was conducted to monitor changes in insulin secretion and active GLP-1 and total GIP values. Ten subjects (5 males, 5 females) of 54.9 ± 6.9 years with BMI 25.9 ± 5.2 kg/m² and HbAlc 9.2 ± 1.2% were enrolled. In the meal tolerance test, active GLP-1 values before and after acarbose administration were 17.0 ± 5.8 and 24.1 ± 9.3 pmol·hr/mL (p=0.054), respectively, showing an increasing tendency, and total GIP(AUC0-180) values were 685.9 ± 209.7 and 404.4 ± 173.7 pmol·hr/mL, respectively, showing a significant decrease (p=0.010). The results indicate that the combined administration of both inhibitors is effective not only in decreasing blood glucose fluctuations and preventing postprandial insulin secretion. The beneficial effects may also protect the endocrine pancreas and inhibit body weight gain.

Topics: Acarbose; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Enzyme Inhibitors; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Glycoside Hydrolase Inhibitors; Humans; Hyperglycemia; Hypoglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Male; Middle Aged; Overweight; Piperidines; Uracil; Weight Gain

Mosapride citrate, a selective agonist of the 5-hydroxytryptaine (5-HT)₄ receptor, is typically used to treat heartburn, nausea, and vomiting associated with chronic gastritis or to prepare for a barium enema X-ray examination. Mosapride citrate reportedly improves insulin sensitivity in patients with type 2 diabetes. As mosapride citrate activates the motility of the gastrointestinal tract, we hypothesized that mosapride citrate affects incretin secretion. We examined the effect of the administration of mosapride citrate on the plasma glucose, serum insulin, plasma glucagon, and plasma incretin levels before breakfast and at 60, 120, and 180 min after breakfast in men with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT) to exclude gastropathy. Mosapride citrate was administered according to two different intake schedules (C: control (no drug), M: mosapride citrate 20 mg) in each of the subject groups. The area under the curve (AUC) of the plasma glucose levels was smaller in the M group than in the C group. The time profiles for the serum insulin levels at 60 and 120 min after treatment with mosapride citrate tended to be higher, although the difference was not statistically significant. The AUCs of the plasma active and total glucagon-like peptide-1 (GLP-1) levels were significantly larger in the M group than in the C group. No significant difference in the AUC of the plasma glucose-dependent insulinotropic polypeptide (GIP) level was observed between the two groups. Our results suggest that mosapride citrate may have an antidiabetic effect by increasing GLP-1 secretion.

Topics: Adult; Benzamides; Blood Glucose; Gastric Inhibitory Polypeptide; Gastrointestinal Agents; Gastrointestinal Tract; Glucagon; Glucagon-Like Peptide 1; Glucose Intolerance; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Male; Morpholines; Postprandial Period; Serotonin 5-HT4 Receptor Agonists; Up-Regulation

Exenatide once weekly (QW) is an extended-release formulation of exenatide, a glucagon-like peptide-1 receptor agonist that reportedly improves glycemic control in patients with type 2 diabetes.. The goal of this study was to test the hypothesis that exenatide QW is noninferior to insulin glargine, as measured by change in glycosylated hemoglobin (HbA(1c)) from baseline to end point (week 26 [primary end point]) in Japanese patients with type 2 diabetes who have inadequate glycemic control with oral antidiabetes drugs.. In this open-label, parallel-group, multicenter, noninferiority registration study, patients were randomized (1:1) to add exenatide QW (2 mg) or once-daily insulin glargine (starting dose, 4 U) to their current oral antidiabetes drug treatment. The primary analysis was change in HbA(1c) from baseline to end point, evaluated by using a last-observation-carried-forward ANCOVA model, with a predefined noninferiority margin of 0.4%. Secondary analyses (a priori) included analysis of superiority for between-group comparisons of change in weight and the proportion of patients reaching HbA(1c) target levels of ≤7.0% or ≤6.5%.. The baseline characteristics of the exenatide QW (215 patients) and insulin glargine (212 patients) treatment groups were similar: mean (SD) age, 57 (10) years and 56 (11) years, respectively; 66.0% and 69.8% male; mean HbA(1c), 8.5% (0.82%) and 8.5% (0.79%); and mean weight, 69.9 (13.2) kg and 71.0 (13.9) kg. Exenatide QW was statistically noninferior to insulin glargine for the change in HbA(1c) from baseline to end point (least squares mean difference, -0.43% [95% CI, -0.59 to -0.26]; P < 0.001), with the 95% CI upper limit less than the predefined noninferiority margin (0.4%). A significantly greater proportion of patients receiving exenatide QW compared with insulin glargine achieved HbA(1c) target levels of ≤7.0% (89 of 211 [42.2%] vs 44 of 210 [21.0%]) or ≤6.5% (44 of 214 [20.6%] vs 9 of 212 [4.2%]) at end point (P < 0.001 for both). Patient weight was reduced with exenatide QW compared with insulin glargine at end point (least squares mean difference, -2.01 kg [95% CI, -2.46 to -1.56]; P < 0.001). Exenatide QW was well tolerated, with a lower risk of hypoglycemia compared with insulin glargine but a higher incidence of injection-site induration.. Exenatide QW was statistically noninferior to insulin glargine for the change in HbA(1c) from baseline to end point; these results suggest that exenatide QW may provide an effective alternative treatment for Japanese patients who require additional therapy to control their diabetes. ClinicalTrials.gov identifier: NCT00935532.

Topics: Administration, Oral; Aged; Blood Glucose; Body Weight; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Japan; Least-Squares Analysis; Male; Middle Aged; Peptides; Venoms

To assess the efficacy and safety of adding liraglutide to established insulin therapy in poorly controlled Chinese subjects with type 2 diabetes and abdominal obesity compared with increasing insulin dose.. A 12-week, randomized, parallel-group study was carried out. A total of 84 patients completed the trial who had been randomly assigned to either the liraglutide-added group or the insulin-increasing group while continuing current insulin based treatment. Insulin dose was reduced by 0-30% upon the initiation of liraglutide. Insulin doses were subsequently adjusted to optimized glycemic control. Glycosylated hemoglobin (HbA1c) values, blood glucose, total daily insulin dose, body weight, waist circumference, and the number of hypoglycemic events and adverse events were evaluated.. At the end of study, the mean reduction in HbA1c between the liraglutide-added group and the insulin-increasing group was not significantly different (1.9% vs. 1.77%, p>0.05). However, the percentage of subjects reaching the composite endpoint of HbA1c ≤ 7.0% with no weight gain and no hypoglycemia, was significantly higher in the liraglutide-added group than in the insulin-increasing group (67% vs. 19%, p<0.001). Add-on liraglutide treatment significantly reduced mean body weight (5.62 kg, p<0.01), waist circumference (5.70 cm, p<0.01), body mass index (BMI) (1.93 kg/m2, p<0.01) and daily total insulin dose (dropped by 66%) during 12-week treatment period, while all of these significantly increased with insulin increasing treatment. Add-on liraglutide treated patients had lower rate of hypoglycemic events and greater insulin and oral antidiabetic drugs discontinuation. Gastrointestinal disorders were the most common adverse events in the liraglutide added treatment, but were transient.. Addition of liraglutide to abdominally obese, insulin-treated patients led to improvement in glycemic control similar to that achieved by increasing insulin dosage, but with a lower daily dose of insulin and fewer hypoglycemic events. Adding liraglutide to insulin also induced a significant reduction in body weight and waist circumference. Liraglutide combined with insulin may be the best treatment option for poorly controlled type 2 diabetes and abdominal obesity.

Topics: Adult; Asian People; Biomarkers; Blood Glucose; China; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Liraglutide; Male; Middle Aged; Obesity, Abdominal; Time Factors; Treatment Outcome; Waist Circumference; Weight Gain

The Liraglutide Effect and Action in Diabetes 6 trial was an open-label trial comparing liraglutide with exenatide as an 'add-on' to metformin and/or sulphonylurea.. Patients with Type 2 diabetes were randomized to liraglutide 1.8 mg once daily or exenatide 10 μg twice daily for 26 weeks. This was followed by a 14-week extension phase, in which all patients received liraglutide 1.8 mg once daily.. Patient-reported outcomes were measured in 379 patients using Diabetes Treatment Satisfaction Questionnaire status (DTSQs) and DTSQ change (DTSQc). The change in overall treatment satisfaction (DTSQs score) from baseline at week 26 with liraglutide was 4.71 and with exentaide was 1.66 [difference between groups 3.04 (95% CI 1.73-4.35), P<0.0001]. Five of the six items on the DTSQs improved significantly more with liraglutide than with exenatide (differences: current treatment 0.37, P=0.0093; convenience 0.68, P<0.0001; flexibility 0.57, P=0.0002; recommend 0.49, P=0.0003; continue 0.66, P=0.0001). Patients perceived a greater reduction in hypoglycaemia at week 26 with liraglutide than with exenatide [difference in DTSQc score 0.48 (0.08-0.89), P=0.0193] and a greater reduction in perceived hyperglycaemia [difference 0.74 (0.31-1.17), P=0.0007]. During the extension phase, when all patients received liraglutide, DTSQs scores remained stable in patients who continued on liraglutide and increased significantly (P=0.0026) in those switching from exenatide.. These results demonstrate significant improvements in patients' treatment satisfaction with liraglutide compared with exenatide.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Glucose; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Liraglutide; Male; Middle Aged; Patient Satisfaction; Sulfonylurea Compounds; Surveys and Questionnaires; Treatment Outcome; Young Adult

To determine whether miglitol administration improves glycemic control and reduces the frequency of hypoglycemia in type 1 diabetes mellitus (T1DM) patients treated with intensive insulin therapy, we analyzed the effect of miglitol on daily insulin doses, body weight, hypoglycemia, and incretin hormone responses during meal tolerance tests (MTT). Eleven T1DM subjects (21-77 years) undergoing intensive insulin therapy, took 25 mg (weeks 0-4) and 50 mg miglitol (weeks 4-12) thrice daily, immediately before meals. At weeks 0 and 12, 9 of 11 subjects underwent MTT. In present study, mean HbA1c, glycoalbumin, and 1,5-anhydroglucitol levels were significantly improved. The blood glucose level 1 h after dinner was significantly lower at week 12 than at week 0 (p = 0.008). From week 0 to 12, there was a significant decrease in the body mass index (BMI; p = 0.0051), frequency of preprandial hypoglycemic events (p = 0.012), and daily bolus insulin dosage (p = 0.018). The change in active glucagon-like peptide-1 (GLP-1) at 120 min significantly increased at week 12 (p = 0.015). The change in total glucose-dependent insulinotropic peptide (GIP) significantly decreased in the MTT at week 12. These results demonstrate that addition of miglitol on intensive insulin therapy in T1DM patients has beneficial effects on reducing BMI, bolus and total insulin dosage, and frequency of preprandial hypoglycemic events. MTT findings suggest that this combination therapy improves blood glucose control by delaying carbohydrate absorption and modifying the responses of incretins, GIP, and GLP-1.

Topics: 1-Deoxynojirimycin; Adult; Aged; Deoxyglucose; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Enzyme Inhibitors; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Glycated Serum Albumin; Glycation End Products, Advanced; Glycoside Hydrolase Inhibitors; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Male; Middle Aged; Serum Albumin; Weight Loss; Young Adult

Patient-reported outcomes for liraglutide or glimepiride on metformin were investigated. Patients' treatment satisfaction on liraglutide was higher than with metformin alone and comparable with glimepiride+metformin. Patients perceived lower frequency of hypoglycaemia than glimepiride+metformin and lower frequency of hyperglycaemia than metformin. Impact of weight on quality of life did not differ.

Topics: Aged; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Liraglutide; Male; Metformin; Middle Aged; Patient Satisfaction; Quality of Life; Sulfonylurea Compounds; Treatment Outcome

As weight gain and hypoglycaemia associated with glimepiride therapy can negatively impact weight perceptions, psychological well-being and overall quality of life in type 2 diabetes, we investigated whether liraglutide treatment could improve these factors.. Seven hundred and thirty-two patients with type 2 diabetes completed a 77-item questionnaire during a randomized, 52-week, double-blind study with liraglutide 1.2 mg (n = 245) or 1.8 mg (n = 242) compared with glimepiride 8 mg (n = 245).. Mean (SE) decreases in glycated haemoglobin levels were greater with liraglutide 1.2 mg [-0.84 (0.08)%] and 1.8 mg [-1.14 (0.08)%] than glimepiride [-0.51 (0.08)%; p = 0.0014 and p < 0.0001, respectively]. Patients gained weight on glimepiride [mean (SE), 1.12 (0.27) kg] but lost weight on liraglutide [1.2 mg: -2.05 (0.28) kg; 1.8 mg: -2.45 (0.28) kg; both p < 0.0001]. Patient weight assessment was more favourable with liraglutide 1.8 mg [mean (SE) score: 40.0 (2.0)] than glimepiride [48.7 (2.0); p = 0.002], and liraglutide 1.8 mg patients were 52% less likely to feel overweight [odds ratio (OR) 0.48; 95% confidence interval (CI): 0.331-0.696]. Mean (SE) weight concerns were less with liraglutide [1.2 mg: 30.0 (1.2); 1.8 mg: 32.8 (1.2)] than glimepiride [38.8 (1.2); p < 0.0001 and p < 0.001, respectively], with liraglutide groups 45% less likely to report weight concern (OR 0.55, 95% CI: 0.41-0.73). Mean (SE) mental and emotional health and general perceived health improved more with liraglutide 1.8 mg [476.1 (2.8) and 444.2 (3.2), respectively] than glimepiride [466.3 (2.8) and 434.5 (3.2), respectively; p = 0.012 and p = 0.033, respectively].. Improved glycaemic control and decreased weight with liraglutide 1.8 mg vs. glimepiride can improve psychological and emotional well-being and health perceptions by reducing anxiety and worry associated with weight gain.

Topics: Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Sulfonylurea Compounds; Treatment Outcome; Weight Gain

It is uncertain whether the ability to avoid hypoglycaemia during fasting is preserved, and the risk of reactive hypoglycaemia after an oral glucose stimulus following a prolonged fasting period is increased at augmented glucagon-like peptide-1 (GLP-1) levels.. A randomized, double-blind placebo-controlled cross-over study in eight healthy men to assess the safety, in terms of hypoglycaemia, of a continuously infused pharmacological dose of native GLP-1 during long-term fasting. After an overnight fast the fasting period continued for 48 h and was followed by a 3-h oral glucose tolerance test (OGTT). GLP-1(7-36 amide) or placebo was continuously infused subcutaneously and titrated to a dose of 4.8 pmol/kg per min.. Two subjects in the GLP-1 group and one subject in the placebo group were withdrawn due to protocol specified plasma glucose (PG) < or = 2.8 mm and neuroglycopaenic symptoms. The infusion of GLP-1 resulted in pharmacological levels of intact GLP-1. During the fasting period PG, insulin and C-peptide levels declined and glucagon, GH and free fatty acid (FFA) levels increased with no differences between GLP-1 and placebo. During OGTT circulating levels of insulin and C-peptide were higher with GLP-1 infusion. However, PG was similar during GLP-1 vs. placebo infusions. GLP-1 infusion increased norepinephrine and cortisol levels during OGTT.. The counter-regulatory response during 48 h of subcutaneous GLP-1 infusion was preserved despite long-term fasting with no apparent increased risk of hypoglycaemic episodes. No reactive hypoglycaemia was observed when the fast was followed by an OGTT. Thus use of long-acting GLP-1 analogues may not increase the risk of hypoglycaemia.

Topics: Adult; Blood Glucose; C-Peptide; Cross-Over Studies; Fasting; Fatty Acids, Nonesterified; Glucagon-Like Peptide 1; Glucose Tolerance Test; Human Growth Hormone; Humans; Hypoglycemia; Infusions, Subcutaneous; Insulin; Male; Norepinephrine; Peptide Fragments

Dipeptidyl peptidase-4 inhibitors act by increasing plasma levels of glucagon-like peptide-1 and suppressing excessive glucagon secretion in patients with type 2 diabetes. However, their effects on the glucagon response to hypoglycemia are not established.. The aim of the study was to assess effects of the dipeptidyl peptidase-4 inhibitor vildagliptin on alpha-cell response to hyper- and hypoglycemia.. We conducted a single-center, randomized, double-blind, placebo-controlled, two-period crossover study of 28-d treatment, with a 4-wk between-period washout.. We studied drug-naive patients with type 2 diabetes and baseline glycosylated hemoglobin of 7.5% or less.. Participants received vildagliptin (100 mg/d) or placebo as outpatients. PRIMARY OUTCOME MEASURE(S): We measured the following: 1) change in plasma glucagon levels during hypoglycemic (2.5 mm glucose) clamp; and 2) incremental (Delta) glucagon area under the concentration-time curve from time 0 to 60 min (AUC(0-60 min)) during standard meal test. Before the study, it was hypothesized that vildagliptin would suppress glucagon secretion during meal tests and enhance the glucagon response to hypoglycemia.. The mean change in glucagon during hypoglycemic clamp was 46.7 +/- 6.9 ng/liter with vildagliptin treatment and 33.9 +/- 6.7 ng/liter with placebo; the between-treatment difference was 12.8 +/- 7.0 ng/liter (P = 0.039), representing a 38% increase with vildagliptin. In contrast, the mean glucagon DeltaAUC(0-60 min) during meal test with vildagliptin was 512 +/- 163 ng/liter x min vs. 861 +/- 130 ng/liter x min with placebo; the between-treatment difference was -349 +/- 158 ng/liter x min (P = 0.019), representing a 41% decrease with vildagliptin.. Vildagliptin enhances alpha-cell responsiveness to both the suppressive effects of hyperglycemia and the stimulatory effects of hypoglycemia. These effects likely contribute to the efficacy of vildagliptin to improve glycemic control as well as to its low hypoglycemic potential.

Topics: Adamantane; Aged; Blood Glucose; Body Mass Index; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Middle Aged; Nitriles; Pyrrolidines; Vildagliptin

To compare the effects of combining liraglutide (0.6, 1.2 or 1.8 mg/day) or rosiglitazone 4 mg/day (all n >or= 228) or placebo (n = 114) with glimepiride (2-4 mg/day) on glycaemic control, body weight and safety in Type 2 diabetes.. In total, 1041 adults (mean +/- sd), age 56 +/- 10 years, weight 82 +/- 17 kg and glycated haemoglobin (HbA(1c)) 8.4 +/- 1.0% at 116 sites in 21 countries were stratified based on previous oral glucose-lowering mono : combination therapies (30 : 70%) to participate in a five-arm, 26-week, double-dummy, randomized study.. Liraglutide (1.2 or 1.8 mg) produced greater reductions in HbA(1c) from baseline, (-1.1%, baseline 8.5%) compared with placebo (+0.2%, P < 0.0001, baseline 8.4%) or rosiglitazone (-0.4%, P < 0.0001, baseline 8.4%) when added to glimepiride. Liraglutide 0.6 mg was less effective (-0.6%, baseline 8.4%). Fasting plasma glucose decreased by week 2, with a 1.6 mmol/l decrease from baseline at week 26 with liraglutide 1.2 mg (baseline 9.8 mmol/l) or 1.8 mg (baseline 9.7 mmol/l) compared with a 0.9 mmol/l increase (placebo, P < 0.0001, baseline 9.5 mmol/l) or 1.0 mmol/l decrease (rosiglitazone, P < 0.006, baseline 9.9 mmol/l). Decreases in postprandial plasma glucose from baseline were greater with liraglutide 1.2 or 1.8 mg [-2.5 to -2.7 mmol/l (baseline 12.9 mmol/l for both)] compared with placebo (-0.4 mmol/l, P < 0.0001, baseline 12.7 mmol/l) or rosiglitazone (-1.8 mmol/l, P < 0.05, baseline 13.0 mmol/l). Changes in body weight with liraglutide 1.8 mg (-0.2 kg, baseline 83.0 kg), 1.2 mg (+0.3 kg, baseline 80.0 kg) or placebo (-0.1 kg, baseline 81.9 kg) were less than with rosiglitazone (+2.1 kg, P < 0.0001, baseline 80.6 kg). Main adverse events for all treatments were minor hypoglycaemia (< 10%), nausea (< 11%), vomiting (< 5%) and diarrhoea (< 8%).. Liraglutide added to glimepiride was well tolerated and provided improved glycaemic control and favourable weight profile.

Topics: Aged; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Middle Aged; Rosiglitazone; Sulfonylurea Compounds; Thiazolidinediones

Hyperglycaemia occurs frequently in the critically ill, affects outcome adversely, and is exacerbated by enteral feeding. Furthermore, treatment with insulin in this group is frequently complicated by hypoglycaemia. In healthy patients and those with type 2 diabetes, exogenous glucagon-like peptide-1 (GLP-1) decreases blood glucose by suppressing glucagon, stimulating insulin and slowing gastric emptying. Because the former effects are glucose-dependent, the use of GLP-1 is not associated with hypoglycaemia. The objective of this study was to establish if exogenous GLP-1 attenuates the glycaemic response to enteral nutrition in patients with critical illness induced hyperglycaemia.. Seven mechanically ventilated critically ill patients, not previously known to have diabetes, received two intravenous infusions of GLP-1 (1.2 pmol/kg/min) and placebo (4% albumin) over 270 minutes. Infusions were administered on consecutive days in a randomised, double-blind fashion. On both days a mixed nutrient liquid was infused, via a post-pyloric feeding catheter, at a rate of 1.5 kcal/min between 30 and 270 minutes. Blood glucose and plasma GLP-1, insulin and glucagon concentrations were measured.. In all patients, exogenous GLP-1 infusion reduced the overall glycaemic response during enteral nutrient stimulation (AUC30-270 min GLP-1 (2077 +/- 144 mmol/l min) vs placebo (2568 +/- 208 mmol/l min); P = 0.02) and the peak blood glucose (GLP-1 (10.1 +/- 0.7 mmol/l) vs placebo (12.7 +/- 1.0 mmol/l); P < 0.01). The insulin/glucose ratio at 270 minutes was increased with GLP-1 infusion (GLP-1 (9.1 +/- 2.7) vs. placebo (5.8 +/- 1.8); P = 0.02) but there was no difference in absolute insulin concentrations. There was a transient, non-sustained, reduction in plasma glucagon concentrations during GLP-1 infusion (t = 30 minutes GLP-1 (90 +/- 12 pmol/ml) vs. placebo (104 +/- 10 pmol/ml); P < 0.01).. Acute, exogenous GLP-1 infusion markedly attenuates the glycaemic response to enteral nutrition in the critically ill. These observations suggest that GLP-1 and/or its analogues have the potential to manage hyperglycaemia in the critically ill.. Australian New Zealand Clinical Trials Registry number: ACTRN12609000093280.

Topics: Adult; Aged; Area Under Curve; Blood Glucose; Critical Illness; Cross-Over Studies; Double-Blind Method; Enteral Nutrition; Female; Glucagon; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemia; Incretins; Infusions, Intravenous; Insulin; Male; Middle Aged

Unlike most antihyperglycaemic drugs, glucagon-like peptide-1 (GLP-1) receptor agonists have a glucose-dependent action and promote weight loss. We compared the efficacy and safety of liraglutide, a human GLP-1 analogue, with exenatide, an exendin-based GLP-1 receptor agonist.. Adults with inadequately controlled type 2 diabetes on maximally tolerated doses of metformin, sulphonylurea, or both, were stratified by previous oral antidiabetic therapy and randomly assigned to receive additional liraglutide 1.8 mg once a day (n=233) or exenatide 10 microg twice a day (n=231) in a 26-week open-label, parallel-group, multinational (15 countries) study. The primary outcome was change in glycosylated haemoglobin (HbA(1c)). Efficacy analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00518882.. Mean baseline HbA(1c) for the study population was 8.2%. Liraglutide reduced mean HbA(1c) significantly more than did exenatide (-1.12% [SE 0.08] vs -0.79% [0.08]; estimated treatment difference -0.33; 95% CI -0.47 to -0.18; p<0.0001) and more patients achieved a HbA(1c) value of less than 7% (54%vs 43%, respectively; odds ratio 2.02; 95% CI 1.31 to 3.11; p=0.0015). Liraglutide reduced mean fasting plasma glucose more than did exenatide (-1.61 mmol/L [SE 0.20] vs -0.60 mmol/L [0.20]; estimated treatment difference -1.01 mmol/L; 95% CI -1.37 to -0.65; p<0.0001) but postprandial glucose control was less effective after breakfast and dinner. Both drugs promoted similar weight losses (liraglutide -3.24 kg vs exenatide -2.87 kg). Both drugs were well tolerated, but nausea was less persistent (estimated treatment rate ratio 0.448, p<0.0001) and minor hypoglycaemia less frequent with liraglutide than with exenatide (1.93 vs 2.60 events per patient per year; rate ratio 0.55; 95% CI 0.34 to 0.88; p=0.0131; 25.5%vs 33.6% had minor hypoglycaemia). Two patients taking both exenatide and a sulphonylurea had a major hypoglycaemic episode.. Liraglutide once a day provided significantly greater improvements in glycaemic control than did exenatide twice a day, and was generally better tolerated. The results suggest that liraglutide might be a treatment option for type 2 diabetes, especially when weight loss and risk of hypoglycaemia are major considerations.. Novo Nordisk A/S.

Topics: Analysis of Variance; Blood Glucose; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Exenatide; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Injections, Subcutaneous; Linear Models; Liraglutide; Logistic Models; Male; Middle Aged; Nausea; Peptides; Treatment Outcome; Venoms; Weight Loss

Topics: Adamantane; Adult; Diabetes Mellitus, Type 1; Feeding Behavior; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Nitriles; Pyrrolidines; Vildagliptin

Alogliptin is a highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor that is under development for the treatment of type 2 diabetes.. This study was conducted to characterize the pharmacokinetics, pharmacodynamics, and tolerability of single oral doses of alogliptin in healthy male subjects.. This was a randomized, double-blind, placebo-controlled study in which healthy, nonobese male subjects between the ages of 18 and 55 years were assigned to 1 of 6 cohorts: alogliptin 25, 50, 100, 200, 400, or 800 mg. One subject in each cohort received placebo. An ascending-dose strategy was used, in which each cohort received its assigned dose only after review of the safety data from the previous cohort. Blood and urine were collected over 72 hours after dosing for pharmacokinetic analysis and determination of plasma DPP-4 inhibition and active glucagon-like peptide -1(GLP-1) concentrations.. Thirty-six subjects (66 per cohort) were enrolled and completed the study (29/36 [81% ] white; mean age, 26.6 years; mean weight, 76.0 kg). Alogliptin was rapidly absorbed (median T(max), 1-2 hours) and eliminated slowly (mean t(1/2), 12.4-21.4 hours), primarily via urinary excretion (mean fraction of drug excreted in urine from 0 to 72 hours after dosing, 60%-71%). C(max) and AUC(0-infinity) increased dose proportionally over the range from 25 to 100 mg. The metabolites M-I (N-demethylated) and M-II (N-acetylated) accounted for <2% and <6%, respectively, of alogliptin concentrations in plasma and urine. Across alogliptin doses, mean peak DPP-4 inhibition ranged from 93% to 99%, and mean inhibition at 24 hours after dosing ranged from 74% to 97%. Exposure to active GLP-1 was 2- to 4-fold greater for all alogliptin doses compared with placebo; no dose response was apparent. Hypoglycemia (asymptomatic) was reported in 5 subjects (11 receiving alogliptin 50 mg, 2 receiving alogliptin 200 mg, 1 receiving alogliptin 400 mg, 1 receiving placebo). Other adverse events were reported in 1 subject each: dizziness (alogliptin 100 mg), syncope (alogliptin 200 mg), constipation (alogliptin 200 mg), viral infection (alogliptin 400 mg), hot flush (placebo), and nausea (placebo).. In these healthy male subjects, alogliptin at single doses up to 800 mg inhibited plasma DPP-4 activity, increased active GLP-1, and was generally well tolerated, with no dose-limiting toxicity.

Topics: Adolescent; Adult; Area Under Curve; Chromatography, High Pressure Liquid; Cohort Studies; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Male; Middle Aged; Molecular Structure; No-Observed-Adverse-Effect Level; Piperidines; Reference Values; Tandem Mass Spectrometry; Time Factors; Uracil

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Liraglutide; Placebos; Safety; Weight Loss

Inhibition of dipeptidyl peptidase 4 by vildagliptin enhances the concentrations of the active form of the incretin hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP). The present study asked whether vildagliptin accentuates glibenclamide-induced hypoglycemia or affects endogenous secretion of GLP-1 and GIP after an oral glucose tolerance test.. There were 16 healthy male subjects studied on four occasions after an overnight fast in a double-blind, four-way crossover study. In random order, vildagliptin (100 mg) or placebo, with and without glibenclamide (5 mg), was administered 30 min before 75 g oral glucose. Blood was sampled to measure glucose, and total (sum of active and inactive) GLP-1 and GIP. Statistical evaluation was done using repeated-measures ANOVA.. Glibenclamide provoked hypoglycemia (

Topics: Adamantane; Adult; Algorithms; C-Peptide; Dipeptidyl-Peptidase IV Inhibitors; Drug Interactions; Enzyme-Linked Immunosorbent Assay; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Glyburide; Humans; Hydrocortisone; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Nitriles; Pyrrolidines; Vildagliptin

Glucagon-like peptide 1 (GLP-1) is a proglucagon derivative secreted primarily from the L-cells of the small intestinal mucosa in response to the ingestion of meals. GLP-1 stimulates insulin secretion and inhibits glucagon secretion. It has previously been shown that intravenous or subcutaneous administration of GLP-1 concomitant with intravenous glucose results in hypoglycemia in healthy subjects. Because GLP-1 is also effective in type 2 diabetic patients and is currently being evaluated as a therapeutic agent, it is important to investigate whether GLP-1 may cause hypoglycemia in such patients. We have previously shown that GLP-1 does not cause hypoglycemia in obese type 2 diabetic patients with insulin resistance amounting to 5.4 +/- 1.1 according to homeostasis model assessment (HOMA). In this study, we investigated diabetic patients with normal or close to normal insulin sensitivity.. Eight lean type 2 diabetic patients (group 1) aged 60 years (range 50-72) with BMI 23.1 kg/m(2) (20.3-25.5) and HbA(1c) 8.0% (6.9-11.4) and eight patients with type 2 diabetes secondary to chronic pancreatitis (group 2) aged 52 years (41-62) with BMI 21.9 kg/m(2) (17.6-27.3) and HbA(1c) 7.8% (6.2-12.4) were given a subcutaneous injection of 1.5 nmol GLP-1/kg body wt. Then, 15 min later, at the time of peak GLP-1 concentration, plasma glucose (PG) was raised to 15 mmol/l with an intravenous glucose bolus. HOMA (mean +/- SEM) showed insulin resistance amounting to 1.9 +/- 0.3 and 1.7 +/- 0.5 in the two groups, respectively.. In both groups, PG decreased rapidly and stabilized at 7.5 mmol/l (range 3.9-10.1) and 7.2 mmol/l (3.1-10.9) in groups 1 and 2, respectively, after 90 min. Neither symptoms of hypoglycemia nor biochemical hypoglycemia were observed in any patient.. We conclude that a GLP-1-based therapy would not be expected to be associated with an increased risk of hypoglycemia in insulin-sensitive type 2 diabetic patients.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Chronic Disease; Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Injections, Subcutaneous; Insulin; Kinetics; Middle Aged; Pancreatitis; Peptide Fragments; Protein Precursors

Glucagon-like peptide 1 (GLP-1) and analogues are being evaluated as a new therapeutic principle for the treatment of type 2 diabetes. GLP-1 suppresses glucagon secretion, which could lead to disturbances of hypoglycemia counterregulation. This has, however, not been tested. Nine healthy volunteers with normal oral glucose tolerance received infusions of regular insulin (1 mU x kg(-1) x min(-1)) over 360 min on two occasions in the fasting state. Capillary glucose concentrations were clamped at plateaus of 4.3, 3.7, 3.0, and 2.3 mmol/liter for 90 min each (stepwise hypoglycemic clamp); on one occasion, GLP-1 (1.2 pmol x kg(-1) x min(-1)) was administered i.v. (steady-state concentration, approximately 125 pmol/liter); on the other occasion, NaCl was administered as placebo. Glucagon, cortisol, GH (immunoassays), and catecholamines (radioenzymatic assay) were determined, autonomous and neuroglucopenic symptoms were assessed, and cognitive function was tested at each plateau. Insulin secretion rates were estimated by deconvolution (two-compartment model of C-peptide kinetics). At insulin concentrations of approximately 45 mU/liter, glucose infusion rates were similar with and without GLP-1 (P = 0.26). Only during the euglycemic plateau (4.3 mmol/liter), GLP-1 suppressed glucagon concentrations (4.1 +/- 0.4 vs. 6.5 +/- 0.7 pmol/liter; P = 0.012); at all hypoglycemic plateaus, glucagon increased similarly with GLP-1 or placebo, to maximum values greater than 20 pmol/liter (P = 0.97). The other counterregulatory hormones and autonomic or neuroglucopenic symptom scores increased, and cognitive functions decreased with decreasing glucose concentrations, but there were no significant differences comparing experiments with GLP-1 or placebo, except for a significant reduction of GH responses during hypoglycemia with GLP-1 (P = 0.04). GLP-1 stimulated insulin secretion only at plasma glucose concentrations of at least 4.3 mmol/liter. In conclusion, the suppression of glucagon by GLP-1 does occur at euglycemia, but not at hypoglycemic plasma glucose concentrations (< or = 3.7 mmol/liter). GLP-1 does not impair overall hypoglycemia counterregulation except for a reduction in GH responses, which is in line with other findings demonstrating pituitary actions of GLP-1. Below plasma glucose concentrations of 4.3 mmol/liter, the insulinotropic action of GLP-1 is negligible.

Topics: Adult; Blood Glucose; Cognition; Glucagon; Glucagon-Like Peptide 1; Glucose Clamp Technique; Hormones; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Secretion; Male; Osmolar Concentration; Peptide Fragments; Protein Precursors; Reference Values

GLP-1 administration decreases blood glucose levels in normal subjects and non-insulin-dependent diabetes mellitus patients and is therefore proposed as a treatment for diabetic hyperglycaemia. The glucose lowering effect of GLP-1 is glucose dependent and therefore self-limiting, but it is not known to which extent counterregulatory mechanisms participate in this. GLP-1 was infused i.v. into 8 healthy subjects after an overnight fast at a rate of 100 pmol kg-1 h-1 for 1 h with and without beta-adrenoceptor blockade (i.v. bolus of 5 mg propranolol followed by a continuous infusion of 0.08 mg min-1). In a control experiment, saline and propranolol were infused. Hepatic glucose production was measured and blood was analysed for plasma glucose, insulin, glucagon, catecholamines, and radioactivity. Plasma GLP-1 levels were similar on the two GLP-1 infusion days and resulted in: (1) a significant decrease in plasma glucose from 5.2 +/- 0.2 to 4.1 +/- 0.1 mmol l-1 with GLP-1/propranolol infusion, and from 5.2 +/- 0.1 to 4.0 +/- 0.1 mmol l-1 with GLP-1/saline infusion (NS); (2) a corresponding significant increase in plasma insulin from 58.0 +/- 6.3 to 144.5 +/- 22.3 pmol l-1 and from 61.7 +/- 6.4 to 148.2 +/- 34.0 pmol l-1, respectively (NS); (3) a significant decrease in plasma glucagon from 11.7 +/- 1.6 to 6.5 +/- 1.5 pmol l-1 and from 10.4 +/- 1.6 to 4.6 +/- 1.0 pmol l-1, respectively; (4) a significant decrease in the rate of glucose appearance which was not significantly different on the two GLP-1 infusion days; and (5) an increase in catecholamine levels in the GLP-1/saline experiment and also in the beta-blockade experiments. We conclude that adrenergic counterregulation plays an insignificant role in curtailing GLP-1's glucose lowering effect.

Topics: Adrenergic beta-Antagonists; Adult; Analysis of Variance; Drug Interactions; Epinephrine; Fasting; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Infusions, Intravenous; Insulin; Male; Norepinephrine; Peptide Fragments; Propranolol; Protein Precursors; Reference Values

Diclofenac is commonly used as pain relief. Hypoglycemia has rarely been reported due to aspirin and indomethacin use but not of any other nonsteroidal anti-inflammatory drugs.. A 69-years old endocrinologist participated as a control in a glucagon-like peptide-1 (GLP-1) study. He decreased his plasma glucose to 1.8 mmol/L and developed full-blown hypoglycemic symptoms during an oral glucose tolerance test (OGTT). He had taken a 50 mg diclofenac tablet at 10 pm the evening before for a harmless muscle stretch in the lower back. Apart from well-controlled hypothyroidism he was healthy. During medical school he often had reactive hypoglycemia which came after intake of a carbohydrate rich but otherwise poor breakfast followed by bicycling. However, he had never experienced problems later in life after more decent meals containing slower absorbable carbohydrates. A 3-day continuous glucose monitoring (CGM) was performed three weeks after the OGTT test. A glucose value of 3.1 mmol/L was registered on the third CGM day in the afternoon after intake of 500 mg aspirin in the early morning the same day. Otherwise, all values were normal. A second OGGT where no medications apart from levothyroxine had been taken during at least a 2-week period adjacent was normal. Detailed analyses of the OGTTs showed that the GLP-1 levels before the test were higher after diclofenac exposure while the insulin levels increased after the glucose challenge which suggesting uncoupling.. With this case report we would like to draw attention to that diclofenac may cause hypoglycemia.

Topics: Aged; Blood Glucose; Blood Glucose Self-Monitoring; Diclofenac; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemia; Insulin; Male

Investigate the effectiveness of IDegLira, a fixed-ratio combination of insulin degludec/liraglutide, in a real-world setting in patients with type 2 diabetes mellitus in the United Arab Emirates.. This non-interventional study enrolled adults switching to IDegLira from basal insulin (BI) or glucagon-like peptide-1 receptor agonists (GLP-1 RAs) with/without concomitant oral antidiabetic drugs (OADs). Primary endpoint was change in HbA1c from baseline, assessed using a mixed model for repeated measurements.. Among 263 patients (BI ± OADs, n = 206; GLP-1 RA ± OADs, n = 57), mean baseline HbA1c was 9.29 % (78 mmol/mol). After 26 weeks, HbA1c was significantly reduced (BI ± OADs, -0.83 % [-9.0 mmol/mol] and GLP-1 RA ± OADs, -1.24 % [-13.5 mmol/mol]; both p < 0.0001). Fasting plasma glucose (FPG) was significantly reduced (-39.48 mg/dL [BI ± OADs] and -82.49 mg/dL [GLP-1 RA ± OADs]; both p < 0.0001). Before treatment initiation, 3/263 patients experienced ≥ 1 severe hypoglycaemic episode and 7/263 patients experienced ≥ 1 non-severe hypoglycaemic episode compared with 1/263 patients who had ≥ 1 severe and 1/263 who had ≥ 1 non-severe episode at end of study. Body weight decreased significantly among patients switching from BI ± OADs (-1.05 kg [p < 0.0001]). Treatment was well tolerated.. IDegLira significantly reduced HbA1c and FPG in this real-world setting, along with less frequent episodes of hypoglycaemia. Switching to IDegLira offers effective treatment intensification for type 2 diabetes patients with inadequate glycaemic control.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Drug Combinations; Glucagon-Like Peptide 1; Glycated Hemoglobin; Glycemic Control; Humans; Hypoglycemia; Hypoglycemic Agents; Liraglutide; Prospective Studies; United Arab Emirates

Despite the increasing prevalence of postbariatric hypoglycemia (PBH), a late metabolic complication of bariatric surgery, our understanding of its diverse manifestations remains incomplete.. To contrast parameters of glucose-insulin homeostasis in 2 distinct phenotypes of PBH (mild versus moderate hypoglycemia) based on nadir plasma glucose.. University Hospital (Bern, Switzerland).. Nadir glucose was 43.3 ± 6.0mg/dL (mean ± standard deviation) and 60.1 ± 9.1mg/dL in L2- and L1-PBH, respectively. Insulin exposure was significantly higher in L2 versus L1 (P = .004). Mathematical modeling revealed higher BCF in L2 versus L1 (34.3 versus 18.8 10. Our results suggest that higher insulin exposure in PBH patients with lower postprandial nadir glucose values mainly relate to a higher responsiveness to glucose, rather than GLP-1.

Topics: Blood Glucose; Gastric Bypass; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemia; Insulin

Type 2 diabetes mellitus (T2DM) affects 25% of adults over age 65. Nevertheless, few clinical trials include patients over age 75.. This case series reports retrospective data on a cohort of 85 patients aged 80 and over (mean 88.1, range 80-104) with T2DM, managed by a single endocrinologist. The practice's computerized data base was searched for all patients 80 years of age and older with a diagnosis of T2DM.. The major observations were the significant decrease in the use of agents associated with hypoglycemia (sulfonylureas and insulin), and the beneficial and well-tolerated use of glucagon like peptide-1 receptor analogues (GLP-1 RA). The mean A1c in the entire cohort dropped from 7.6% to 6.6% over a mean of 9 months. Nearly one-half of the cohort were treated with GLP1-RA, reflecting studies demonstrating the safety and efficacy of this class of drugs in less elderly patients. At presentation, 75% were on sulfonylurea and/or insulin; this number was reduced to 27%. Furthermore, none of the patients required short-acting (bolus) insulin to achieve the individualized A1c target.. Patients with T2DM aged 80 and over respond well to GLP1-RA drugs, drastically reducing the need for agents associated with hypoglycemia. The important question, which will require larger and prospective studies, is whether the lowering of A1c, as shown in this paper, and the use of GLP-1 RA specifically, are associated with improved morbidity and mortality in the very elderly.

Topics: Adult; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin, Regular, Human; Prospective Studies; Retrospective Studies; Sulfonylurea Compounds

Public safety (prevention of accidents) is the primary objective in assessing fitness to drive a motor vehicle. However, general access to mobility should not be restricted if there is no particular risk to public safety. For people with diabetes mellitus, the Führerscheingesetz (Driving Licence Legislation) and the Führerscheingesetz-Gesundheitsverordnung (Driving Licence Legislation Health enactment) regulate important aspects of driving safety in connection with acute and chronic complications of the disease. Critical complications that may be relevant to road safety include severe hypoglycemia, pronounced hyperglycemia and hypoglycemia perception disorder as well as severe retinopathy and neuropathy, endstage renal disease and certain cardiovascular manifestations. If there is a suspicion of the presence of one of these complications, a detailed evaluation is required.In addition, the individual antihyperglycemic medication should be checked for existing potential for hypoglycemia. Sulfonylureas, glinides and insulin belong to this group and are therefore associated with the requirement of a 5-year limitation of the driver's license. Other antihyperglycemic drugs without potential for hypoglycemia such as Metformin, SGLT‑2 inhibitors (Sodium-dependent-glucose-transporter‑2 inhibitors, gliflozins), DPP-4-inhibitors (Dipeptidyl-Peptidase inhibitors, gliptins), and GLP‑1 analogues (GLP‑1 rezeptor agonists) are not associated with such a time limitation.The relevant laws which regulate driving safety give room for interpretation, so that specific topics on driving safety for people with diabetes mellitus are elaborated from a medical and traffic-relevant point of view. This position paper is intended to support people involved in this challenging matter.. Bei der Beurteilung der gesundheitlichen Eignung zum Lenken eines Kraftfahrzeuges ist die öffentliche Sicherheit (Unfallprävention) das vorrangige Ziel. Der generelle Zugang zu Mobilität sollte jedoch nicht eingeschränkt werden, wenn kein besonderes Risiko für die öffentliche Sicherheit besteht. Für Menschen mit Diabetes mellitus sind im Führerscheingesetz (FSG) und in der Führerscheingesetz-Gesundheitsversorgung (FSG-GV) wichtige Aspekte zur Fahrsicherheit in Zusammenhang mit akuten und chronischen Komplikationen der Erkrankung geregelt. Zu den kritischen Komplikationen, die für die Verkehrssicherheit relevant sind, gehören schwere Hypoglykämie, ausgeprägte Hyperglykämie und Hypoglykämiewahrnehmungsstörung, sowie schwere Retinopathie und Neuropathie, weiters fortgeschrittene Nierenerkrankung und bestimmte kardiovaskuläre Manifestationen. Bei Verdacht auf Präsenz einer dieser Akutkomplikationen oder Folgeschäden ist eine genaue Evaluierung erforderlich.Darüber hinaus ist die individuelle antihyperglykämische Medikation auf vorhandenes Potenzial für Hypoglykämien zu überprüfen. Sulfonylharnstoffe, Glinide und Insulin gehören in diese Gruppe und sind daher automatisch mit der Auflage einer 5‑jährigen Befristung des Führerscheines assoziiert. Metformin, DPP-4-Hemmer (Dipeptidyl-Peptidase-4-Hemmer, Gliptine), SGLT2-Hemmer (Sodium-dependent-glucose-transporter‑2 inhibitors, Gliflozine), Glitazone und die zu injizierenden GLP-1 Analoga (GLP‑1 Rezeptor Agonisten) weisen kein Hypoglykämiepotential auf und sind daher nicht mit einer Befristung verbunden.Die FSG-GV gibt Spielraum für Interpretation, sodass im Folgenden spezifische Themen zur Fahrsicherheit für Menschen mit Diabetes mellitus aus fachärztlicher und verkehrsrelevanter Sicht aufgearbeitet wurden. Dieses Positionspapier dient zur Unterstützung von Personen, die mit dieser herausfordernden Materie befasst sind.

Topics: Accidents, Traffic; Austria; Automobile Driving; Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents

To provide real-world data on the addition of basal insulin (BI) in people with type 2 diabetes mellitus (PWD2) suboptimally controlled with glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy. However, real-world data on the addition of BI to GLP-1RA therapy are limited.. We used a US electronic medical record data source (IBM® Explorys®) that includes approximately 4 million PWD2 to assess the real-world impact of adding the second-generation BI analogue insulin glargine 300 U/mL (Gla-300) to GLP-1RA therapy. Insulin-naïve PWD2 receiving GLP-1RAs who also received Gla-300 between March 1, 2015 and September 30, 2019 were identified; participants were required to have data for ≥12 months before, and ≥6 months after, addition of Gla-300.. The mean (standard deviation [SD]) age of participants (N = 271) was 57.9 (10.8) years. Baseline glycated haemoglobin (HbA1c) was 9.16% and was significantly reduced (-0.97 [SD 1.60]%; P < 0.0001) after addition of Gla-300; a significant increase in the proportion of PWD2 achieving HbA1c control was observed after addition of Gla-300 (HbA1c <7.0%: 4.80% vs. 22.14%, P < 0.0001; HbA1c <8.0%: 19.56% vs. 51.29%, P < 0.0001). The incidence of overall (8.49% vs. 9.59%; P = 0.513) and inpatient/emergency department (ED)-associated hypoglycaemia (0.37% vs. 0.74%; P = 1.000), as well as overall (0.33 vs. 0.46 per person per year [PPPY]; P = 0.170) and inpatient/ED-associated hypoglycaemia events (0.01 vs. 0.04 PPPY; P = 0.466) were similar before and after addition of Gla-300.. In US real-world clinical practice, adding Gla-300 to GLP-1RA significantly improved glycaemic control without significantly increasing hypoglycaemia in PWD2. Further research into the effect of adding Gla-300 to GLP-1RA therapy is warranted.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine; Middle Aged

Exaggerated postprandial incretin and insulin responses are well documented in postbariatric surgery hypoglycemia (PBH) after Roux-en-Y gastric bypass (RYGB). However, less is known about PBH after sleeve gastrectomy (SG).. We sought to compare meal-stimulated hormonal response in those with PBH after SG vs RYGB.. We enrolled 23 post-SG (12 with and 11 without PBH) and 20 post-RYGB (7 with and 13 without PBH) individuals who underwent bariatric surgery at our institution. PBH was defined as plasma glucose less than 60 mg/dL on 4-hour mixed-meal tolerance test (MTT). Islet and incretin hormones were compared across the 4 groups.. Participants (N = 43) were on average 5 years post surgery, with a mean age of 48 years, mean preoperative body mass index of 48.4, 81% female, 61% White, and 53% post SG. Regardless of PBH, the SG group showed lower glucose, glucagon, and glucagon-like peptide 1 (GLP-1) responses to MTT and similar insulin and glucose-dependent insulinotropic polypeptide (GIP) responses compared to the RYGB group. Among those with PBH, the SG group following the MTT showed a lower peak glucose (P = .02), a similar peak insulin (90.3 mU/L vs 171mU/L; P = .18), lower glucagon (P < .01), early GLP-1 response (AUC0-60 min; P = .01), and slower time to peak GIP (P = .02) compared to PBH after RYGB.. Among individuals with PBH, those who underwent SG were significantly different compared to RYGB in meal-stimulated hormonal responses, including lower glucagon and GLP-1 responses, but similar insulin and GIP responses. Future studies are needed to better understand the differential contribution of insulin and non-insulin-mediated mechanisms behind PBH after SG vs RYGB.

Topics: Blood Glucose; Female; Gastrectomy; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemia; Incretins; Insulin; Male; Middle Aged; Obesity, Morbid

Like other peptide hormones, glucose-dependent insulinotropic polypeptide (GIP) is rapidly cleared from the circulation. Dipeptidyl peptidase-4 (DPP-4) is known to be involved. Information on the overall pharmacokinetics of GIP in rodents is, however, lacking. We investigated the pharmacokinetics of exogenous GIP after intravenous, subcutaneous and intraperitoneal injection with and without DPP-4 inhibition in conscious female C57Bl/6 mice. Secondly, we compared total and intact GIP levels measured by an in-house RIA and commercially available ELISA kits to determine the suitability of these methods for in vivo and in vitro measurements. GIP half-life following intravenous injection amounted to 93 ± 2 s, which was extended to 5 ± 0.6 min by inhibition of DPP-4. Intact GIP levels following subcutaneous and intraperitoneal GIP administration were approximately 15 % of total GIP. The area under the curve of intact GIP (GIP exposure) following GIP injection was significantly increased by DPP-4 inhibition, whereas total GIP levels remained unchanged. We found significant variation between measurements of total, but not intact GIP performed with our in-house RIA and ELISAs in samples obtained after in vivo administration of GIP. Different preanalytical sample preparation (EDTA plasma, heparin plasma, assay buffer and PBS) significantly influenced results for all ELISA kits used. Thus, in experiments involving exogenous GIP(1-42) administration in mice, it is important to consider that this will result in a very low ratio of intact:total peptide but co-administration of a DPP-4 inhibitor greatly elevates this ratio. Furthermore, for comparison of GIP levels, it is essential to maintain uniformity concerning assay methodology and sample preparation.

Topics: Animals; Blood Glucose; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Mice; Peptide Fragments; Proteolysis; Receptors, Gastrointestinal Hormone

To develop a dual-functional medicine for hypoglycemic and anti-thrombus.. The long-acting glucagon like peptide-1 (5×GLP-1) and nattokinase (NK) were cloned by SOE PCR and gained the GLP-1 and NK fusion polypeptide after transformed into E. coli. Use of mice models for the hypoglycemic and anti-thrombus activity of the fusion polypeptide. Balb/C mice were given the carrageenan by intraperitoneal injection to induce tail thrombus models. Type 2 diabetes mellitus mice model was used to research the hypoglycemic function of the fusion polypeptide.. Results showed that the fusion polypeptide could significantly prevent thrombus formation after oral administration. Continuous administration for 15 days, fasting blood glucose levels of the experimental group decreased to nearly normal levels.. The present study investigated the expression, purification and functional activity of the rolGLP-1 and NK fusion polypeptide, which provided a foundation for further studying the detailed pharmaceutical mechanism and drug development.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Disease Models, Animal; Glucagon-Like Peptide 1; Hypoglycemia; Insulin; Male; Mice; Mice, Inbred BALB C; Peptides; Subtilisins; Thrombosis

Dumping syndrome is a frequent and potentially severe complication after gastric surgery. Beinaglutide, a recombinant human glucagon-like peptide-1 (GLP-1) which shares 100% homology with human GLP-1(7-36), has never been reported in the treatment of dumping syndrome before.. The patient had undergone distal gastrectomy for gastric signet ring cell carcinoma 16 months ago. He presented with symptoms of paroxysmal palpitation, sweating, and dizziness for 4 months.. He was diagnosed with late dumping syndrome.. The patient was treated with dietary changes and acarbose for 4 months before admitted to our hospital. The treatment with dietary changes and acarbose did not prevent postprandial hyperinsulinemia and hypoglycemia according to the 75 g oral glucose tolerance test (OGTT) and continuous glucose monitoring (CGM) on admission.Therefore, the patient was treated with beinaglutide 0.1 mg before breakfast and lunch instead of acarbose. After the treatment of beinaglutide for 1 month, OGTT showed a reduction in postprandial hyperinsulinemia compared with before starting treatment, and the time in the range of 3.9 to 10 mmol/L became 100% in CGM. No side effect was observed in this patient during beinaglutide treatment.. These findings suggest that beinaglutide may be effective for treating post-gastrectomy late dumping syndrome.

Topics: Blood Glucose; Carcinoma, Signet Ring Cell; Dumping Syndrome; Gastrectomy; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Hyperinsulinism; Hypoglycemia; Male; Middle Aged; Peptide Fragments; Postprandial Period; Recombinant Proteins; Stomach Neoplasms; Treatment Outcome

The enteroendocrine cell (EEC)-derived incretins play a pivotal role in regulating the secretion of glucagon and insulins in mammals. Although glucagon-like and insulin-like hormones have been found across animal phyla, incretin-like EEC-derived hormones have not yet been characterised in invertebrates. Here, we show that the midgut-derived hormone, neuropeptide F (NPF), acts as the sugar-responsive, incretin-like hormone in the fruit fly, Drosophila melanogaster. Secreted NPF is received by NPF receptor in the corpora cardiaca and in insulin-producing cells. NPF-NPFR signalling resulted in the suppression of the glucagon-like hormone production and the enhancement of the insulin-like peptide secretion, eventually promoting lipid anabolism. Similar to the loss of incretin function in mammals, loss of midgut NPF led to significant metabolic dysfunction, accompanied by lipodystrophy, hyperphagia, and hypoglycaemia. These results suggest that enteroendocrine hormones regulate sugar-dependent metabolism through glucagon-like and insulin-like hormones not only in mammals but also in insects.

Topics: Animals; Animals, Genetically Modified; Drosophila melanogaster; Enteroendocrine Cells; Female; Glucagon; Glucagon-Like Peptide 1; Hormones; Humans; Hypoglycemia; Incretins; Insulin; Insulin Secretion; Lipid Metabolism; Mutation; Neuropeptides; Receptors, Neuropeptide; Sugars

Early dumping and post-bariatric hypoglycemia (PBH) are often addressed as two separate postprandial complications after Roux-en-Y gastric bypass (RYGB). The aim of the study was to evaluate the occurrence of early dumping in RYGB-operated individuals with PBH with and without treatment intervention.. Eleven RYGB-operated women with documented PBH each underwent a baseline liquid mixed meal test (MMT) followed by five MMTs preceded by treatment with: acarbose 50 mg for 1 week, sitagliptin 100 mg for 1 week, verapamil 120 mg for 1 week, liraglutide 1.2 mg for 3 weeks, and pasireotide 300 μg as a single dose. Repetitive venous blood sampling and continuous electrocardiogram recordings were performed at fasting and during a 3-h postprandial period.. During the baseline MMT, there was a significant increase in HR (from 65 ± 2 to 90 ± 4 bpm, p < 0.0001) within 30 min after meal intake, while hypoglycemia occurred in the later postprandial period. The HR increase was accompanied by significant increases in serum albumin, plasma norepinephrine, blood glucose, serum insulin, and plasma GLP-1 concentrations. The postprandial HR changes were positively correlated with the changes in insulin and GLP-1 concentrations. Treatment with acarbose and pasireotide both reduced HR, plasma norepinephrine, and serum insulin, and pasireotide also decreased plasma GLP-1.. RYGB-operated individuals with PBH also have large early postprandial HR increases, hemoconcentration, and sympathetic activation, consistent with early dumping. Moreover, hormone excursions associated with PBH appear to be related to measures of early dumping, suggesting a causal relationship between early dumping and PBH.. NCT02527993.

Topics: Blood Glucose; Female; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Insulin; Obesity, Morbid; Postprandial Period

The vast number of antihyperglycemic medications and growing amount of evidence make clinical decision making difficult. The aim of this study was to investigate the safety of antihyperglycemic dual and triple therapies for type 2 diabetes management with respect to major adverse cardiovascular events, severe hypoglycemia, and all-cause mortality in a real-life clinical setting.. Cox regression models were constructed to analyze 20 years of data from the Danish National Patient Registry with respect to effect of the antihyperglycemic therapies on the three end points.. A total of 66,807 people with type 2 diabetes were treated with metformin (MET) plus a combination of second- and third-line therapies. People on MET plus sulfonylurea (SU) had the highest risk of all end points, except for severe hypoglycemia, for which people on MET plus basal insulin (BASAL) had a higher risk. The lowest risk of major adverse cardiovascular events was seen for people on a regimen including a glucagon-like peptide 1 (GLP-1) receptor agonist. People treated with MET, GLP-1, and BASAL had a lower risk of all three end points than people treated with MET and BASAL, especially for severe hypoglycemia. The lowest risk of all three end points was, in general, seen for people treated with MET, sodium-glucose cotransporter 2 inhibitor, and GLP-1.. Findings from this study do not support SU as the second-line treatment choice for patients with type 2 diabetes. Moreover, the results indicate that adding a GLP-1 in people treated with MET and BASAL could be considered, especially if those people suffer from severe hypoglycemia.

Topics: Aged; Cardiovascular Diseases; Cause of Death; Cohort Studies; Denmark; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Metformin; Middle Aged; Registries; Risk Factors; Severity of Illness Index; Sulfonylurea Compounds; Treatment Outcome

Hypoglycemia in cystic fibrosis (CF), in the absence of glucose-lowering therapies, has long been identified as an important issue in the management of CF. There is currently still no unifying hypothesis for its etiology.. The aims of this study were to perform a 3-h oral glucose tolerance test (OGTT) in participants with CF and (1) document glucose, insulin, glucagon, glucagon-like-peptide-1 (GLP-1), and glucose-dependent insulinotropic peptide (GIP) release patterns within varying glucose tolerance groups during the OGTT; (2) determine the prevalence of hypoglycemic during the OGTT; and (3) define any association between hypoglycemia and patterns of insulin, glucagon, GLP-1, and GIP release.. Eligible participants attending an adult CF clinic completed a 3-h OGTT. Hypoglycemia on OGTT was defined as mild (glucose 3.4-3.9 mmol/L), moderate (glucose 3.1-3.3 mmol/L), and severe (glucose ≤ 3 mmol/L). Hormones were measured at fasting, 30, 60, 120, and 180 min.. Twenty-four participants completed the study, of which 7 had normal glucose tolerance, 12 had abnormal glucose tolerance, and 5 had cystic fibrosis related diabetes (CFRD). All participants had a delayed insulin response compared with normative data. All glucose tolerance groups showed appropriate and similar suppression of fasting glucagon. Four participants (17%) had mild hypoglycemic, three (13%) had moderate hypoglycemic, and eight (33%) had severe hypoglycemic. No participant with CFRD demonstrated hypoglycemic. Of the 19 participants without CFRD, 15 (79%) experienced hypoglycemic. Participants with hypoglycemic had greater peak glucose and insulin responses than those that did not have hypoglycemic, and this approached significance (p = .0625 for glucose and p = .0862 for insulin). No significant mean differences between GLP-1 and GIP release were found. There was no relationship between hypoglycemic and modulator therapy.. Postprandial hypoglycemic was unmasked by the extension of an OGTT to 3 h. Delayed and abnormal insulin release, and ineffective counter-regulatory action of glucagon may have a role in its etiology.

Topics: Adolescent; Adult; Blood Glucose; Cystic Fibrosis; Fasting; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Humans; Hypoglycemia; Insulin; Male; Young Adult

Glucagon-like peptide 1 (GLP-1) receptors are expressed by pancreatic beta cells and GLP-1 receptor signalling promotes insulin secretion. GLP-1 receptor agonists have neural effects and are therapeutically promising for mild cognitive impairment and Alzheimer's disease. Our previous results showed that insulin is released by neurogliaform neurons in the cerebral cortex, but the expression of GLP-1 receptors on insulin-producing neocortical neurons has not been tested. In this study, we aimed to determine whether GLP-1 receptors are present in insulin-containing neurons.. We harvested the cytoplasm of electrophysiologically and anatomically identified neurogliaform interneurons during patch-clamp recordings performed in slices of rat neocortex. Using single-cell digital PCR, we determined copy numbers of Glp1r mRNA and other key genes in neurogliaform cells harvested in conditions corresponding to hypoglycaemia (0.5 mmol/l glucose) and hyperglycaemia (10 mmol/l glucose). In addition, we performed whole-cell patch-clamp recordings on neurogliaform cells to test the effects of GLP-1 receptor agonists for functional validation of single-cell digital PCR results.. Single-cell digital PCR revealed GLP-1 receptor expression in neurogliaform cells and showed that copy numbers of mRNA of the Glp1r gene in hyperglycaemia exceeded those in hypoglycaemia by 9.6 times (p < 0.008). Moreover, single-cell digital PCR confirmed co-expression of Glp1r and Ins2 mRNA in neurogliaform cells. Functional expression of GLP-1 receptors was confirmed with whole-cell patch-clamp electrophysiology, showing a reversible effect of GLP-1 on neurogliaform cells. This effect was prevented by pre-treatment with the GLP-1 receptor-specific antagonist exendin-3(9-39) and was absent in hypoglycaemia. In addition, single-cell digital PCR of neurogliaform cells revealed that the expression of transcription factors (Pdx1, Isl1, Mafb) are important in beta cell development.. Our results provide evidence for the functional expression of GLP-1 receptors in neurons known to release insulin in the cerebral cortex. Hyperglycaemia increases the expression of GLP-1 receptors in neurogliaform cells, suggesting that endogenous incretins and therapeutic GLP-1 receptor agonists might have effects on these neurons, similar to those in pancreatic beta cells.

Topics: Animals; Cerebral Cortex; Cytoplasm; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hyperglycemia; Hypoglycemia; Insulin; Interneurons; Male; Neocortex; Rats; Rats, Wistar; Signal Transduction

Hypoglycemia is an increasingly recognized complication of bariatric surgery. Mechanisms contributing to glucose lowering remain incompletely understood. We aimed to identify differentially abundant plasma proteins in patients with post-bariatric hypoglycemia (PBH) after Roux-en-Y gastric bypass (RYGB), compared to asymptomatic post-RYGB.. Proteomic analysis of blood samples collected after overnight fast and mixed meal challenge in individuals with PBH, asymptomatic RYGB, severe obesity, or overweight recruited from outpatient hypoglycemia or bariatric clinics.. The top-ranking differentially abundant protein at 120 min after mixed meal was fibroblast growth factor 19 (FGF-19), an intestinally derived hormone regulated by bile acid-FXR signaling; levels were 2.4-fold higher in PBH vs. asymptomatic post-RYGB (mean + SEM, 1094 ± 141 vs. 428 ± 45, P < 0.001, FDR < 0.01). FGF-19 ELISA confirmed 3.5-fold higher concentrations in PBH versus asymptomatic (360 ± 70 vs. 103 ± 18, P = 0.025). To explore potential links between increased FGF-19 and GLP-1, residual samples from other human studies in which GLP-1 was modulated were assayed. FGF-19 levels did not change in response to infusion of GLP-1 and PYY in overweight/obese individuals. Infusion of the GLP-1 receptor antagonist exendin 9-39 in recently operated asymptomatic post-RYGB did not alter FGF-19 levels after mixed meal. By contrast, GLP-1 receptor antagonist infusion yielded a significant increase in FGF-19 levels after oral glucose in individuals with PBH. While plasma bile acids did not differ between PBH and asymptomatic post-RYGB, these data suggest unique interrelationships between GLP-1 and FGF-19 in PBH.. Taken together, these data support FGF-19 as a potential contributor to insulin-independent pathways driving postprandial hypoglycemia in PBH.

Topics: Adult; Bariatric Surgery; Blood Glucose; Blood Proteins; Case-Control Studies; Female; Fibroblast Growth Factors; Gastric Bypass; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Male; Meals; Middle Aged; Obesity, Morbid; Peptide Fragments; Postoperative Complications; Proteome; Proteomics; Up-Regulation

A retrospective cohort study was conducted in patients with type 2 diabetes in an electronic medical record database to compare real-world, 6-month glycated haemoglobin (HbA1c) and weight outcomes for exenatide once weekly with those for dulaglutide and albiglutide. The study included 2465 patients: exenatide once weekly, n = 2133; dulaglutide, n = 201; and albiglutide, n = 131. The overall mean (standard deviation [s.d.]) age was 60 (11) years and 54% were men; neither differed among the comparison groups. The mean (s.d.) baseline HbA1c was similar in the exenatide once-weekly (8.3 [1.7]%) and dulaglutide groups (8.5 [1.5]%; P = .165), but higher in the albiglutide group (8.7 [1.7]%; P < .001). The overall mean (s.d.) HbA1c change was -0.5 (1.5)% (P < .001) and this did not differ among the comparison groups in either adjusted or unadjusted analyses. The mean (s.d.) weight change was -1.4 (4.7) kg for exenatide once weekly and -1.6 (3.7) kg for albiglutide (P = .579), but was greater for dulaglutide, at -2.7 (5.7) kg (P = .001). Outcomes were similar in subsets of insulin-naive patients with baseline HbA1c ≥7.0% or ≥9.0%. All agents significantly reduced HbA1c at 6 months, with no significant differences among agents or according to baseline HbA1c in insulin-naive subgroups.

Topics: Adult; Aged; Body Mass Index; Cohort Studies; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Male; Middle Aged; Obesity; Recombinant Fusion Proteins; Retrospective Studies; Weight Loss

Altered enteroendocrine hormone responses are widely believed to underlie the beneficial effects of bariatric surgery in type 2 diabetes. While elevated postprandial glucagon-like peptide-1 (GLP-1) is considered one of the mediators, increased postprandial glucagon levels have recently been implicated.. We investigated hormonal responses in lean patients after prophylactic total gastrectomy (PTG), as a model of Roux-en-Y gastric bypass without the confounding effects of obesity or massive weight loss.. University hospital, United Kingdom.. PTG participants exhibited accelerated plasma glucose appearance, followed, in 3 of 10 cases, by hypoglycemia (<3 mM glucose). Plasma GLP-1, peptide YY, glucose-dependent insulinotropic-polypeptide, glicentin, and oxyntomodulin responses were elevated, and glucagon appeared to rise in PTG participants when measured with a glucagon-specific enzyme-linked immunosorbent assay. We revisited the specificity of this assay, and demonstrated significant cross-reactivity with glicentin and oxyntomodulin at concentrations observed in PTG plasma. Reassessment of glucagon with the same assay using a modified protocol, and by liquid chromatography-mass spectrometry, demonstrated suppression of glucagon secretion after oral glucose tolerance tests in both PTG and control cohorts.. Care should be taken when assessing glucagon levels in the presence of elevated plasma levels of other proglucagon products. Substantial elevation of GLP-1 and insulin responses after PTG likely contribute to the observed hypoglycemia, and mirror similar hormone levels and complications observed in bariatric weight loss patients.

Topics: Adult; Bariatric Surgery; Blood Glucose; Case-Control Studies; Female; Gastrectomy; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Hypoglycemia; Insulin; Male; Peptide YY; Proglucagon; Thinness

This study aimed to quantify the effect of the immediate release (IR) of exenatide, a short-acting glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA), on gastric emptying rate (GER) and the glucose rate of appearance (GluRA), and evaluate the influence of drug characteristics and food-related factors on postprandial plasma glucose (PPG) stabilization under GLP-1RA treatment. A quantitative systems pharmacology (QSP) approach was used, and the proposed model was based on data from published sources including: (1) GLP-1 and exenatide plasma concentration-time profiles; (2) GER estimates under placebo, GLP-1 or exenatide IR dosing; and (3) GluRA measurements upon food intake. According to the model's predictions, the recommended twice-daily 5- and 10-μg exenatide IR treatment is associated with GluRA flattening after morning and evening meals (48%-49%), whereas the midday GluRA peak is affected to a lesser degree (5%-30%) due to lower plasma drug concentrations. This effect was dose-dependent and influenced by food carbohydrate content, but not by the lag time between exenatide injection and meal ingestion. Hence, GER inhibition by exenatide IR represents an important additional mechanism of its effect on PPG.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Digestion; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Liberation; Exenatide; Gastric Emptying; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Intestinal Absorption; Models, Biological; Postprandial Period; Systems Biology

To elucidate the effects of rs2289669, an intron variant of the SLC47A1 gene, on glucose response to metformin in Chinese people with newly diagnosed Type 2 diabetes.. Rs2289669 was genotyped, using Sequenom, in 291 participants receiving 48 weeks of metformin monotherapy. The changes in HbA. We found that, compared with participants with a homozygous G allele, those carrying the minor A allele had significantly greater HbA. Our findings suggest that rs2289669 might help predict the glycaemic response to metformin in Chinese people newly diagnosed with Type 2 diabetes, and that differential increases in basal glucagon-like peptide-1 concentration among rs2289669 genotypes might be associated with inter-individual response to metformin.

Topics: Adult; China; Cohort Studies; Diabetes Mellitus, Type 2; Drug Resistance; Female; Follow-Up Studies; Genetic Association Studies; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Introns; Linear Models; Male; Metformin; Middle Aged; Organic Cation Transport Proteins; Polymorphism, Single Nucleotide; Prospective Studies

Glucagon-like peptide-1 (GLP-1) receptor agonists are currently used for the treatment of type 2 diabetes. Their main mechanism of action is enhancement of glucose-induced insulin secretion (from increased beta cell glucose sensitivity) and inhibition of glucagon secretion. The latter has been demonstrated to account for about half of their blood glucose-lowering activity. Whereas the effect of GLP-1 on insulin secretion is clearly dependent on ambient glucose concentrations and has been described in detail, the mechanism responsible for the inhibitory effect of GLP-1 on glucagon secretion is heavily debated. Glucagon inhibition is also said to be glucose-dependent, although it is unclear what is meant by this. We hypothesise here that GLP-1 does not inhibit glucagon secretion during hypoglycaemia because the inhibition depends on somatostatin secretion, which in turn is dependent on glucose levels.. We used the perfused mouse pancreas model to investigate this hypothesis.. We found that, in this model, GLP-1 was able to significantly inhibit glucagon secretion from pancreatic alpha cells at all glucose levels tested: 6.0, 1.5 and 0.5 mmol/l (-27.0%, -37.1%, and -23.6%, respectively), and the decrease in glucagon secretion was invariably accompanied by an increase in somatostatin secretion (+286.8%, +158.7%, and +118.8%, respectively). Specific blockade of somatostatin receptor 2 increased glucagon secretion (+118.8% at 1.5 mmol/l glucose and +162.9% at 6.0 mmol/l glucose) and completely eliminated the inhibitory effect of GLP-1.. We have shown here that the glucagon-lowering effect of GLP-1 is entirely mediated through the paracrine actions of somatostatin in the perfused mouse pancreas. However, in this model, the inhibitory effect of GLP-1 was preserved at hypoglycaemic levels, leaving unanswered the question of how this is avoided in vivo in individuals treated with GLP-1 receptor agonists.

Topics: Animals; Blood Glucose; Female; Glucagon; Glucagon-Like Peptide 1; Hypoglycemia; Mice; Mice, Inbred C57BL; Pancreas; Receptors, Somatostatin; Somatostatin

Topics: Adrenal Gland Neoplasms; Blood Glucose; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Insulin; Iodine Radioisotopes; Magnetic Resonance Imaging; Pheochromocytoma; Radionuclide Imaging

Roux-en-Y gastric bypass (RYGB) surgery is currently the most effective treatment for diabetes and obesity. An increasingly recognized and highly disabling complication of RYGB is postprandial hypoglycaemia (PPH). The pathophysiology of PPH remains unclear with multiple mechanisms suggested including nesidioblastosis, altered insulin clearance and increased glucagon-like peptide-1 (GLP-1) secretion. Whilst many PPH patients respond to dietary modification, some have severely disabling symptoms. Multiple treatments are proposed, including dietary modification, GLP-1 antagonism, GLP-1 analogues and even surgical reversal, with none showing a more decided advantage over the others. A greater understanding of the pathophysiology of PPH could guide the development of new therapeutic strategies.. We studied a cohort of PPH patients at the Imperial Weight Center. We performed continuous glucose monitoring to characterize their altered glycaemic variability. We also performed a mixed meal test (MMT) and measured gut hormone concentrations.. We found increased glycaemic variability in our cohort of PPH patients, specifically a higher mean amplitude glucose excursion (MAGE) score of 4.9. We observed significantly greater and earlier increases in insulin, GLP-1 and glucagon in patients who had hypoglycaemia in response to an MMT (MMT Hypo) relative to those that did not (MMT Non-Hypo). No significant differences in oxyntomodulin, GIP or peptide YY secretion were seen between these two groups.. An early peak in GLP-1 and glucagon may together trigger an exaggerated insulinotropic response to eating and consequent hypoglycaemia in patients with PPH.

Topics: Blood Glucose; Cohort Studies; Combined Modality Therapy; Diabetes Mellitus, Type 2; Diet, Diabetic; Diet, Reducing; Female; Gastric Bypass; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Insulin; Insulin Secretion; London; Male; Middle Aged; Monitoring, Ambulatory; Obesity; Postoperative Complications; Postprandial Period; Prevalence; Risk Factors

Topics: Bariatric Surgery; Gastric Bypass; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemia

To evaluate the safety and efficacy of once weekly albiglutide added to a single oral antidiabetic drug (OAD) in Japanese patients with inadequately controlled type 2 diabetes mellitus (T2DM).. In this phase 3, 1 year study (NCT01777282), patients (N = 374) received albiglutide 30 mg plus a single OAD (sulfonylurea [n = 120], biguanide [n = 67)], glinide [n = 65], thiazolidinedione [n = 61], or α-glucosidase inhibitor [n = 61]). Albiglutide could be increased to 50 mg after Week 4, based on glycemic criteria. Primary endpoints were the incidence of adverse events (AEs) and hypoglycemia; secondary endpoints were changes from baseline at Week 52 in HbA. On-therapy AEs occurred in 78.6% of patients and serious AEs in 2.1%. Common AEs were nasopharyngitis (32.6%), constipation (7.2%), and diabetic retinopathy (5.3%). No serious AEs occurred more than once or were reported in >1 patient. Hypoglycemia occurred in 6.4% of patients, mostly in the albiglutide + sulfonylurea (14.2%) and the albiglutide + glinide (6.2%) groups. Albiglutide was uptitrated in 53.2% of patients. Mean baseline HbA. When combined with a single OAD in Japanese patients with inadequately controlled T2DM, albiglutide led to favorable changes in all glycemic parameters, with minor changes in body weight depending on the background OAD. No new safety concerns were noted.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Male; Middle Aged; Recombinant Proteins

Glucagon-like peptide-1 (GLP-1) is a type of incretin secreted from enteroendocrine L-cells. Our previous studies demonstrated that curcumin (a yellow pigment of turmeric) significantly increases the secretion of GLP-1 in enteroendocrine L cell line (GLUTag cells). However, it is not clear whether its action in vivo directly enhances GLP-1 secretion, which then leads to a reduction in blood glucose levels via the stimulation of insulin secretion. In addition, the molecular target of curcumin-induced GLP-1 secretion has not been clarified.. Glucose tolerance was significantly improved in rats after pre-administered curcumin (1.5 mg/kg) followed by intraperitoneal glucose injections via the stimulation of GLP-1 secretion and the induction of insulin secretion. In GLUTag cells, curcumin-induced GLP-1 secretion was associated with G protein-coupled receptor (GPR) 40/120. Furthermore, the glucose-lowering effect induced by curcumin was significantly reduced after the administration of a GPR40/120 antagonist in rats.. These findings demonstrate the biological function of curcumin as a GLP-1 secretagogue and the possible molecular target that mediates GLP-1 secretion. Increases in the secretion of endogenous GLP-1 induced by curcumin may allow the dosages of other diabetic medicines to be reduced and aid in the prevention of diabetes.

Topics: Administration, Oral; Animals; Benzoates; Blood Glucose; Cell Line; Curcumin; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Hypoglycemia; Injections, Intraperitoneal; Insulin; Male; Mice; Pyrimidines; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled

Although patients with diabetes mellitus (DM) often exhibit hypertension, the mechanisms responsible for this correlation are not well known. We hypothesized that the bulbospinal neurons in the rostral ventrolateral medulla (RVLM) are affected by the levels of glucose, insulin, or incretins (glucagon like peptide-1 [GLP-1] or glucose-dependent insulinotropic peptide [GIP]) in patients with DM. To investigate whether RVLM neurons are activated by glucose, insulin, GLP-1, or GIP, we examined changes in the membrane potentials of bulbospinal RVLM neurons using whole-cell patch-clamp technique during superfusion with various levels of glucose or these hormones in neonatal Wistar rats. A brainstem-spinal cord preparation was used for the experiments. A low level of glucose stimulated bulbospinal RVLM neurons. During insulin superfusion, almost all the RVLM neurons were depolarized, while during GLP-1 or GIP superfusion, almost all the RVLM neurons were hyperpolarized. Next, histological examinations were performed to examine transporters for glucose and receptors for insulin, GLP-1, and GIP on RVLM neurons. Low-level glucose-depolarized RVLM neurons exhibited the presence of glucose transporter 3 (GLUT3). Meanwhile, insulin-depolarized, GLP-1-hyperpolarized, and GIP-hyperpolarized RVLM neurons showed each of the respective specific receptor. These results indicate that a low level of glucose stimulates bulbospinal RVLM neurons via specific transporters on these neurons, inducing hypertension. Furthermore, an increase in insulin or a reduction in incretins may also activate the sympathetic nervous system and induce hypertension by activating RVLM neurons via their own receptors.

Topics: Animals; Animals, Newborn; Central Nervous System Agents; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Glucose Transporter Type 3; Hyperinsulinism; Hypoglycemia; Insulin; Medulla Oblongata; Membrane Potentials; Neurons; Peptide Fragments; Peptides; Rats, Wistar; Tetrodotoxin; Tissue Culture Techniques

Dumping syndrome is a common complication in children after fundoplication and other gastric surgeries and is characterized by postprandial hypoglycemia (PPH). Children with PPH have an exaggerated GLP-1 response to a meal with an exaggerated insulin surge and subsequent hypoglycemia. We evaluated the role of GLP-1 in the pathogenesis of PPH by examining the effects of GLP-1 receptor blockade on glucose and insulin response to a meal.. Six children with known PPH after surgery underwent a mixed meal tolerance test with/without the GLP-1 receptor antagonist exendin-(9-39) using an open-label crossover design.. Average nadir plasma glucose concentration was ≥65 mg/dl in all treatment conditions; however, 3 out of the 6 subjects had a nadir plasma glucose <65 mg/dl during vehicle infusion, while only 1 out of the 6 had a nadir plasma glucose <65 mg/dl during infusion of exendin-(9-39). Exendin-(9-39) suppressed postmeal insulin concentrations when compared to vehicle, with a lower peak insulin concentration observed in the children who received 500 pmol/kg/min of exendin-(9-39) (131.3 ± 125.1 pmol/l) compared to children who received 300 pmol/kg/min (231.1 ± 153.4 pmol/l) or vehicle (259.7 ± 120.2 pmol/l). Gastric emptying was not different between groups.. Our results suggest that the exaggerated insulin response to a meal is at least in part due to the effects of GLP-1 on the pancreatic β-cell and suggest that GLP-1 receptor antagonists may represent a potential avenue of treatment for children with PPH.

Topics: Adolescent; Child; Child, Preschool; Female; Fundoplication; Gastric Emptying; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Male; Peptide Fragments; Postoperative Complications

TGR5 activation of enteroendocrine cells increases glucagon-like peptide 1 (GLP-1) release, which maintains glycemic homeostasis. However, TGR5 activation in the gallbladder and heart is associated with severe side effects. Therefore, intestinally-targeted TGR5 agonists were suggested as potential hypoglycemic agents with minimal side effects. However, until now no such compounds with robust glucose-lowering effects were reported, especially in diabetic animal models. Herein, we identify a TGR5 agonist, 26a, which was proven to be intestinally-targeted through pharmacokinetic studies. 26a was used as a tool drug to verify the intestinally-targeted strategy. 26a displayed a robust and long-lasting hypoglycemic effect in ob/ob mice (once a day dosing (QD) and 18-day treatment) owing to sustained stimulation of GLP-1 secretion, which suggested that robust hypoglycemic effect could be achieved with activation of TGR5 in intestine alone. However, the gallbladder filling effect of 26a was rather complicated. Although the gallbladder filling effect of 26a was decreased in mice after once a day dosing, this side effect was still not eliminated. To solve the problem above, several research strategies were raised for further optimization.

Topics: Ammonium Compounds; Animals; Blood Glucose; Disease Models, Animal; Enteroendocrine Cells; Female; Gallbladder; Glucagon-Like Peptide 1; Glucose Tolerance Test; HEK293 Cells; Homeostasis; Humans; Hypoglycemia; Hypoglycemic Agents; Intestinal Mucosa; Male; Mice; Mice, Inbred ICR; Mice, Obese; Permeability; Quaternary Ammonium Compounds; Receptors, G-Protein-Coupled

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Costs; Financing, Government; Glucagon-Like Peptide 1; Glycated Hemoglobin; Health Services Accessibility; Healthcare Financing; Humans; Hypoglycemia; Hypoglycemic Agents; New Zealand; Practice Guidelines as Topic; Sodium-Glucose Transporter 2 Inhibitors

The aim of this study was to assess the utility of [Lys40(Ahx-HYNIC-99mTc/EDDA)NH2]-exendin-4 scintigraphy in the management of patients with hypoglycemia, particularly in the detection of occult insulinoma.. Forty patients with hypoglycemia and increased/confusing results of serum insulin and C-peptide concentration and negative/inconclusive results of other imaging examinations were enrolled in the study. In all patients GLP-1 receptor imaging was performed to localise potential pancreatic lesions.. Positive results of GLP-1 scintigraphy were observed in 28 patients. In 18 patients postsurgical histopathological examination confirmed diagnosis of insulinoma. Two patients had contraindications to the surgery, one patient did not want to be operated. One patient, who presented with postprandial hypoglycemia, with positive result of GLP-1 imaging was not qualified for surgery and is in the observational group. Eight patients were lost for follow up, among them 6 patients with positive GLP-1 scintigraphy result. One patient with negative scintigraphy was diagnosed with malignant insulinoma. In two patients with negative scintigraphy Munchausen syndrome was diagnosed (patients were taking insulin). Other seven patients with negative results of 99mTcGLP-1 scintigraphy and postprandial hypoglycemia with C-peptide and insulin levels within the limits of normal ranges are in the observational group. We would like to mention that 99mTc-GLP1-SPECT/CT was also performed in 3 pts with nesidioblastosis (revealing diffuse tracer uptake in two and a focal lesion in one case) and in two patients with malignant insulinoma (with the a focal uptake in the localization of a removed pancreatic headin one case and negative GLP-1 1 scintigraphy in the other patient).. 99mTc-GLP1-SPECT/CT could be helpful examination in the management of patients with hypoglycemia enabling proper localization of the pancreatic lesion and effective surgical treatment. This imaging technique may eliminate the need to perform invasive procedures in case of occult insulinoma.

Topics: Adolescent; Adult; Aged; Blood Glucose; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Insulinoma; Isotope Labeling; Male; Middle Aged; Organotechnetium Compounds; Peptides; Radionuclide Imaging; Venoms; Young Adult

Teneligliptin is a novel peptidomimetic-chemotype prolylthiazolidine-based inhibitor of dipeptidyl peptidase-4 (DPP-4). The aim of this study was to evaluate the effects of teneligliptin on 24 h blood glucose control and gastrointestinal hormone responses to a meal tolerance test, and to investigate the glucose-lowering mechanisms of teneligliptin. Ten patients with type 2 diabetes mellitus (T2DM) were treated for 3 days with teneligliptin (20 mg/day). Postprandial profiles for glucose, insulin, glucagon, active glucagon-like peptide-1 (GLP-1), active glucose-dependent insulinotropic polypeptide (GIP), ghrelin, des-acyl ghrelin, and 24 h glycemic fluctuations were measured via continuous glucose monitoring for 4 days. Once daily teneligliptin administration for 3 days significantly lowered postprandial and fasting glucose levels. Significant elevations of fasting and postprandial active GLP-1 and postprandial active GIP levels were observed. Teneligliptin lowered postprandial glucose elevations, 24 h mean blood glucose levels, standard deviation of 24 h glucose levels and mean amplitude of glycemic excursions (MAGE) without hypoglycemia. Serum insulin levels in the fasting state and 30 min after a meal were similar before and after teneligliptin treatment; however significant reductions at 60 to 180 min after treatment were observed. A significant elevation in early-phase insulin secretion estimated by insulinogenic and oral disposition indices, and a significant reduction in postprandial glucagon AUC were observed. Both plasma ghrelin and des-acyl ghrelin levels were unaltered following teneligliptin treatment. Teneligliptin improved 24 h blood glucose levels by increasing active incretin levels and early-phase insulin secretion, reducing the postprandial insulin requirement, and reducing glucagon secretion. Even short-term teneligliptin treatment may offer benefits for patients with T2DM.

Topics: Aged; Blood Glucose; Combined Modality Therapy; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Japan; Middle Aged; Monitoring, Ambulatory; Postprandial Period; Pyrazoles; Thiazolidines

Bariatric surgery rapidly improves Type 2 diabetes mellitus (T2DM). Our objective was to profile and compare the extent and duration of improved glycemic control following Roux-en-Y gastric (RYGB) bypass surgery and vertical sleeve gastrectomy (SG) and compare against calorie restriction/weight loss and medical combination therapy-based approaches using the Zucker diabetic fatty rat (ZDF) rodent model of advanced T2DM. Male ZDF rats underwent RYGB (n = 15) or SG surgery (n = 10) at 18 wk of age and received postsurgical insulin treatment, as required to maintain mid-light-phase glycemia within a predefined range (10-15 mmol/l). In parallel, other groups of animals underwent sham surgery with ad libitum feeding (n = 6), with body weight (n = 8), or glycemic matching (n = 8) to the RYGB group, using food restriction or a combination of insulin, metformin, and liraglutide, respectively. Both bariatric procedures decreased the daily insulin dose required to maintain mid-light-phase blood glucose levels below 15 mmol/l, compared with those required by body weight or glycemia-matched rats (P < 0.001). No difference was noted between RYGB and SG with regard to initial efficacy. SG was, however, associated with higher food intake, weight regain, and higher insulin requirements vs. RYGB at study end (P < 0.05). Severe hypoglycemia occurred in several rats after RYGB. RYGB and SG significantly improved glycemic control in a rodent model of advanced T2DM. While short-term outcomes are similar, long-term efficacy appears marginally better after RYGB, although this is tempered by the increased risk of hypoglycemia.

Topics: Age Factors; Animals; Behavior, Animal; Biomarkers; Blood Glucose; Caloric Restriction; Combined Modality Therapy; Diabetes Mellitus, Type 2; Disease Models, Animal; Drug Therapy, Combination; Eating; Feeding Behavior; Gastrectomy; Gastric Bypass; Glucagon-Like Peptide 1; Hypoglycemia; Hypoglycemic Agents; Insulin; Liraglutide; Male; Metformin; Obesity; Rats, Zucker; Risk Factors; Time Factors; Weight Gain; Weight Loss

Glucagon-like peptide (GLP)-1 analogues such as liraglutide have gained popularity in the treatment of type 2 diabetes over the last years. By mimicking the effects of the native GLP-1, it enhances the glucose-dependent secretion of insulin, suppresses elevated glucagon secretion, increases satiety and slows down gastric emptying. Because of its ways of action it is not likely to cause hypoglycaemia in cases of overdosage. We present a 45-fold overdose of liraglutide (confirmed by P-liraglutide measurements) leading to nausea and vomiting, but no hypoglycaemia and no sign of pancreatitis.

Topics: Adult; Blood Glucose; Drug Overdose; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Liraglutide; Male; Nausea; Vomiting

Topics: Adult; Antigens, CD; Diabetes Mellitus, Type 1; Endoglin; Female; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemia; Male; Matrix Metalloproteinase 14; Receptors, Cell Surface; Young Adult

The relationship between genetic polymorphisms of the glucagon-like peptide-1 (GLP-1) receptor (GLP1R) gene and unresponsiveness to GLP-1 analogue treatment in patients with poorly controlled type 2 diabetes mellitus (DM) is unclear.. Thirty-six patients with poorly controlled type 2 DM were enrolled and they received six days of continuous subcutaneous insulin infusion for this study. After the normalization of blood glucose in the first 3 days, the patients then received a combination therapy with injections of the GLP-1 analogue, exenatide, for another 3 days. All 13 exons and intron-exon boundaries of the GLP1R gene were amplified to investigate the association.. The short tandem repeat at 8GA/7GA (rs5875654) had complete linkage disequilibrium (LD, with r2 = 1) with single nucleotide polymorphism (SNP) rs761386. Quantitative trait loci analysis of GLP1R gene variation with clinical response of GLP1 analogue showed the missense rs3765467 and rs761386 significantly associated with changes in the standard deviation of plasma glucose (SDPG(baseline) - SDPG(treatment with GLP-1 analogue)) (P = 0.041 and 0.019, resp.). The reported P values became insignificant after multiple testing adjustments.. The variable response to the GLP-1 analogue was not statistically correlated with polymorphisms of the GLP1R gene in patients with poorly controlled type 2 DM.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Female; Genotype; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Hospitalization; Humans; Hypoglycemia; Infusions, Subcutaneous; Insulin; Linkage Disequilibrium; Male; Microsatellite Repeats; Middle Aged; Mutation, Missense; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Sequence Analysis, DNA

Due to the progressive nature of type 2 diabetes (T2D), the majority of patients require increasing levels of therapy to achieve and maintain good glycemic control. At present, once patients become uncontrolled on oral antidiabetic therapies, the two primary treatment options are glucagon-like peptide-1 receptor agonists (GLP-1RAs) or basal insulin, although earlier use of GLP-1RAs has also been advocated. While both of these drug classes have proven efficacy in treating T2D, there can be limitations to their use in some patients, and resistance to further treatment intensification among both patients and physicians. More recently, treatment incorporating both a GLP-1RA and a basal insulin has been used successfully in the clinic and the first such combination product, IDegLira (insulin degludec+liraglutide), has recently been approved for use in Europe. IDegLira combines insulin degludec and the GLP-1RA liraglutide in a single injection. In both insulin-naïve and basal insulin-treated individuals with T2D, IDegLira has demonstrated greater reductions in glycated hemoglobin (HbA1c) than either of the individual components, with a low rate of hypoglycemia and weight loss. IDegLira may provide a new option for patients requiring treatment intensification but for whom increased weight or a higher risk of hypoglycemia are barriers. This article discusses the rationale behind combining these two drug classes and reviews the available clinical evidence for the efficacy and safety of IDegLira.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Drug Combinations; Europe; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Insulin; Insulin, Long-Acting; Liraglutide; Treatment Outcome; Weight Gain

Bariatric operations in obese patients with type 2 diabetes often improve diabetes before weight loss is observed. In patients mainly Roux-en-Y-gastric bypass with partial stomach resection is performed. Duodenojejunal bypass (DJB) and ileal interposition (IIP) are employed in animal experiments. Due to increased glucose exposition of L-cells located in distal ileum, all bariatric surgery procedures lead to higher secretion of antidiabetic glucagon like peptide-1 (GLP-1) after glucose gavage. After DJB also downregulation of Na(+)-d-glucose cotransporter SGLT1 was observed. This suggested a direct contribution of decreased glucose absorption to the antidiabetic effect of bariatric surgery. To investigate whether glucose absorption is also decreased after IIP, we induced diabetes with decreased glucose tolerance and insulin sensitivity in male rats and investigated effects of IIP on diabetes and SGLT1. After IIP, we observed weight-independent improvement of glucose tolerance, increased insulin sensitivity, and increased plasma GLP-1 after glucose gavage. The interposed ileum was increased in diameter and showed increased length of villi, hyperplasia of the epithelial layer, and increased number of L-cells. The amount of SGLT1-mediated glucose uptake in interposed ileum was increased 2-fold reaching the same level as in jejunum. Thus, improvement of glycemic control by bariatric surgery does not require decreased glucose absorption.

Topics: Animals; Bariatric Surgery; Blood Glucose; Diabetes Mellitus, Type 2; Enteroendocrine Cells; Glucagon-Like Peptide 1; Glucose; Hyperglycemia; Hyperplasia; Hypoglycemia; Ileum; Insulin Resistance; Intestinal Absorption; Male; Microvilli; Obesity; Rats, Inbred Lew; Sodium-Glucose Transporter 1; Specific Pathogen-Free Organisms

The aim of this study was to investigate whether the efficacy of liraglutide observed in randomized controlled trials translates into therapeutic benefits in the French population during routine clinical practice.. This observational, prospective, multicenter study included 3152 adults with type 2 diabetes who had recently started or were about to start liraglutide treatment. During 2 years of follow-up, an evaluation of the reasons for prescribing liraglutide, maintenance dose of liraglutide, changes in combined antidiabetic treatments, level of glycemic control, change in body weight and body mass index (BMI), patient satisfaction with diabetes treatment and safety of liraglutide were investigated. The primary study endpoint was the proportion of patients still receiving liraglutide and presenting with HbA1c <7.0% after 2 years of follow-up.. At the end of the study, 29.5% of patients maintained liraglutide treatment and reached the HbA(1c) target. Mean (±SD) HbA(1c), fasting plasma glucose concentration, body weight and BMI were significantly reduced from baseline [8.46% (±1.46) to 7.44% (±1.20); 180 (±60) to 146 (±44) mg/dL; 95.2 (±20.0) to 91.1 (±19.6) kg; 34.0 (±7.2) to 32.5 (±6.9) kg/m(2); respectively, all P < 0.0001]. Patient treatment satisfaction increased, with the mean diabetes treatment satisfaction questionnaire status version score increasing from 22.17 (±7.64) to 28.55 (±5.79), P < 0.0001. The main adverse event type was gastrointestinal, with a frequency of 10.9%, and the percentage of patients suffering ≥1 hypoglycemic episode decreased from 6.9% to 4.4%.. The results of the EVIDENCE study suggest that the effectiveness of liraglutide in real-world clinical practice is similar to that observed in randomized controlled trials.. Novo Nordisk A/S.. ClinicalTrials.gov identifier, NCT01226966.

Topics: Aged; Blood Glucose; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Liraglutide; Male; Medication Adherence; Middle Aged; Product Surveillance, Postmarketing; Prospective Studies

Idiopathic reactive hypoglycemia (IRH) is characterized by recurrent episodes of symptomatic hypoglycemia occurring within 4 hours after meals. The underlying mechanisms remain obscure.. This study aimed to investigate the response of the glucoregulatory and gastrointestinal hormones to an oral glucose load (OGTT) in individuals with documented IRH.. This was a cross-sectional study composed of outpatients referred to "Federico II" University of Naples.. We enrolled subjects with IRH documented by a mixed meal under ordinary life conditions and healthy subjects as controls.. We measured plasma glucose, insulin, glucagon-like peptide 1 (GLP-1), GIP, and glucagon response to a 75-g OGTT in cases and controls.. Ten IRH and eight control subjects were enrolled. During the OGTT, mean plasma glucose tended to be lower in IRH than in control subjects, reaching a statistically significant difference at 240 minutes (T240) (43 ± 1.6 vs 72 ± 0.3 mg/dL; P = .001). Accordingly, the insulin response was higher in IRH than in control subjects (P < .019) with a statistically significant difference (46%) at T90 (P = .045) and was associated with significantly lower glucagon levels in the late phase of the OGTT: at T120 (P = .031) and T180 (P = .048) in IRH than in control subjects. A greater GLP-1 response was found among IRH compared with control subjects (P = .005); GLP-1 peak was 2-fold higher in IRH individuals (9.77 ± 2.52 pmol/L) than in the control group (4.19 ± 0.53 pmol/L; P = .041). In the IRH group, GLP-1 peak inversely correlated with the nadir of plasma glucose (r = -0.66; P = .039). A multivariate analysis confirmed that GLP-1 peak independently predicted the plasma glucose nadir (β = -0.593; P = .026).. GLP-1 may play a significant role in the pathogenesis of idiopathic IRH.

Topics: Adult; Blood Glucose; Cross-Sectional Studies; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Hypoglycemia; Insulin; Male; Pilot Projects

Postprandial glycemia excursions increase after gastric bypass surgery; this effect is even greater among patients with recurrent hypoglycemia. These patients also have increased postprandial levels of insulin and glucagon-like peptide 1 (GLP-1). We performed a clinical trial to determine the role of GLP-1 in postprandial glycemia in patients with hyperinsulinemic hypoglycemia syndrome after gastric bypass.. Nine patients with recurrent hypoglycemia after gastric bypass (H-GB), 7 patients who were asymptomatic after gastric bypass (A-GB), and 8 healthy control subjects underwent a mixed-meal tolerance test (350 kcal) using a dual glucose tracer method on 2 separate days. On 1 day they received continuous infusion of the GLP-1 receptor antagonist exendin (9-39) (Ex-9), and on the other day they received a saline control. Glucose kinetics and islet and gut hormone responses were measured before and after the meal.. Infusion of Ex-9 corrected hypoglycemia in all patients with H-GB. The reduction in postprandial insulin secretion by Ex-9 was greater in the H-GB group than in the other groups (H-GB, 50% ± 8%; A-GB, 13% ± 10%; controls, 14% ± 10%) (P < .05). The meal-derived glucose appearance was significantly greater in subjects who had undergone gastric bypass compared to the controls and in the H-GB group compared to the A-GB group. Ex-9 shortened the time to reach peak meal-derived glucose appearance in all groups without a significant effect on overall glucose flux. Postprandial glucagon levels were higher among patients who had undergone gastric bypass than controls and increased with administration of Ex-9.. Hypoglycemia after gastric bypass can be corrected by administration of a GLP-1 receptor antagonist, which might be used to treat this disorder. These findings are consistent with reports that increased GLP-1 activity contributes to hypoglycemia after gastric bypass. ClinicalTrials.gov, Number: NCT01803451.

Topics: Adult; Blood Glucose; Case-Control Studies; Female; Gastric Bypass; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Secreting Cells; Humans; Hypoglycemia; Insulin; Insulin-Secreting Cells; Male; Middle Aged; Peptide Fragments; Receptors, Glucagon; Treatment Outcome

The impact of the hepatic branch of the vagus and Roux-en-Y gastric bypass (RYGB) on the hypoglycemic effect and glucagon-like peptide-1 (GLP-1) in rats with type 2 diabetes mellitus (T2DM) was investigated, and interactions were preliminarily analyzed.. A total of 45 rats with T2DM were divided into four groups: sham operation (S, n = 10), sham operation with the hepatic branch of the vagus resected (SV, n = 11), RYGB (n = 12), and RYGB without preservation of the vagus (RYGBV, n = 12). Body mass, fasting blood glucose (FBG), fasting serum insulin, and concentrations of fasting serum GLP-1 were examined in the first, second, fourth, and eighth week before and after surgery. The effects of RYGB and the hepatic branch of the vagus on GLP-1 levels in the eighth postoperative week were also analyzed.. RYGB caused a significant reduction in the weight of rats with T2DM (P < 0.05), improved the levels of serum GLP-1 and insulin (P < 0.05), and decreased FBG level (P < 0.05). Retention of the hepatic branch of the vagus maintained weight reduction for a longer period (P < 0.05) and increased the levels of serum GLP-1 and insulin (P < 0.05), but had no impact on FBG level (P > 0.05).. RYGB had better therapeutic efficacy in rats with T2DM. Care should be taken during RYGB surgery to preserve the hepatic branch of the vagus.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Gastric Bypass; Glucagon-Like Peptide 1; Hypoglycemia; Insulin; Liver; Male; Obesity; Postoperative Period; Rats, Sprague-Dawley; Vagotomy; Vagus Nerve; Weight Loss

Topics: Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Insulin; Insulinoma; Liraglutide; Middle Aged; Pancreatic Neoplasms; Receptors, Glucagon; Severity of Illness Index

Hemorrhagic shock (HS) may contribute to organ failure, by profoundly altering mitochondrial function. Resveratrol (RSV), a naturally occurring polyphenol, has been shown to promote mitochondrial function and regulate glucose homeostasis in diabetes. We hypothesized that RSV during resuscitation would ameliorate HS-induced mitochondrial dysfunction and improve hyperglycemia following acute blood loss.. With the use a decompensated HS model, male Long-Evans rats (n = 6 per group) were resuscitated with lactated Ringer's solution with or without RSV (30 mg/kg) and were killed before hemorrhage (sham), at severe shock, following resuscitation, and 18 hours after resuscitation. At each time point, the liver and kidney mitochondria were isolated to assess individual respiratory complexes (CI, CII, and CIV) and the production of reactive oxygen species (ROS). Blood samples were assayed for glucose, insulin, corticosterone, total glucagon-like peptide (GLP-1), glucagon, and serum cytokine levels. The Homeostatic Model Assessment-Insulin Resistance index was used to quantify insulin resistance.. RSV supplementation following HS significantly improved mitochondrial function and decreased mitochondrial ROS production in both liver and kidney. RSV-treated animals had significantly lower blood glucose levels following resuscitation when compared with sham animals (116.0 ± 20.2 mg/dL vs. 227.7 ± 8.3 mg/dL, p < 0.05) or those resuscitated with lactated Ringer's solution (116.0 ± 20.2 mg/dL vs. 359.0 ± 79.5 mg/dL, p < 0.05). RSV supplementation was associated with significantly decreased plasma insulin levels (1.0 ± 0.4 ng/mL vs. 6.5 ± 3.7 ng/mL, p < 0.05), increased total GLP-1 levels (385.8 ± 56.6 ng/mL vs. 187.3 ± 11.1 ng/mL, p < 0.05), and a lower natural Log Homeostatic Model Assessment-Insulin Resistance index (1.30 ± 0.42 vs. 4.18 ± 0.68, p < 0.05) but had minimal effect on plasma corticosterone, glucagon, or cytokine levels.. Resuscitation with RSV restores mitochondrial function and decreases insulin resistance but may be associated with increased hypoglycemia. The observed antiglycemic effects of RSV may be mediated by decreased mitochondrial ROS and increased GLP-1 secretion.

Topics: Animals; Blood Glucose; Corticosterone; Glucagon; Glucagon-Like Peptide 1; Hypoglycemia; Insulin; Insulin Resistance; Kidney; Male; Mitochondria; Mitochondria, Liver; Rats, Long-Evans; Reactive Oxygen Species; Resuscitation; Resveratrol; Shock, Hemorrhagic; Stilbenes

Real-world data on emerging combination approaches for type 2 diabetes mellitus (T2DM) management are limited. The objective of the current study was to document the characteristics and clinical outcomes of patients with T2DM initiating prandial insulin or a glucagon-like peptide-1 (GLP-1) receptor agonist while on basal insulin.. This was a retrospective analysis of an electronic medical records database of patients with T2DM managed in a community practice setting in the United States. The main outcome measures were glycated hemoglobin (HbA1c), body weight, hypoglycemia, and health care resource utilization at baseline and at 6-month and 1-year follow-up.. A total of 33 810 patients were included in the study: 31 848 on prandial insulin and 1962 on a GLP-1 receptor agonist. At baseline there were significant differences in mean age (60 vs 56 years), mean Charlson Comorbidity Index score (1.1 vs 0.7), mean HbA1c (8.8% vs 8.4%), and mean body weight (99 vs 112 kg) between the prandial insulin and GLP-1 receptor agonist groups, respectively (P < 0.001 for each). After matching for baseline differences, significant and similar changes from baseline were observed between the prandial insulin and the GLP-1 receptor agonist groups during follow-up at the 6 months/1 year post-index date for HbA1c (-0.45/-0.60% vs -0.44/-0.58%, respectively; P = 0.907/0.723 between groups). Body weight changes between the groups were significantly different at 6 months/1 year (+1.7/-1.7 vs -0.9/-3.7 kg; P < 0.001). Hypoglycemia incidence and health care resource utilization were significantly greater in the prandial insulin versus GLP-1 receptor agonist group.. The results of this real-world analysis of patients with T2DM adding a GLP-1 receptor agonist or prandial insulin to basal insulin suggest an association between adding a GLP-1 receptor agonist with similar glycemic control, greater reduction in body weight, lower hypoglycemia incidence, and lower health care utilization compared with adding prandial insulin.

Topics: Aged; Community Health Services; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Endocrinology; Family Practice; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Male; Middle Aged; Retrospective Studies; United States; Weight Gain

Severe hypoglycemia is a rare and challenging complication of Roux-en-Y gastric bypass (RYGB), which is characterized by hypersecretion of insulin and incretin hormones in the postprandial state.. The objective of the study was to determine the clinical and hormonal responses to a mixed-meal challenge after the reversal of RYGB in 2 patients with post-RYGB hypoglycemia. We hypothesized that the reversal of RYGB would lead to clinical improvement in hypoglycemia through the attenuation of incretin hormone secretion. DESIGN/SETTING/SUBJECTS/OUTCOME MEASURES: Two patients with post-RYGB hypoglycemia underwent a standardized meal tolerance test prior to and 8 and 18 months after RYGB reversal, respectively, with the measurement of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), insulin, and glucose levels. Gastric bypass was reversed by reattaching the small gastric pouch to the bypassed distal stomach and resecting the Roux limb to restore the normal flow of food bolus.. Both subjects showed persistent evidence of hypoglycemia with marked hyperinsulinemia after the RYGB reversal. GLP-1 levels after the RYGB reversal decreased by 76% and 70%, respectively, from their prereversal levels and to the level of nonhypoglycemic post-RYGB controls. In contrast, GIP levels after the RYGB reversal increased by 3-10 times the level before the reversal and 8-26 times that of the nonhypoglycemic post-RYGB controls.. Reversal of RYGB did not alleviate hyperinsulinemic hypoglycemia upon a mixed-meal challenge in our patients, thus suggesting its limited clinical benefit as treatment of post-RYGB hypoglycemia. The marked increase in GIP levels and concurrent decrease in GLP-1 levels in our patients suggest a possible role of GIP in persistent hyperinsulinemic hypoglycemia after the reversal of RYGB.

Topics: Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Insulin; Insulin Secretion; Meals; Middle Aged; Postoperative Complications; Postprandial Period; Reoperation; Severity of Illness Index; Treatment Outcome

The number of morbidly obese subjects submitted to bariatric surgery is rising worldwide. In a fraction of patients undergoing gastric bypass (GBP), episodes with late postprandial hypoglycemia (PPHG) develop 1-3 years after surgery. The pathogenesis of this phenomenon is not fully understood; meal-induced rapid and exaggerated increases of circulating incretins and insulin appear to be at least partially responsible. Current treatments include low-carbohydrate diets, inhibition of glucose intestinal uptake, reduction of insulin secretion with calcium channel blockers, somatostatin analogs, or diazoxide, a KATP channel opener. Even partial pancreatectomy has been advocated. In type 2 diabetes, GLP1 analogs have a well-documented effect of stabilizing glucose levels without causing hypoglycemia.. We explored GLP1 analogs as open treatment in five consecutive GBP cases seeking medical attention because of late postprandial hypoglycemic symptoms.. Glucose measured in connection with the episodes in four of the cases had been 2.7, 2.5, 1.8, and 1.6 mmol/l respectively. The patients consistently described that the analogs eliminated their symptoms, which relapsed in four of the five patients when treatment was reduced/discontinued. The drug effect was further documented in one case by repeated 24-h continuous glucose measurements.. These open, uncontrolled observations suggest that GLP1 analogs might provide a new treatment option in patients with problems of late PPHG.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Incretins; Male; Middle Aged; Obesity, Morbid; Postprandial Period; Treatment Outcome

Topics: Automobile Driving; Blood Glucose; Device Approval; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Licensure; Liraglutide; Male; Middle Aged; Peptides; United Kingdom; Venoms

To evaluate the effects of adding glucagon-like peptide-1 (GLP-1) analogue therapy to insulin on glycated hemoglobin (HbA1c), weight, insulin dosage, treatment satisfaction, and risk of hypoglycaemia.. Type 2 diabetes patients with insulin therapy receiving a GLP-1 analogue at 4 Swedish centers were studied. Hypoglycemia was evaluated using glucometers and patient self-report. The Diabetes Treatment Satisfaction Questionnaire (DTSQ) was used to evaluate treatment satisfaction.. Among 65 patients studied, 4 discontinued therapy, none due to hypoglycemia, and there were no suspected severe adverse events. Among 61 patients who remained on therapy over a mean of 7.0 months, 40 were treated with liraglutide and 21 with exenatide. HbA1c decreased from a mean of 8.9% (82.4 mmol/mol) to 7.9% (71.9 mmol/mol) (p<0.001), weight decreased from 111.1 kg to 104.0 kg (p<0.001) and insulin doses were reduced from 91.1U to 52.2U (p<0.001). There was one patient with severe hypoglycemia. The mean number of asymptomatic hypoglycemia per patient and month, reported for the last month (0.085 below 4.0 mmol/l and 0 below 3.0 mmol/l) and documented symptomatic hypoglycemia (0.24 below 4.0 mmol/l and 0.068 below 3.0 mmol/l) was low. The DTSQc showed higher treatment satisfaction than with the previous regimen of 11.9 (scale -18 to +18 points, p<0.001).. The addition of GLP-1 analogues to insulin in patients with type 2 diabetes is associated with reductions in HbA1c, weight, and insulin dose, along with a low risk of hypoglycemia and high treatment satisfaction.

Topics: Aged; Body Weight; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Patient Satisfaction; Risk Factors; Surveys and Questionnaires; Sweden

Postprandial hypoglycaemia is a severe complication of Roux-en-Y gastric bypass (RYGBP). Acarbose, an α-glucosidase inhibitor (AGI), is employed in its treatment. Several studies have shown that AGIs increase the postprandial levels of glucagon-like peptide 1 (GLP-1). However, an excessive level of GLP-1 is one of the factors involved in the physiopathology of this condition. We analysed the effect of acarbose oral administration in eight RYBGP patients with clinically significant hypoglycaemia or dumping syndrome.. Glucose, insulin and GLP-1 plasma levels in fasting and after ingestion of a standard meal (Ensure Plus®; 13 g protein, 50 g carbohydrate, 11 g fat) were measured. The test was repeated the following week with the oral administration of 100 mg of acarbose 15 min prior to the meal.. Five patients developed asymptomatic hypoglycaemia during the test (glucose level <50 mg/dl) with inappropriately high insulin levels and exaggerated GLP-1 response. Acarbose ingestion avoided hypoglycaemia in all of the patients and increased the lowest plasma glucose level (46.4 ± 4.8 vs. 59.0 ± 2.6 mg/dl, p < 0.01). Acarbose ingestion decreased the area under the curve for serum insulin and GLP-1 levels at 15 min after the meal.. Acarbose avoided postprandial hypoglycaemia following RYGBP by decreasing the hyperinsulinemic response. This was associated with a decrease in early GLP-1 secretion, in contrast to that observed in non-surgical subjects. This finding could be explained by the reduction of glucose load in the jejunum produced by the α-glucosidase inhibition, which is the main stimulus for GLP-1 secretion.

Topics: Acarbose; Administration, Oral; Adult; Blood Glucose; Diabetes Mellitus; Dumping Syndrome; Female; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Insulin; Male; Obesity, Morbid; Postprandial Period; Treatment Outcome

Topics: Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Liraglutide; Male; Obesity; Prevalence

The incretin effect, reflecting the enhancement of postprandial insulin secretion by factors including the intestinal hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide, increases in proportion to meal size. However, it is unknown whether the incretin effect is dependent on ambient glucose. The goal of this study was to determine the effect of plasma glycemia on the incretin effect. Thirteen healthy subjects consumed 50 g oral glucose solution mixed with d-xylose during fixed hyperglycemia at 8 and 10.5 mmol/L, on 3 separate days, twice at lower glycemia (LOW) and once at higher values (HIGH). The relative increase in insulin release after glucose ingestion at fixed hyperglycemia, a surrogate for the incretin effect, was similar among all three studies. The GLP-1 response to oral glucose was significantly lower at higher plasma glycemia, as was the appearance of d-xylose after the meal. Between the two LOW studies, the reproducibility of insulin release in response to intravenous glucose alone and intravenous plus ingested glucose was similar. These findings indicate that the incretin contribution to postprandial insulin release is independent of glycemia in healthy individuals, despite differences in GLP-1 secretion. The incretin effect is a reproducible trait among humans with normal glucose tolerance.

Topics: Administration, Oral; Adult; Blood Glucose; Cohort Studies; Female; Gastrointestinal Tract; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Humans; Hyperglycemia; Hypoglycemia; Incretins; Infusions, Intravenous; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged; Postprandial Period; Young Adult

Glucagon-like peptide-1 (GLP-1) is a gut peptide that promotes insulin release from pancreatic β-cells and stimulates β-cell hyperplasia. GLP-1 secretion causing hypoglycemia has been described once from an ovarian neuroendocrine tumor (NET) but has not been reported from a pancreatic NET (pNET).. A 56-yr-old male with a previous diagnosis of diabetes presented with fasting hypoglycemia and was found to have a metastatic pNET secreting glucagon. Neither the primary tumor nor metastases stained for insulin, whereas the resected normal pancreas showed histological evidence of islet cell hyperplasia. We provide evidence that GLP-1 secretion from the tumor was the cause of hyperinsulinemic hypoglycemia.. GLP-1 levels were determined in the patient, and immunohistochemistry for GLP-1 was performed on the tumor metastases. Ex vivo tissue culture and a bioassay constructed by transplantation of tumor into nude mice were performed to examine the tumor secretory products and their effects on islet cell function.. The patient had high levels of glucagon and GLP-1 with an exaggerated GLP-1 response to oral glucose. Immunohistochemistry and primary tissue culture demonstrated secretion of glucagon and GLP-1 from the tumor metastases, whereas insulin secretion was almost undetectable. Ex vivo coculture of the tumor with normal human islets resulted in inhibition of insulin release, and transplanted mice developed impaired glucose tolerance.. This is the first description of glucagon and GLP-1 secretion from a metastatic pNET causing sequential diabetes and hypoglycemia. Hypoglycemia was caused by insulin secretion from hyperplastic β-cells stimulated by tumor-derived GLP-1.

Topics: Adenoma, Islet Cell; Animals; Cells, Cultured; Diabetes Mellitus; Glucagon; Glucagon-Like Peptide 1; Hepatectomy; Humans; Hyperinsulinism; Hypoglycemia; Immunohistochemistry; Male; Mice; Mice, Nude; Middle Aged; Neuroendocrine Tumors; Pancreatectomy; Pancreatic Neoplasms; Real-Time Polymerase Chain Reaction; Splenectomy

Topics: Adult; Blood Glucose; Fasting; Female; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Ileum; Insulin; Insulin Secretion; Obesity, Morbid; Postgastrectomy Syndromes; Postprandial Period; Recurrence; Reoperation; Secretory Rate

Patients with insulin-treated type 2 diabetes and high insulin requirements are subject to undesirable treatment-related weight gain. These patients would potentially benefit from the insulin-sparing and weight loss benefits of glucagon-like peptide 1 (GLP-1) receptor agonist therapy; however, GLP-1 receptor agonists currently are not approved for use in combination with insulin. We examined the effects of adding liraglutide at a daily dose of 1.2 or 1.8 mg to an intensive regimen (either multiple daily injections or continuous subcutaneous insulin infusion) of U-500 insulin on hemoglobin A1c (HbA1c), total daily insulin dose, and weight in 15 patients with type 2 diabetes and high insulin requirements (initial mean daily insulin dose of 192 ± 77 units per day; initial mean weight, 300.9 ± 55.7 lbs) in a clinical practice setting.. In this observational case series, we identified 15 patients treated with a combination of U-500 insulin and liraglutide for at least 12 weeks at routine follow-up office visits. The U-500 insulin dose was reduced by 0-30% upon initiation of liraglutide. Insulin doses were subsequently adjusted to optimize glycemic control. Endpoints included change in HbA1c, change in total daily insulin dose, change in weight, and incidence of hypoglycemia. Comparisons of 12-week and baseline values were evaluated by paired two-tailed t tests.. At 12 weeks, the reduction in HbA1c from baseline (8.48%) was 1.4% (P = 0.0001). Weight fell by an average of 11.2 LB (5.1 KG) (P = 0.0001). Total daily insulin dose was reduced by 28% (P = 0.0001). No severe episodes of hypoglycemia occurred.. Adding liraglutide to U-500 insulin resulted in significant improvements in glycemic control, weight loss, and reduced insulin requirements in patients with type 2 diabetes and high insulin requirements.

Topics: Body Mass Index; Cohort Studies; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Liraglutide; Male; Medical Records; Middle Aged; Obesity; Receptors, Glucagon; Retrospective Studies; Severity of Illness Index; Weight Loss

Profound hypoglycemia occurs rarely as a late complication after Roux-en-Y gastric bypass (RYGB). We investigated the role of glucagon-like-peptide-1 (GLP-1) in four subjects who developed recurrent neuro-glycopenia 2 to 3 y after RYGB.. A standardized test meal (STM) was administered to all four subjects. A 2 h hyperglycemic clamp with GLP-1 infusion during the second hour was performed in one subject, before, during a 4 wk trial of octreotide (Oc), and after 85% distal pancreatectomy. After cessation of both glucose and GLP-1 infusion at the end of the 2 h clamp, blood glucose levels were monitored for 30 min. Responses were compared with a control group (five subjects 12 mo status post-RYGB without hypoglycemic symptoms).. During STM, both GLP-1 and insulin levels were elevated 3- to 4-fold in all subjects, and plasma glucose-dependent insulinotropic peptide (GIP) levels were elevated 2-fold. Insulin responses to hyperglycemia ± GLP-1 infusion in one subject were comparable to controls, but after cessation of glucose infusion, glucose levels fell to 40 mg/dL. During Oc, the GLP-1 and insulin responses to STM were reduced (>50%). During the clamp, insulin response to hyperglycemia alone was reduced, but remained unchanged during GLP-1. Glucagon levels during hyperglycemia alone were suppressed and further suppressed after the addition of GLP-1. With the substantial drop in glucose during the 30 min follow-up, glucagon levels failed to rise. Due to persistent symptoms, one subject underwent 85% distal pancreatectomy; postoperatively, the subject remained asymptomatic (blood glucose: 119-220 mg/dL), but a repeat STM showed persistence of elevated levels of GLP-1. Histologically enlarged islets, and β-cell clusters scattered throughout the acinar parenchyma were seen, as well as β-cells present within pancreatic duct epithelium. An increase in pancreatic and duodenal homeobox-1 protein (PDX-1) expression was observed in the subject compared with control pancreatic tissue.. A persistent exaggerated hypersecretion of GLP-1, which has been shown to be insulinotropic, insulinomimetic, and glucagonostatic, is the likely cause of post-RYGB hypoglycemia. The hypertrophy and ectopic location of β-cells is likely due to overexpression of the islet cell transcription factor, PDX-1, caused by prolonged hypersecretion of GLP-1.

Topics: Blood Glucose; Endocrine System; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Gastrointestinal Tract; Glucagon-Like Peptide 1; Glycogen; Homeodomain Proteins; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Middle Aged; Obesity; Pancreas; Trans-Activators

Managing elderly patients with type 2 diabetes poses particular challenges, so it is important to evaluate the efficacy and tolerability profile of antidiabetic therapies specifically in this patient population.. The aim of our study was to compare the efficacy and tolerability profile of liraglutide, a GLP-1 analog, in elderly (≥65 years) and younger (<65 years) patients with type 2 diabetes.. A pooled analysis of 6 randomized, placebo-controlled, multinational trials included data from 3967 patients aged18 to 80 years with type 2 diabetes and glycosylated hemoglobin (HbA(1c)) of 7% to 11%. Of these, 552 patients ≥65 years received liraglutide 1.8 mg, liraglutide 1.2 mg, or placebo; 2231 patients <65 years received liraglutide 1.8 mg, liraglutide 1.2 mg, or placebo for 26 weeks. End points were: change in HbA(1c), fasting plasma glucose, body weight, and blood pressure: as marked to identify elements tracked for change from baseline; hypoglycemic episodes; and adverse events.. Reduction in HbA(1c) from baseline was significantly greater with liraglutide 1.8 mg versus placebo (least squares mean difference: ≥65 years, 0.91% [95% CI, 0.69-1.12]; <65 years, 1.17% [95% CI, 1.06-1.28]; both, P < 0.0001) and with liraglutide 1.2 mg versus placebo (≥65 years, 0.87% [95% CI, 0.64-1.11]; <65 years, 1.10% [95% CI, 0.98-1.22]; both, P < 0.0001). For fasting plasma glucose, comparable results were observed between liraglutide 1.8 mg or 1.2 mg and placebo for both age groups (P < 0.0001). No statistically significant difference in body weight change was seen with liraglutide between the age groups. The proportion of patients reporting minor hypoglycemia was low and appeared comparable between the ≥65-year-old (4.3%-15.2%) and <65-year-old (8%-13.2%) groups. Likewise, adverse events appeared comparable in nature and frequency.. Liraglutide provides effective glycemic control and is well tolerated in patients ≥65 and <65 years of age with type 2 diabetes. These data suggest that liraglutide may be a suitable treatment option for older patients who may have additional age-related complications.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Blood Glucose; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Randomized Controlled Trials as Topic; Young Adult

The glucose-lowering effect of fat and protein is attenuated or absent in diabetic patients, which suggests that the same may occur in insulin-resistant subjects without diabetes.. The objective was to determine whether the postprandial metabolic responses elicited by fat and protein were influenced by the insulin sensitivity of the subjects and whether fat and protein modulate glucose responses through different mechanisms.. Healthy nondiabetic subjects aged 18-45 y took 50 g oral glucose with 0-30-g doses of canola oil and whey protein on 11 separate mornings after fasting overnight. The subjects were classified into 3 fasting serum insulin (FSI) groups: FSI < 40 pmol/L (n = 9), 40 < or = FSI < 70 pmol/L (n = 8), and FSI > or = 70 pmol/L (n = 8). The relative glycemic response was expressed as the incremental area under the curve (AUC) after each test meal divided by the mean AUC of the glucose control in each subject.. Protein significantly decreased glucose (P < 0.0001) and hepatic insulin extraction (P <0.0001) and increased insulin (P < 0.0001) and glucagon-like peptide 1 (P = 0.004); however, protein had no significant effect on C-peptide (P = 0.69) or on the insulin secretion rate (P = 0.13). No significant FSI x fat (P = 0.19) or FSI x protein (P = 0.08) interaction effects on glucose AUC were observed. In addition, the changes in relative glycemic response per gram of fat (r = -0.05, P = 0.82) or protein (r = -0.08, P = 0.70) were not related to FSI.. The hypoglycemic effect of fat and protein was not blunted by insulin resistance. Protein increased insulin but had no effect on C-peptide or the insulin secretion rate, which suggests decreased hepatic insulin extraction or increased C-peptide clearance.

Topics: Adult; Blood Glucose; Blood Pressure; Body Height; Body Mass Index; Body Weight; C-Peptide; Dietary Fats; Dietary Proteins; Ethnicity; Fasting; Fatty Acids, Monounsaturated; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Insulin; Liver; Male; Middle Aged; Milk Proteins; Racial Groups; Rapeseed Oil; Reference Values; Waist Circumference; Whey Proteins; Young Adult

A 61-year-old woman with fasting hypoglycemia following total gastrectomy was diagnosed as insulinoma. GIP and GLP-1 levels after a mixed meal were extremely increased. Administration of miglitol, an alpha-glucosidase inhibitor, suppressed the GIP and GLP-1 elevations.

Topics: 1-Deoxynojirimycin; Female; Gastrectomy; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemia; Insulinoma; Middle Aged; Pancreatic Neoplasms; Postprandial Period

Severe hypoglycemia after Roux-en-Y gastric bypass surgery (RYGB) is an increasingly recognized condition, characterized by neuroglycopenia and inappropriately elevated insulin concentrations that occur primarily in the postprandial state. Both pathophysiology and treatment of this disorder remain elusive, but it has been postulated that hyperplasia and/or hypertrophy of beta-cells due to morbid obesity and/or postsurgical nesidioblastosis may contribute.. The objective of this study was to elucidate the pathophysiology of this condition; specifically, we hypothesized that metabolic abnormalities were a function of altered nutrient transit through the gastrointestinal tract rather than anatomical changes to pancreatic beta-cells that would lead to consistently high insulin secretion irrespective of nutrient transit route. DESIGN/SETTING/SUBJECT/OUTCOME MEASURES: We describe a unique case wherein gastrostomy tube (GT) insertion into the remnant stomach reversed neuroglycopenic symptoms. This subject was admitted to a university hospital research center for standardized measurement of glucose, insulin, and incretin hormones including glucagon-like peptide-1, gastric-inhibitory peptide, and glucagon.. Standardized liquid meal administration via GT vs. oral route demonstrated complete reversal of severe metabolic abnormalities that included hypersecretion of insulin and GLP-1.. Post-RYGB hyperinsulinemia and hypoglycemia result entirely from altered nutrient delivery rather than generalized hyperfunction of beta-cells due to presurgical hypertrophy/hyperfunction or postsurgical nesidioblastosis. These findings support the use of GT for treatment of severe cases and have implications for surgical manipulations that may reverse/prevent this condition.

Topics: Adult; Blood Glucose; Body Mass Index; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Nutritional Status; Obesity, Morbid; Postoperative Complications

Topics: Acarbose; Aged, 80 and over; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents

The aim of the study was to determine whether reactive hypoglycaemia in pancreas transplant recipients that followed administration of glucagon-like peptide-1 (GLP-1) was associated with excessive insulin, insufficient glucagon, or both. Methodology involved six portally drained pancreas recipients who received GLP-1 (1.5 pmol/kg/min) or placebo infusion on randomized occasions during glucose-potentiated arginine testing. The second subject developed symptomatic hypoglycaemia [plasma glucose (PG) 42 mg/dl] 1 h after GLP-1 administration; subsequent subjects received intravenous glucose following GLP-1, but not placebo, infusion for PG levels <65 mg/dl. Following GLP-1 vs. placebo infusion, PG was lower (58 +/- 4 vs. 76 +/- 5 mg/dl; p < 0.05) despite administration of intravenous glucose. During hypoglycaemia, insulin levels and the insulin-to-glucagon ratio were greater after GLP-1 vs. placebo infusion (p < 0.05), while glucagon did not vary. It can be concluded from the study that GLP-1 can induce reactive hypoglycaemia in pancreas transplant recipients through excessive insulin secretion associated with an increased insulin-to-glucagon ratio.

Topics: Adult; Arginine; Diabetes Mellitus, Type 1; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Insulin-Secreting Cells; Male; Pancreas Transplantation

The overall safety profiles of GLP-1 agonists and DPP-4 inhibitors are favorable, with a low incidence of hypoglycemia. This attribute, along with their weight and cardiovascular benefits, particularly with the GLP-1 agonists, make them appropriate choices in our 3 patient cases. Ongoing safety investigations with GLP-1 agonists and DPP-4 inhibitors will provide further clarity to the complete safety profiles of these agents.

Topics: Adamantane; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Liraglutide; Male; Metformin; Middle Aged; Peptides; Pyrazines; Receptors, Glucagon; Risk; Sitagliptin Phosphate; Triazoles; Venoms; Weight Loss

Despite advances in the management of type 2 diabetes, glycaemic control remains suboptimal for many patients because of the complexities of disease progression and the need to balance improved glycaemic control against adverse treatment effects, particularly weight gain and hypoglycaemia. Thus, the development of new antidiabetes therapies continues in earnest. Incretin hormones have been the recent focus of research, as they account for up to 70% of the insulin response following a meal. There is also a high concordance between the physiological actions of one hormone, glucagon-like peptide-1 (GLP-1), and the therapeutic needs of patients. As native human GLP-1 has a half life of only approximately 2 min, researchers have developed molecules that act as GLP-1 receptor agonists or inhibit the enzyme responsible for GLP-1 degradation (dipeptidyl peptidase-4). Liraglutide, a human GLP-1 analogue sharing 97% of its amino acid sequence identity with native GLP-1, has been approved for use as monotherapy (not in Europe) and in combination with selected oral agents. In this supplement, we summarise key liraglutide data, offer practical insight into what we might expect of liraglutide in clinical use and examine selected case studies. For reasons of the safety and efficacy of GLP-1 receptor agonists, many thought leaders believe that these will become background therapy for majority of patients in the coming years. This supplement will serve as a resource from which readers can extract information concerning the potential benefits for patients who are overweight, losing pancreatic beta-cell function and drifting towards the ravaging effects of chronic hyperglycaemia.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Drug Approval; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Half-Life; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Liraglutide; Obesity; Receptors, Glucagon

To use time trade-off (TTO) to compare patient preferences for profiles of two glucagon-like peptide (GLP-1) products for the treatment of type 2 diabetes (liraglutide and exenatide) that vary on four key attributes - efficacy (as measured by hemoglobin A(1C)), incidence of nausea, incidence of hypoglycemia, and dosing frequency (QD vs. BID) - and measure the contribution of those attributes to preferences.. A total of 382 people with T2DM were recruited to participate in an internet-based survey consisting of a series of health-related questions, a conjoint exercise and a set of time trade-off items. In the conjoint exercise, respondents were presented with eight pairs of hypothetical GLP-1 profiles, and completed a time-tradeoff exercise for each pair.. The product profile representing liraglutide was preferred by 96% of respondents and resulted in significantly higher health utilities (0.038) than the product profile representing exenatide (0.978 vs. 0.94, p < 0.05). Estimated preference scores from the conjoint analysis revealed that efficacy measured by hemoglobin A(1C) is the most important attribute, followed by nausea, hypoglycemia, and dosing schedule.. On-line participants may not represent 'typical' type 2 diabetes patients, and brief product profiles represented results from clinical trials, not clinical practice. Based on the four attributes presented, patients prefer liraglutide over exenatide. Preference is based on superior efficacy and less nausea more than less hypoglycemia and once-daily dosing.

Topics: Adult; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Nausea; Patient Preference; Peptides; Quality of Life; Socioeconomic Factors; Venoms

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Liraglutide; Pyrazines; Randomized Controlled Trials as Topic; Sitagliptin Phosphate; Triazoles

Postprandial hypoglycemia (PPH) is a frequent complication of Nissen fundoplication in children. The mechanism responsible for the PPH is poorly understood, but involves an exaggerated insulin response to a meal and subsequent hypoglycemia. We hypothesize that increased glucagon-like peptide-1 (GLP-1) secretion contributes to the exaggerated insulin surge and plays a role in the pathophysiology of this disorder.. The aim of the study was to characterize glucose, insulin, and GLP-1 response to an oral glucose load in children with symptoms of PPH after Nissen fundoplication.. Ten patients with suspected PPH and a history of Nissen fundoplication and eight control subjects underwent a standard oral glucose tolerance test at The Children's Hospital of Philadelphia. Blood glucose (BG), insulin, and intact GLP-1 levels were obtained at various time points.. Children ages 4 months to 13 years old were studied.. Change scores for glucose, insulin, and intact GLP-1 were recorded after an oral glucose tolerance test.. All cases had hypoglycemia after the glucose load. Mean BG at nadir (+/- sd) was 46.7 +/- 11 mg/dl for cases (vs. 85.9 +/- 21.3 mg/dl; P < 0.0005). Mean change in BG from baseline to peak (+/- sd) was 179.3 +/- 87.4 mg/dl for cases (vs. 57.8 +/- 39.5 mg/dl; P = 0.003). Mean change in BG (+/- sd) from peak to nadir was 214.4 +/- 85.9 mg/dl for cases (vs. 55.9 +/- 41.1 mg/dl, P < 0.0005). Mean change in insulin (+/- sd) from baseline to peak was 224.3 +/- 313.7 microIU/ml for cases (vs. 35.5 +/- 22.2 microIU/ml; P = 0.012). Mean change in GLP-1 (+/- sd) from baseline to peak was 31.2 +/- 24 pm (vs. 6.2 +/- 9.5 pm; P = 0.014).. Children with PPH after Nissen fundoplication have abnormally exaggerated secretion of GLP-1, which may contribute to the exaggerated insulin surge and resultant hypoglycemia.

Topics: Adolescent; Blood Glucose; Child; Child, Preschool; Female; Fundoplication; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Hypoglycemia; Infant; Insulin; Male

Incretins such as glucagon-like peptide-1 (GLP-1) are gut-derived hormones that stimulate insulin secretion and suppress glucagon secretion, thus playing a key role in glucose homeostasis. While incretin mimetics and enhancers are approved for treatment of outpatients with diabetes, evidence is only starting to accumulate regarding the therapeutic potential of incretins in hospitalized patients. Small exploratory studies suggest that GLP-1 safely reduces hyperglycemia without causing hypoglycemia, a key advantage over insulin if efficacy is established in larger studies. Potential limitations include the need for a continuous infusion for delivery, attenuation but not normalization of glucose levels, increased deceleration of gastric emptying and nausea. The exact mechanism of action, dosing, adverse effects, patient subgroups that would be most suitable and safety of combination treatment with insulin remain to be studied. While promising, additional research is required studying effects on hard clinical endpoints.

Topics: Female; Glucagon; Glucagon-Like Peptide 1; Homeostasis; Humans; Hyperglycemia; Hypoglycemia; Incretins; Insulin; Intensive Care Units; Male; Outcome Assessment, Health Care

Topics: Animals; Diabetes Mellitus, Type 2; Gastric Bypass; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Insulin; Insulin Secretion; Insulin-Secreting Cells; Intestinal Mucosa; Obesity; Postoperative Complications

Hyperinsulinemic hypoglycemia is newly recognized as a rare but important complication after Roux-en-Y gastric bypass (GB). The etiology of the syndrome and metabolic characteristics remain incompletely understood. Recent studies suggest that levels of incretin hormones are increased after GB and may promote excessive beta-cell function and/or growth.. We performed a cross-sectional analysis of metabolic variables, in both the fasting state and after a liquid mixed-meal challenge, in four subject groups: 1) with clinically significant hypoglycemia [neuroglycopenia (NG)] after GB surgery, 2) with no symptoms of hypoglycemia at similar duration after GB surgery, 3) without GB similar to preoperative body mass index of the surgical cohorts, and 4) without GB similar to current body mass index of the surgical cohorts.. Insulin and C-peptide after the liquid mixed meal were both higher relative to the glucose level achieved in persons after GB with NG compared with asymptomatic individuals. Glucagon, glucagon-like peptide 1, and glucose-dependent insulinotropic peptide levels were higher in both post-GB surgical groups compared with both overweight and morbidly obese persons, and glucagon-like peptide 1 was markedly higher in the group with NG. Insulin resistance, assessed by homeostasis model assessment of insulin resistance, the composite insulin sensitivity index, or adiponectin, was similar in both post-GB groups. Dumping score was also higher in both GB groups but did not discriminate between asymptomatic and symptomatic patients. Notably, the frequency of asymptomatic hypoglycemia after a liquid mixed meal was high in post-GB patients.. A robust insulin secretory response was associated with postprandial hypoglycemia in patients after GB presenting with NG. Increased incretin levels may contribute to the increased insulin secretory response.

Topics: Adult; Aged; Blood Glucose; Body Mass Index; C-Peptide; Eating; Female; Food; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Incretins; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Obesity, Morbid; Postoperative Complications

Topics: C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin-Secreting Cells; Insulin, Long-Acting; Metformin; Peptides; Randomized Controlled Trials as Topic; Risk Factors; Time Factors; Venoms; Weight Gain; Weight Loss

(1) When type 2 diabetes is inadequately controlled with oral antidiabetic therapy, one option is to add subcutaneous insulin injections (or to accept less stringent glycaemic control). However, since the effects of adding insulin have only been evaluated in the short-term, effects on long-term clinical outcomes remain unknown. (2) Exenatide, a drug belonging to a new pharmacological class (incretin analogues), is marketed as a subcutaneously administered adjunct to inadequately effective oral antidiabetic therapy in adults with type 2 diabetes. (3) Three placebo-controlled trials lasting 7 months showed that adding exenatide to metformin and/or a glucose-lowering sulphonylurea yielded an HbA1c level of 7% or less in about 40% of patients treated with exenatide 10 micrograms twice a day, versus about 10% of patients on placebo. The potential impact of exenatide on morbidity and mortality is not known. (4) In two trials versus insulin glargine and in one trial versus insulin aspart (+ isophane insulin), exenatide was as effective as the various insulins in controlling HbA1c levels. (5) During clinical trials, patients receiving exenatide lost an average of about 2 kg after 6 months, while insulin was associated with a weight gain of about 2 kg. (6) There was a similar incidence of hypoglycaemia with exenatide and insulin. In patients treated with exenatide, concomitant use of glucose-lowering sulphonylurea increases the risk of hypoglycaemia. (7) More than half of patients on exenatide experienced nausea, versus fewer than 10% of patients on insulin glargine. (8) The long-term consequences of the presence of antiexenatide antibodies on the effectiveness of treatment are not known. (9) Exenatide is administered in two subcutaneous injections a day, at fixed doses. Insulin is administered in one or several injections a day, at doses adjusted to self-monitored blood glucose levels. (10) Adding insulin rather than exenatide is a better option in general when oral antidiabetic therapy fails in patients with type 2 diabetes, as we have more experience with insulin and there is no evidence of important advantages with exenatide. The latter should be reserved for situations in which weight gain is a major problem.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Metformin; Overweight; Peptides; Sulfonylurea Compounds; Venoms; Weight Gain; Weight Loss

Glucagon-like peptide 1 (GLP-1) lowers glycemia by modulating gastric emptying and endocrine pancreatic secretion. Rapidly after its secretion, GLP-1-(7-36) amide is degraded to the metabolite GLP-1-(9-36) amide. The effects of GLP-1-(9-36) amide in humans are less well characterized. Fourteen healthy volunteers were studied with intravenous infusion of GLP-1-(7-36) amide, GLP-1-(9-36) amide, or placebo over 390 min. After 30 min, a solid test meal was served, and gastric emptying was assessed. Blood was drawn for GLP-1 (total and intact), glucose, insulin, C-peptide, and glucagon measurements. Administration of GLP-1-(7-36) amide and GLP-1-(9-36) amide significantly raised total GLP-1 plasma levels. Plasma concentrations of intact GLP-1 increased to 21 +/- 5 pmol/l during the infusion of GLP-1-(7-36) amide but remained unchanged during GLP-1-(9-36) amide infusion [5 +/- 3 pmol/l; P < 0.001 vs. GLP-1-(7-36) amide administration]. GLP-1-(7-36) amide reduced fasting and postprandial glucose concentrations (P < 0.001) and delayed gastric emptying (P < 0.001). The GLP-1 metabolite had no influence on insulin or C-peptide concentrations. Glucagon levels were lowered by GLP-1-(7-36) amide but not by GLP-1-(9-36) amide. However, the postprandial rise in glycemia was reduced significantly (by approximately 6 mg/dl) by GLP-1-(9-36) amide (P < 0.05). In contrast, gastric emptying was completely unaffected by the GLP-1 metabolite. The GLP-1 metabolite lowers postprandial glycemia independently of changes in insulin and glucagon secretion or in the rate of gastric emptying. Most likely, this is because of direct effects on glucose disposal. However, the glucose-lowering potential of GLP-1-(9-36) amide appears to be small compared with that of intact GLP-1-(7-36) amide.

Topics: Adult; Blood Glucose; C-Peptide; Gastric Emptying; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Insulin; Lipid Metabolism; Male; Peptides; Time Factors

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Stimulation, Chemical; Weight Gain

Insulin resistance is present in the setting of congestive heart failure. Glucagon-like peptide-1 (GLP-1) is a naturally occurring incretin with both insulinotropic and insulinomimetic properties.. We investigated the safety and efficacy of a 5-week infusion of GLP-1 (2.5 pmol/kg/min) added to standard therapy in 12 patients with New York Heart Association class III/IV heart failure and compared the results with those of 9 patients with heart failure on standard therapy alone. Echocardiograms, maximum myocardial ventilation oxygen consumption (VO2 max), 6-minute walk test, and Minnesota Living with Heart Failure quality of life score (MNQOL) were assessed. Baseline demographics, background therapy, and the degree of left ventricular dysfunction were similar between groups. GLP-1 significantly improved left ventricular ejection fraction (21 +/- 3% to 27 +/- 3% P < .01), VO2 max (10.8 +/- .9 ml/O2/min/kg to 13.9 +/- .6 ml/O2/min/kg; P < .001), 6-minute walk distance (232 +/- 15 m to 286 +/- 12 m; P < .001) and MNQOL score (64 +/- 4 to 44 +/- 5; P < .01). Benefits were seen in both diabetic and non-diabetic patients. There were no significant changes in any of the parameters in the control patients on standard therapy. GLP-1 was well tolerated with minimal episodes of hypoglycemia and gastrointestinal side effects.. Chronic infusion of GLP-1 significantly improves left ventricular function, functional status, and quality of life in patients with severe heart failure.

Topics: Aged; Cardiac Output, Low; Chronic Disease; Diabetes Complications; Drug Administration Schedule; Female; Gastrointestinal Diseases; Glucagon-Like Peptide 1; Heart; Humans; Hypoglycemia; Injections, Subcutaneous; Male; Middle Aged; Pilot Projects; Quality of Life; Stroke Volume; Treatment Outcome; Ventricular Function, Left

Topics: Animals; Cell Proliferation; Comorbidity; Diabetes Mellitus, Type 2; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Hyperinsulinism; Hyperplasia; Hypertrophy; Hypoglycemia; Incidence; Insulin; Insulin Secretion; Insulin-Secreting Cells; Nesidioblastosis; Obesity, Morbid; Postoperative Complications; Rats

Topics: Adenosine Deaminase Inhibitors; Dipeptidyl Peptidase 4; Gastric Bypass; Glucagon; Glucagon-Like Peptide 1; Glycoproteins; Humans; Hyperinsulinism; Hyperplasia; Hypoglycemia; Islets of Langerhans; Nesidioblastosis; Obesity; Peptide Fragments; Postoperative Complications; Protein Precursors; Signal Transduction

The G protein G(s)alpha is essential for hormone-stimulated cAMP generation and is an important metabolic regulator. We investigated the role of liver G(s)-signaling pathways by developing mice with liver-specific G(s)alpha deficiency (LGsKO mice). LGsKO mice had increased liver weight and glycogen content and reduced adiposity, whereas survival, body weight, food intake, and metabolic rates at ambient temperature were unaffected. LGsKO mice had increased glucose tolerance with both increased glucose-stimulated insulin secretion and increased insulin sensitivity in liver and muscle. Fed LGsKO mice were hypoglycemic and hypoinsulinemic, with low expression of hepatic gluconeogenic enzymes and PPARgamma coactivator-1. However, LGsKO mice maintained normal fasting glucose and insulin levels, probably due to prolonged breakdown of glycogen stores and possibly increased extrahepatic gluconeogenesis. Lipid metabolism was unaffected in fed LGsKO mice, but fasted LGsKO mice had increased lipogenic and reduced lipid oxidation gene expression in liver and increased serum triglyceride and FFA levels. LGsKO mice had very high serum glucagon and glucagon-like peptide-1 levels and pancreatic alpha cell hyperplasia, probably secondary to hepatic glucagon resistance and/or chronic hypoglycemia. Our results define novel roles for hepatic G(s)-signaling pathways in glucose and lipid regulation, which may prove useful in designing new therapeutic targets for diabetes and obesity.

Topics: Adiposity; Animals; Eating; Fasting; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; GTP-Binding Protein alpha Subunits, Gs; Hypoglycemia; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Lipid Metabolism; Liver; Male; Mice; Mice, Knockout; Mice, Transgenic; Oxygen Consumption; Signal Transduction

Topics: Animals; Diabetes Mellitus, Type 2; Exenatide; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Hyperinsulinism; Hypoglycemia; Insulin-Secreting Cells; Nesidioblastosis; Peptides; Postoperative Complications; Venoms

Glucagon-like peptide 1 (GLP-1), an insulinotropic hormone normally synthesised in the intestinal mucosa and released in response to a meal, is essential for normal glucose homoeostasis. There is much interest in the use of GLP-1 to treat diabetes, since the risk of hypoglycaemia is thought to be low. We report an instance of a 45-year-old woman with a GLP-1 and somatostatin secreting neuroendocrine tumour who presented with reactive hypoglycaemia and hyperglycaemia, but who was subsequently cured by surgery. This case, of a neuroendocrine tumour secreting GLP-1 and causing reactive hypoglycaemia, indicates a potential adverse effect of GLP-1 therapy for diabetes.

Topics: Blood Glucose; Carcinoid Tumor; Diabetes Complications; Female; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Hypoglycemia; Hysterectomy; Middle Aged; Ovarian Neoplasms; Peptide Fragments; Protein Precursors; Somatostatin

It has previously been shown that intravenous and subcutaneous administration of glucagon-like peptide (GLP)-1 concomitant with intravenous glucose results in reactive hypoglycaemia in healthy subjects. Since GLP-1 is also effective in Type 2 diabetic patients and is presently being evaluated as a therapeutic agent in this disease, it is important to investigate whether GLP-1 can cause hypoglycaemia in such patients.. Eight Type 2 diabetic patients (age 54 (49-67) years; body mass index 31 (27-38) kg/m2; HbA1c 9.4 (7.0-12.5)%) and seven matched non-diabetic subjects (HbA1c 5.5 (5.2-5.8)%, fasting plasma glucose 5.4 (5.0-5.7) mmol/l) were given a subcutaneous injection of 1.5 nmol GLP-1/kg body weight (maximally tolerated dose), and 15 min later, plasma glucose (PG) was raised to 15 mmol/l with an intravenous glucose bolus.. Hypoglycaemia with a PG at or below 2.5 mmol/l was seen in five of the seven healthy subjects after 60-70 min, but PG spontaneously increased again, reaching 3.7 (3.3-4.0) mmol/l at 90 min. In the patients, PG fell slowly and stabilized at 8.6 (4.2-12.1) mmol/l after 80 min. In both groups, glucagon levels initially decreased, but later increased, exceeding basal levels in healthy subjects, in spite of persistent, high concentrations of GLP-1 (P < 0.02).. Subcutaneous GLP-1 plus intravenous glucose induced reactive hypoglycaemia in healthy subjects, but not in Type 2 diabetic patients. Therefore, a GLP-1-based therapy would not be expected to be associated with an increased risk of hypoglycaemia in Type 2 diabetes mellitus.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemia; Hypoglycemic Agents; Infusions, Intravenous; Injections, Subcutaneous; Insulin; Kinetics; Male; Middle Aged; Peptide Fragments; Protein Precursors; Reference Values

Methyl pyruvate (MP) stimulates insulin release both in vivo and in vitro. The present study aims at investigating whether MP is also able to enhance the B-cell secretory response to glucagon-like peptide 1 (GLP-1). In anaesthetized rats receiving a primed constant infusion of MP, the ester augmented plasma insulin concentration before GLP-1 injection and potentiated the insulinotropic action of the intestinal hormone. MP infusion also augmented plasma D-glucose concentration, whether in the absence or presence of GLP-1. A further rise in plasma D-glucose concentration was observed when the infusion of MP was halted, this coinciding with a fall in plasma insulin concentration. Whilst documenting that MP indeed enhances the B-cell secretory response to GLP-1, these findings do not suggest that MP is an appropriate tool for optimizing the hypoglycaemic action of the enteric hormone in the treatment of type-2 diabetes mellitus.

Topics: Animals; B-Lymphocytes; Blood Glucose; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Glucose; Hypoglycemia; Insulin; Male; Peptide Fragments; Protein Precursors; Pyruvates; Rats; Rats, Wistar; Time Factors

Rapid gastric emptying and exaggerated plasma concentrations of the insulinotropic hormone GLP-1 precede reactive hypoglycemia after oral glucose in gastrectomy patients. We suspected that the plasma volume drop associated with rapid gastric emptying (early dumping) would be accompanied by elevated plasma concentrations of norepinephrine. In order to study any relationship between postprandial norepinephrine, the enteroinsular axis, and plasma glucose, twelve patients with dumping syndrome and nine controls were studied. The plasma concentrations of norepinephrine, GLP-1, GIP, glucagon, insulin, and glucose were measured following a 1.5 g/kg lean body mass glucose meal. The early (0-30 min) integrated norepinephrine concentration was significantly higher in dumpers (22.1 +/- 3.8 nmol/ml/min) compared to controls (14.7 +/- 3.1 nmol/ml/min; P < 0.001) and correlated closely with the postprandial hematocrit increment (r = 0.71; P < 0.05). Early immunoreactivities of GLP-1, GIP, and glucagon peaked 30 min after glucose ingestion and were significantly higher in dumpers. Insulin peaked after 60 min and correlated with early GLP-1. In 11 of the patients glucose fell below baseline after a median interval of 120 min. Glucose at 120 min, when most of the nadirs occurred was lowest in patients with high early GLP-1 concentrations (r = 0.78; P < 0.001). Gel filtration chromatography of the dumpers' plasma revealed that pancreatic glucagon was detectable at time 0 and after 20 min, but not after 120 min. It is concluded that in dumpers pancreatic glucagon is augmented in the early postprandial period, probably through stimulation by catecholamines. At 120 min, when most of the hypoglycemias are encountered, pancreatic glucagon is no longer detectable, probably through inhibition by GLP-1.

Topics: Chromatography, Gel; Dumping Syndrome; Glucagon; Glucagon-Like Peptide 1; Hematocrit; Humans; Hypoglycemia; Middle Aged; Norepinephrine; Peptide Fragments; Postprandial Period; Protein Precursors

In plasma, glucagon-like peptide-1 7-36 amide (GLP-1) is rapidly degraded from the N terminus, generating the endogenous metabolite GLP-1 9-36 amide. This cleavage of GLP-1 eliminates its incretin effect, and the metabolite even may act as an antagonist. We have shown previously that GLP-1 strongly inhibited cephalic-induced antral motility in pigs. We decided, therefore, to examine the effect of GLP-1 9-36 amide, with and without GLP-1, on cephalic-induced motility in pigs. In one series of experiments, we studied the effect of three different doses of GLP-1 9-36 amide (2, 4, and 10 pmol/kg/min) on insulin-induced (hypoglycemia) antral motility in anaesthetized pigs (n = 9). In another series, we studied the effect of infusion of GLP-1 9-36 amide in two different doses (1 and 5 pmol/kg/min) in six pigs in which the antral motility was inhibited by GLP-1 7-36 amide in a dose of 2 pmol/kg/min. Plasma levels of intact GLP-1 7-36 amide and GLP-1 9-36 amide were determined using specific radioimmunoassays. Insulin-induced hypoglycemia increased the antral motility index from 0.4 +/- 0.1 to 8.3 +/- 3.5 (cm/min). The motility was constant throughout the experimental period and was absolutely unaffected by the infusion of GLP-1 9-36 amide at 10 pmol/kg/min, which resulted in a plasma concentration of 351 +/- 60 pmol/l. The inhibitory effect of GLP-1 7-36 amide on antral motility was reduced from 93 +/- 3% to 33 +/- 9% (p < 0.05) by concomitant infusion of GLP-1 9-36 amide in a dose of 5 pmol/kg/min. The metabolite GLP-1 9-36 amide has no effect on antral motility in pigs but is able to antagonize the inhibitory effect of GLP-1. Thus, an intact N terminus is essential for the gastrointestinal actions of GLP-1. Its primary metabolite may act as an endogenous antagonist.

Topics: Animals; Dose-Response Relationship, Drug; Gastrointestinal Hormones; Gastrointestinal Motility; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Hypoglycemia; Peptide Fragments; Peptides; Pyloric Antrum; Swine

Glucagon-like peptide-2 is formed from proglucagon in the intestinal L-cells and is secreted postprandially in parallel with the insulinotropic hormone GLP-1 (glucagon-like peptide-1), which in addition acts to inhibit gastric motility (enterogastrone effect) by inhibiting central parasympathetic outflow. GLP-2 has no effect on the endocrine pancreas. We here tested the hypothesis that GLP-2 acts as an enterogastrone.. Fourteen anesthetized pigs with their splanchnic nerves cut were subjected to insulin hypoglycemia, and force transducers were sutured to the antrum to record motility. GLP-2 was infused intravenously in doses from 1 to 6 pmol/kg/min after the onset of antral motility in response to hypoglycemia.. Insulin hypoglycemia invariably and greatly increased the frequency and amplitude of antral phasic contractions. Infusions of GLP-2 dose dependently (1-6 pmol/kg/min) inhibited antral motility. At 2 pmol/kg/min, resulting in plasma GLP-2 concentrations of 102.5+/-19 pmol/l (normal postprandial range, 30-82 pmol/l), the motility index was inhibited by 91%+/-14%.. Both of the intestinal glucagon-like peptides may operate as hormonal transmitters of the ileal brake effect.

Topics: Animals; Gastric Emptying; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Hypoglycemia; Peptides; Postprandial Period; Pyloric Antrum; Swine

The plasma concentrations of the insulinotropic incretin hormone, glucagon-like peptide-1 (GLP-1) are abnormally high after oral glucose in partially gastrectomised subjects with reactive hypoglycaemia, suggesting a causal relationship. Because of the glucose-dependency of its effects, it is impossible to induce hypoglycaemia in normal subjects in the basal state by exogenous GLP-1, regardless of dose. To further assess the role of the incretin hormones in reactive hypoglycaemia, we reproduced the glucose and hormone profiles of the patients with reactive hypoglycaemia in 8 healthy volunteers in 4 separate protocols: 1) i.v. infusion of glucose (25 g) alone, 2) glucose together with i.v. GLP-1 infusion, and 3) and 4) glucose together with i.v. infusion of the other incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), at two different infusion rates. The plasma glucose, GLP-1 and GIP concentrations (low dose) obtained were comparable with those of the patients. With GLP-1, infusion of a total of 33.4 +/- 1.3 g glucose was required to obtain plasma glucose concentrations similar to those obtained by glucose infusion alone; with low GIP, 28.0 +/- 1.2 g and with high GIP 38.4 +/- 3.5 g. Insulin concentrations increased 10-fold with GLP-1 compared with i.v. glucose alone, but less with high and low GIP. In contrast, C-peptide concentrations were similar after GLP-1 and high GIP. After termination of i.v. glucose the lowest glucose concentrations were 4.5 (3.7-4.9) (median, range) for glucose alone; 2.4 (1.9-2.8) mmol/l with GLP-1; 3.7 (2.6-4.0) with low GIP and 3.3 (2.1-4.2) with high GIP. Thus, the exaggerated GLP-1 response to nutrients in patients with accelerated gastric emptying could be responsible for their high incidence of postprandial reactive hypoglycaemia.

Topics: Adult; Blood Glucose; C-Peptide; Dumping Syndrome; Female; Gastrectomy; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemia; Kinetics; Male; Peptide Fragments; Protein Precursors

The mechanism(s) of an inappropriate secretion of insulin is poorly understood. We report a case of reactive hypoglycemia associated with an unusually exaggerated insulin secretion. The patient, a 32-year-old man, developed frequent episodes of postprandial hypoglycemia after interferon treatment was begun for chronic type C hepatitis. Oral glucose challenge test confirmed the patient's extremely high plasma IRI response, i.e., more than 1000 microU/ml, and that of plasma C-peptide 56.9 ng/ml at 90 min, followed by symptomatic hypoglycemia (plasma glucose 34 mg/dl) at 240 min. The plasma proinsulin level also was high, but the molar ratio of immuno reactive insulin (IRI)/plasma C-peptide and IRI/proinsulin was within the normal range. Antibodies to insulin or insulin-receptor were negative. Plasma IRI response was apparently greater when the glucose was given orally than when given intravenously. The response of plasma glucagon-like-peptide (GLP)-1 to oral glucose was quite high (from baseline of 45.5 to 303.2 pmol/L) and showed a close parallel with the change in the plasma IRI concentration. The greatly enhanced insulin secretion leading to reactive hypoglycemia in this patient may therefore be attributed to the increased secretion of GLP-1.

Topics: Adult; C-Peptide; Fasting; Food; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose Tolerance Test; Humans; Hypoglycemia; Insulin; Insulin Secretion; Male; Peptide Fragments; Proinsulin

Glucagon-like peptide-1 is a peptide hormone from the distal small intestine which stimulates insulin secretion and inhibits glucagon secretion and thereby lowers blood glucose. This hormone, therefore, could be involved in the pathogenesis of postprandial reactive hypoglycemia. We subjected 8 patients showing symptoms of early dumping after partial gastrectomy to an oral 100 g glucose load and measured blood glucose and plasma insulin, C-peptide, glucagon, enteroglucagon and GLP-1 concentrations for 3.5 h after ingestion. Ten matched controls were treated similarly. The patients had higher blood glucose concentrations for the initial 60 min, but lower values for the remaining test period with a nadir of 2.76 +/- 0.19 mmol/l at 146 +/- 17 min after glucose (controls: 3.36 +/- 0.21 mmol/l at 210 +/- 9 min). GLP-1 and enteroglucagon responses were grossly elevated in patients compared to controls and insulin and C-peptide levels were higher during the initial 60 min. Glucagon concentrations increased in patients and decreased in controls. When hypoglycemia occurred, GLP-1 levels were only moderately elevated and insulin and C-peptide levels were lower and glucagon levels higher in patients than in controls. Thus, mechanisms other than release of GLP-1 seem to be responsible for the observed changes in the concentrations of glucose and glucoregulatory hormones.

Topics: Administration, Oral; Adult; Blood Glucose; C-Peptide; Chromatography, Gel; Data Interpretation, Statistical; Female; Gastrectomy; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemia; Insulin; Insulin Secretion; Male; Middle Aged; Peptide Fragments; Protein Precursors; Radioimmunoassay

Postprandial glucagon-like peptide-1 (GLP-1), pancreatic glucagon, and insulin were measured in 27 tumor-free patients 43 months (median) after total gastrectomy and in four controls using a 99technetium-labeled 100-g carbohydrate solid test meal. Emptying of the gastric substitute was measured by scintigraphy. Fourteen patients suffered from early dumping symptoms, and five of them also reported symptoms suggestive of reactive hypoglycemia (late dumping). The median emptying half-time (T1/2) of the gastric substitute was 480 sec. Sigstad's dumping score was 8.5 +/- 1.6 (mean +/- SE) in patients with rapid emptying (T1/2 less than 480 sec), and 3.0 +/- 1.5 in patients with slow emptying of the gastric substitute (P = 0.02). The peak postprandial concentration of GLP-1 was 44 +/- 20 pmol/liter in controls, 172 +/- 50 in patients without reactive hypoglycemia, and 502 +/- 116 in patients whose glucose fell below 3.8 mmol/liter during the second postprandial hour. Plasma GLP-1 concentrations peaked at 15 min, and insulin concentrations at 30 min after the end of the meal. A close correlation between integrated GLP-1 responses and integrated insulin responses (r = 0.68) was observed. Multiple regression revealed that three factors were significantly associated with the integrated glucose concentrations during the second hour (60-120 min): Early (first 30 min) integrated GLP-1 (inverse correlation; P = 0.006), age (P = 0.006), and early integrated pancreatic glucagon (P = 0.005). There was a close (inverse) relationship of T1/2 with early integrated GLP-1 and pancreatic glucagon, but not with insulin. Gel filtration of pooled postprandial plasma of gastrectomized individuals revealed that all glucagon-like immunoreactivity eluted at Kd 0.30 (Kd, coefficient of distribution), the elution position of glicentin. Almost all of the GLP-1 like immunoreactivity eluted at Kd 0.60, the elution position of gut GLP-1. The authors contend that GLP-1-induced insulin release and inhibition of pancreatic glucagon both contribute to the reactive hypoglycemia encountered in some patients following gastric surgery. Rapid emptying seems to be one causative factor for the exaggerated GLP-1 release in these subjects.

Topics: Blood Glucose; Dumping Syndrome; Eating; Gastrectomy; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Hypoglycemia; Insulin; Peptide Fragments; Protein Precursors