glucagon-like-peptide-1 and Diabetes-Mellitus--Type-1

Insulin is a life-saving drug for patients with type 1 diabetes; however, even today, no pharmacotherapy can prevent the loss or dysfunction of pancreatic insulin-producing β cells to stop or reverse disease progression. Thus, pancreatic β cells have been a main focus for cell-replacement and regenerative therapies as a curative treatment for diabetes. In this Review, we highlight recent advances toward the development of diabetes therapies that target β cells to enhance proliferation, redifferentiation and protection from cell death and/or enable selective killing of senescent β cells. We describe currently available therapies and their mode of action, as well as insufficiencies of glucagon-like peptide 1 (GLP-1) and insulin therapies. We discuss and summarize data collected over the last decades that support the notion that pharmacological targeting of β cell insulin signalling might protect and/or regenerate β cells as an improved treatment of patients with diabetes.

Topics: Diabetes Mellitus, Type 1; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells

Type 2 Diabetes Mellitus (T2DM) is one of the most prevalent chronic metabolic disorders, and insulin has been placed at the epicentre of its pathophysiological basis. However, the involvement of impaired alpha (α) cell function has been recognized as playing an essential role in several diseases, since hyperglucagonemia has been evidenced in both Type 1 and T2DM. This phenomenon has been attributed to intra-islet defects, like modifications in pancreatic α cell mass or dysfunction in glucagon's secretion. Emerging evidence has shown that chronic hyperglycaemia provokes changes in the Langerhans' islets cytoarchitecture, including α cell hyperplasia, pancreatic beta (β) cell dedifferentiation into glucagon-positive producing cells, and loss of paracrine and endocrine regulation due to β cell mass loss. Other abnormalities like α cell insulin resistance, sensor machinery dysfunction, or paradoxical ATP-sensitive potassium channels (K

Topics: Animals; Autocrine Communication; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Humans; Hypoglycemic Agents; Insulin-Secreting Cells; Paracrine Communication

The aim of this study is to provide an overview of several emerging anti-diabetic molecules.. Diabetes is a complex metabolic disorder involving the dysregulation of glucose homeostasis at various levels. Insulin, which is produced by β-pancreatic cells, is a chief regulator of glucose metabolism, regulating its consumption within cells, which leads to energy generation or storage as glycogen. Abnormally low insulin secretion from β-cells, insulin insensitivity, and insulin tolerance lead to higher plasma glucose levels, resulting in metabolic complications. The last century has witnessed extraordinary efforts by the scientific community to develop anti-diabetic drugs, and these efforts have resulted in the discovery of exogenous insulin and various classes of oral anti-diabetic drugs.. Despite these exhaustive anti-diabetic pharmaceutical and therapeutic efforts, long-term glycemic control, hypoglycemic crisis, safety issues, large-scale economic burden and side effects remain the core problems.. The last decade has witnessed the development of various new classes of anti-diabetic drugs with different pharmacokinetic and pharmacodynamic profiles. Details of their FDA approvals and advantages/disadvantages are summarized in this review.. The salient features of insulin degludec, sodium-glucose co-transporter 2 inhibitors, glucokinase activators, fibroblast growth factor 21 receptor agonists, and GLP-1 agonists are discussed.. In the future, these new anti-diabetic drugs may have broad clinical applicability. Additional multicenter clinical studies on these new drugs should be conducted.

Topics: Animals; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Enzyme Activators; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin, Long-Acting; Receptors, Fibroblast Growth Factor

Antidiabetic therapeutics, including insulin as well as glucagon-like peptide 1 (GLP-1) and its analogs, are essential for people with diabetes to regulate their blood glucose levels. Nevertheless, conventional treatments based on hypodermic administration is commonly associated with poor blood glucose control, a lack of patient compliance, and a high risk of hypoglycemia. Closed-loop drug delivery strategies, also known as self-regulated administration, which can intelligently govern the drug release kinetics in response to the fluctuation in blood glucose levels, show tremendous promise in diabetes therapy. In the meantime, the advances in the development and use of microneedle (MN)-array patches for transdermal drug delivery offer an alternative method to conventional hypodermic administration. Hence, glucose-responsive MN-array patches for the treatment of diabetes have attracted increasing attentions in recent years. This review summarizes recent advances in glucose-responsive MN-array patch systems. Their opportunities and challenges for clinical translation are also discussed.

Topics: Animals; Blood Glucose; Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucose; Humans; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hypoglycemic Agents; Insulin Infusion Systems; Insulin-Secreting Cells; Kinetics; Needles; Transdermal Patch; Translational Research, Biomedical

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

Sotagliflozin is the first dual SGLT1/SGLT2 inhibitor developed for use in diabetes. Sotagliflozin blocks SGLT2 in the kidneys and SGLT1 in the intestines resulting in reduced early phase glucose absorption and increased blood levels of GLP-1 and PYY. Urinary glucose excretion is lower than with other agents as a result of decreased glucose absorption. The primary development effort to date has been in Type 1 diabetes. Areas covered: The published information on sotagliflozin is reviewed, along with the recent results of several pivotal Type 1 diabetes trials. Expert opinion: Sotagliflozin treatment lowers HbA1c and reduces glucose variability, with a trend to less hypoglycemic events. In the Type 1 trials, sotagliflozin treated individuals experienced DKA at a higher rate than placebo treated patients. An additional safety issue arises from the as yet unknown potential risks in women of child bearing potential in whom DKA is of utmost concern. The sotagliflozin development program has now been extended to trials in Type 2 diabetes, and long term studies will be needed to assess the benefits and risks of the agent in comparison to other currently marketed SGLT2 inhibitors.

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Glucagon-Like Peptide 1; Glycosides; Humans; Hypoglycemic Agents; Peptide YY; Sodium-Glucose Transporter 1; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Obesity is a major risk factor for type 2 diabetes and may complicate type 1 diabetes. In parallel with the global epidemic of obesity, the incidence of type 2 diabetes is increasing exponentially. To reverse these alarming trends, weight loss becomes a major therapeutic priority in prevention and treatment of type 2 diabetes. Given that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improve glycaemic control and cause weight loss, they are receiving increasing attention for the treatment of diabetes-obesity. This review discusses current and emerging therapeutic options with GLP-1 RAs and considers the next generation of novel peptide co-agonists with the potential for improved therapeutic outcomes in obesity and type 2 diabetes.

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Obesity; Peptides

Glucagon-like peptide-1 (GLP-1) released from gut enteroendocrine cells controls meal-related glycemic excursions through augmentation of insulin and inhibition of glucagon secretion. GLP-1 also inhibits gastric emptying and food intake, actions maximizing nutrient absorption while limiting weight gain. Here I review the circuits engaged by endogenous versus pharmacological GLP-1 action, highlighting key GLP-1 receptor (GLP-1R)-positive cell types and pathways transducing metabolic and non-glycemic GLP-1 signals. The role(s) of GLP-1 in the benefits and side effects associated with bariatric surgery are discussed and actions of GLP-1 controlling islet function, appetite, inflammation, and cardiovascular pathophysiology are highlighted. Refinement of the risk-versus-benefit profile of GLP-1-based therapies for the treatment of diabetes and obesity has stimulated development of orally bioavailable agonists, allosteric modulators, and unimolecular multi-agonists, all targeting the GLP-1R. This review highlights established and emerging concepts, unanswered questions, and future challenges for development and optimization of GLP-1R agonists in the treatment of metabolic disease.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Eating; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Insulin; Mice; Obesity; Rats; Weight Gain

In healthy individuals, the incretin hormone glucagon-like peptide 1 (GLP1) potentiates insulin release and suppresses glucagon secretion in response to the ingestion of nutrients. GLP1 also delays gastric emptying and increases satiety. In patients with type 2 diabetes mellitus (T2DM), supraphysiological doses of GLP1 normalize the endogenous insulin response during a hyperglycaemic clamp. Owing to the short plasma half-life of native GLP1, several GLP1 receptor agonists (GLP1RAs) with longer half-lives have been developed for the treatment of T2DM. These compounds vary in chemical structure, pharmacokinetics and size, which results in different clinical effects on hyperglycaemia and body weight loss; these variations might also explain the difference in cardiovascular effect observed in large-scale cardiovascular outcome trials, in which certain GLP1RAs were shown to have a positive effect on cardiovascular outcomes. Owing to their metabolic effects, GLP1RAs are also considered for the treatment of several other lifestyle-induced conditions, such as obesity, prediabetes and liver disease. This Review provides insights into the physiology of GLP1 and its involvement in the pathophysiology of T2DM and an overview of the currently available and emerging GLP1RAs. Furthermore, we review the results from the currently available large-scale cardiovascular outcome trials and the use of GLP1RAs for other indications.

Topics: Biomarkers; Blood Glucose; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Gastric Emptying; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin; Male; Reference Values; Treatment Outcome

Bone is a tissue with multiple functions that is built from the molecular to anatomical levels to resist and adapt to mechanical strains. Among all the factors that might control the bone organization, a role for several gut hormones called "incretins" has been suspected. The present review summarizes the current evidences on the effects of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) in bone physiology.

Topics: Animals; Bone and Bones; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Enteroendocrine Cells; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Osteoblasts; Osteoclasts; Receptors, Gastrointestinal Hormone; Stress, Mechanical

Insulin is the mainstay of current treatment for patients with type 1 diabetes mellitus (T1DM). Due to increasing insulin resistance, insulin doses are often continually increased, which may result in weight gain for patients. Medications currently approved for the treatment of type 2 diabetes offer varying mechanisms of action that can help to reduce insulin resistance and prevent or deter weight gain. A MEDLINE search was conducted to review literature evaluating the use of metformin, alpha-glucosidase inhibitors, pioglitazone, glucagon-like peptide 1 agonists, dipeptidyl peptidase, and sodium-dependent glucose transporter 2 inhibitors, in patients with T1DM. Varying results were found with some benefits including reductions in hemoglobin A1c, decreased insulin doses, and favorable effects on weight. Of significance, a common fear of utilizing multiple therapies for diabetes treatment is the risk of hypoglycemia, and this review displayed limited evidence of hypoglycemia with multiple agents.

Topics: Diabetes Mellitus, Type 1; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glycoside Hydrolase Inhibitors; Humans; Insulin; Metformin; Pioglitazone; Sodium-Glucose Transporter 2 Inhibitors; Thiazolidinediones

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

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 increased prevalence of type 2 diabetes follows the increased prevalence of obesity. Both diseases share common pathophysiological pathways; obesity is in most cases the first step, whereas diabetes is the second one. Weight gain occurs during the treatment of diabetes with drugs causing endogenous or exogenous hyperinsulinemia. Insulin and sulfonylurea are making patients more obese and more insulin resistant. Glucagon-like peptide-1 receptor agonists (GLP-1 agonists) and sodium/glucose cotransporter 2 inhibitors (SGLT2 inhibitors) are antidiabetic drugs with weight loss property. GLP-1 agonists mimic an incretin action. They release insulin after a meal during hyperglycemia and suppress glucagon. The weight loss effect is a consequence of central action increased satiety. Some of GLP-1 agonists weight loss is a result of decelerated gastric emptying rate. SGLT2 inhibitors block sodium glucose cotransporter in proximal tubule brush border and produce glucose excretion with urinary loss. Urinary glucose leak results in calories and weight loss. Even a modest weight loss has positive outcome on metabolic features of diabetic patient; such drugs have important role in treatment of type 2 diabetic patients. However, there are some still unresolved questions. The weight loss they produce is modest. Those drugs are expensive and not available to many diabetic patients, they are significantly more expensive compared to "traditional" hypoglycemic drugs. The hypoglycemic endpoint of GLP-1 agonists and SGLT2 inhibitors often requires adding another antidiabetic drug. The most radical and most effective therapy of type 2 diabetes and obesity is bariatric surgery having significant number of diabetes remission.

Topics: Anti-Obesity Agents; Bariatric Surgery; Biological Transport; Clinical Trials as Topic; Comorbidity; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Gastric Emptying; Glucagon; Glucagon-Like Peptide 1; Glucose; Glycosuria; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Kidney Tubules, Proximal; Microvilli; Multicenter Studies as Topic; Obesity; Peptides; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Venoms; Weight Loss

Patients with type 1 diabetes mellitus (T1DM) traditionally had a low body mass index and microangiopathic complications were common. The Diabetes Control and Complications Trial, published in 1993, demonstrated that therapy aimed at maintaining HbA1c levels as close to normal as feasible reduced the incidence of microangiopathy. Since then, the use of intensive insulin therapy to optimise metabolic control became generalised, with two main side effects: a higher rate of severe hypoglycaemia and increased weight gain. Approximately 50% of patients with T1DM are currently obese or overweight, which reduces or nullifies the benefits of good metabolic control, and which has other negative consequences; therefore, strategies to achieve weight control in patients with T1DM are necessary. At present, treatment with GLP-1 and SGLT-2 inhibitors has yielded promising short-term results that need to be confirmed in studies with larger numbers of patients and long-term follow-up. It is possible that, in coming years, the applicability of bariatric surgery in obese patients with T1DM will be similar to that of the general population or T2DM.

Topics: Adolescent; Adult; Bariatric Surgery; Body Mass Index; Depression; Diabetes Complications; Diabetes Mellitus, Type 1; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Hirsutism; Humans; Hypoglycemic Agents; Hypogonadism; Insulin; Life Style; Male; Metabolic Syndrome; Obesity; Osteoporosis; Overweight; Polycystic Ovary Syndrome; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Weight Gain

The management of type 1 diabetes remains a challenge for clinicians. Current practice is to administer insulin analogues to best mimic normal physiological insulin profiles. However, despite our best efforts the majority of individuals with type 1 diabetes continue to suffer from suboptimal glucose control, significant hypoglycemia and microvascular tissue complications of the disease. There is thus a significant unmet need in the treatment of T1DM to obtain better glycemic control.. We discuss the use of α-glucosidase inhibitors, dipeptidyl-peptidase inhibitors, glucagon-like peptide 1 agonists, biguanides, thiazolidinediones and sodium glucose co-transporter 2 inhibitors in individuals with T1DM.. Non-insulin therapies present a unique and exciting adjunctive treatment for individuals with type 1 diabetes. Although data are scarce, the classes of medications discussed help to lower glucose, decrease glycemic excursions and in some cases improve body weight, along with allowing dose reductions in total daily insulin. Glucagon-like peptide 1 agonists and sodium glucose co-transporter 2 inhibitors, in particular, have been demonstrated to provide clinical improvements in individuals with T1DM and we feel their use can be explored in obese, insulin-resistant patients with T1DM, those with frequent and significant glycemic excursions or individuals with persistently elevated hemoglobin A1c.

Topics: Biguanides; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glycated Hemoglobin; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Insulin Resistance; Obesity; Sodium-Glucose Transporter 2 Inhibitors; Thiazolidinediones

Type 1 diabetes (T1DM) is a disease characterized by autoimmune mediated destruction of the insulin producing beta cells of endocrine pancreas. Beside insulin deficiency, T1DM is also characterized by abnormal suppression of glucagon secretion in response to hyperglycemia. All these abnormalities are likely to leave patients dependent upon exogenous insulin administration for survival. GLP-1 is a hormone secreted by L-cells of distal small intestine and colon. GLP-1 exerts its effects through the interaction with GLP-1 receptor expressed in the pancreatic islets, lung, hypothalamus, stomach, heart and kidney. It belongs to the group of incretin peptides and it stimulates insulin and inhibits glucagon secretion. Actions of GLP-1 also include delaying of gastric emptying, reduction of appetite and induction of satiety. On the other hand, evidences mainly collected from animal models, have indicated the role of GLP-1 in increasing beta cell proliferation and differentiation and in decreasing the rate of beta cell apoptosis. GLP-1 receptor agonists are approved for the treatment of type 2 diabetes where they have established very important position. However, they are still not approved for use in T1DM, although they could have beneficial effects in both new onset and longstanding T1DM patients, mainly as an adjunctive therapy to insulin in order to improve glycemic control and body weight management in longstanding disease or to reduce insulin requirements or even to delay the absolute dependence upon insulin administration in new onset T1DM. Randomized, long-term, placebo controlled clinical trials are warranted before the official implementation of GLP-1 receptor agonists in the treatment of T1DM.

Topics: Animals; Diabetes Mellitus, Type 1; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells

The number of young diabetics is increasing and therapeutic options for these patients are limited. Glucagon-like peptide-1 (GLP-1) is secreted from the gut after meals and enhances glucose-induced insulin secretion, inhibits glucagon secretion, suppresses appetite, and delays the gastric-emptying rate. GLP-1 analogs are already widely used in the adult population to improve glycemic control and induce weight loss in overweight subjects with type 2 diabetes. The glucose-lowering effects resulting from the inhibition of glucagon secretion and the gastric-emptying rate could be of clinical importance in type 1 diabetes. In this article we review clinical data regarding the use of GLP-1 receptor agonists in youth and address the potential benefits and safety aspects of these compounds. Large scale clinical trials are still needed in the pediatric population.

Topics: Adolescent; Adult; Child; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Gastric Emptying; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Liraglutide; Male; Pediatric Obesity; Randomized Controlled Trials as Topic; Receptors, Glucagon

The glucagon-like peptide-1 (GLP-1) axis has emerged as a major therapeutic target for the treatment of type 2 diabetes. GLP-1 mediates its key insulinotropic effects via a G-protein coupled receptor expressed on β-cells and other pancreatic cell types. The insulinotropic activity of GLP-1 is terminated via enzymatic cleavage by dipeptidyl peptidase-4. Until recently, GLP-1-derived metabolites were generally considered metabolically inactive; however, accumulating evidence indicates some have biological activity that may contribute to the pleiotropic effects of GLP-1 independent of the GLP-1 receptor. Recent reports describing the putative effects of one such metabolite, the GLP-1-derived nonapeptide GLP-1(28-36) amide, are the focus of this review. Administration of the nonapeptide elevates cyclic adenosine monophosphate (cAMP) and activates protein kinase A, β-catenin, and cAMP response-element binding protein in pancreatic β-cells and hepatocytes. In stressed cells, the nonapeptide targets the mitochondria and, via poorly defined mechanisms, helps to maintain mitochondrial membrane potential and cellular adenosine triphosphate levels and to reduce cytotoxicity and apoptosis. In mouse models of diet-induced obesity, treatment with the nonapeptide reduces weight gain and ameliorates associated pathophysiology, including hyperglycemia, hyperinsulinemia, and hepatic steatosis. Nonapeptide administration in a streptozotocin-induced model of type 1 diabetes also improves glucose disposal concomitant with elevated insulin levels and increased β-cell mass and proliferation. Collectively, these results suggest some of the beneficial effects of GLP-1 receptor analogs may be mediated by the nonapeptide. However, the concentrations required to elicit some of these effects are in the micromolar range, leading to reservations about potentially related therapeutic benefits. Moreover, although controversial, concerns have been raised about the potential for incretin-based therapies to promote pancreatitis and pancreatic and thyroid cancers. The effects ascribed to the nonapeptide make it a potential contributor to such outcomes, raising additional questions about its therapeutic suitability. Notwithstanding, the nonapeptide, like other GLP-1 metabolites, appears to be biologically active. Increasing understanding of such noncanonical GLP-1 activities should help to improve future incretin-based therapeutics.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Peptide Fragments

The health burden of type 2 diabetes mellitus (T2DM) is increasing worldwide, with a substantial portion of this burden being due to the development of cardiovascular (CV) disease. Multiple individual randomised clinical trials of intensive versus conventional glucose control, based on the use of traditional oral hypoglycaemic agents, have failed to convincingly show that intensive glucose control significantly reduces CV disease outcomes. In recent times, two new approaches to lowering glucose levels have become available. One targets the "incretin effect" which involves the modulation of peptide hormones that normally regulate glucose levels when nutrients are given orally. The other approach is based on inhibiting the sodium-glucose co-transporter 2 (SGLT-2) in the tubules of the kidney to promote glycosuria. Incretin-based therapies, especially glucagon-like peptide-1 receptor analogues, reduce glucose levels, with a low risk of hypoglycaemia, by increasing insulin secretion, inhibiting glucagon release and increasing satiety. Clinical and experimental studies have also shown favourable effects on CV disease risk factors such as dyslipidaemia, blood pressure, and improvements in endothelial function and cardiac contractility. Similarly, SGLT-2 inhibitors reduce glucose levels with a low risk for hypoglycaemia and have positive effects on multiple CV disease risk factors. Whether the beneficial effects of these new glucose lowering approaches on surrogate markers of CV disease risk translates to an improvement in CV events remains unknown. Several CV outcome trials are currently being performed to show that at a minimum, these novel glucose lowering agents are safe, but also have positive CV benefits.

Topics: Blood Glucose; Diabetes Complications; Diabetes Mellitus, Type 1; Glucagon-Like Peptide 1; Humans; Incretins; Kidney Tubules; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

The insulin replacement is essential in the treatment of type 1 diabetes. Insulin therapy has been coupled with relevant side effects such as hypoglycemia and weight gain. Glucagon-like Peptide 1(GLP-1) analogues (liraglutide) and incretin mimetics (exenatide) are approved only for the treatment of type 2 diabetes mellitus. This review aims to answer the question of what effects exercise GLP-1 analogues on glucose metabolism in people with type 1 diabetes mellitus.. A systematic literature search. We included studies in people with diabetes mellitus type 1 and GLP-1 analogues intervention. The report quality, the methodological quality of the studies and reviews was based on CONSORT and PRISMA assessed.. A total of 19 potentially relevant publications 219 hits were identified. Included were four randomized-controlled trials, two non-randomized-controlled trials and five reviews. The studies and reviews have shown a different methodological quality. There were significant changes in insulin dose (p ≤ 0.01) reduced Hyperglykämierate detected (p ≤ 0.01) reduction of blood glucose variations (p ≤ 0.01) and a reduction in glucagon (p ≤ 0.05).. The delayed gastric emptying and reduction of glucagon is the main mechanism of the improved glycemic control in the glucose metabolism of type 1 diabetes. The present literature shows promising results for the additional substitution of GLP-1 analogues in the treatment of type 1 diabetes mellitus. Based on the current data, there is a need to carry out large randomized-controlled trials.

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Evidence-Based Medicine; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Treatment Outcome

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

Despite years of research in the field of type 1 diabetes, patients with the disease remain without a therapeutic agent that can alter the underlying immune response in a clinically beneficial way. Glucagon-like peptide 1 agonist therapies have shown some promising effects in terms of positively affecting overall beta cell health and increasing beta cell mass, primarily in mouse models. The three agents of this class currently available for patients with type 2 diabetes have shown beneficial clinical effects on glucose control in this patient population. The purpose of this article is to review the preclinical and clinical data of these agents to date with a focus on the potential immunological and clinical benefits these drugs may have on patients with type 1 diabetes.

Topics: Animals; Biomarkers; Blood Glucose; C-Peptide; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin-Secreting Cells; Liraglutide; Peptides; Venoms

The assumption that patients with an extended duration of type 1 diabetes mellitus (T1D) do not retain residual functional β cells and endogenous insulin production has recently been challenged. The purpose to this review is to highlight some of the key emerging evidence supporting residual insulin and C-peptide secretion in long-standing T1D.. Recent investigations conducted in a group of type 1 diabetics of long-term duration, characterized clinically and histologically, provided solid evidence to suggest that pancreatic β cells are still present even after 50 years in a majority of these individuals. These residual β cells can secrete insulin in a physiologically regulated manner. Several published reports showed promising effects of glucagon-like peptide 1 (GLP-1) agonists on the glycemic control and residual C-peptide production in long-term T1D, although prospective studies are needed to rule out the potential long-term adverse effects of these drugs.. C-peptide is no longer considered an irrelevant by-product of insulin biosynthesis. In-depth basic and translational investigations aimed at understanding the molecular immunology and the pathophysiology are needed to elucidate the mechanisms underlying the residual insulin and C-peptide production in long-term T1D. This may shed light on to the regenerative capacity of β cells, the genetic susceptibility of the mechanisms of resistance to β-cell destruction, and possibly identifying new therapeutic strategies for T1D. Studies evaluating the long-term effects of insulin secretogogue agents along with immune intervention hold promise for their use in future clinical trials for long-term T1D.

Topics: C-Peptide; Diabetes Mellitus, Type 1; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells

The purpose of this review is to examine recently published literature in the areas of incretins and amylin in the management of pediatric diabetes.. Recent studies have begun to explore the use of longer-acting GLP-1 analogues that can be given once daily, such as liraglutide, and the use of DPP-IV inhibitors in the management of type 2 diabetes. In addition, recent studies have been published on the use of exenatide in the management of pediatric obesity and newly diagnosed type 1 diabetes.. Very few medications are approved for management of type 2 diabetes in youth. In addition, monotherapy of type 1 diabetes in youth with insulin does not achieve HbA1c targets in the majority of youth despite the use of rapid-acting insulin analogues, insulin pump therapy, and continuous glucose monitoring. Novel therapies that target physiologic modalities other than enhancing or replacing insulin secretion or improving insulin sensitivity have shown efficacy in adults. Studies with these drugs are being done in the pediatric population and should provide additional treatment options for these patients.

Topics: Adolescent; Child; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Disease Management; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Islet Amyloid Polypeptide; Pediatric Obesity

Human islet transplantation is an effective and promising therapy for type I diabetes. However, long-term insulin independence is both difficult to achieve and inconsistent. De novo or early administration of incretin-based drugs is being explored for improving islet engraftment. In addition to its glucose-dependent insulinotropic effects, incretins also lower postprandial glucose excursion by inhibiting glucagon secretion, delaying gastric emptying, and can protect beta-cell function. Incretin therapy has so far proven clinically safe and tolerable with little hypoglycemic risk. The present review aims to highlight the new frontiers in research involving incretins from both in vitro and in vivo animal studies in the field of islet transplant. It also provides an overview of the current clinical status of incretin usage in islet transplantation in the management of type I diabetes.

Topics: Animals; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Incretins; Islets of Langerhans Transplantation

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

Several research groups have begun to associate the Alzheimer Disease (AD) to Diabetes Mellitus (DM), obesity and cardiovascular disease. This relationship is so close that some authors have defined Alzheimer Disease as Type 3 Diabetes. Numerous studies have shown that people with type 2 diabetes have twice the incidence of sporadic AD. Insulin deficiency or insulin resistance facilitates cerebral β-amyloidogenesis in murine model of AD, accompanied by a significant elevation in APP (Amyloid Precursor Protein) and BACE1 (β-site APP Cleaving Enzime 1). Similarly, deposits of Aβ produce a loss of neuronal surface insulin receptors and directly interfere with the insulin signaling pathway. Furthermore, as it is well known, these disorders are both associated to an increased cardiovascular risk and an altered cholesterol metabolism, so we have analyzed several therapies which recently have been suggested as a remedy to treat together AD and DM. The aim of the present review is to better understand the strengths and drawbacks of these therapies.

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypoglycemic Agents; Incidence; Liraglutide; Male; Metformin; Receptor, Insulin; Risk Factors; tau Proteins

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

Finding a cure for type 1 diabetes (T1D) has been elusive. Incretin-based therapies, since their approval, have demonstrated their clinical utilities in type 2 diabetes (T2D). Yet, their potential clinical benefits in T1D remain to be appraised. GLP-1, in addition to its insulinotropic action in alleviating hyperglycemia, possesses beneficial effects in protecting progressive impairment of pancreatic β-cell function, preservation of β-cell mass and suppression of glucagon secretion, gastric emptying and appetite. Preclinical data using incretin-based therapies in diabetic NOD mice demonstrated additional effects including immuno-modulation, anti-inflammation and β-cell regeneration. Thus, data accumulated hold the promise that incretin-based therapies may be effective in delaying the new-onset, halting the further progression, or reversing T1D in subjects with newly diagnosed or long-standing, established disease.

Topics: Animals; Diabetes Mellitus, Type 1; Glucagon-Like Peptide 1; Humans; Incretins; Insulin-Secreting Cells

Unfortunately, the only approved medical treatment for type 1 diabetes mellitus (DM) is insulin, despite the fact that tight control cannot be reached without some serious side effects such as hypoglycemia and weight gain. More and more importance is now shifted towards developing new drugs that can reach a better glycemic control with lesser side effects. Some of these promising drugs are the glucagon-like peptides 1 (GLP-1) and their agonists, which have been FDA approved for the treatment of type 2 DM. The purpose of this article is to review all of the relevant literature on the potential role of GLP-1 in the treatment of type 1 DM. The major source of data acquisition included Medline search strategies, using the words "type 1 diabetes mellitus" and "GLP-1." Articles published in the last 20 years were screened. GLP-1 increases insulin secretion in humans with existing beta cells; it also decreases glucagon secretion, and blunts appetite. Of note, new animal studies demonstrate a role in beta cell-proliferation and decreased apoptosis. Because of all the effects mentioned above, GLP-1 seems to be a promising drug for type 1 DM treatment, but more studies are still needed before solid conclusions can be drawn.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 1; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin

Both diabetes mellitus and thyroid disorders are common diseases. According to epidemiologic studies the prevalence of specific thyroid disorders in diabetic subjects is two times higher. Risk factors are age, female gender and autoimmune diabetes mellitus. However, thyroid disorders are diagnosed only half of the cases in diabetic population. The review briefly summarizes the association of autoimmune diabetes mellitus and thyreoiditis, the risk of thyroid disorders in type 1 diabetic pregnant women. Furthermore, the influence of obesity in the risk on thyroid cancer and the effect of glucagon-like peptide 1 analogue on thyroid medullary C-cells are discussed.

Topics: Age Factors; Autoimmunity; Carbohydrate Metabolism; Comorbidity; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Type 1; Female; Glucagon-Like Peptide 1; Humans; Hyperthyroidism; Hypothyroidism; Iodide Peroxidase; Obesity; Pregnancy; Pregnancy Complications; Pregnancy in Diabetics; Risk Factors; Sex Factors; Thyroid Diseases; Thyroid Hormones; Thyroid Neoplasms; Thyroiditis, Autoimmune

Novel therapeutic options for type 2 diabetes based on the action of the incretin hormone glucagon-like peptide-1 (GLP-1) were introduced in 2005. Incretin-based therapies consist of two classes: (1) the injectable GLP-1 receptor agonists solely acting on the GLP-1 receptor and (2) dipeptidyl-peptidase inhibitors (DPP-4 inhibitors) as oral medications raising endogenous GLP-1 and other hormone levels by inhibiting the degrading enzyme DPP-4. In type 2 diabetes therapy, incretin-based therapies are attractive and more commonly used due to their action and safety profile. Stimulation of insulin secretion and inhibition of glucagon secretion by the above-mentioned agents occur in a glucose-dependent manner. Therefore, incretin-based therapies have no intrinsic risk for hypoglycemias. GLP-1 receptor agonists allow weight loss; DPP-4 inhibitors are weight neutral. This review gives an overview on the mechanism of action and the substances and clinical data available.

Topics: Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Guidelines as Topic; Humans; Hypoglycemic Agents; Incretins

Type 2 diabetes is making up to 90% of the all diabetic cases. In addition to insulin resistance, insufficient B-cell function also plays an important role in the pathogenesis of the disease. The insufficient production and secretion of insulin can be increased by secretagogue drugs, like sulfonylureas and incretin mimetics/enhancers. In recent years growing number of genetic failures of the B-cells has been detected. These genetic variants can influence the efficacy of secretagogue drugs. Some of these gene polymorphisms were identified in the genes encoding the KATP channel (KCNJ11 and ABCC8). These mutations are able either to reduce or increase the insulin secretion and can modify the insulin response to sulfonylurea treatment. Other polymorphisms were found on genes encoding enzymes or transcription factors. In recent years, the genetic variants of TCF7L2 and its clinical importance have been intensely studied. Authors give a summary of the above gene polymorphisms and their role in insulin secretion.

Topics: ATP-Binding Cassette Transporters; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Genetic Predisposition to Disease; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Resistance; Insulin Secretion; KATP Channels; Mutation; Polymorphism, Genetic; Potassium Channels, Inwardly Rectifying; Receptors, Drug; Sulfonylurea Compounds; Sulfonylurea Receptors

Glucagon-like peptide (GLP)-1 receptor agonists are in widespread clinical use for the treatment of diabetes. While effective, these peptides require frequent injections to maintain efficacy. Therefore, alternative delivery methods including gene therapy are currently being evaluated.. Here, we review the biology of GLP-1, evidence supporting the clinical use of the native peptide as well as synthetic GLP-1 receptor agonists, and the rationale for their delivery by gene therapy. We then review progress made in the field of GLP-1 gene therapy for both type 1 and type 2 diabetes.. Efforts to improve the biological half-life of GLP-1 receptor agonists are discussed. We focus on the development of both viral and non-viral gene delivery methods, highlighting vector designs and the strengths and weaknesses of these approaches. We also discuss the utility of targeting regulated GLP-1 production to tissues including the liver, muscle, islet and gut.. GLP-1 is a natural peptide possessing several actions that effectively combat diabetes. Current delivery methods for GLP-1-based drugs are cumbersome and do not recapitulate the normal secretion pattern of the native hormone. Gene therapy offers a useful method for directing long-term production and secretion of the native peptide. Targeted production of GLP-1 using tissue-specific promoters and delivery methods may improve therapeutic efficacy, while also eliminating the burden of frequent injections.

Topics: Animals; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Disease Models, Animal; Genetic Therapy; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Receptors, Glucagon; Treatment Outcome

Insulin administration is the primary therapy for type 1 diabetes mellitus (T1DM). Current available insulin therapies do not successfully enable children with T1DM to reach glycemic goals without side effects such as hypoglycemia and weight gain. Pramlintide is a synthetic analog of human amylin that acts in conjunction with insulin to delay gastric emptying and inhibit the release of glucagon and is indicated for use in patients with type 1 and type 2 diabetes. Recent studies in adult patients have examined the role of glucagon-like peptide 1 (GLP-1) and agents that bind to its receptor in type 1 diabetes. It is hypothesized that a major component of the glycemic effect is attributable to the known action of GLP-1 to delay gastric emptying and to inhibit glucagon secretion. Further studies with the use of amylin analogs and long-acting GLP-1 agonists as congeners with insulin in T1DM are indicated in children. In recent years, our better understanding of the pathophysiology of diabetes has led to the development of new therapies for diabetes. This article reviews the potential use of these newer pharmacologic agents as adjunctive therapy in T1DM in children and adolescents.

Topics: Amyloid; Blood Glucose; Body Weight; Child; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Exenatide; Gastric Emptying; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Islet Amyloid Polypeptide; Pancreas; Peptides; Treatment Outcome; Venoms

GLP-1 (glucagon-like peptide-1) is a peptide hormone secreted from endocrine cells in the intestinal mucosa in response to meals. The major effects of GLP-1 are to increase glucose-induced insulin secretion and reduce glucagon release, but GLP-1 also inhibits gastric emptying rate and reduces appetite and bodyweight in obese subjects. In vivo studies using animal models of type 2 diabetes and in vitro studies using human islet cells have suggested that GLP-1 or GLP-1 analogues are also able to increase beta-cell mass, but in animal models of type 1 diabetes, there is much less evidence for a beta-cell preserving effect. This review summarizes the present knowledge of GLP-1 and its analogues regarding its role as a possible treatment in patients with type 1 diabetes. The studies that address the effect of GLP-1 and GLP-1 analogues on beta-cell mass in both type 2 and type 1 diabetes, as well as the potential of GLP-1 as an adjuvant therapy in islet cell transplantation, will be reviewed. Suggestions for future studies of GLP-1 treatment in type 1 diabetes may include early treatment in order to preserve beta-cell mass and prolong the remission period, but should also take a potential insulin sparing effect and changes in the risk of hypoglycemia into account.

Topics: Animals; Diabetes Mellitus, Type 1; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Peptides; Receptors, Glucagon; Venoms

Tightening of the diabetes control criteria in the last few years induces searches for adjunctive drugs to reinforce the basic treatment typical for the specific type of the disease. These agents are meant to stimulate insulin secretion, increase insulin sensitivity or inhibit the antagonists of the hormone. Up till now that kind of studies included adults, mainly with type 2 diabetes. Nowadays, however, the increasing number of research focuses on type 1 diabetic patients. The attempts to introduce this type of treatment in adolescent patients encounter many limitations, mostly of formal nature due to drug registration requirements. Nevertheless, more and more studies point at the efficacy of these agents and the possibility of their usage also in adolescents with different types of diabetes.

Topics: Adipose Tissue; Adolescent; Adult; Amyloid; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Islet Amyloid Polypeptide; Male; Receptors, Cannabinoid

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

Topics: Animals; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin-Secreting Cells

A number of alternative therapies for type 2 diabetes are currently under development that take advantage of the actions of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide on the pancreatic beta-cell. One such approach is based on the inhibition of dipeptidyl peptidase IV (DP IV), the major enzyme responsible for degrading the incretins in vivo. DP IV exhibits characteristics that have allowed the development of specific inhibitors with proven efficacy in improving glucose tolerance in animal models of diabetes and type 2 human diabetics. While enhancement of insulin secretion, resulting from blockade of incretin degradation, has been proposed to be the major mode of inhibitor action, there is also evidence that inhibition of gastric emptying, reduction in glucagon secretion and important effects on beta-cell differentiation, mitogenesis and survival, by the incretins and other DP IV-sensitive peptides, can potentially preserve beta-cell mass, and improve insulin secretory function and glucose handling in diabetics.

Topics: Amino Acid Sequence; Animals; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose; Glucose Tolerance Test; Humans; Molecular Sequence Data; Peptide Fragments; Protease Inhibitors

The remission phase of Type 1 diabetes mellitus is associated with substantial recovery of beta-cell function and with marked improvement of endogenous insulin responses to meals in the early months after diagnosis, accompanied by little or no improvement in the insulin response to parenteral glucose, suggesting that the incretin function may be important in glycaemic regulation in this phase of diabetes. Preservation of the insulin response to parenteral glucagon-like peptide-1 (GLP-1), contrasting with lack of stimulation of insulin secretion by the other known incretin gastric inhibitory polypeptide (GIP), prompted studies with exogenous GLP-1 in recent-onset Type 1 diabetes. These studies showed substantial reduction of glycaemic excursions after ingestion of mixed nutrients during intravenous infusion of GLP-1 without administration of insulin, in subjects with a range of endogenous secretion of insulin in response to meals as demonstrated by blood levels of the insulin-connecting peptide (CP). These effects were independent of stimulation of blood levels of CP and were reproduced in volunteers with no endogenous release of CP in response to meals. The glycaemic effects were associated with inhibition of abnormal rises of blood levels of glucagon, and with suppression of endogenous release of human pancreatic polypeptide (HPP), by GLP-1. It was hypothesized that a major component of the glycaemic effect is attributable to the known action of GLP-1 to inhibit gastric emptying and to inhibit glucagon secretion. Studies of the effects of GLP-1 agonists (GLP-1 and exendin-4) given together with established insulin doses before a meal supported the hypothesis. The more prolonged actions of exendin-4 were accompanied by greater and more prolonged reduction of glycaemic effects of ingestion of meals in volunteers with CP-negative Type 1 diabetes mellitus, during intensive insulin therapy, in whom delay of gastric emptying was confirmed by studies of blood levels of acetaminophen ingested with the meals. Side effect-free doses of exendin-4 given together with insulin in volunteers with CP-negative Type 1 diabetes receiving continuing intensive insulin therapy demonstrated the capacity of this combination therapy to normalize blood glucose levels after ingestion of meals that were consistent with the dietary program of the volunteers, without apparent increased risk of hypoglycaemia within a normal between-meals interval. It is suggested that further and more

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Food; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Peptide Fragments; Protein Precursors; Time Factors

This article reviews the advantages to and caveats of the use of newer insulin formulations (insulin analogues) and regimens in children and teens who have type 1 diabetes, their affect on glycemic control, frequency of hypoglycemic events, daily insulin requirements, and adverse affects such as excessive weight gain, which provides a further major challenge in adolescents. We also address briefly the use of adjunctive agents in the treatment of type 1 diabetes in children and teens.

Topics: Adolescent; Amyloid; Child; Diabetes Mellitus, Type 1; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Islet Amyloid Polypeptide; Metformin

Topics: Blood Glucose; Cell Differentiation; Cell Division; Diabetes Mellitus, Type 1; Exenatide; Genetic Therapy; Glucagon; Glucagon-Like Peptide 1; Homeostasis; Humans; Immunotherapy; Islets of Langerhans; Islets of Langerhans Transplantation; Peptide Fragments; Peptides; Protein Precursors; Stem Cells; Venoms

Glucagon-like peptide 1 (GLP-1) is an intestine-derived insulinotropic hormone that stimulates glucose-dependent insulin production and secretion from pancreatic beta-cells. Other recognized actions of GLP-1 are to suppress glucagon secretion and hepatic glucose output, delay gastric emptying, reduce food intake, and promote glucose disposal in peripheral tissues. All of these actions are potentially beneficial for the treatment of type 2 diabetes mellitus. Several GLP-1 agonists are in clinical trials for the treatment of diabetes. More recently, GLP-1 agonists have been shown to stimulate the growth and differentiation of pancreatic beta-cells, as well as to exert cytoprotective, antiapoptotic effects on beta-cells. Recent evidence indicates that GLP-1 agonists act on receptors on pancreas-derived stem/progenitor cells to prompt their differentiation into beta-cells. These new findings suggest an approach to create beta-cells in vitro by expanding stem/progenitor cells and then to convert them into beta-cells by treatment with GLP-1. Thus GLP-1 may be a means by which to create beta-cells ex vivo for transplantation into patients with insulinopenic type 1 diabetes and severe forms of type 2 diabetes.

Topics: Animals; Cell Division; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Humans; Islets of Langerhans; Islets of Langerhans Transplantation; Peptide Fragments; Protein Precursors

Glucagon-like peptide 1 (GLP-1) is a product of proglucagon that is secreted by specialized intestinal endocrine cells after meals. GLP-1 is insulinotropic and plays a role in the incretin effect, the augmented insulin response observed when glucose is absorbed through the gut. GLP-1 also appears to regulate a number of processes that reduce fluctuations in blood glucose, such as gastric emptying, glucagon secretion, food intake, and possibly glucose production and glucose uptake. These effects, in addition to the stimulation of insulin secretion, suggest a broad role for GLP-1 as a mediator of postprandial glucose homeostasis. Consistent with this role, the most prominent effect of experimental blockade of GLP-1 signaling is an increase in blood glucose. Recent data also suggest that GLP-1 is involved in the regulation of beta-cell mass. Whereas other insulinotropic gastrointestinal hormones are relatively ineffective in stimulating insulin secretion in persons with type 2 diabetes, GLP-1 retains this action and is very effective in lowering blood glucose levels in these patients. There are currently a number of products in development that utilize the GLP-1-signaling system as a mechanism for the treatment of diabetes. These compounds, GLP-1 receptor agonists and agents that retard the metabolism of native GLP-1, have shown promising results in clinical trials. The application of GLP-1 to clinical use fulfills a long-standing interest in adapting endogenous insulinotropic hormones to the treatment of diabetes.

Topics: Animals; Diabetes Mellitus, Type 1; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Peptide Fragments; Protein Precursors

Despite a number of incremental, beneficial improvements in diabetes mellitus therapy over the past few decades, the fundamental challenge of replicating the physiological entry into, and uptake of glucose from, the circulation remains unresolved. Pramlintide is an analogue of the beta-cell hormone amylin that simulates its important glucoregulatory actions. In humans, pramlintide slows gastric emptying and suppresses glucagon secretion during the prandial/postprandial period to slow and reduce the entry of glucose into the circulation. These actions, in conjunction with the glucose cellular uptake function of insulin, help normalise fluctuations in circulating glucose levels to a greater degree than is possible with insulin treatment alone. In clinical studies, pramlintide treatment as an adjunct to insulin decreased glycosylated haemoglobin levels (0.39-0.62%) with a concomitant weight loss (0.5-1.4kg) and no significant increase in severe hypoglycaemia. Pramlintide treatment as a potential adjunct to insulin therapy is in late-stage development for patients with type 1 diabetes and insulin-using patients with type 2 diabetes.

Topics: Amyloid; Animals; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Islet Amyloid Polypeptide; Peptide Fragments; Protein Precursors

Two landmark intervention studies, the Diabetes Control and Complications Trial (DCCT) in patients with type 1 diabetes mellitus and the United Kingdom Prospective Diabetes Study (UKPDS) in patients with type 2 diabetes mellitus, have unequivocally demonstrated that intensive diabetes therapy reduces the risk of long-term diabetic complications. As a result, the commonly accepted treatment goal for most patients with diabetes is the achievement and maintenance of glycemic control that is as close to the normal range as safely possible. Important adverse effects of intensive diabetes therapy, particularly when the treatment includes insulin or several of the oral antihyperglycemic agents, are an increased risk of hypoglycemia and undesired weight gain. Improvement of glycemic control with insulin, insulin secretagogues (sulfonylureas, meglitinides), and insulin sensitizers (thiazolidinediones) is often accompanied by weight gain. The etiology of this weight gain is likely multifaceted, including a reduction of glucosuria, increased caloric intake to prevent hypoglycemia, and anabolic effects on adipose tissue. Biguanides and alpha-glucosidase inhibitors have a neutral or even positive effect (decrease) on weight, which may partly be attributable to their non-insulinotropic mechanism of action, a modest effect on satiety, and to their gastrointestinal adverse effect profile. Several antihyperglycemic agents that are currently in clinical development may improve glycemic control in conjunction with weight reduction. These include an analog of the pancreatic beta-cell hormone amylin (pramlintide), as well as glucagon-like peptide-1 (GLP-1) and exendin, and their analogs. Pharmacological agents with antihyperglycemic and positive weight effects have the potential to become important additions to our therapeutic armamentarium, in that they may help to achieve glycemic targets while addressing the long-standing clinical problem of weight gain as an adverse effect of intensive diabetes therapy.

Topics: Amyloid; Benzamides; Biguanides; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Insulin; Islet Amyloid Polypeptide; Obesity; Peptide Fragments; Protein Precursors; Sulfonylurea Compounds; Thiazolidinediones; Weight Gain

Topics: Animals; Antigens, Neoplasm; Betacellulin; Biomarkers, Tumor; Cell Differentiation; Cell Division; Diabetes Mellitus, Type 1; Genetic Therapy; Glucagon; Glucagon-Like Peptide 1; Humans; Intercellular Signaling Peptides and Proteins; Islets of Langerhans; Islets of Langerhans Transplantation; Lectins, C-Type; Niacinamide; Pancreatitis-Associated Proteins; Peptide Fragments; Protein Precursors; Proteins; Regeneration; Stem Cell Transplantation; Stem Cells; Tissue Engineering

Recent availability of expanded treatment options for both type 1 and type 2 diabetes has not translated into easier and significantly better glycemic and metabolic management. Patients with type 1 diabetes continue to experience increased risk of hypoglycemic episodes and progressive weight gain resulting from intensive insulin treatment, despite the recent availability of a variety of insulin analog. Given the progressive nature of the disease, most patients with type 2 diabetes inevitably proceed from oral agent monotherapy to combination therapy and, ultimately, require exogenous insulin replacement. Insulin therapy in type 2 diabetes is also accompanied by untoward weight gain. Both type 1 and type 2 diabetes continue to be characterized by marked postprandial hyperglycemia. Two hormones still in development are candidates for pharmacologic intervention, have novel modes of action (some centrally mediated), and show great promise in addressing some of the unmet needs of current diabetes management. Pramlintide acetate, an analog of the beta cell hormone amylin and the first non-insulin related therapeutic modality for type 1 and type 2 diabetic patients with severe beta cell failure, may be useful as adjunctive therapy to insulin. The principal anti-diabetic effects of pramlintide arise from interactions via its cognate receptors located in the central nervous system resulting in postprandial glucagon suppression, modulation of nutrient absorption rate, and reduction of food intake. Another polypeptide hormone, exendin-4, exerts at least some of its pharmacologic actions as an agonist at the glucagon-like peptide-1 (GLP-1) receptor. GLP-1 and related compounds exhibit multiple modes of action, the most notable being a glucose-dependent insulinotropic effects and the potential to preserve or improve the beta-cell function. The latter effect could potentially halt or delay the progressive deterioration of the diabetic state associated with type 2 diabetes. Physiologically, both amylin and glucagon-like peptide (GLP)-1, along with insulin, are involved in a coordinated and concerted interplay between hormones acting both centrally and peripherally to provide meticulous control over the rate of appearance of exogenous and endogenous glucose and to match that rate to the rate of glucose disappearance. Both hormones are deficient in diabetes. Therapies directed at restoring this complex physiology have the potential to facilitate glucose control and thus m

Topics: Amyloid; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Design; Exenatide; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Islet Amyloid Polypeptide; Peptide Fragments; Peptides; Postprandial Period; Protein Precursors; Venoms

Treatment of type 1 diabetes mellitus has made tremendous advances within the last decades. With concern to insulin delivery there are two promising new approaches. One is the intrapulmonary insulin delivery which has become feasible by the development of new inhalation devices which provide a sufficient degree of intrapulmonary drug retention. Also oral insulin delivery seems feasible when surface active substances are used to cross the mucosal membrane in the gut. Clinical research has also focussed on coatings for the insulin molecules to solve the problem raised by the proteolytic activity of the digestive system. A very new agent produced by a fungus called Pseudomassaria has been demonstrated to reverse the clinical signs of diabetes mellitus in mice. The compound diffuses through the cell membrane, binds to the inner part of the insulin receptor and activates the insulin typical biological effects. Nowadays a variety of insulin analogs are designed and tested for their clinical use. By shifting the isoelectric point towards to a slightly acidic pH, HOE 901 precipitates at physiologic pH resulting in a constant and peakless insulin delivery. NN 304 is a 14-carbon aliphatic fatty acid acylated analog that binds to serum albumin resulting in a flatter time-action profile than NPH insulin. Also rapid acting insulin analogs are or will be launched in the near future aiming to ensure an improved postprandial glucose regulation. Glucagon-like peptide-1 (GLP-1) improves metabolic control by a variety of effects, e.g. the enhancement of insulin secretion and inhibition of glucagon secretion. Moreover, GLP-1 reduces food and water intake controlled by the brain, and inhibits gastric emptying. A disadvantage of GLP-1 is its very short half-life. Novel derivatives with the beneficial effects of GLP-1 but a better resistance against degradation have been designed. In addition substances have been developed inhibiting GLP-1 degradation or augmenting GLP-1 release from its abundant endogenous pool. Finally, there is a variety of interesting approaches aiming to improve or ease blood glucose self-monitoring. One is the development of subcutaneous catheters for continuous blood glucose control. In another system reverse iontophoresis is used for sampling interstitial fluid which reflects capillary blood glucose levels. Instead of using an electric current, a brandnew system creates micropores in the skin by a laser ablation system. Through these micropores a specif

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 1; Endocrinology; Glucagon-Like Peptide 1; Humans; Insulin; Monitoring, Physiologic; Peptides

Proglucagon contains the sequence of two glucagon-like peptides, GLP-1 and GLP-2, secreted from enteroendocrine cells of the small and large intestine. GLP-1 lowers blood glucose in both NIDDM and IDDM patients and may be therapeutically useful for treatment of patients with diabetes. GLP-1 regulates blood glucose via stimulation of glucose-dependent insulin secretion, inhibition of gastric emptying, and inhibition of glucagon secretion. GLP-1 may also regulate glycogen synthesis in adipose tissue and muscle; however, the mechanism for these peripheral effects remains unclear. GLP-1 is produced in the brain, and intracerebroventricular GLP-1 in rodents is a potent inhibitor of food and water intake. The short duration of action of GLP-1 may be accounted for in part by the enzyme dipeptidyl peptidase 4 (DPP-IV), which cleaves GLP-1 at the NH2-terminus; hence GLP-1 analogs or the lizard peptide exendin-4 that are resistant to DPP-IV cleavage may be more potent GLP-1 molecules in vivo. GLP-2 has recently been shown to display intestinal growth factor activity in rodents, raising the possibility that GLP-2 may be therapeutically useful for enhancement of mucosal regeneration in patients with intestinal disease. This review discusses recent advances in our understanding of the biological activity of the glucagon-like peptides.

Topics: Amino Acid Sequence; Animals; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucagon-Like Peptide-1 Receptor; Humans; Molecular Sequence Data; Peptide Fragments; Peptides; Protein Precursors; Receptors, Glucagon

Glucagon-like peptide 1 (GLP-1) is a physiological incretin hormone from the lower gastrointestinal tract, partially explaining the augmented insulin response after oral compared to intravenous glucose administration in normal humans. In addition, GLP-1 also lowers glucagon concentrations, slows gastric emptying, stimulates (pro)insulin biosynthesis, and reduces food intake upon intracerebroventricular administration in animals. Therefore, GLP-1 offers some interesting perspective for the treatment of type 2, and perhaps also for type 1 diabetic patients. The other incretin hormone, gastric inhibitory polypeptide (GIP), has lost almost all its activity in type-2 diabetic patients. In contrast, GLP-1 glucose-dependently stimulates insulin secretion in type-2 diabetic patients and exogenous administration of GLP-1 ([7-37] or [7-36 amide]) in doses elevating plasma concentrations to approximately three to four times physiological postprandial levels fully normalizes fasting hyperglycaemia and reduces postprandial glycaemic increments. Due to rapid proteolytic cleavage, which results in an inactive or even antagonistic fragment. GLP-1 [9-36 amide], and to rapid elimination, the half-life of GLP-1 is too short to maintain therapeutic plasma levels for sufficient periods by subcutaneous injections of the natural peptide hormone. Current research aims to characterize GLP-1 analogues with more suitable pharmacokinetic properties than the original peptide. Given the large amount of GLP-1 present in L cells, it also appears worthwhile to search for more agents that could 'mobilize' this endogenous pool of GLP-1.

Topics: Animals; Cerebral Ventricles; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Feeding Behavior; Gastric Emptying; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Insulin; Models, Biological; Peptide Fragments; Proinsulin; Protein Precursors

Topics: Animals; Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Type 1; Digestive System; Digestive System Physiological Phenomena; Glucagon; Glucagon-Like Peptide 1; Homeostasis; Humans; Islets of Langerhans; Peptide Fragments; Proglucagon; Protein Precursors; Protein Processing, Post-Translational; Reference Values

Basic research on the cellular mechanisms that control the expression of the gene encoding glucagon has led to the discovery of proglucagon, which is processed alternatively by tissue-specific proteolysis to produce glucagon in the pancreatic alpha cells and a GLP-1 in the intestines. GLP-1 hormone is released into the circulation from intestinal L cells in response to meals and is the most potent incretin hormone known; GLP-1 and GIP appear to account for most, if not all, of the intestinal incretin effect in the augmentation of glucose-stimulated insulin secretion. Analyses of the mechanisms of action of GLP-1 and of glucose on isolated cultured rat beta cells using patch-clamp techniques to record ion channel activities has led to the glucose competence concept in which the combined glucose-signaling and GLP-1/cAMP-signaling pathways are required to affect depolarization of beta cells and to thereby stimulate insulin secretion. It is hypothesized that, among other possible target channels, the K-ATP channel is key first event in GLP-1/glucose-mediated activation of the beta cell secretory response. It is proposed that at least one factor contributing to the pathogenesis of NIDDM is a desensitization of the GLP-1 receptor on beta cells induced by the hypersecretion of GLP-1. Because of the discoveries that GLP-1 stimulates both secretion and production of insulin, and that the actions of GLP-1 are entirely glucose-dependent, GLP-1 may provide unique advantages over the sulfonylurea drugs in the treatment of NIDDM.

Topics: Amino Acid Sequence; Animals; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Insulin; Insulin Secretion; Molecular Sequence Data; Peptide Fragments; Protein Precursors

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Double-Blind Method; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Insulin

To evaluate the potential for glycaemic, renal and vascular benefits of bromocriptine quick release (BCQR) in adolescents and adults with type 1 diabetes.. Forty adolescents and 40 adults with type 1 diabetes aged 12-60 years old were enrolled in a double-blind, placebo-controlled, random order crossover study of 4 weeks of treatment in the morning with BCQR (titrated weekly from 0.8 mg to 1.6 mg to 3.2 mg, minimum dose 1.6 mg). Study assessments after each phase included blood pressure (BP), lipids, peripheral arterial stiffness and autonomic function, mixed meal tolerance test, continuous glucose monitoring (CGM), creatinine, estimated glomerular filtration rate, estimated insulin sensitivity, insulin dose and indirect calorimetry.. Adolescents displayed baseline hyperglycaemia, insulin resistance, metabolic dysfunction and increased renal filtration compared with adults. In both age groups, continuous glucose monitoring measures, estimated insulin sensitivity and insulin dose did not differ with BCQR treatment. In adolescents, BCQR decreased systolic BP, diastolic BP and triangular index and increased serum creatinine. In adults, systolic BP, mean arterial pressure, systemic vascular resistance, and mixed meal tolerance test glucose and glucagon-like peptide 1 areas under the curve were lower, and the orthostatic drop in systolic BP was greater with BCQR.. Greater hyperglycaemia, insulin resistance, metabolic dysfunction and renal hyperfiltration in adolescents argues for increased attention during this high-risk age period. Although BCQR had little impact on glycaemia or insulin sensitivity, initial vascular and renal responses suggest potential benefits of BCQR in adolescents and adults with type 1 diabetes requiring further study.

Topics: Adolescent; Adult; Blood Glucose; Blood Glucose Self-Monitoring; Bromocriptine; Child; Creatinine; Cross-Over Studies; Diabetes Mellitus, Type 1; Double-Blind Method; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Insulin; Insulin Resistance; Lipids; Middle Aged; Young Adult

Dietary fat and protein impact postprandial hyperglycemia in people with type 1 diabetes, but the underlying mechanisms are poorly understood. Glucoregulatory hormones are also known to modulate gastric emptying and may contribute to this effect.. Investigate the effects of fat and protein on glucagon-like peptide (GLP-1), glucagon-dependent insulinotropic polypeptide (GIP) and glucagon secretion.. 2 crossover euglycemic insulin clamp clinical trials at 2 Australian pediatric diabetes centers. Participants were 12-21 years (n = 21) with type 1 diabetes for ≥1 year. Participants consumed a low-protein (LP) or high-protein (HP) meal in Study 1, and low-protein/low-fat (LPLF) or high-protein/high-fat (HPHF) meal in Study 2, all containing 30 g of carbohydrate. An insulin clamp was used to maintain postprandial euglycemia and plasma glucoregulatory hormones were measured every 30 minutes for 5 hours. Data from both cohorts (n = 11, 10) were analyzed separately. The main outcome measure was area under the curve of GLP-1, GIP, and glucagon.. Meals low in fat and protein had minimal effect on GLP-1, while there was sustained elevation after HP (80.3 ± 16.8 pmol/L) vs LP (56.9 ± 18.6), P = .016, and HPHF (103.0 ± 26.9) vs LPLF (69.5 ± 31.9) meals, P = .002. The prompt rise in GIP after all meals was greater after HP (190.2 ± 35.7 pmol/L) vs LP (152.3 ± 23.3), P = .003, and HPHF (258.6 ± 31.0) vs LPLF (151.7 ± 29.4), P < .001. A rise in glucagon was also seen in response to protein, and HP (292.5 ± 88.1 pg/mL) vs LP (182.8 ± 48.5), P = .010.. The impact of fat and protein on postprandial glucose excursions may be mediated by the differential secretion of glucoregulatory hormones. Further studies to better understand these mechanisms may lead to improved personalized postprandial glucose management.

Topics: Adult; Australia; Biomarkers; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 1; Dietary Fats; Dietary Proteins; Female; Follow-Up Studies; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Insulin; Male; Meals; Prognosis

Adipose tissue is the primary energy reservoir of the human body, which also possesses endocrine functions. The glucagon-like peptide agonist liraglutide produces weight loss, although the specific effects on adipose tissue are unknown. We aimed to characterize the white adipose tissue composition and pericellular fibrosis of subcutaneous adipose tissue in response to liraglutide treatment. Furthermore, we explored the level of circulating free fatty acids, cluster of differentiation 163 (CD163) macrophage marker, leptin and adiponectin. Thirty-nine adults with type 1 diabetes and polyneuropathy were randomly assigned to 26 weeks of liraglutide or placebo treatment. Biopsies of subcutaneous tissue were formalin-fixed stained with picrosirius red to visualize collagen or immunohistochemically stained for CD163. Serum concentrations of free fatty acids, CD163, leptin and adiponectin were assessed with immunoassays or multiplex panels. In comparison with placebo, liraglutide induced weight loss (3.38 kg, 95% CI -5.29; -1.48, P < 0.001), but did not cause any differences in cell size, distribution of CD163-positive cells, pericellular fibrosis and serum levels of free fatty acids, CD163, leptin or adiponectin (all P < 0.1). Additionally, no associations between weight loss, cell size and serum markers were found (all P > 0.08). In conclusion, despite liraglutide's effect on weight loss, sustained alterations in subcutaneous adipose tissue did not seem to appear.

Topics: Adipose Tissue, White; Adult; Aged; Aged, 80 and over; Diabetes Mellitus, Type 1; Double-Blind Method; Female; Fibrosis; Glucagon-Like Peptide 1; Humans; Inflammation; Liraglutide; Male; Middle Aged; Subcutaneous Fat; Weight Loss

Hyperglucagonemia is a well-known contributor to diabetic hyperglycemia, and glucagon-like peptide 1 (GLP-1) suppresses glucagon secretion. Reduced inhibitory effects of glucose and GLP-1 on glucagon secretion may contribute to the hyperglucagonemia in diabetes and influence the success of GLP-1 receptor agonist therapy. We examined the dose-response relationship for GLP-1 on glucose-induced glucagon suppression in healthy individuals and patients with type 2 and type 1 diabetes. In randomized order, 10 healthy individuals with normal glucose tolerance, 10 patients with type 2 diabetes, and 9 C-peptide-negative patients with type 1 diabetes underwent 4 separate stepwise glucose clamps (five 30-min steps from fasting level to 15 mmol/L plasma glucose) during simultaneous intravenous infusions of saline or 0.2, 0.4, or 0.8 pmol GLP-1/kg/min. In healthy individuals and patients with type 2 diabetes, GLP-1 potentiated the glucagon-suppressive effect of intravenous glucose in a dose-dependent manner. In patients with type 1 diabetes, no significant changes in glucagon secretion were observed during the clamps whether with saline or GLP-1 infusions. In conclusion, the glucagonostatic potency of GLP-1 during a stepwise glucose clamp is preserved in patients with type 2 diabetes, whereas our patients with type 1 diabetes were insensitive to the glucagonostatic effects of both glucose and GLP-1.

Topics: Blood Glucose; Denmark; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Fasting; Female; Glucagon; Glucagon-Like Peptide 1; Glucose Clamp Technique; Glycated Hemoglobin; Healthy Volunteers; Humans; Male; Middle Aged; Treatment Outcome

GLP-1 receptor agonists are an established therapy in patients with type 2 diabetes; however, their role in type 1 diabetes remains to be determined.. Determine efficacy and safety of once-weekly albiglutide 30 mg (up-titration to 50 mg at week 6) versus placebo together with insulin in patients with new-onset type 1 diabetes and residual insulin production.. 52-week, randomized, phase 2 study (NCT02284009).. A prespecified Bayesian approach, incorporating placebo data from a prior study, allowed for 3:1 (albiglutide:placebo) randomization. The primary endpoint was 52-week change from baseline in mixed meal tolerance test (MMTT) stimulated 2-h plasma C-peptide area under the curve (AUC). Secondary endpoints included metabolic measures and pharmacokinetics of albiglutide.. 12/17 (70.6%, placebo) and 40/50 (80.0%, albiglutide) patients completed the study. Within our study, mean (standard deviation) change from baseline to week 52 in MMTT-stimulated 2-h plasma C-peptide AUC was -0.16 nmol/L (0.366) with placebo and -0.13 nmol/L (0.244) with albiglutide. For the primary Bayesian analysis (including prior study data) the posterior treatment difference (95% credible interval) was estimated at 0.12 nmol/L (0-0.24); the probability of a difference ≥0.2 nmol/L between treatments was low (0.097). A transient significant difference in maximum C-peptide was seen at week 28. Otherwise, no significant secondary endpoint differences were noted. On-therapy adverse events were reported in 82.0% (albiglutide) and 76.5% (placebo) of patients.. In newly diagnosed patients with type 1 diabetes, albiglutide 30 to 50 mg weekly for 1 year had no appreciable effect on preserving residual β-cell function versus placebo.

Topics: Adolescent; Adult; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Humans; Incretins; Male; Prognosis; Young Adult

Delayed gastric emptying (GE) is common but often asymptomatic in diabetes. The relationship between symptoms, glycemia, and neurohormonal functions, including glucagonlike peptide 1 (GLP-1), are unclear.. To assess whether GE disturbances, symptoms during a GE study, and symptoms during enteral lipid infusion explain daily symptoms and whether GLP-1 mediates symptoms during enteral lipid infusion.. In this randomized controlled trial, GE, enteral lipid infusion, gastrointestinal (GI) symptoms during these assessments, autonomic functions, glycosylated hemoglobin (HbA1c), and daily GI symptoms (2-week Gastroparesis Cardinal Symptom Index diary) were evaluated. During enteral lipid infusion, participants received the GLP-1 antagonist exendin 9-39 or placebo.. Single tertiary referral center.. 24 healthy controls and 40 patients with diabetic gastroenteropathy.. GE, symptoms during enteral lipid infusion, and the effect of exendin 9-39 on the latter.. In patients, GE was normal (55%), delayed (33%), or rapid (12%). During lipid infusion, GI symptoms tended to be greater (P = 0.06) in patients with diabetes mellitus (DM) than controls; exendin 9-39 did not affect symptoms. The HbA1c was inversely correlated with the mean symptom score during the GE study (r = -0.46, P = 0.003) and lipid infusion (r = -0.47, P < 0.01). GE and symptoms during GE study accounted for 40% and 32%, respectively, of the variance in daily symptom severity and quality of life.. In DM gastroenteropathy, GE and symptoms during a GE study explain daily symptoms. Symptoms during enteral lipid infusion were borderline increased but not reduced by a GLP-1 antagonist.

Topics: Administration, Oral; Adult; Asymptomatic Diseases; Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Emulsions; Female; Gastric Emptying; Gastrointestinal Diseases; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Lipids; Male; Middle Aged; Peptide Fragments; Quality of Life; Treatment Outcome

To explore the possible mechanisms behind the lower glycemic response observed when extra-virgin olive oil (EVOO) is added to a high-glycemic index meal in patients with type 1 diabetes (T1D).. According to a randomized cross-over design, eleven T1D patients (6 women, 5 men) on insulin pump consumed in the metabolic ward, one week apart, three high-glycemic index meals differing only for amount and quality of fat: high-monounsaturated fat (EVOO), high-saturated fat (Butter), and low-fat (LF). Before and after the meals, blood glucose (continuous glucose monitoring), gastric emptying rate (ultrasound technique), and plasma concentrations of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide GIP (ELISA), glucagon (RIA), and lipids (colorimetric assays) were evaluated.. Blood glucose iAUC (mmol/lx360 min) was lower after the EVOO (690 ± 431) than after the Butter (1320 ± 600) and LF meals (1007 ± 990) (M ± SD, p = 0.041 by repeated measures ANOVA). Gastric antrum volume was significantly larger in the early (60-90 min) postprandial phase (106 ± 21 vs. 90 ± 16 ml, p = 0.048) and significantly smaller in the late phase (330-360 min) (46 ± 10 vs. 57 ± 22 ml, p = 0.045) after the EVOO than after Butter meal. EVOO significantly increased postprandial GLP-1 iAUC (261 ± 311) compared to Butter (189 ± 349) (pmol/Lx180 min, p = 0.009). Postprandial GIP and glucagon responses were not significantly different between EVOO and Butter. Postprandial triglyceride iAUC was significantly higher after EVOO (100 ± 53) than after Butter (65 ± 60) (mmol/l × 360 min, p = 0.048).. Changes in gastric emptying and GLP-1 secretion and reduced glucose absorption through glucose-lipid competition may contribute to lower glycemia after a high-glycemic index meal with EVOO in T1D patients.. NCT02330939.

Topics: Adult; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 1; Female; Gastric Emptying; Glucagon-Like Peptide 1; Humans; Male; Middle Aged; Olive Oil; Postprandial Period

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

To test the effect of normoglycemia and glucagon-like peptide-1 (GLP-1), alone or in combination, on the possible normalization of endothelial function in type 1 diabetes.. Fifteen people with type 1 diabetes participated in three experiments: reaching and maintaining normoglycemia for 4h; reaching and maintaining hyperglycemia plus GLP-1 infusion for 4h; and reaching and maintaining normoglycemia for 4h with simultaneous infusion of GLP-1.. Both normoglycemia and GLP-1 infusion restored endothelial function and decreased and plasma 8-iso prostaglandin F2α levels. However, only the combination of normoglycemia and GLP-1 was able to normalize endothelial function.. This study confirms that long-lasting hyperglycemia in type 1 diabetes induces a permanent alteration which contributes to maintaining endothelial dysfunction even when glycemia is normalized, and that in the presence of normoglycemia, GLP-1 can contribute to normalizing endothelial function.

Topics: Adult; Blood Glucose; Case-Control Studies; Diabetes Mellitus, Type 1; Dinoprost; Endothelium, Vascular; Female; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Infusions, Parenteral; Male; Oxidative Stress; Vascular Diseases; Young Adult

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

Few studies have focused on postprandial incretin responses to different carbohydrate meals. Therefore, we designed a study to compare the different effects of two carbohydrates (75 g oral glucose, a monosaccharide and 100 g standard noodle, a polysaccharide, with 75 g carbohydrates equivalently) on postprandial glucose, insulin and incretin responses in different glucose tolerance groups.. This study was an open-label, randomized, two-way crossover clinical trial. 240 participants were assigned to take two carbohydrates in a randomized order separated by a washout period of 5-7 days. The plasma glucose, insulin, c-peptide, glucagon and active glucagon-like peptide-1 (AGLP-1) were measured. The incremental area under curve above baseline from 0 to 120 min of insulin (iAUC(0 -120 min)- INS) and AGLP-1(iAUC(0 -120 min)- AGLP-1) was calculated.. Compared with standard noodles, the plasma glucose and insulin after consumption of oral glucose were higher at 30 min (both P < 0.001) and 60 min (both P < 0.001), while lower at 180 min (both P < 0.001), but no differences were found at 120 min. The glucagon at 180 min was higher after consumption of oral glucose (P = 0.010). The AGLP-1 response to oral glucose was higher at 30 min (P < 0.001), 60 min (P < 0.001) and 120 min (P = 0.022), but lower at 180 min (P = 0.027). In normal glucose tolerance (NGT), oral glucose elicited a higher insulin response to the corresponding AGLP-1 (P < 0.001), which was represented by iAUC(0 -120 min) -INS /iAUC(0 -120 min)- AGLP-1, while in type 2 diabetes mellitus (T2DM), standard noodles did (P = 0.001).. Monosaccharide potentiated more rapid and higher glycemic and insulin responses. Oral glucose of liquid state would elicit a more potent release of AGLP-1. The incretin effect was amplified after consumption of standard noodles in T2DM.

Topics: Adolescent; Adult; Aged; Biomarkers; Blood Glucose; C-Peptide; China; Cross-Over Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Female; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Insulin; Male; Middle Aged; Postprandial Period; Predictive Value of Tests; Time Factors; Young Adult

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 observe the clinical efficacy of sitagliptin plus insulin on patients with brittle diabetes and to determine the effect of the combined therapy on glucagon secretion.
. This randomized, double-blinded and placebo-controlled trial included 30 patients with brittle diabetes. Participants were randomly assigned (1:1) to receive the treatment of either sitagliptin plus insulin or placebo plus insulin for 12 weeks. The blood glucose, hemoglobin A1c, insulin dose, C-peptide, glucagon, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and other parameters were determined.
. After 12 weeks of treatment, blood glucose was controlled better by sitagliptin plus insulin (P<0.01). The patients had significantly lower glucose variability indices, lower daily insulin requirement and hemoglobin A1c in the group of sitagliptin plus insulin (P<0.01). After steamed bun test, past-meal GLP-1 levels at 30 min were higher (P<0.01) while GIP levels were lower (P<0.01), with glucagon suppression in the sitagliptin plus insulin group. No significant change was observed at any time point in placebo plus insulin group.
. Sitagliptin significantly decreases blood glucose level and blood glucose fluctuation, which may contribute to the ability of sitagliptin in decreasing glucagon secretion.. 目的：观察西格列汀联合胰岛素治疗脆性糖尿病的临床疗效以及二者联合治疗对胰高血糖素的影响。方法：对30例脆性糖尿病患者进行1:1随机双盲分组，分为西格列汀联合胰岛素组和安慰剂联合胰岛素组，治疗12周，观察治疗后患者的血糖控制、血糖波动、糖化血红蛋白、胰岛素剂量、C肽、胰高血糖素、胰高血糖素样肽-1 (glucagon-like peptide-1，GLP-1)和葡萄糖依赖性促胰岛素肽(glucose-dependent insulinotropic polypeptide，GIP)水平等指标的变化。结果：治疗脆性糖尿病患者12周后，西格列汀联合胰岛素组血糖控制的水平和达标率明显优于治疗前和安慰剂联合胰岛素组(P<0.01)；胰岛素用量和糖化血红蛋白较治疗前和安慰剂联合胰岛素组明显减少(P<0.01)；行馒头餐试验，餐后30 min西格列汀联合胰岛素组的胰高血糖素和GIP水平明显低于治疗前和安慰剂联合胰岛素组(P<0.01)，而GLP-1(60 min)水平较治疗前和安慰剂联合胰岛素组升高(P<0.05)。安慰剂联合胰岛素组各指标在治疗前后比较，差异无统计学意义(P>0.05)。结论：在加用西格列汀后，能够更好地控制脆性糖尿病患者血糖和降低血糖波动的幅度；可能是通过降低餐后胰高血糖素水平来稳定脆性糖尿病患者的血糖水平。.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Sitagliptin Phosphate

OBJECTIVE Glucagon-like peptide 1 (GLP-1) is an incretin hormone that is released from the gastrointestinal tract. Treatment with GLP-1 analogs has proven to be of clinical use for patients with type 2 diabetes. Patients with type 1 diabetes, particularly those with residual β-cell function, may also respond to treatment, but the acute metabolic effects of GLP-1 analogs on these patients in reaction to both oral and intravenous glucose challenges are not well understood. RESEARCH DESIGN AND METHODS Seventeen patients with type 1 diabetes, half of whom had residual insulin production, underwent two mixed-meal tolerance tests (MMTTs) and two intravenous glucose tolerance tests (IVGTTs), with and without pretreatment with exenatide. No exogenous bolus insulin was administered for the studies. Glucose excursions, insulin secretion rates (ISRs), and levels of glucagon, endogenous GLP-1, and gastric inhibitory polypeptide were measured after the meal or glucose loads. RESULTS During the MMTT, glucose levels were suppressed with exenatide in patients with or without residual insulin production (P = 0.0003). Exenatide treatment did not change the absolute ISR, but the ISR to glucose levels were increased (P = 0.0078). Gastric emptying was delayed (P = 0.0017), and glucagon was suppressed (P = 0.0015). None of these hormonal or glucose changes were detected during the IVGTT with exenatide administration. CONCLUSIONS Exenatide showed a significant antidiabetogenic effect prior to an oral meal in patients with type 1 diabetes involving glucagon suppression and gastric emptying, while preserving increased insulin secretion. GLP-1 analogs may be useful as an adjunctive treatment in type 1 diabetes.

Topics: Administration, Intravenous; Administration, Oral; Adolescent; Adult; Diabetes Mellitus, Type 1; Exenatide; Female; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Male; Middle Aged; Peptides; Venoms; Young Adult

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

Glucagon-like peptide 1 (GLP-1) is a glucose-lowering, intestinal-derived factor with multiple physiological effects, making it attractive for diabetes therapy. However, the therapeutic potential of endogenous GLP-1 is limited, because of rapid inactivation by dipeptidyl peptidase-4. Recently, enhanced incretin preparations, such as liraglutide, have emerged, which are more resistant to degradation and longer lasting. Liraglutide is a long-acting acylated human GLP-1 receptor agonist, with a 97% amino acid sequence identity to endogenous human GLP-1, and 100% amino acid sequence homology with canine GLP-1. Since liraglutide has yet to be examined for use in dogs, and the incretin effect has been reported to exist in dogs, we sought to initially characterize liraglutide's ability for glycemic control in healthy dogs, under an oral glucose tolerance test (OGTT) environment initially. This was followed up a more realistic scenario involving food with insulin injection +/- liraglutide injection resulting in a glucose curve based study involving dogs suffering from Type 1 diabetes mellitus (T1DM). Overall, liraglutide had a stabilizing effect on glucose levels, maintaining circulating levels between 77.0 and 137.0mg/ml throughout the OGTT test period, resulting in a significant reduction of 13.8% in glucose AUC0-120 min (total area under the curve for 0-120 min) as compared to baseline control in healthy dogs (n=5). Interestingly, the liraglutide associated reduction in circulating glucose was not accompanied by any significant increase in insulin. Moreover, T1DM dogs (n=4) responded favorably to liraglutide treatment, which lead to a significant reduction of 46.0% in glucose AUC0-12h (total area under the curve for 0-12h), and a significant reduction of 66.5% in serum glucose as compared to baseline controls (insulin treatment only). Therefore, liraglutide's prandial glucagon suppressive ability appears to play a key role in its glucose-lowering capability, and offers great potential for use with dogs suffering from T1DM.

Topics: Animals; Area Under Curve; Blood Glucose; Case-Control Studies; Diabetes Mellitus, Type 1; Dog Diseases; Dogs; Female; Glucagon-Like Peptide 1; Insulin; Liraglutide; Male

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

Type 1 diabetes mellitus (T1DM) is mainly caused by reduction of the endogenous insulin secretion due to autoimmune destruction of pancreatic β cells, and a promising therapeutic approach for T1DM is pancreas and islet cell replacement. The major obstacle is the limited source of insulin-producing cells. Here, we report an efficient approach to induce human adipose-derived stromal cells (hADSCs) to differentiate into insulin-producing cells, with glucagon-like peptide-1 (GLP-1). hADSCs were successfully isolated from the adipose tissue, with adipogenic and osteogenic differentiation potency. Islet-like cell clusters formed in the culture, which was enhanced with the treatment of GLP-1. Reverse transcription polymerase chain reaction analysis showed the expression of the pancreas-related genes in the differentiated cells, such as pdx-1, ngn3, insulin, glucagon, somatostatin, glucokinase n and glut2. Immunocytochemical analysis showed that the induced cells co-expressed insulin, C-peptide and PDX-1. The GLP-1 receptor was present in the differentiated cells. In addition, flow cytometry analysis and ELISA showed that, in the presence of GLP-1, the percentage of insulin-producing cells was increased from 5.9% to 28.0% and the release of insulin increased from 9.53±0.7 pmol/106 cells to 15.86±1.3 pmol/106 cells. Insulin was released in response to glucose stimulation in a manner comparable to that of adult human islets. These results indicated that hADSCs isolated from adipose tissues can be induced to differentiate into insulin-producing cells, which is further enhanced with the treatment of GLP-1. These findings confirm that the differentiation of hADSCs to insulin-producing cells is indeed possible and indicate that the differentiated insulin-producing cells can be used as a potential source for transplantation into patients with T1DM.

Topics: Adipose Tissue; Adult; Antigens, Differentiation; Cell Differentiation; Cells, Cultured; Diabetes Mellitus, Type 1; Female; Glucagon-Like Peptide 1; Humans; Incretins; Insulin-Secreting Cells; Male; Stromal Cells

In patients with type 2 diabetes, but not type 1 diabetes, abnormal secretion of incretins in response to oral nutrients has been described. In healthy youths, we recently reported accentuated glucagon-like peptide 1 (GLP-1) secretion in response to a diet soda sweetened with sucralose and acesulfame-K. In this study, we examined the effect of diet soda on gut hormones in youths with diabetes.. Subjects aged 12-25 years with type 1 diabetes (n = 9) or type 2 diabetes (n = 10), or healthy control participants (n = 25) drank 240 mL cola-flavored caffeine-free diet soda or carbonated water, followed by a 75-g glucose load, in a randomized, cross-over design. Glucose, C-peptide, GLP-1, glucose-dependent insulinotropic peptide (GIP), and peptide Tyr-Tyr (PYY) were measured for 180 min. Glucose and GLP-1 have previously been reported for the healthy control subjects.. GLP-1 area under the curve (AUC) was 43% higher after ingestion of diet soda versus carbonated water in individuals with type 1 diabetes (P = 0.020), similar to control subjects (34% higher, P = 0.029), but was unaffected by diet soda in patients with type 2 diabetes (P = 0.92). Glucose, C-peptide, GIP, and PYY AUC were not statistically different between the two conditions in any group.. Ingestion of diet soda before a glucose load augmented GLP-1 secretion in type 1 diabetic and control subjects but not type 2 diabetic subjects. GIP and PYY secretion were not affected by diet soda. The clinical significance of this increased GLP-1 secretion, and its absence in youths with type 2 diabetes, needs to be determined.

Topics: Adolescent; Adult; Blood Glucose; C-Peptide; Carbonated Beverages; Child; Cross-Over Studies; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Glucose; Humans; Male; Peptide YY; Young Adult

colesevelam is indicated to lower low density lipoprotein cholesterol (LDL-C) in hyperlipidaemia and improve glycaemic control in adults with type 2 diabetes. This short-term pilot study evaluates its effects in type 1 diabetes.. this double-blind, randomized, investigator-initiated, single-centred, 12-week pilot study evaluated 40 adults (age = 36.4 ± 9.4 years) with type 1 diabetes (duration = 20.4 ± 8.5 years) and hyperlipidaemia. It was powered to show a treatment difference of >10% LDL-C reduction. Subjects received 3.75 g/day colesevelam (n = 20) or placebo (n = 20) for 12 weeks. LDL-C and haemoglobin A1c (A1c) levels were assessed at screening (week 2), baseline (week 0) and every 4 weeks throughout the treatment duration. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) levels were measured during 4-h meal (Boost Plus, Nestle HealthCare Nutrition Inc., Florham Park, New Jersey, USA) challenge tests (MCT) at baseline and 12 weeks.. colesevelam treatment resulted in a significant reduction in LDL-C values at 4 weeks [-12.1% (95% CI: -20.1 to -4.1), p = 0.004] which was sustained for the study duration (p = 0.005 at 12 weeks). The treatment group also showed a significant change in A1c from baseline at week 4; however, this was not significant for the study duration. There was a significant median increase in GLP-1 levels during the first 2 h of the baseline MCT in the treated group but no difference at 12 weeks.. during this short-term pilot study, colesevelam treatment effectively lowered LDL-C in patients with type 1 diabetes. Improvements in A1c seen at week 4 were not sustained. Effects on glycaemic control in subjects with type 1 diabetes may be related to a postprandial rise in GLP-1 levels and require further clinical study.

Topics: Adolescent; Adult; Aged; Allylamine; Anticholesteremic Agents; Blood Glucose; Cholesterol, LDL; Colesevelam Hydrochloride; Diabetes Mellitus, Type 1; Double-Blind Method; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hyperlipidemias; Male; Middle Aged; Patient Compliance; Pilot Projects; Young Adult

To investigate the effect of exogenous as well as endogenous glucagon-like peptide 1 (GLP-1) on postprandial glucose excursions and to characterize the secretion of incretin hormones in type 1 diabetic patients with and without residual β-cell function.. Eight type 1 diabetic patients with (T1D+), eight without (T1D-) residual β-cell function, and eight healthy matched control subjects were studied during a mixed meal with concomitant infusion of GLP-1 (1.2 pmol/kg/min), saline, or exendin 9-39 (300 pmol/kg/min). Before the meal, half dose of usual fast-acting insulin was injected. Plasma glucose (PG), glucagon, C-peptide, total GLP-1, intact glucose-dependent insulinotropic polypeptide (GIP), free fatty acids, triglycerides, and gastric emptying rate (GE) by plasma acetaminophen were measured.. Incretin responses did not differ between patients and control subjects. Infusion of GLP-1 decreased peak PG by 45% in both groups of type 1 diabetic patients. In T1D+ patients, postprandial PG decreased below fasting levels and was indistinguishable from control subjects infused with saline. In T1D- patients, postprandial PG remained at fasting levels. GLP-1 infusion reduced GE and glucagon levels in all groups and increased fasting C-peptide in T1D+ patients and control subjects. Blocking endogenous GLP-1 receptor action increased endogenous GLP-1 secretion in all groups and increased postprandial glucose, glucagon, and GE in T1D+ and T1D- patients. The insulinogenic index (the ratio of insulin to glucose) decreased in T1D+ patients during blockade of endogenous GLP-1 receptor action.. Type 1 diabetic patients have normal incretin responses to meals. In type 1 diabetic patients, exogenous GLP-1 decreases peak postprandial glucose by 45% regardless of residual β-cell function. Endogenous GLP-1 regulates postprandial glucose excursions by modulating glucagon levels, GE, and β-cell responsiveness to glucose. Long-term effects of GLP-1 in type 1 diabetic patients should be investigated in future clinical trials.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Female; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Male; Peptide Fragments; Triglycerides; Young Adult

To investigate the effect of 4 weeks of treatment with liraglutide on insulin dose and glycemic control in type 1 diabetic patients with and without residual β-cell function.. Ten type 1 diabetic patients with residual β-cell function (C-peptide positive) and 19 without (C-peptide negative) were studied. All C-peptide-positive patients were treated with liraglutide plus insulin, whereas C-peptide-negative patients were randomly assigned to liraglutide plus insulin or insulin monotherapy. Continuous glucose monitoring with identical food intake and physical activity was performed before (week 0) and during (week 4) treatment. Differences in insulin dose; HbA1c; time spent with blood glucose<3.9, >10, and 3.9-9.9 mmol/L; and body weight were evaluated.. Insulin dose decreased from 0.50±0.06 to 0.31±0.08 units/kg per day (P<0.001) in C-peptide-positive patients and from 0.72±0.08 to 0.59±0.06 units/kg per day (P<0.01) in C-peptide-negative patients treated with liraglutide but did not change with insulin monotherapy. HbA1c decreased in both liraglutide-treated groups. The percent reduction in daily insulin dose was positively correlated with β-cell function at baseline, and two patients discontinued insulin treatment. In C-peptide-positive patients, time spent with blood glucose<3.9 mmol/L decreased from 3.0 to 1.0 h (P=0.03). A total of 18 of 19 patients treated with liraglutide lost weight during treatment (mean [range] -2.3±0.3 kg [-0.5 to -5.1]; P<0.001). Transient gastrointestinal adverse effects occurred in almost all patients treated with liraglutide.. Treatment with liraglutide in type 1 diabetic patients reduces insulin dose with improved or unaltered glycemic control.

Topics: Adolescent; Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Exercise Test; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Liraglutide; Male; Middle Aged; Weight Loss

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

Postprandial plasma immunoreactive active glucagon-like peptide-1 (p-active GLP-1) levels in type 1 diabetic patients who did not use bolus insulin responded normally following ingestion of test meal, while a small response of p-active GLP-1 levels was seen in type 2 diabetic patients. To determine whether p-active GLP-1 levels are affected by ingestion of test meal in type 1 diabetic Japanese patients who used bolus rapid-acting insulin analogues, plasma glucose (PG), serum immunoreactive insulin (s-IRI), serum immunoreactive C-peptide (s-CPR), and p-active GLP-1 levels were measured 0, 30, and 60 min after ingestion of test meal in Japanese patients without diabetic complications (n=10, group 1) and control subjects with normal glucose tolerance (n=15, group 2). HbA1c levels were also measured in these groups. The patients in group 1 were treated with multiple daily injections or CSII using injections of bolus rapid-acting insulin analogues before ingestion of test meal. There was no significant difference in mean of sex, age, or BMI between groups. Means of HbA1c, basal and postprandial PG, and postprandial s-IRI levels with integrated areas under curves (0-60 min) (AUC) in group 1 were significantly higher than those in group 2. Means of basal and postprandial s-CPR, and postprandial p-active GLP-1 levels with AUCs were significantly lower in group 1 than in group 2. These results indicated that postprandial p-active GLP-1 levels following ingestion of test meal in type 1 diabetic Japanese patients using bolus rapid-acting insulin analogues were decreased relative to those in controls.

Topics: Biphasic Insulins; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin, Short-Acting; Male; Middle Aged; Postprandial Period

Amylin, cosecreted with insulin, has like glucagon-like peptide-1 (GLP-1) been reported to inhibit glucagon secretion, delay gastric emptying, and reduce appetite and food intake. We investigated whether the effects of GLP-1 on gastric emptying, appetite, and food intake are mediated directly or indirectly via release of amylin.. Eleven C-peptide and amylin-negative patients with type 1 diabetes mellitus (T1DM) and 12 matched healthy controls participated in a placebo-controlled, randomized, single-blinded, crossover study. With glucose clamped between 6 and 9 mm, near-physiological infusions of GLP-1, human amylin, pramlintide, or saline were given for 270 min during and after a fixed meal. Gastric emptying was measured using paracetamol, appetite using visual analog scales, and food intake during a subsequent ad libitum meal (at 240 min).. In T1DM, gastric emptying, food intake, and appetite were reduced equally during low GLP-1 and amylin infusion compared with the saline infusion (P < 0.05). The controls showed stronger suppression of gastric emptying (P < 0.0001) and food intake (P < 0.01) with GLP-1 compared to amylin. Postprandial glucagon responses were reduced in controls and T1DM during GLP-1 and amylin infusions (P < 0.05). Amylin and pramlintide infusion had similar effects.. GLP-1 exerts its effect on gastric emptying, appetite, food intake, and glucagon secretion directly, although secretion of amylin may contribute to some of these effects in healthy control subjects.

Topics: Adult; Amyloid; Appetite; Body Mass Index; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 1; Gastric Emptying; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Islet Amyloid Polypeptide; Reference Values; Single-Blind Method

Liraglutide is a glucagon-like peptide-1 (GLP-1) analog developed for type 2 diabetes. Long-term liraglutide exposure in rodents was associated with thyroid C-cell hyperplasia and tumors. Here, we report data supporting a GLP-1 receptor-mediated mechanism for these changes in rodents. The GLP-1 receptor was localized to rodent C-cells. GLP-1 receptor agonists stimulated calcitonin release, up-regulation of calcitonin gene expression, and subsequently C-cell hyperplasia in rats and, to a lesser extent, in mice. In contrast, humans and/or cynomolgus monkeys had low GLP-1 receptor expression in thyroid C-cells, and GLP-1 receptor agonists did not activate adenylate cyclase or generate calcitonin release in primates. Moreover, 20 months of liraglutide treatment (at >60 times human exposure levels) did not lead to C-cell hyperplasia in monkeys. Mean calcitonin levels in patients exposed to liraglutide for 2 yr remained at the lower end of the normal range, and there was no difference in the proportion of patients with calcitonin levels increasing above the clinically relevant cutoff level of 20 pg/ml. Our findings delineate important species-specific differences in GLP-1 receptor expression and action in the thyroid. Nevertheless, the long-term consequences of sustained GLP-1 receptor activation in the human thyroid remain unknown and merit further investigation.

Topics: Animals; Blotting, Western; Calcitonin; Cell Line; Cell Proliferation; Cells, Cultured; Cyclic AMP; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Gene Expression; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Immunohistochemistry; In Situ Hybridization; Liraglutide; Macaca fascicularis; Mice; Mice, Knockout; Obesity; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Species Specificity; Thyroid Gland

Glucagon-like peptide-1 (GLP-1) is a potent insulinotropic peptide expressed in the gut and brain, which is secreted in response to food intake. The levels of GLP-1 within the brain have been related to the activity of the hypothalamic-pituitary-adrenal (HPA) axis, and hence, this peptide might mediate some responses to stress. Nevertheless, there is little information regarding the effects of circulating GLP-1 on the neuroendocrine control of HPA activity. Here, we have studied the response of corticoadrenal steroids to the peripheral administration of GLP-1 (7-36)-amide and related peptides [exendin (Ex)-3, Ex-4, and Ex-4(3-39)] in rats, mice, and humans. GLP-1 increases circulating corticosterone levels in a time-dependent manner, both in conscious and anaesthetized rats, and it has also increased aldosterone levels. Moreover, GLP-1 augmented cortisol levels in healthy subjects and diabetes mellitus (DM)-1 patients. The effects of GLP-1/Ex-4 on the HPA axis are very consistent after distinct means of administration (intracerebroventricular, iv, and ip), irrespective of the metabolic state of the animals (fasting or fed ad libitum), and they were reproduced by different peptides in this family, independent of glycaemic changes and their insulinotropic properties. Indeed, these effects were also observed in diabetic subjects (DM-1 patients) and in the DM-1 streptozotocin-rat or DM-2 muscle IGF-I receptor-lysine-arginine transgenic mouse animal models. The mechanisms whereby circulating GLP-1 activates the HPA axis remain to be elucidated, although an increase in ACTH after Ex-4 and GLP-1 administration implicates the central nervous system or a direct effect on the pituitary. Together, these findings suggest that GLP-1 may play an important role in regulating the HPA axis.

Topics: Adrenocorticotropic Hormone; Adult; Animals; Corticosterone; Diabetes Mellitus, Type 1; Exenatide; Glucagon-Like Peptide 1; Humans; Hypothalamo-Hypophyseal System; Injections, Intraperitoneal; Injections, Intravenous; Male; Mice; Mice, Transgenic; Peptides; Pituitary-Adrenal System; Rats; Rats, Sprague-Dawley; Venoms; Young Adult

To compare the responses of GIP, GLP-1, ghrelin and IGFBP-1 between meals with different fat and energy content in adolescents with type 1 diabetes (T1DM) and to relate them to gastric emptying and glycaemia.. On different days and in a random order, 7 adolescents with T1DM ingested a high- and low-fat meal (fat content: 38 and 2 g, energy content: 640 and 320 kcal, respectively). At normoglycaemia, the same prandial insulin dose was given at both meals and to all subjects. Postprandial blood samples were taken repeatedly over 4 hours. Gastric emptying was estimated by the paracetamol absorption method.. The area under the curve (AUC) for GIP(0-240 min) and for GLP-1(0-120 min) was larger, but smaller for relative ghrelin(0-240 min), after the high-fat meal (p = 0.002, 0.030 and 0.043, respectively). IGFBP-1 decreased significantly, but not differently, after the meals. Larger GLP-1 secretion correlated with slower gastric emptying (p = 0.029) and higher fasting ghrelin levels correlated with lower postprandial glycaemia (p = 0.007).. In adolescents with T1DM, the postprandial responses of GIP, GLP-1 and ghrelin, but not that of IGFBP-1, depend more on meal size than on insulin.

Topics: Adolescent; Area Under Curve; Blood Glucose; Diabetes Mellitus, Type 1; Dietary Fats; Energy Intake; Female; Gastric Emptying; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Insulin-Like Growth Factor Binding Protein 1; Male; Pilot Projects; Postprandial Period

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

To examine the insulinomimetic insulin-independent effects of glucagon-like peptide (GLP)-1 on glucose uptake in type 1 diabetic patients.. We used the hyperinsulinemic-euglycemic clamp (480 pmol. m(-2) x min(-1)) in paired randomized studies of six women and five men with type 1 diabetes. In the course of one of the paired studies, the subjects also received GLP-1 at a dose of 1.5 pmol. kg(-1) x min(-1). The patients were 41 +/- 3 years old with a BMI of 25 +/- 1 kg/m(2). The mean duration of diabetes was 23 +/- 3 years.. Plasma glucose was allowed to fall from a fasting level of approximately 11 mmol/l to 5.3 mmol/l in each study and thereafter was held stable at that level. Plasma insulin levels during both studies were approximately 900 pmol/l. Plasma C-peptide levels did not change during the studies. In the GLP-1 study, plasma total GLP-1 levels were elevated from the fasting level of 31 +/- 3 to 150 +/- 17 pmol/l. Plasma glucagon levels fell from the fasting levels of approximately 14 pmol/l to 9 pmol/l during both paired studies. Hepatic glucose production was suppressed during the glucose clamps in all studies. Glucose uptake was not different between the two studies ( approximately 40 micromol. kg(-1) x min(-1)).. GLP-1 does not augment insulin-mediated glucose uptake in lean type 1 diabetic patients.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose Clamp Technique; Humans; Hyperinsulinism; Insulin; Liver; Male; Neurotransmitter Agents; Peptide Fragments; Peptides

The effect of the insulinotropic incretin hormone, glucagon-like peptide-1 (GLP-1), is preserved in typical middle-aged, obese, insulin-resistant type 2 diabetic patients, whereas a defective amplification of the so-called late-phase plasma insulin response (20-120 min) to glucose by the other incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), is seen in these patients. The aim of the present investigation was to evaluate plasma insulin and C-peptide responses to GLP-1 and GIP in five groups of diabetic patients with etiology and phenotype distinct from the obese type 2 diabetic patients. We studied (six in each group): 1) patients with diabetes mellitus secondary to chronic pancreatitis; 2) lean type 2 diabetic patients (body mass index < 25 kg/m(2)); 3) patients with latent autoimmune diabetes in adults; 4) diabetic patients with mutations in the HNF-1alpha gene [maturity-onset diabetes of the young (MODY)3]; and 5) newly diagnosed type 1 diabetic patients. All participants underwent three hyperglycemic clamps (2 h, 15 mM) with continuous infusion of saline, 1 pmol GLP-1 (7-36)amide/kg body weight.min or 4 pmol GIP pmol/kg body weight.min. The early-phase (0-20 min) plasma insulin response tended to be enhanced by both GIP and GLP-1, compared with glucose alone, in all five groups. In contrast, the late-phase (20-120 min) plasma insulin response to GIP was attenuated, compared with the plasma insulin response to GLP-1, in all five groups. Significantly higher glucose infusion rates were required during the late phase of the GLP-1 stimulation, compared with the GIP stimulation. In conclusion, lack of GIP amplification of the late-phase plasma insulin response to glucose seems to be a consequence of diabetes mellitus, characterizing most, if not all, forms of diabetes.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Chronic Disease; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; DNA-Binding Proteins; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose; Hepatocyte Nuclear Factor 1; Hepatocyte Nuclear Factor 1-alpha; Hepatocyte Nuclear Factor 1-beta; Humans; Hyperglycemia; Insulin; Islets of Langerhans; Male; Middle Aged; Neurotransmitter Agents; Nuclear Proteins; Pancreatitis; Peptide Fragments; Phenotype; Protein Precursors; Transcription Factors

We have recently described a novel phenotype in a group of subjects with type 1 diabetes that is manifested by glucose >11.1 mmol/l 120 min after an oral glucose load, but with normal fasting glucose levels. We now describe the metabolic characteristics of these subjects by comparing parameters of islet hormone secretion and glucose disposal in these subjects to age-matched nondiabetic control subjects. The patients with type 1 diabetes had fasting glucose, insulin, and glucagon values similar to those of control subjects. Additionally, the insulin secretory response to intravenous arginine at euglycemia was similar in the control and diabetic groups (264 +/- 33.5 and 193 +/- 61.3 pmol/l; P = 0.3). However, marked differences in beta-cell function were found in response to hyperglycemia. Specifically, the first-phase insulin response was lower in diabetic subjects (329.1 +/- 39.6 vs. 91.3 +/- 34.1 pmol/l; P < 0.001), as was the slope of glucose potentiation of the insulin response to arginine (102 +/- 18.7 vs. 30.2 +/- 6.1 pmol/l per mmol/l; P = 0.005) and the maximum insulin response to arginine (2,524 +/- 413 vs. 629 +/- 159 pmol/l; P = 0.001). Although plasma levels of glucagon-like peptide (GLP)-1 and gastric inhibitory peptide (GIP) did not differ between control and diabetic subjects, the incretin effect was lower in the diabetic patients (70.3 +/- 5.4 vs. 52.1 +/- 5.9%; P = 0.03). Finally, there was a lack of suppression of glucagon in the patients after both oral and intravenous glucose administration, which may have contributed to their postprandial hyperglycemia. Glucose effectiveness did not differ between patients and control subjects, nor did insulin sensitivity, although there was a tendency for the patients to be insulin resistant (9.18 +/- 1.59 vs. 5.22 +/- 1.17 pmol.(-1).min(-1); P = 0.08). These data characterize a novel group of subjects with type 1 diabetes manifested solely by hyperglycemia following an oral glucose load in whom islet function is normal at euglycemia, but who have marked defects in both alpha- and beta-cell secretion at hyperglycemia. This pattern of abnormalities may be characteristic of islet dysfunction early in the development of type 1 diabetes.

Topics: Arginine; Autoantibodies; Blood Glucose; Diabetes Mellitus, Type 1; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Peptide Fragments; Reference Values

The primary objective of this double-blind, placebo-controlled, randomised cross-over study was to investigate the influence of acarbose on insulin requirement in patients with Type 1 diabetes (T1DM) following a standardised meal. In addition, the study assessed the effects of acarbose on post-prandial triglyceride, glucagon and gastrointestinal peptide levels, gastric emptying, and oxidative glucose metabolism. Following normalisation of their blood glucose, 10 patients received a standardised meal together with acarbose (100 mg) or placebo. Each patient was evaluated twice (separated by 10+/-3 days), and the cross-over study design ensured that they received both acarbose and placebo. The insulin requirement for maintenance of normoglycaemia was assessed using a closed-loop insulin infusion system (artificial pancreas, Biostator). Acarbose produced a statistically significant reduction in mean insulin requirement over a 3-hr period following the meal compared with placebo (5171.7+/-2282.6 mU vs 8074.5+/-3045.4 mU; p=0.003). The level of blood glucose control over the same period was similar in the two groups. Gastric inhibitory polypeptide levels also showed a statistically significant decrease with acarbose treatment compared with placebo for AUC (area under the curve; p=0.006) and Cmax (maximum plasma concentration; p=0.022), but not tmax (time to reach Cmax from the start of the standardised meal; p>0.05). Analysis of the other efficacy parameters revealed no statistically significant differences between acarbose treatment and placebo (p>0.05). These results indicate that acarbose decreases insulin requirement in patients with T1DM without affecting gastric emptying.

Topics: Acarbose; Adult; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 1; Double-Blind Method; Female; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Male; Peptide Fragments; Postprandial Period; Protein Precursors; Triglycerides

Exogenous glucagon-like peptide 1(GLP-1) bioactivity is preserved in type 2 diabetic patients, resulting the peptide administration in a near-normalization of plasma glucose mainly through its insulinotropic effect. GLP-1 also reduces meal-related insulin requirement in type 1 diabetic patients, suggesting an impairment of the entero-insular axis in both diabetic conditions. To investigate this metabolic dysfunction, we evaluated endogenous GLP-1 concentrations, both at fasting and in response to nutrient ingestion, in 16 type 1 diabetic patients (age = 40.5 +/- 14yr, HbA1C = 7.8 +/- 1.5%), 14 type 2 diabetics (age = 56.5 +/- 13yr, HbA1C = 8.1 +/- 1.8%), and 10 matched controls. In postabsorptive state, a mixed breakfast (230 KCal) was administered to all subjects and blood samples were collected for plasma glucose, insulin, C-peptide and GLP-1 determination during the following 3 hours. In normal subjects, the test meal induced a significant increase of GLP-1 (30', 60': p < 0.01), returning the peptide values towards basal concentrations. In type 2 diabetic patients, fasting plasma GLP-1 was similar to controls (102.1 +/- 1.9 vs. 97.3 +/- 4.01 pg/ml), but nutrient ingestion failed to increase plasma peptide levels, which even decreased during the test (p < 0.01). Similarly, no increase in postprandial GLP-1 occurred in type 1 diabetics, in spite of maintained basal peptide secretion (106.5 +/- 1.5 pg/ml). With respect to controls, the test meal induced in both diabetic groups a significant increase in plasma glucagon levels at 60' (p < 0.01). In conclusion, either in condition of insulin resistance or insulin deficiency chronic hyperglycemia, which is a common feature of both metabolic disorders, could induce a progressive desensitization of intestinal L-cells with consequent peptide failure response to specific stimulation.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Eating; Female; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Insulin; Male; Middle Aged; Peptide Fragments; Radioimmunoassay

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Male; Middle Aged; Pancreatic Polypeptide; Peptide Fragments; Time Factors

Glucagon-like peptide I(7-36) amide (GLP-1) is a physiological incretin hormone that, in slightly supraphysiological doses, stimulates insulin secretion, lowers glucagon concentrations, and thereby normalizes elevated fasting plasma glucose concentrations in type II diabetic patients. It is not known whether GLP-1 has effects also in fasting type I diabetic patients.. In 11 type I diabetic patients (HbA1c 9.1 +/- 2.1%; normal, 4.2-6.3%), fasting hyperglycemia was provoked by halving their usual evening NPH insulin dose. In random order on two occasions, 1.2 pmol . kg-1 . min-1 GLP-1 or placebo was infused intravenously in the morning (plasma glucose 13.7 +/- 0.9 mmol/l; plasma insulin 26 +/- 4 pmol/l). Glucose (glucose oxidase method), insulin, C-peptide, glucagon, GLP-1, cortisol, growth hormone (immunoassays), triglycerides, cholesterol, and nonesterified fatty acids (enzymatic tests) were measured.. Glucagon was reduced from approximately 8 to 4 pmol/l, and plasma glucose was lowered from 13.4 +/- 1.0 to 10.0 +/- 1.2 mmol/l with GLP-1 administration (plasma concentrations approximately 100 pmol, P < 0.0001), but not with placebo (14.2 +/- 0.7 to 13.2 +/- 1.0). Transiently, C-peptide was stimulated from basal 0.09 +/- 0.02 to 0.19 +/- 0.06 nmol/l by GLP-1 (P < 0.0001), but not by placebo (0.07 +/- 0.02 to 0.07 +/- 0.02). There was no significant effect on nonesterified fatty acids (P = 0.34), triglycerides (P = 0.57), cholesterol (P = 0.64), cortisol (P = 0.40), or growth hormone (P = 0.53).. Therefore, exogenous GLP-1 is able to lower fasting glycemia also in type I diabetic patients, mainly by reducing glucagon concentrations. However, this alone is not sufficient to normalize fasting plasma glucose concentrations, as was previously observed in type II diabetic patients, in whom insulin secretion (C-peptide response) was stimulated 20-fold.

Topics: Adult; Analysis of Variance; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Fasting; Fatty Acids, Nonesterified; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Insulin; Male; Peptide Fragments; Protein Precursors; Time Factors

This study evaluated whether adding sodium-glucose cotransporter-2 inhibitors (SGLT2i) and/or glucagon-like peptide-1 receptor agonists (GLP1-RA) to insulin reduced weight and glycemia in people with type 1 diabetes.. This retrospective analysis of electronic health records evaluated 296 people with type 1 diabetes over 12 months after medications were first prescribed. Four groups were defined: control n = 80, SGLT2i n = 94, GLP1-RA n = 82, and combination of drugs (Combo) n = 40. We measured changes at 1 year in weight and glycated hemoglobin (HbA1c).. The control group did not have changes in weight or glycemic control. The mean (SD) percentage weight loss after 12 months was 4.4% (6.0%), 8.2%  (8.5%), and 9.0% (8.4%) in the SGLT2i, GLP1-RA, and Combo groups, respectively (p < 0.001). The Combo group lost the most weight (p < 0.001). The HbA1c reduction was 0.4%  (0.7%), 0.3% (0.7%), and 0.6% (0.8%) in the SGLT2i, GLP1-RA, and Combo groups, respectively (p < 0.001). The Combo group had the biggest improvements in glycemic control and total and low-density lipoprotein cholesterol compared with baseline (all p < 0.01). Severe adverse events were similar between all the groups, with no increased risk of diabetic ketoacidosis.. The SGLT2i and GLP1-RA agents on their own improved body weight and glycemia, but combining the medications resulted in more weight loss. Treatment intensification appears to result in benefits with no difference in severe adverse events.

Topics: Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Retrospective Studies; Sodium; Sodium-Glucose Transporter 2 Inhibitors; Weight Loss

Type 1 diabetes is an autoimmune disease that results in the specific destruction of insulin-producing beta cells in the pancreas. The aim of this study was to investigate the mechanism of exopolysaccharide from Leuconostoc pseudomesenteroides XG5 (XG5 EPS) against type 1 diabetes.. Long-term drench of XG5 EPS delayed the onset of autoimmune diabetes and had fewer islets with high-grade infiltration (an insulitis score of 3 or 4) than untreated NOD mice. Oral administration of 50 mg kg. Long-term drench of 50 mg kg

Topics: Animals; Diabetes Mellitus, Type 1; Glucagon-Like Peptide 1; Insulin; Leuconostoc; Mice; Mice, Inbred NOD

Mangiferin (MGF) is found in many natural plants, such as Rhizoma Anemarrhenae, and has anti-diabetes effects. However, its clinical applications and development are limited by poor solubility and low-concentration enrichment in pancreatic islets. In this paper, targeted polymeric nanoparticles were constructed for MGF delivery with the desired drug loading content (6.86 ± 0.60%), excellent blood circulation, and missile-like delivery to the pancreas. Briefly, Glucagon-like peptide 1 (GLP-1) as an active targeting agent to the pancreas was immobilized on the block copolymer polyethyleneglycol-polycaprolactone (PEG-PCL) to obtain final GLP-1-PEG-PCL amphiphiles. Spherical MGF-loaded polymeric nanoparticles were acquired from the self-assembly of the targeted GDPP nanoparticles and MGF with a homogeneous size of 158.9 ± 1.7 nm and a negative potential for a good steady state in circulation. In this drug vehicle, GLP-1 acts as the missile vanguard via the GLP-1 receptor on the surface of the pancreas for improving the accumulation and efficiency of MGF in the pancreas, the hypoglycemic effect of MGF, and the restorative effect on pancreatic islets, which were investigated. As compared to free MGF, MGF/GDPP nanoparticles appeared to be more concentrated in the pancreas, with better blood glucose and glucose tolerance, enhanced insulin levels, increased β-cell proliferation, reduced β-cell apoptosis, and islet repair in vivo. This targeted drug delivery system provided a novel strategy and hope for enhancing MGF delivery and anti-diabetes efficacy.

Topics: Animals; Cell Line; Diabetes Mellitus, Type 1; Drug Liberation; Glucagon-Like Peptide 1; Hemolysis; Hypoglycemic Agents; Islets of Langerhans; Mice; Mice, Inbred NOD; Nanoparticles; Polymers; Protective Agents; Surface-Active Agents; Xanthones

Oral formulations of insulin are typically designed to improve its intestinal absorption and increase its blood bioavailability. Here we show that polymerized ursodeoxycholic acid, selected from a panel of bile-acid polymers and formulated into nanoparticles for the oral delivery of insulin, restored blood-glucose levels in mice and pigs with established type 1 diabetes. The nanoparticles functioned as a protective insulin carrier and as a high-avidity bile-acid-receptor agonist, increased the intestinal absorption of insulin, polarized intestinal macrophages towards the M2 phenotype, and preferentially accumulated in the pancreas of the mice, binding to the islet-cell bile-acid membrane receptor TGR5 with high avidity and activating the secretion of glucagon-like peptide and of endogenous insulin. In the mice, the nanoparticles also reversed inflammation, restored metabolic functions and extended animal survival. When encapsulating rapamycin, they delayed the onset of diabetes in mice with chemically induced pancreatic inflammation. The metabolic and immunomodulatory functions of ingestible bile-acid-polymer nanocarriers may offer translational opportunities for the prevention and treatment of type 1 diabetes.

Topics: Animals; Bile; Bile Acids and Salts; Diabetes Mellitus, Type 1; Glucagon-Like Peptide 1; Insulin; Mice; Polymers; Receptors, G-Protein-Coupled; Sirolimus; Swine

The intestines have been recognized as important tissues for metabolic regulation, including glycemic control, but their vital role in promoting the anti-diabetic effects of bitter melon, the fruit of

Topics: Cell Line; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Enterocytes; Enteroendocrine Cells; Glucagon-Like Peptide 1; Glucose; Humans; Insulin; Insulin Resistance; Intestinal Mucosa; Momordica charantia; Plant Extracts

Topics: Aged; Aged, 80 and over; Atrial Fibrillation; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged; Risk Assessment; Sulfonylurea Compounds

Type 1 diabetes is an autoimmune disease caused by the destruction of the insulin-producing β-cells. An ideal immunotherapy should combine the blockade of the autoimmune response with the recovery of functional target cell mass. With the aim to develop new therapies for type 1 diabetes that could contribute to β-cell mass restoration, a drug repositioning analysis based on systems biology was performed to identify the β-cell regenerative potential of commercially available compounds. Drug repositioning is a strategy used for identifying new uses for approved drugs that are outside the scope of the medical indication. A list of 28 non-synonymous repurposed drug candidates was obtained, and 16 were selected as diabetes mellitus type 1 treatment candidates regarding pancreatic β-cell regeneration. Drugs with poor safety profile were further filtered out. Lastly, we selected liraglutide for its predictive efficacy values for neogenesis, transdifferentiation of α-cells, and/or replication of pre-existing β-cells. Liraglutide is an analog of glucagon-like peptide-1, a drug used in patients with type 2 diabetes. Liraglutide was tested in immunodeficient NOD-

Topics: Animals; Cellular Reprogramming; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Glucagon-Like Peptide 1; Hyperglycemia; Hypoglycemic Agents; Insulin-Secreting Cells; Liraglutide; Male; Mice; Mice, Inbred NOD; Mice, SCID

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 1; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans

Topics: Adult; Diabetes Mellitus, Type 1; Female; Gastric Mucosa; Gastrins; Gastrointestinal Agents; Gastrointestinal Motility; Glucagon-Like Peptide 1; Humans; Incretins; Male; Postprandial Period; Research Design; Secretory Pathway; Stomach

Recent studies have demonstrated that residual beta cells may be present in some people with long-standing type 1 diabetes, but little is known about the potential impact of this finding on alpha cell function and incretin levels. This study aimed to evaluate whether insulin microsecretion could modulate glucagon and glucagon-like peptide-1 (GLP-1) responses to a mixed meal tolerance test (MMTT).. Adults with type 1 diabetes onset after the age of 15 years (n = 29) underwent a liquid MMTT after an overnight fast. Insulin microsecretion was defined when peak C-peptide levels were >30 pmol/l using an ultrasensitive assay. Four individuals with recent-onset type 1 diabetes were included as controls. Glucagon and GLP-1 responses were analysed according to C-peptide patterns.. We found comparable peak values, Δ. The glucagon response to an MMTT in people with long-standing type 1 diabetes is not reduced by the presence of residual beta cells. The reduction of GLP-1 responses according to residual C-peptide levels suggests specific regulatory pathways.

Topics: Adult; Area Under Curve; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin-Secreting Cells; Male; Young Adult

Sitagliptin is a dipeptidyl peptidase-4 inhibitor (iDPP-4), which has been used for type 2 diabetes treatment. Recently, iDPP-4 has been described as a promising treatment of type 1 diabetes (T1D) but is still necessary to evaluate immune effects of sitagliptin. C57BL/6 mice were induced by multiple low doses of streptozotocin. Diabetes incidence, insulin, glucagon, glucagon-like peptide-1 (GLP-1) serum levels, and inflammatory cytokine levels were quantified in pancreas homogenate after 30 and 90 days of treatment. In addition, frequencies of inflammatory and regulatory T cell subsets were determined in the spleen and in the pancreatic lymph nodes. iDPP-4 decreased blood glucose level while increased GLP-1 and insulin levels. After long-term treatment, treated diabetic mice presented decreased frequency of CD4

Topics: Animals; Blood Glucose; Cytokines; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Insulin; Lymph Nodes; Mice; Mice, Inbred C57BL; Pancreas; Sitagliptin Phosphate; Streptozocin; T-Lymphocyte Subsets; Treatment Outcome

The aim of present study is to examine the effect of glucagon-like peptide-1(GLP-1) on diabetes-induced liver injury and explore detailed mechanisms of GLP-1 hepatoprotective effect. 150 male Sprague-Dawley rats were randomly assigned into three groups with equal number, including Sham group, diabetes group and GLP-1 intervention group. Diabetes rat model was performed with intraperitoneal injection of streptozotocin (STZ, 65mg/kg). Fasting blood-glucose of rat model was assessed at 72h after STZ injection to verify diabetes rat model. Rats in Sham group were normally fed. Rats in GLP-1 intervention group received 2 ng/kg GLP-1 intervention, at 2, 4, 6 and 8 weeks after intervention, TUNEL staining were performed to examine apoptosis of liver tissue. PCR and Western blot were performed to examine insulin, GLP-1R, autophagy-associated gene and HDAC-1. Compared with diabetes group, insulin expression of GLP-1 intervention group increased significantly (P<0.05). TUNEL staining at different time showed apoptosis levels of liver tissues were reduced gradually after GLP-1 intervention (P<0.05). Compared with diabetes groups, the expressions of BCL2 and GLP-1R were increased, while the levels of caspase3 and LC3 were reduced in GLP-1 intervention group (P<0.05). GLP-1 treatment decreased levels of phosphorylated AKT, phosphorylated ERK1/2, and HDAC6 in liver tissues (P<0.05). GLP-1 treatment alleviated diabetes-induced liver injury via regulating autophagy. The mechanism of GLP-1 hepatoprotective effect could be via GLP-1R-ERK1/2-HDAC6 signaling pathway.

Topics: Animals; Apoptosis; Autophagy; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Histone Deacetylase 6; Insulin; Liver; Male; MAP Kinase Signaling System; Rats, Sprague-Dawley; Streptozocin

The glucagon-like peptide-1 (GLP-1) and the glucose- dependent Insulinotropic peptide (GIP) are natural incretin hormones, which are secreted respectively by the L- and K-cells of the intestinal mucosa in response to the physiological gastrointestinal glucose absorption. In patients with type 2 diabetes mellitus, the incretin effect is reduced, whereas the results in type 1 diabetes mellitus (T1DM) are heterogeneous, in some patients normal incretin response is observed.. Comparative analysis of the basal serum levels of the incretin hormones GLP-1 and GIP in patients with type 1 DM and in individuals without carbohydrate disorders.. The study included 27 patients with diagnosed T1DM and a control group of 39 individuals without carbohydrate disorders. All participants in the study were subjected to the following clinical measurements and laboratory tests - height, weight, bioimpedance analysis of body composition, fasting blood sugar (BS 0'), postprandial blood sugar (PPBS), glycated haemoglobin (HbA1c) in T1DM patients, total cholesterol (TC), HDL cholesterol (HDL chol), triglycerides (TG), transaminase (AST and ALT), basal serum levels of GLP-1 and GIP.. The serum levels of GIP in the patients with type T1DM were significantly higher, compared to the individuals without carbohydrate disorders (P<0.05), while there was no statistically significant difference in the GLP-1 levels.. The significantly higher GIP levels and the similar GLP-1 levels in our patients with type 1 DM, compared to the individuals without carbohydrate disorders, support the hypothesis of intact incretin effect in this type of diabetes mellitus Key Words: Glucagon-like peptide-1, Glucose-dependent insulinotropic peptide, Type 1 diabetes mellitus.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 1; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Lipids; Male; Middle Aged

Diabetes mellitus is associated with gastrointestinal (GI) motility dysfunction, ranging from delayed to accelerated gastric emptying (GE).. To evaluate GE in patients with type 1 diabetes mellitus (T1DM) without chronic complications and to investigate its relation with postprandial glucose and GI hormone responses.. Cross-sectional study.. Forty-two patients with T1DM free of chronic complications referred to Federico II University and 31 healthy controls similar for age, sex, and body mass index.. GE was assessed by using the 13C-octanoate breath test with a standardized solid meal. During the meal, plasma glucose, ghrelin, and glucagon-like peptide 1 (GLP-1) responses were assessed, and GI symptoms were evaluated by a specific questionnaire.. Patients with T1DM showed a significantly slower GE half-emptying time (GE t1/2) (113 ± 34 minutes) than did controls (89 ± 17 minutes; P < 0.001). Thirty-six percent of T1DM showed a delayed GE (t1/2 > 120 minutes), whereas all controls showed a normal GE. When patients with T1DM were stratified according to GE t1/2, postmeal glucose response was significantly different between those with delayed and those with normal GE (P = 0.013). In particular, patients with T1DM and delayed GE showed a significantly longer mean time to peak glucose than did patients with normal GE (P = 0.004). In addition, GE t1/2 was an independent predictor of the time to peak glucose (β = 0.329; P = 0.025). GLP-1 and ghrelin responses to the test meal, as well as the prevalence of GI symptoms, were similar between patients with T1DM and controls and between patients with T1DM with normal GE and those with delayed GE.. Delayed GE time is associated with a longer time to peak glucose. GE evaluation could be useful for individualizing the timing of preprandial insulin bolus in patients with T1DM.

Topics: Adult; Blood Glucose; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Female; Gastric Emptying; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Male; Meals; Postprandial Period; Surveys and Questionnaires; Young Adult

Recent randomized and controlled trials of drugs derived from the gut hormone glucagon-like peptide-1 (GLP-1) show that the most frequent adverse symptoms are gastrointestinal, including gallbladder-related side effects such as cholithiasis and cholecystitis. Since the gut hormone cholecystokinin (CCK) stimulates bile secretion and regulates gallbladder motility and emptying, we examined the effect of GLP-1 on the secretion of CCK in normal subjects and patients with type 1 diabetes mellitus.. Plasma was sampled from 10 healthy subjects and 10 patients with diabetes. With plasma glucose concentrations clamped between 6 and 9 nmol/l, GLP-1 or saline was infused for 240 min during and after a meal. The plasma concentrations of CCK were measured with a highly specific radioimmunoassay.. Basal plasma concentrations of CCK were similar in the normal subjects and in the diabetes patients. During the meal, the CCK concentrations rose significantly during saline infusion, whereas the GLP-1 infusion suppressed the secretion of CCK significantly in both normal subjects and in the diabetes patients.. The results show that GLP-1 suppresses the secretion of CCK after a meal in normal and diabetic subjects. The suppression attenuates the gallbladder contractility. Our data, therefore, offer an explanation for the increased risk of adverse gallbladder events during treatment with GLP-1-derived drugs.

Topics: Adult; Blood Glucose; Case-Control Studies; Cholecystokinin; Diabetes Mellitus, Type 1; Female; Gallbladder; Gallbladder Emptying; Glucagon-Like Peptide 1; Humans; Male; Young Adult

The purpose of our study is to assess the effects of glucagon-like peptide-1 receptor agonists (GLP-1R agonists) on early markers of kidney damage in patients with type 1 diabetes mellitus (DM).. The study included 27 patients with type 1 diabetes with normo- (n=16) and microalbuminuria (n=11) on intensive insulin injection regimen with insulin analogs. Patients were divided into two groups: 15 patients continued insulin therapy throughout the follow-up period, 12 patients were given 1.2 mg GLP-1R agonist (Liraglutide) once a day in addition to the insulin therapy for 6 months. HbA1c, lipid profile, classic markers of kidney damage (albuminuria, creatinine, glomerular filtration rate); plazma (neutrophilic gelatinase-associated lipoxalin - NGAL, molecule renal damage of type 1 - KIM-1, cystatin C, osteopontin) and urinary kidney biomarkers (nephrin, podocyne, uromodulin, NGAL, KIM-1, collagen type IV, cystatin C) were evaluated prior and in dynamics at 6 months. Kidney biomarkers levels were assessed by the enzyme-linked immunosorbent assay (ELISA).. We observed a significant decrease in the urinary excretion of type IV collagen, cystatin C, increased uromodulin excretion and decrease in the plasma levels of osteopontin, NGAL and cystatin C in the group of combined insulin and GLP-1R agonist therapy.. Changes in the level of sensitive kidney biomarkers indicate a possible renoprotective effect of GLP-1R agonist therapy in patients with type 1 diabetes at an early stages of kidney damage.

Topics: Albuminuria; Biomarkers; Diabetes Mellitus, Type 1; Glucagon-Like Peptide 1; Glucagon-Like Peptide Receptors; Humans; Hypoglycemic Agents; Kidney

Type 1 diabetes is a chronic organ-specific autoimmune disease in which selective destruction of insulin-producing β-cells leads to impaired glucose metabolism and its attendant complications. A series of Dipeptidyl peptidase 4 (DPP4) inhibitors have been developed and granted approval in the treatment of type 2 diabetes mellitus by inhibiting the enzymatic degradation of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). An increasing number of studies have shown the potential benefits of DPP4 inhibitors for type 1 diabetes. In this report, we describe a novel multi-epitope vaccine comprising a B cell epitope of DPP4, an anti-diabetic B cell epitope of Insulinoma antigen-2 (IA-2) and a Th2 epitope of P277 peptide in human heat shock protein 60 (HSP60). Immunization with the multi-epitope vaccine in streptozotocin (STZ) treated mice successfully induced specific anti-DPP4 antibody and increased serum GLP-1 level. Moreover, this antibody lasted for more than 7 weeks. Inoculation of this vaccine in C57BL/6J mice significantly reduced blood glucose level, improved glucose excursion and increased plasma insulin concentration. Consistent with a lower diabetic and insulitis incidence, induced splenic T cell proliferation and tolerance were observed. IFN-γ and IL-2 secretion reduced, but IL-10 and IL-4 increased significantly in the Dipeptidyl Peptidase 41-Insulinoma antigen-2(5)-P2-1 (D41-IP) treated mice compared to the Insulinoma antigen-2(5)-P2-1 (IA2(5)P2-1) and control group due to the potential immunomodulatory effect of the epitopes in the vaccine. Our results demonstrate that this multi-epitope vaccine may serve as a promising therapeutic approach against type 1 diabetes.

Topics: Animals; B-Lymphocytes; Blood Glucose; Cell Proliferation; Chaperonin 60; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Epitopes; Glucagon-Like Peptide 1; Glucose; Humans; Immunologic Factors; Insulin; Interleukins; Male; Mice; Mice, Inbred C57BL; Streptozocin; T-Lymphocytes; Vaccines

Endogenous Takeda G-protein-coupled receptor 5 (TGR5), G-protein-coupled bile acid receptor 1 (GPBAR1), regulates glucose metabolism. In animals, TGR5 activation by a chemical agonist may increase incretin secretion and reduce the blood sugar level. Recently, betulinic acid has been suggested to activate TGR5. Ursolic acid is a well-known pentacyclic triterpenoid that is similar to betulinic acid. It is of special interest to determine the potential effect of ursolic acid on TGR5. Therefore, we transfected cultured Chinese hamster ovary (CHO-K1) cells with the TGR5 gene. The functions of the transfected cells were confirmed via glucose uptake using a fluorescent indicator. Moreover, NCI-H716 cells that secreted incretin were also investigated, and the glucagon-like peptide (GLP-1) levels were quantified using ELISA kits. In addition, streptozotocin (STZ)-induced type 1-like diabetic rats were used to identify the effect of ursolic acid in vivo. Ursolic acid concentration dependently increased glucose uptake in CHO-K1 cells expressing TGR5. In NCI-H716 cells, ursolic acid induced a concentration-dependent elevation in GLP-1 secretion, which was inhibited by triamterene at the effective concentrations to block TGR5. Ursolic acid also increased the plasma GLP-1 level via TGR5 activation, which was further characterized in vivo with type 1-like diabetic rats. Moreover, ursolic acid is more effective than betulinic acid in reduction of hyperglycemia and increase of GLP-1 secretion. Therefore, we demonstrated that ursolic acid can activate TGR5, enhancing GLP-1 secretion in vitro and in vivo. Therefore, ursolic acid is suitable for use in TGR5 activation.

Topics: Animals; Blood Glucose; Cell Line; CHO Cells; Cricetulus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Glucagon-Like Peptide 1; Humans; Male; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Triterpenes; Ursolic Acid

Glycyrrhizic acid (GA) is belonged to triterpenoid saponin that is contained in the root of licorice and is known to affect metabolic regulation. Recently, glucagon like peptide-1 (GLP-1) has widely been applied in diabetes therapeutics. However, the role of GLP-1 in GA-induced anti-diabetic effects is still unknown. Therefore, we are interested in understanding the association of GLP-1 with GA-induced effects. In type 1-like diabetic rats induced by streptozotocin (STZ-treated rats), GA increased the level of plasma GLP-1, which was blocked by triamterene at a dose sufficient to inhibit Takeda G-protein-coupled receptor 5 (TGR5). The direct effect of GA on TGR5 has been identified using the cultured Chinese hamster ovary cells (CHO-K1 cells) transfected TGR5 gene. Moreover, in intestinal NCI-H716 cells that secreted GLP-1, GA promoted GLP-1 secretion with a marked elevation of calcium levels. However, both effects of GA were reduced by ablation of TGR5 with siRNA in NCI-H716 cells. Therefore, we demonstrated that GA can enhance GLP-1 secretion through TGR5 activation.

Topics: Animals; Blood Glucose; CHO Cells; Cricetinae; Cricetulus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Glucagon-Like Peptide 1; Glycyrrhizic Acid; Intestinal Mucosa; Male; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled

Type 1 diabetes is a chronic organ-specific autoimmune disease in which selective destruction of insulin-producing β cells leads to impaired glucose metabolism and its attendant complications. IA2(5)P2-1, a potent immunogenic carrier which designed by our laboratory, can induce high titer specific antibodies when carry a B cell epitope, such as B cell epitopes of DPP4, xanthine oxidase, and Urate transporter protein. In this report, we describe a novel multi-epitope vaccine composing a peptide of DPP4, an anti-diabetic B epitope of Insulinoma antigen-2(IA-2) and a Th2 epitope (P2:IPALDSLTPANED) of P277 peptide in human heat shock protein 60 (HSP60). Immunization with the multi-epitope vaccine in non-obese diabetic (NOD) mice successfully induced specific anti-DPP4 antibody, inhibited plasma DPP4 activity, and increased serum GLP-1 level. Moreover, this antibody titer was correlated with the dose of immunization (20μg, 100μg). Inoculation of this vaccine in NOD mice significantly control blood glucose level, improved glucose excursion and increased insulin level in vivo. Consistent with a lower diabetic and insulitis incidence, a induced splenic T cells proliferation and tolerance were observed. IFN-γ secretion reduced and IL-10 increased significantly in the D41-IA2(5)-P2-1 treated mice compared to P277 and control group due to the potential immunomodulatory effect of the epitope in the vaccine. Immunohistochemical analysis and cytometry showed a rebalance of Th1/Th2 in NOD mice. Our results demonstrate that this multi-epitope vaccine may serve as a promising therapeutic approach for type 1 diabetes.

Topics: Animals; Antibody Formation; Blood Glucose; Chaperonin 60; Cytokines; Diabetes Mellitus, Type 1; Dipeptidyl Peptidase 4; Epitopes, B-Lymphocyte; Glucagon-Like Peptide 1; Humans; Insulin; Mice; Mice, Inbred NOD; Receptor-Like Protein Tyrosine Phosphatases, Class 8; T-Lymphocytes; Vaccines; Vaccines, Subunit

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

A defining characteristic of type 1 diabetes mellitus (T1DM) pathophysiology is pancreatic β-cell death and dysfunction, resulting in insufficient insulin secretion to properly control blood glucose levels. Treatments that promote β-cell replication and survival, thus reversing the loss of β-cell mass, while also preserving β-cell function, could lead to a real cure for T1DM. The α-subunit of the heterotrimeric Gz protein, Gαz, is a tonic negative regulator of adenylate cyclase and downstream cAMP production. cAMP is one of a few identified signaling molecules that can simultaneously have a positive impact on pancreatic islet β-cell proliferation, survival, and function. The purpose of our study was to determine whether mice lacking Gαz might be protected, at least partially, from β-cell loss and dysfunction after streptozotocin treatment. We also aimed to determine whether Gαz might act in concert with an activator of the cAMP-stimulatory glucagon-like peptide 1 receptor, exendin-4 (Ex4). Without Ex4 treatment, Gαz-null mice still developed hyperglycemia, albeit delayed. The same finding held true for wild-type mice treated with Ex4. With Ex4 treatment, Gαz-null mice were protected from developing severe hyperglycemia. Immunohistological studies performed on pancreas sections and in vitro apoptosis, cytotoxicity, and survival assays demonstrated a clear effect of Gαz signaling on pancreatic β-cell replication and death; β-cell function was also improved in Gαz-null islets. These data support our hypothesis that a combination of therapies targeting both stimulatory and inhibitory pathways will be more effective than either alone at protecting, preserving, and possibly regenerating β-cell mass and function in T1DM.

Topics: Adenylyl Cyclases; Animals; Blood Glucose; Cell Line, Tumor; Cell Proliferation; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Exenatide; Glucagon-Like Peptide 1; Glucose; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Mice; Mice, Inbred C57BL; Mice, Knockout; Pancreas; Peptides; Rats; Signal Transduction; Streptozocin; Venoms

Chronically deregulated blood-glucose concentrations in diabetes mellitus result from a loss of pancreatic insulin-producing β cells (type 1 diabetes, T1D) or from impaired insulin sensitivity of body cells and glucose-stimulated insulin release (type 2 diabetes, T2D). Here, we show that therapeutically applicable β-cell-mimetic designer cells can be established by minimal engineering of human cells. We achieved glucose responsiveness by a synthetic circuit that couples glycolysis-mediated calcium entry to an excitation-transcription system controlling therapeutic transgene expression. Implanted circuit-carrying cells corrected insulin deficiency and self-sufficiently abolished persistent hyperglycemia in T1D mice. Similarly, glucose-inducible glucagon-like peptide 1 transcription improved endogenous glucose-stimulated insulin release and glucose tolerance in T2D mice. These systems may enable a combination of diagnosis and treatment for diabetes mellitus therapy.

Topics: Animals; Biomimetics; Blood Glucose; Calcium; Calcium Channels, L-Type; Cell Engineering; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; HEK293 Cells; Humans; Hyperglycemia; Insulin; Insulin Secretion; Insulin-Secreting Cells; Transcription, Genetic; Transgenes

The role of glucagon-like peptide-1 (GLP-1) has become a new scientific interest in the field of pathophysiology of type 1 diabetes mellitus (T1DM), but the results of the published studies were contradictory. The aim of our study was therefore to measure fasting and postprandial GLP-1 concentrations in T1DM patients and in healthy controls and to examine the difference in those concentrations between the two groups of subjects.. The cross-sectional study included 30 C-peptide negative T1DM patients, median age 37 years (20-59), with disease duration 22 years (3-45), and 10 healthy controls, median age 30 years (27-47). Fasting and postprandial total and active GLP-1 concentrations were measured by ELISA (ALPCO, USA). The data were statistically analysed by SPSS, and significance level was accepted at P < 0.05.. Both fasting total and active GLP-1 concentrations were significantly lower in T1DM patients (total 0.4 pmol/L, 0-6.4 and active 0.2 pmol/L, 0-1.9) compared with healthy controls (total 3.23 pmol/L, 0.2-5.5 and active 0.8 pmol/L, 0.2-3.6), P = 0.008 for total GLP-1 and P = 0.001 for active GLP-1. After adjustment for age, sex and body mass index, binary logistic regression showed that both fasting total and active GLP-1 remained significantly independently lower in T1DM patients (total GLP-1: OR 2.43, 95% CI 1.203-4.909 and active GLP-1: OR 8.73, 95% CI 1.472-51.787).. T1DM patients had independently lower total and active GLP-1 fasting concentrations in comparison with healthy people, which supports the potential therapeutic role of incretin therapy, along with insulin therapy, in T1DM patients.

Topics: Adult; C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Fasting; Female; Glucagon-Like Peptide 1; Hospitals, University; Humans; Hypoglycemic Agents; Insulin; Logistic Models; Male; Middle Aged; Outpatient Clinics, Hospital; Postprandial Period; Sex Characteristics; Young Adult

Metabolic syndrome (MS) is found in approximately% 30-40% of patients with type 1 diabetes mellitus (T1DM). Meal-induced glucagon-like peptide-1 (GLP-1) secretion in T1DM patients with MS is yet to be clarified. The aim of the present study was to analyse the relationship between total fasting GLP-1 concentrations and the meal-induced GLP-1 response with MS prevalence in T1DM patients compared with lean, normal glucose tolerance (NGT), control subjects.. The study included 77 T1DM patients (61% male), 26 (34%) with MS, who had a mean age of 45.08 years, mean body mass index (BMI) of 25.42 kg/m(2) , and median diabetes duration of 21 years. Ten age-, gender, and BMI-matched NGT control subjects were also included in the study. Circulating GLP-1 concentrations ere measured before and 30 min after a meal by ELISA. The difference between the 30-min postprandial and fasting GLP-1 concentration (ΔGLP-1) was calculated by subtracting fasting GLP-1 concentrations from postprandial GLP-1 concentrations.. The NGT group had significantly higher total fasting, postprandial, and meal-induced GLP-1 concentrations than the T1DM groups. The T1DM patients without MS had a higher increase in circulating GLP-1 concentrations compared with the T1DM group with MS. After adjustment for age, gender, disease duration, and meal caloric value, GLP-1 response levels were inversely correlated with MS prevalence in binary logistic regression analysis.. A higher meal-induced GLP-1 response is associated with lower MS prevalence, but whether GLP-1 has a protective role in MS development is yet to be determined. This may provide further insight into the implementation of GLP-1-based therapies in the T1DM population.

Topics: Adult; Blood Glucose; Case-Control Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Diet; Fasting; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Male; Metabolic Syndrome; Middle Aged; Postprandial Period; Prevalence

Topics: Diabetes Mellitus, Type 1; Down-Regulation; Female; Glucagon-Like Peptide 1; Humans; Male

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Infusion Systems; Metformin; Sodium-Glucose Transport Proteins; Sulfonylurea Compounds

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

Fetal exposure to maternal diabetes is associated with increased risk of type 2 diabetes mellitus (T2DM) later in life. The pathogenesis of T2DM involves dysfunction of the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), as well as hyperglucagonemia.. Our aim was to investigate circulating plasma levels of GLP-1, GIP, and glucagon during the oral glucose tolerance test (OGTT) in adult offspring of women with diabetes in pregnancy.. We conducted a follow-up study of 567 offspring, aged 18-27 years. We included two groups exposed to maternal diabetes in utero: offspring of women with diet-treated gestational diabetes mellitus (O-GDM; n = 163) or type 1 diabetes (O-T1DM; n = 146). Two reference groups were included: offspring of women with risk factors for GDM, but normoglycemia during pregnancy (O-NoGDM; n = 133) and offspring from the background population (O-BP; n = 125). The subjects underwent a 75-g OGTT with venous samples at 0, 30, and 120 minutes.. Fasting plasma levels of GLP-1 were lower in the two diabetes-exposed groups compared to O-BP (O-GDM, P = .040; O-T1DM, P = .008). Increasing maternal blood glucose during OGTT in pregnancy was associated with reduced postprandial suppression of glucagon in the offspring. Lower levels of GLP-1 and higher levels of glucagon during the OGTT were present in offspring characterized by overweight or prediabetes/T2DM at follow-up, irrespective of exposure status.. Lower levels of fasting GLP-1 and impaired glucagon suppression in adult offspring exposed to maternal diabetes during pregnancy are diabetogenic traits that may contribute to glucose intolerance in these persons, but further investigations are needed.

Topics: Adolescent; Adult; Adult Children; Diabetes Mellitus, Type 1; Diabetes, Gestational; Female; Follow-Up Studies; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Male; Pregnancy; Prenatal Exposure Delayed Effects; Young Adult

T2DM patients demonstrate reduced GLP-1 receptor (GLP-1R) expression in their gastric glands. Whether induced T2DM and T1DM differently affect the gastric GLP-1R expression is not known. This study assessed extrapancreatic GLP-1R system in glandular stomach of rodents with different types of experimental diabetes. T2DM and T1DM were induced in Psammomys obesus (PO) by high-energy (HE) diet and by streptozotocin (STZ) in Sprague Dawly (SD) rats, respectively. GLP-1R expression was determined in glandular stomach by RT PCR and immunohistomorphological analysis. The mRNA expression and cellular association of the GLP-1R in principal glands were similar in control PO and SD rats. However, nutrient and chemical induced diabetes resulted in opposite alterations of glandular GLP-1R expression. Diabetic PO demonstrated increased GLP-1R mRNA expression, intensity of cellular GLP-1R immunostaining, and frequency of GLP-1R positive cells in the neck area of principal glands compared with controls. In contrast, SD diabetic rats demonstrated decreased GLP-1 mRNA, cellular GLP-1R immunoreactivity, and frequency of GLP-1R immunoreactive cells in the neck area compared with controls. In conclusion, nutrient and chemical induced experimental diabetes result in distinct opposite alterations of GLP-1R expression in glandular stomach. These results suggest that induced T1DM and T2DM may differently modulate GLP-1R system in enteropancreatic axis.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Disease Models, Animal; Female; Gastric Mucosa; Gerbillinae; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Pancreas; Rats; Rats, Sprague-Dawley; RNA, Messenger; Streptozocin

Over the past three decades there have been a number of clinical trials directed at interdicting the type 1 diabetes (T1D) disease process in an attempt to prevent the development of the disease in those at increased risk or to stabilize-potentially even reverse-the disease in people with T1D, usually of recent onset. Unfortunately, to date there has been no prevention trial that has resulted in delay or prevention of T1D. And, trials in people with T1D have had mixed results with some showing promise with at least transient improvement in β-cell function compared with randomized control groups, while others have failed to slow the decline in β-cell function when compared with placebo. This Perspective will assess the past and present challenges in this effort and provide an outline for potential future opportunities.

Topics: Alum Compounds; Animals; Antibodies, Monoclonal, Humanized; Antigens; Antilymphocyte Serum; BCG Vaccine; Chaperonin 60; Diabetes Mellitus, Type 1; Forecasting; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin-Secreting Cells; Interleukin-2; Mice; Peptide Fragments; Pilot Projects; Randomized Controlled Trials as Topic; Research Design; Treatment Outcome

Type 1 diabetes mellitus is associated with a high risk for bone fractures. Although bone mass is reduced, bone quality is also dramatically altered in this disorder. However, recent evidences suggest a beneficial effect of the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) pathways on bone quality. The aims of the present study were to conduct a comprehensive investigation of bone strength at the organ and tissue level; and to ascertain whether enzyme resistant GIP or GLP-1 mimetic could be beneficial in preventing bone fragility in type 1 diabetes mellitus. Streptozotocin-treated mice were used as a model of type 1 diabetes mellitus. Control and streptozotocin-diabetic animals were treated for 21 days with an enzymatic-resistant GIP peptide ([D-Ala(2) ]GIP) or with liraglutide (each at 25 nmol/kg bw, ip). Bone quality was assessed at the organ and tissue level by microCT, qXRI, 3-point bending, qBEI, nanoindentation, and Fourier-transform infrared microspectroscopy. [D-Ala2]GIP and liraglutide treatment did prevent loss of whole bone strength and cortical microstructure in the STZ-injected mice. However, tissue material properties were significantly improved in STZ-injected animals following treatment with [D-Ala2]GIP or liraglutide. Treatment of STZ-diabetic mice with [D-Ala(2) ]GIP or liraglutide was capable of significantly preventing deterioration of the quality of the bone matrix. Further studies are required to further elucidate the molecular mechanisms involved and to validate whether these findings can be translated to human patients.

Topics: Animals; Biomechanical Phenomena; Bone Density; Bone Density Conservation Agents; Bone Remodeling; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Hypoglycemic Agents; Incretins; Liraglutide; Male; Mice; Microspectrophotometry; Osteoblasts; Osteoclasts; Spectroscopy, Fourier Transform Infrared; Tibia; Time Factors; X-Ray Microtomography

Previous research indicated that coeliac disease (CD) is associated with type 1 diabetes mellitus (T1DM). However, the gut-brain axis peptide hormones secretion has not been evaluated so far in patients with CD prior to treatment initiation or under treatment, irrespective of patients having concomitant T1DM or not. The aim of the study was therefore to evaluate these gut hormones at the preprandial levels of patients with CD before and under treatment.. Of forty-seven CD children, 12 untreated (UCD), 22 treated with gluten-free diet (TCD) and 13 treated CD with coexisting T1DM (DCD), and 18 healthy controls (HC) were enrolled. Preprandial glucagon-like-peptide-1 (GLP-1), glucose-dependent-insulinotropic-polypeptide (GIP), active amylin, acylated ghrelin (AG), leptin, pancreatic polypeptide (PP) and peptide-tyrosine-tyrosine (PYY) were determined with hormone-map-array technology.. We found in patients with CD compared with HC that the concentration of (i) GLP-1 was reduced remarkably in all patients with CD (P = 0.008), (ii) GIP was lower in patients with UCD (P = 0.008), (iii) amylin was remarkably reduced (P < 0.01) in all patients with CD, (iv) AG was significantly decreased in patients with DCD (P < 0.01), while (v) leptin, PP and PYY were not significantly different. GIP, GLP-1 and amylin levels correlated positively with insulin concentrations (P < 0.001, P = 0.004 and P < 0.01, respectively) in all patients. Amylin and GIP levels were strongly associated with triglycerides concentrations (P < 0.001, for both peptides) in children with CD.. Our study revealed a different secretion pattern of gut-brain axis hormones in children with CD compared with HC. The alterations in the axis were more pronounced in children with both CD and T1DM.

Topics: Adolescent; Case-Control Studies; Celiac Disease; Child; Child, Preschool; Diabetes Mellitus, Type 1; Diet, Gluten-Free; Female; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Humans; Incretins; Islet Amyloid Polypeptide; Leptin; Male; Pancreatic Polypeptide; Peptide YY

OBJECTIVE Previous studies have demonstrated aberrant glucagon physiology in the setting of type 1 diabetes (T1D) but have not addressed the potential impact of ambient glycemia on this glucagon response. Thus, our objective was to evaluate the impact of euglycemia versus hyperglycemia on the glucagon response to an oral glucose challenge in T1D. RESEARCH DESIGN AND METHODS Ten adults with T1D (mean age 56.6 ± 9.0 years, duration of diabetes 26.4 ± 7.5 years, HbA1c 7.5% ± 0.77, and BMI 24.1 kg/m(2) [22.6-25.4]) underwent 3-h 50-g oral glucose tolerance tests (OGTTs) on two separate days at least 24 h apart in random order under conditions of pretest euglycemia (plasma glucose [PG] between 4 and 6 mmol/L) and hyperglycemia (PG between 9 and 11 mmol/L), respectively. RESULTS Glycemic excursion on the OGTT was similar between the euglycemic and hyperglycemic tests (P = 0.72 for interaction between time postchallenge and glycemic setting). Interestingly, glucagon levels increased in response to the OGTT under both glycemic conditions (P < 0.001) and there were no differences in glucagon response between the euglycemic and hyperglycemic days (P = 0.40 for interaction between time postchallenge and glycemic setting). In addition, the incretin responses to the OGTT (glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, glucagon-like peptide-2) were also not different between the euglycemic and hyperglycemic settings. CONCLUSIONS In patients with T1D, there is a paradoxical increase in glucagon in response to oral glucose that is not reversed when euglycemia is achieved prior to the test. This abnormal glucagon response likely contributes to the postprandial hyperglycemia in T1D irrespective of ambient glycemia.

Topics: Blood Glucose; Carbohydrate Metabolism, Inborn Errors; Diabetes Mellitus, Type 1; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Glycerol Kinase; Humans; Hypoadrenocorticism, Familial; Incretins; Male; Middle Aged

Dipeptidyl peptidase-4 (DPP-4) inhibitors are incretin-based drugs in patients with type 2 diabetes. In our previous study, we showed that glucagon-like peptide-1 (GLP-1) receptor agonist has reno-protective effects through anti-inflammatory action. The mechanism of action of DPP-4 inhibitor is different from that of GLP-1 receptor agonists. It is not obvious whether DPP-4 inhibitor prevents the exacerbation of diabetic nephropathy through anti-inflammatory effects besides lowering blood glucose or not. The purpose of this study is to clarify the reno-protective effects of DPP-4 inhibitor through anti-inflammatory actions in the early diabetic nephropathy.. Five-week-old male Sprague-Dawley (SD) rats were divided into three groups; non-diabetes, diabetes and diabetes treated with DPP-4 inhibitor (PKF275-055; 3 mg/kg/day). PKF275-055 was administered orally for 8 weeks.. PKF275-055 increased the serum active GLP-1 concentration and the production of urinary cyclic AMP. PKF275-055 decreased urinary albumin excretion and ameliorated histological change of diabetic nephropathy. Macrophage infiltration was inhibited, and inflammatory molecules were down-regulated by PKF275-055 in the glomeruli. In addition, nuclear factor-κB (NF-κB) activity was suppressed in the kidney.. These results indicate that DPP-4 inhibitor, PKF275-055, have reno-protective effects through anti-inflammatory action in the early stage of diabetic nephropathy. The endogenous biological active GLP-1 might be beneficial on diabetic nephropathy besides lowering blood glucose.

Topics: Adamantane; Animals; Anti-Inflammatory Agents; Cyclic AMP; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Glucagon-Like Peptide 1; Kidney Diseases; Kidney Glomerulus; Male; Nitriles; Protective Agents; Pyrrolidines; Rats; Rats, Sprague-Dawley

Glucagon-like peptide 1 (GLP-1) and glucagon share the same precursor molecule proglucagon, but each arises from a distinct posttranslational process in a tissue-specific manner. Recently, it has been shown that GLP-1 is co-expressed with glucagon in pancreatic islet cells. This study was aimed to investigate the progressive changes of GLP-1 versus glucagon production in pancreatic islets during the course of diabetes development.. Both type 1 (non-obese diabetes mice) and type 2 (db/db mice) diabetes models were employed in this study. The mice were monitored closely for their diabetes progression and were sacrificed at different stages according to their blood glucose levels. GLP-1 and glucagon expression in the pancreatic islets was examined using immunohistochemistry assays. Quantitative analysis was performed to evaluate the significance of the changes.. The ratio of GLP-1-expressing cells to glucagon-expressing cells in the islets showed significant, progressive increase with the development of diabetes in db/db mice. The increase of GLP-1 expression was in agreement with the upregulation of PC1/3 expression in these cells. Interestingly, intra-islet GLP-1 expression was not significantly changed during the development of type 1 diabetes in non-obese diabetes mice.. The study demonstrated that GLP-1 was progressively upregulated in pancreatic islets during type 2 diabetes development. In addition, the data suggest clear differences in intra-islet GLP-1 production between type 1 and type 2 diabetes developments. These differences may have an effect on the clinical and pathophysiological processes of these diseases and may be a target for therapeutic approaches.

Topics: Algorithms; Animals; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Disease Progression; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Immunohistochemistry; Islets of Langerhans; Male; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Mutant Strains; Prediabetic State; Proprotein Convertase 1; Up-Regulation

Islet alpha- and delta-cells are spared autoimmune destruction directed at beta-cells in type 1 diabetes resulting in an apparent increase of non-beta endocrine cells in the islet core. We determined how islet remodeling in autoimmune diabetes compares to streptozotocin (STZ)-induced diabetes. Islet cell mass, proliferation, and immune cell infiltration in pancreas sections from diabetic NOD mice and mice with STZ-induced diabetes was assessed using quantitative image analysis. Serial sections were stained for various beta-cell markers and Ngn3, typically restricted to embryonic tissue, was only upregulated in diabetic NOD mouse islets. Serum levels of insulin, glucagon and GLP-1 were measured to compare hormone levels with respect to disease state. Total pancreatic alpha-cell mass did not change as autoimmune diabetes developed in NOD mice despite the proportion of islet area comprised of alpha- and delta-cells increased. By contrast, alpha- and delta-cell mass was increased in mice with STZ-induced diabetes. Serum levels of glucagon reflected these changes in alpha-cell mass: glucagon levels remained constant in NOD mice over time but increased significantly in STZ-induced diabetes. Increased serum GLP-1 levels were found in both models of diabetes, likely due to alpha-cell expression of prohormone convertase 1/3. Alpha- or delta-cell mass in STZ-diabetic mice did not normalize by replacement of insulin via osmotic mini-pumps or islet transplantation. Hence, the inflammatory milieu in NOD mouse islets may restrict alpha-cell expansion highlighting important differences between these two diabetes models and raising the possibility that increased alpha-cell mass might contribute to the hyperglycemia observed in the STZ model.

Topics: Animals; Blood Glucose; Cell Proliferation; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Immunohistochemistry; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Mice, Inbred BALB C; Mice, Inbred NOD; Somatostatin

We report the results of an independent laboratory's tests of novel agents to prevent or reverse type 1 diabetes (T1D) in the non-obese diabetic (NOD) mouse, BioBreeding diabetes prone (BBDP) rat, and multiple autoimmune disease prone (MAD) rat models. Methods were developed to better mimic human clinical trials, including: prescreening, randomization, blinding, and improved glycemic care of the animals. Agents were suggested by the research community in an open call for proposals, and selected for testing by an NIDDK appointed independent review panel. Agents selected for testing to prevent diabetes at later stages of progression in a rodent model were a STAT4 antagonist (DT22669), alpha1 anti-trypsin (Aralast NP), celastrol (a natural product with anti-inflammatory properties), and a Macrophage Inflammatory Factor inhibitor (ISO-092). Agents tested for reversal of established T1D in rodent models were: alpha1 anti-trypsin (Aralast NP), tolerogenic peptides (Tregitopes), and a long-acting formulation of GLP-1 (PGC-GLP-1). None of these agents were seen to prevent or reverse type 1 diabetes, while the positive control interventions were effective: anti-CD3 treatment provided disease reversal in the NOD mouse, dexamethasone prevented T1D induction in the MAD rat, and cyclosporin prevented T1D in the BBDP rat. For some tested agents, details of previous formulation, delivery, or dosing, as well as laboratory procedure, availability of reagents and experimental design, could have impacted our ability to confirm prior reports of efficacy in preclinical animal models. In addition, the testing protocols utilized here provided detection of effects in a range commonly used in placebo controlled clinical trials (for example, 50% effect size), and thus may have been underpowered to observe more limited effects. That said, we believe the results compiled here, showing good control and repeatability, confirm the feasibility of screening diverse test agents in an independent laboratory.

Topics: Animals; Antibodies; Blood Glucose; CD3 Complex; Diabetes Mellitus, Type 1; Disease Models, Animal; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Mice; Mice, Inbred NOD; Pentacyclic Triterpenes; Rats; Remission Induction; Triterpenes

To observe the efficacy and safety of glucagonlike peptide-1 (GLP-1) analogs in type 1 diabetes in a real-life medical practice setting.. We performed a retrospective chart review of patients with type 1 diabetes initiated on a GLP-1 analog and with at least one follow-up visit at more than 4 weeks.. We identified 11 patients who were initiated on a GLP-1 analog and had a follow-up visit between 4 and 13 weeks (mean (SD) follow-up 10 ± 3 weeks; age 36.5 ± 16.4 years; duration of diabetes 17.3 ± 9.3 years; all on insulin pump therapy; all started on liraglutide). Seven of these patients had a second follow-up visit at approximately 20 weeks. By 10 weeks, there was a significant decrease in weight (4.2% of total body weight), total daily insulin dose (19.2%, of which 14.0% basal and 24.1% bolus), and mean (SD) insulin units/kg (0.57 [0.17] to 0.48 [0.17] units/kg). Hemoglobin A1c was significantly decreased (7.4 [0.7%] to 7.0 [0.7%], P = 0.02) without an increase in hypoglycemia. These effects were sustained at 20 weeks. Nausea was a common adverse effect and lead to drug discontinuation in 4 of 11 patients.. Patients with long-standing type 1 diabetes can achieve weight loss and improved glycemic control on less insulin without an increase in hypoglycemia when liraglutide is added to insulin therapy.

Topics: Adult; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Insulin Infusion Systems; Liraglutide; Male; Middle Aged; Retrospective Studies; Treatment Outcome; Young Adult

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

Type-I diabetes is a chronic disease mediated by autoimmune destruction of insulin-producing β-cells. Although progress has been made towards improving diabetes-associated pathologies and the quality of life for those living with diabetes, no therapy has been effective at eliminating disease manifestations or reversing disease progression. Here, we examined whether double-stranded adeno-associated virus serotype 8 (dsAAV8)-mediated gene delivery to endogenous β-cells of interleukin (IL)-4 in combination with β-cell growth factors can reverse early-onset diabetes in NOD mice. Our results demonstrate that a single treatment with dsAAV8 vectors expressing IL-4 in combination with glucagon-like peptide-1 or hepatocyte growth factor/NK1 under the regulation of the insulin promoter enhanced β-cell proliferation and survival in vivo, significantly delaying diabetes progression in NOD mice, and reversing disease in ∼10% of treated NOD mice. These results demonstrate the ability to reverse hyperglycemia in NOD mice with established diabetes by in vivo gene transfer to β-cells of immunomodulatory factors and β-cell growth factors.

Topics: Animals; Dependovirus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Female; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Glucagon-Like Peptide 1; Hepatocyte Growth Factor; Insulin-Secreting Cells; Interleukin-4; Mice; Mice, Inbred NOD

Proinsulin is a marker of beta-cell distress and dysfunction in type 2 diabetes and transplanted islets. Proinsulin levels are elevated in patients newly diagnosed with type 1 diabetes. Our aim was to assess the relationship between proinsulin, insulin dose-adjusted haemoglobin A1c (IDAA1C), glucagon-like peptide-1 (GLP-1), glucagon, and remission status the first year after diagnosis of type 1 diabetes.. Juvenile patients (n = 275) were followed 1, 6, and 12 months after diagnosis. At each visit, partial remission was defined as IDAA1C ≤ 9%. The patients had a liquid meal test at the 1-, 6-, and 12-month visits, which included measurement of C-peptide, proinsulin, GLP-1, glucagon, and insulin antibodies (IA).. Patients in remission at 6 and 12 months had significantly higher levels of proinsulin compared to non-remitting patients (p < 0.0001, p = 0.0002). An inverse association between proinsulin and IDAA1C was found at 1 and 6 months (p = 0.0008, p = 0.0022). Proinsulin was positively associated with C-peptide (p < 0.0001) and IA (p = 0.0024, p = 0.0068, p < 0.0001) at 1, 6, and 12 months. Glucagon (p < 0.0001 and p < 0.02) as well as GLP-1 (p = 0.0001 and p = 0.002) were significantly lower in remitters than in non-remitters at 6 and 12 months. Proinsulin associated positively with GLP-1 at 1 month (p = 0.004) and negatively at 6 (p = 0.002) and 12 months (p = 0.0002).. In type 1 diabetes, patients in partial remission have higher levels of proinsulin together with lower levels of GLP-1 and glucagon compared to patients not in remission. In new onset type 1 diabetes proinsulin level may be a sign of better residual beta-cell function.

Topics: Adolescent; Age of Onset; Blood Glucose; C-Peptide; Child; Child, Preschool; Cohort Studies; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Glucagon; Glucagon-Like Peptide 1; Humans; Infant; Infant, Newborn; Male; Proinsulin; Remission, Spontaneous

Like insulin, glucagon-like peptide 1 (GLP-1) may have direct trophic actions on the nervous system, but its potential role in supporting diabetic sensory neurons is uncertain. We identified wide expression of GLP-1 receptors on dorsal root ganglia sensory neurons of diabetic and nondiabetic mice. Exendin-4, a GLP-1 agonist, increased neurite outgrowth of adult sensory neurons in vitro. To determine the effects ofexendin-4 in comparison with continuous low- or high-dose insulin in vivo, we evaluated parallel cohorts of type 1 (streptozotocin-induced) and type 2 (db/db) mice of 2 months' diabetes duration with established neuropathy during an additional month of treatment. High-dose insulin alone reversed hyperglycemia in type 1 diabetic mice, partly reversed thermal sensory loss, improved epidermal innervation but failed to reverse electrophysiological abnormalities. Exendin-4 improved both sensory electrophysiology and behavioral sensory loss. Low-dose insulin was ineffective. In type 2 diabetes, hyperglycemia was uncorrected, and neither insulin nor exendin-4 reversed sensory electrophysiology, sensory behavior, or loss of epidermal axons. However, exendin-4 alone improved motor electrophysiology. Receptor for advanced glycosylated end products and nuclear factor-κB neuronal expression were not significantly altered by diabetes or treatment. Taken together, these results suggest that although GLP-1 agonists and insulin alone are insufficient to reverse all features of diabetic neuropathy, in combination, they might benefit some aspects of established diabetic neuropathy.

Topics: Animals; Axons; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Immunohistochemistry; Insulin; Male; Mice; Motor Neurons; Neural Conduction; Peptides; Peripheral Nerves; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Sensory Receptor Cells; Signal Transduction; Venoms

Topics: Administration, Oral; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Injections; Insulin

Adipose-derived mesenchymal stem cells (ADMSCs) display immunosuppressive properties, suggesting a promising therapeutic application in several autoimmune diseases, but their role in type 1 diabetes (T1D) remains largely unexplored. The aim of this study was to investigate the immune regulatory properties of allogeneic ADMSC therapy in T cell-mediated autoimmune diabetes in NOD mice. ADMSC treatment reversed the hyperglycemia of early-onset diabetes in 78% of diabetic NOD mice, and this effect was associated with higher serum insulin, amylin, and glucagon-like peptide 1 levels compared with untreated controls. This improved outcome was associated with downregulation of the CD4(+) Th1-biased immune response and expansion of regulatory T cells (Tregs) in the pancreatic lymph nodes. Within the pancreas, inflammatory cell infiltration and interferon-γ levels were reduced, while insulin, pancreatic duodenal homeobox-1, and active transforming growth factor-β1 expression were increased. In vitro, ADMSCs induced the expansion/proliferation of Tregs in a cell contact-dependent manner mediated by programmed death ligand 1. In summary, ADMSC therapy efficiently ameliorates autoimmune diabetes pathogenesis in diabetic NOD mice by attenuating the Th1 immune response concomitant with the expansion/proliferation of Tregs, thereby contributing to the maintenance of functional β-cells. Thus, this study may provide a new perspective for the development of ADMSC-based cellular therapies for T1D.

Topics: Adipocytes; Animals; Cell Proliferation; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Glucagon-Like Peptide 1; Hyperglycemia; Insulin; Islet Amyloid Polypeptide; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred NOD; T-Lymphocytes, Regulatory

The incretin glucagon-like peptide-1 (GLP-1) and other GLP-1 receptor agonists have been shown to cause both antiapoptotic as well as regenerative effects on beta-cells in different animal models for diabetes. Our aim of this study was to test the hypothesis that spontaneously diabetic non obese diabetic (NOD) mice show an altered expression of GLP-1 compared to normoglycemic age-matched controls as a consequence of a diabetic state. To do this we used an ELISA prototype for mouse GLP-1 to measure plasma total GLP-1 from recently diabetic NOD mice as well as from age-matched normoglycemic NOD mice (controls). We also stained sections of pancreatic glands for GLP-1 from diabetic NOD mice and controls. We found increased levels of plasma total GLP-1 in diabetic NOD mice, when compared to control mice, both from non-fasted mice and from mice fasted for 2h. Furthermore, diabetic NOD mice displayed a higher GLP-1 response to an oral glucose tolerance test, compared to control mice. We also found that sections of pancreatic glands from diabetic NOD mice had an increased GLP-1 positive islet area in regard to relative islet area (i.e. total islet area / total pancreas area of the sections) compared to control mice. To our knowledge, this study is the first to show increased levels of GLP-1 in plasma in spontaneously diabetic NOD mice. We suggest that these results might represent a compensatory mechanism of the diabetic NOD mice to counteract beta-cell loss and hyperglycemia.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 1; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Insulin; Mice; Mice, Inbred NOD; Pancreas

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted from intestinal L cells upon nutrients ingestion, and is currently used for treating diabetes mellitus. It plays an important role in receptor modulation and cross talk with insulin at the coronary endothelium (CE) and cardiomyocytes (CM) in diabetic type 1 rat heart model. We studied the effects of insulin, GLP-1 analogues (exendin-4), and dipeptidyl peptidase-IV (DPP-IV) inhibitor on GLP-1 cardiac receptor modulation. The binding affinity of GLP-1 to its receptor on CE and CM was calculated using a rat heart perfusion model with [(125)I]-GLP-1(7-36). Tissue samples from the heart were used for immunostaining and Western blot analyses. GLP-1 systemic blood levels were measured using ELISA. GLP-1 binding affinity (τ) increased on the CE (0.33 ± 0.01 vs. 0.25 ± 0.01 min; p < 0.001) and decreased on the CM (0.29 ± 0.02 vs. 0.43 ± 0.02 min; p < 0.001) in the diabetic non-treated rats when compared to normal. There was normalization of τ back to baseline on the CE and CM levels with insulin and DPP-IV inhibitor treatment, respectively. Histological sections and immunofluorescence showed receptor up-regulation in diabetic rats with significant decrease and even normalization with the different treatment strategies. Systemic GLP-1 levels increased after 14 days of diabetes induction (10 ± 3.7 vs. 103 ± 58 pM; p = 0.0005). In conclusion, there is a significant GLP-1 receptor affinity modulation on the CE and CM levels in rats with diabetes type 1, and a cross talk with GLP-1 analogues in early prevention of cardiac remodeling.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 1; Dipeptidyl-Peptidase IV Inhibitors; Endothelium, Vascular; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart; Insulin; Male; Myocytes, Cardiac; Peptides; Protein Binding; Rats; Rats, Sprague-Dawley; Receptor Cross-Talk; Receptors, Glucagon; Venoms; Ventricular Remodeling

A 22 year old obese woman with type 1 diabetes for 17 years and poor metabolic control despite continuous insulin infusion (case 1). Case 2 was a 16 year-old girl of normal weight in whom diabetes mellitus type 1 was diagnosed accidentally. Her 54 year old father was and had been treated for diabetes mellitus type 1 for 10 years. He was poorly controlled and associated with polyneuropathy and history of myocardial infarction (case 3).. In Case 1 the C-peptide test was negative, glutamic acid decarboxylase- and IA2-antibodies were not demonstrated. Cases 2 and 3 showed normal C-peptide, tests for GAD-, IA2- and ICA antibodies were negative. A nucleotid substitution in intron 1 of the HNF-4α gene was demonstrated.. All three patients were treated with liraglutide. There was a reduction in HbA(1c), glucose fluctuations, hypoglycaemia, daily insulin dose and body weight, as well as an improvement of well-being and quality of life.. These case reports indicate that GLP-1 analogs may reduce postprandial and fasting glucose levels in non-type 2 diabetic patients, independently or residual beta cell function. Further studies are needed to evaluate the benefits of treatment with liraglutide in patients with type 1 or type 3 diabetes.

Topics: Adolescent; Blood Glucose; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Drug Therapy, Combination; Female; Genetic Predisposition to Disease; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incidental Findings; Insulin; Insulin Resistance; Liraglutide; Male; Middle Aged; Young Adult

To determine whether the addition of liraglutide to insulin to treat patients with type 1 diabetes leads to an improvement in glycemic control and diminish glycemic variability.. In this study, 14 patients with well-controlled type 1 diabetes on continuous glucose monitoring and intensive insulin therapy were treated with liraglutide for 1 week. Of the 14 patients, eight continued therapy for 24 weeks.. In all the 14 patients, mean fasting and mean weekly glucose concentrations significantly decreased after 1 week from 130±10 to 110±8  mg/dl (P<0.01) and from 137.5±20 to 115±12  mg/dl (P<0.01) respectively. Glycemic excursions significantly improved at 1 week. The mean s.d. of glucose concentrations decreased from 56±10 to 26±6  mg/dl (P<0.01) and the coefficient of variation decreased from 39.6±10 to 22.6±7 (P<0.01). There was a concomitant fall in the basal insulin from 24.5±6 to 16.5±6 units (P<0.01) and bolus insulin from 22.5±4 to 15.5±4 units (P<0.01). In patients who continued therapy with liraglutide for 24 weeks, mean fasting, mean weekly glucose concentrations, glycemic excursions, and basal and bolus insulin dose also significantly decreased (P<0.01). HbA1c decreased significantly at 24 weeks from 6.5 to 6.1% (P=0.02), as did the body weight by 4.5±1.5  kg (P=0.02).. Liraglutide treatment provides an additional strategy for improving glycemic control in type 1 diabetes. It also leads to weight loss.

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Liraglutide; Male; Weight Loss

This study focuses on the effects of long-term renin-angiotensin system suppression and/or incretin mimetic therapies on the regulation and binding affinity of GLP-1 to its receptor in the coronary endothelium (CE) and cardiomyocytes (CMs) of type 1 diabetic male Sprague-Dawley rats. The groups assessed are normal (N), streptozotocin-induced diabetic (D), Insulin treated (DI), Exendin-4 treated (DE), Aliskiren treated (DA), cotreated with Insulin and Aliskiren (DIA) and cotreated with exendin-4 and Aliskiren (DEA). Heart perfusion with (125)I-GLP-1 was performed to estimate GLP-1 binding affinity (τ = 1/k-n) to its receptor in the heart. Western Blotting was assessed to determine the expression variation of GLP-1 receptor in the heart. Plasma GLP-1 levels were measured using Enzyme-Linked Immunosorbent Assay (ELISA). Diabetes decreased the τ value on CE and increased it on CMs compared to normal. The combination of Exendin-4 with Aliskiren showed a normalizing effect on the binding affinity of GLP-1 at the coronary endothelium, while at the cardiomyocyte level Exendin-4 treatment alone was the most effective.

Topics: Amides; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Drug Evaluation, Preclinical; Exenatide; Fumarates; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart; Hypoglycemic Agents; Male; Myocardium; Peptides; Protein Binding; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Renin; Streptozocin; Venoms

Topics: Diabetes Mellitus, Type 1; Female; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Pancreas; Peptide Fragments; Postprandial Period

Transgenic mice carrying the human insulin gene driven by the K-cell glucose-dependent insulinotropic peptide (GIP) promoter secrete insulin and display normal glucose tolerance tests after their pancreatic p-cells have been destroyed. Establishing the existence of other types of cells that can process and secrete transgenic insulin would help the development of new gene therapy strategies to treat patients with diabetes mellitus. It is noted that in addition to GIP secreting K-cells, the glucagon-like peptide 1 (GLP-1) generating L-cells share/ many similarities to pancreatic p-cells, including the peptidases required for proinsulin processing, hormone storage and a glucose-stimulated hormone secretion mechanism. In the present study, we demonstrate that not only K-cells, but also L-cells engineered with the human preproinsulin gene are able to synthesize, store and, upon glucose stimulation, release mature insulin. When the mouse enteroendocrine STC-1 cell line was transfected with the human preproinsulin gene, driven either by the K-cell specific GIP promoter or by the constitutive cytomegalovirus (CMV) promoter, human insulin co-localizes in vesicles that contain GIP (GIP or CMV promoter) or GLP-1 (CMV promoter). Exposure to glucose of engineered STC-1 cells led to a marked insulin secretion, which was 7-fold greater when the insulin gene was driven by the CMV promoter (expressed both in K-cells and L-cells) than when it was driven by the GIP promoter (expressed only in K-cells). Thus, besides pancreatic p-cells, both gastrointestinal enteroendocrine K-cells and L-cells can be selected as the target cell in a gene therapy strategy to treat patients with type 1 diabetes mellitus.

Topics: Animals; Diabetes Mellitus, Type 1; Enteroendocrine Cells; Gastric Inhibitory Polypeptide; Genetic Engineering; Genetic Therapy; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Insulin-Secreting Cells; Mice; Mice, Transgenic; Protein Precursors

To investigate whether the local production of glucagon-like peptide-1 (GLP-1) in the intestine can differentiate intestinal stem/progenitor cells into insulin-producing cells, we intra-intestinally injected a recombinant adenovirus expressing GLP-1 (rAd-GLP-1) into diabetic mice. There were no significant differences in body weight or food intake between rAd-GLP-1- and rAd-betaGAL-treated control mice. rAd-GLP-1-treated mice showed intestinal insulin mRNA expression, insulin- and glucagon-positive cells in the intestine, and significantly increased serum insulin, but not glucagon. rAd-GLP-1 injection significantly reduced blood glucose levels and improved glucose tolerance compared with controls. Expression of transcription factors related to beta cell differentiation, neurogenin 3 (ngn3) and neurogenin differentiation factor (NeuroD), was detected in the intestine at 2 weeks after rAd-GLP-1 injection. We suggest that expression of GLP-1 in the intestine by intra-intestinal delivery of rAd-GLP-1 may induce differentiation of intestinal stem/progenitor cells into insulin-producing cells, mediated by ngn3 and NeuroD expression, contributing to lowered blood glucose levels in diabetic mice.

Topics: Adenoviridae; Animals; Cell Differentiation; Diabetes Mellitus, Type 1; Disease Models, Animal; Glucagon-Like Peptide 1; Hyperglycemia; Insulin-Secreting Cells; Intestines; Male; Mice; Mice, Inbred NOD; Reverse Transcriptase Polymerase Chain Reaction; Stem Cells; Time Factors

The mechanism by which glucagon-like peptide-1 (GLP-1) suppresses glucagon secretion is uncertain, and it is not determined whether endogenous insulin is a necessary factor for this effect.. To characterize the alpha- and beta-cell responses to GLP-1 in type 1 diabetic patients without residual beta-cell function.. Nine type 1 diabetic patients, classified as C-peptide negative by a glucagon test, were clamped at plasma glucose of 20 mmol/liter for 90 min with arginine infusion at time 45 min and concomitant infusion of GLP-1 (1.2 pmol/kg x min) or saline.. Infusion with GLP-1 increased C-peptide concentration just above the detection limit of 33 pmol/liter in one patient, but C-peptide remained immeasurable in all other patients. In the eight remaining patients, total area under the curve of glucagon was significantly decreased with GLP-1 compared with saline: 485 +/- 72 vs. 760 +/- 97 pmol/liter x min (P < 0.001). In addition, GLP-1 decreased the arginine-stimulated glucagon release (incremental AUC of 103 +/- 21 and 137 +/- 16 pmol/liter x min, with GLP-1 and saline, respectively, P < 0.05).. In type 1 diabetic patients without endogenous insulin secretion, GLP-1 decreases the glucagon secretion as well as the arginine-induced glucagon response during hyperglycemia. GLP-1 induced endogenous insulin secretion in one of nine type 1 diabetic patients previously classified as being without endogenous insulin secretion.

Topics: Arginine; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Humans; Hyperglycemia; Insulin-Secreting Cells; Serum Albumin

In autoimmune type 1 diabetes mellitus, proinflammatory cytokine-mediated apoptosis of beta-cells has been considered to be the first event directly responsible for beta-cell mass reduction. In the Bio-Breeding (BB) rat, an in vivo model used in the study of autoimmune diabetes, beta-cell apoptosis is observed from 9 wk of age and takes place after an insulitis period that begins at an earlier age. Previous studies by our group have shown an antiproliferative effect of proinflammatory cytokines on cultured beta-cells in Wistar rats, an effect that was partially reversed by Exendin-4, an analogue of glucagon-like peptide-1. In the current study, the changes in beta-cell apoptosis and proliferation during insulitis stage were also determined in pancreatic tissue sections in normal and thymectomized BB rats, as well as in Wistar rats of 5, 7, 9, and 11 wk of age. Although stable beta-cell proliferation in Wistar and thymectomized BB rats was observed along the course of the study, a decrease in beta-cell proliferation and beta-cell mass from the age of 5 wk, and prior to the commencement of apoptosis, was noted in BB rats. Exendin-4, in combination with anti-interferon-gamma antibody, induced a near-total recovery of beta-cell proliferation during the initial stages of insulitis. This highlights the importance of early intervention and, as well, the possibilities of new therapeutic approaches in preventing autoimmune diabetes by acting, initially, in the insulitis stage and, subsequently, on beta-cell regeneration and on beta-cell apoptosis.

Topics: Animals; Antibodies; Apoptosis; Cell Proliferation; Diabetes Mellitus, Type 1; Disease Models, Animal; Exenatide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Hypoglycemic Agents; Immunohistochemistry; Insulin-Secreting Cells; Interferon-gamma; Peptides; Random Allocation; Rats; Rats, Wistar; Venoms

Inhibition of dipeptidyl peptidase IV (DPP-IV) activity by NVP-DPP728, a DPP-IV inhibitor, improves the therapeutic efficacy of glucagon-like peptide-1 (GLP-1). CD26 is a membrane-associated glycoprotein with DPP-IV activity and is expressed on lymphocytes. We investigated the effect of NVP-DPP728 on reversing new-onset diabetes in nonobese diabetic (NOD) mice and modulating the inflammatory response and stimulating beta-cell regeneration. New-onset diabetic NOD mice were treated with NVP-DPP728 for 2, 4, and 6 wk. Blood glucose level was monitored. Regulatory T cells in thymus and secondary lymph nodes, TGF-beta1 and GLP-1 in plasma, and the insulin content in the pancreas were measured. Immunostaining for insulin and bromodeoxyuridine (BrdU) were performed. The correlation of beta-cell replication with inflammation was determined. In NVP-DPP728-treated NOD mice, diabetes could be reversed in 57, 74, and 73% of mice after 2, 4, and 6 wk treatment, respectively. Insulitis was reduced and the percentage of CD4(+)CD25(+)FoxP3(+) regulatory T cells was increased in treated NOD mice with remission. Plasma TGF-beta1 and GLP-1, the insulin content, and both insulin(+) and BrdU(+) beta-cells in pancreas were also significantly increased. No significant correlations were found between numbers of both insulin(+) and BrdU(+) beta-cells in islets and beta-cell area or islets with different insulitis score in NOD mice with remission of diabetes. In conclusion, NVP-DPP728 treatment can reverse new-onset diabetes in NOD mice by reducing insulitis, increasing CD4(+)CD25(+)FoxP3(+) regulatory T cells, and stimulating beta-cell replication. beta-Cell replication is not associated with the degree of inflammation in NVP-DPP728-treated NOD mice.

Topics: Animals; Blood Glucose; CD4 Antigens; Diabetes Mellitus, Type 1; Dipeptidyl-Peptidase IV Inhibitors; Female; Forkhead Transcription Factors; Glucagon-Like Peptide 1; Insulin-Secreting Cells; Interleukin-2 Receptor alpha Subunit; Mice; Mice, Inbred NOD; Nitriles; Pyrrolidines; T-Lymphocytes, Regulatory; Transforming Growth Factor beta1

Dipeptidyl peptidase-4 (DPP-4) has an important role in the carbohydrate metabolism with the degradation of incretin hormones.. We assessed the serum DPP-4 activity both in fasting and postprandial condition in patients with type 1-, type 2 diabetes and healthy controls.. Serum DPP-4 activities were determined at fasting sate and at 60 and 180 minutes after test meal. DPP-4 activity was measured by microplate-based kinetic assay in 41 type 1-, and in 87 type 2 diabetic patients and in 25 healthy volunteers.. Serum DPP-4 activities were found significantly higher both in fasting and postprandial state in patients with type 1 diabetes than in type 2 and control subjects. No change in the enzyme activities was found after test meal. Correlation was neither detected between the fasting plasma glucose nor between the HbA(1C) and the DPP-4 values in any of the groups studied.. RESULTS suggest that it is not the hyperglycemia, rather the type of diabetes which determinates the serum DPP-4 enzymatic activity. The exact background of this phenomenon is not yet clear, however, increased serum DPP-4 enzyme activity in type 1 diabetes mellitus may refer to pancreatic autoimmune process, concomitant autoimmune diseases, hormonal feed back mechanism, or even target organ damage.

Topics: Adult; Aged; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Male; Middle Aged

Incretin-based compounds, including glucagon-like peptide-1 receptor agonists and dipeptidyl-peptidase-4 inhibitors, have emerged as a new class of agents for the treatment of type 2 diabetes. In this article, the potential and supporting evidence for extending their use to early type 1 diabetes are reviewed. The rationale relies on the assumption that these drugs, in addition to their action on insulin secretion and glucose regulation, may be effective in preserving and even expanding the beta-cell mass. This assumption is based on data from in vitro and animal studies, with no clear demonstrations in humans. This class of drugs may represent an entirely new approach to the treatment of type 1 diabetes, focused on protection and preservation of beta-cells, an ideal complement to immune interventions inhibiting or modulating the pathogenetic autoimmune process. The ideal candidates for this treatment are patients at the time of clinical onset of type 1 diabetes or individuals with preclinical type 1 diabetes who still have a significant viable beta-cell mass.

Topics: Antibodies, Monoclonal; Cell Proliferation; Diabetes Mellitus, Type 1; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin-Secreting Cells; Interleukin-2 Receptor alpha Subunit; Peptides; Venoms

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 aim of this study was to investigate the feasibility and mechanisms of controlling blood glucose using hepatic electrical stimulation (HES).. The study was performed in regular Sprague-Dawley (SD) rats, streptozotocin-induced type 1 diabetic rats and Zucker diabetic fatty (ZDF) rats chronically implanted with one pair of stimulation electrodes on two lobes of the liver tissues.. (i) Hepatic electrical stimulation was effective in reducing blood glucose by 27%-31% at time points 60, 75 and 90 min after oral glucose in normal rats; (ii) HES reduced blood glucose in both fasting and fed states in both type 1 and type 2 diabetic rats; (iii) Chronic HES decreased the blood glucose level, and, delayed gastric empty and increased plasma glucagon-like peptide-1 (GLP-1) level; and (iv) No adverse events were noted in any rats during HES. Histopathological analyses and liver function tests revealed no electrode dislodgement, tissue damages or liver enzyme changes with HES.. Hepatic electrical stimulation is capable of reducing both fasting and fed blood glucose in normal, and type 1 and type 2 diabetic rats and the effect may be partially mediated via an increase in GLP-1 release.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Electric Stimulation; Electrodes, Implanted; Fasting; Gastric Emptying; Gastric Inhibitory Polypeptide; Gastrointestinal Transit; Glucagon-Like Peptide 1; Glucose Tolerance Test; Liver; Rats; Rats, Sprague-Dawley; Rats, Zucker

Topics: Administration, Oral; Adult; Anti-Obesity Agents; Combined Modality Therapy; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diet, Reducing; Dose-Response Relationship, Drug; Double-Blind Method; Female; Glucagon-Like Peptide 1; Humans; Injections, Subcutaneous; Lactones; Liraglutide; Male; Middle Aged; Multicenter Studies as Topic; Obesity; Orlistat; Quality of Life; Randomized Controlled Trials as Topic; Surveys and Questionnaires; Weight Loss

This project consisted of two parts: a biochemical part and clinical studies. The overall aim was to elucidate the defective regulation of glucagon secretion in type 2 diabetes (T2DM). The aim in the biochemical part was to develop a glucagon ELISA by using C- and N-terminal antibodies generated in the laboratory. Much effort was put into this attempt; however, we were unsuccessful and had to use an alternative method in our attempt to characterize the paradoxical diabetic glucagon response further. By using Sep-Pac and HPLC separation methods, plasma from patients with T2DM known to have a defective suppression of glucagon was analyzed using three antibodies and RIA. In this way the hyperglucagonaemia was found to consist mainly of authentic glucagon, rather than abnormally processed forms. The first clinical study included ten healthy controls matched to ten patients with T2DM. The aim was to investigate if GLP-1 induced glucagon inhibition was dose dependent and if suppression was equally potent in healthy controls and T2DM patients. Further, we investigated if the potency of the inhibition depended on the prevailing plasma glucose (PG) level. All participants were investigated with increasing doses of GLP-1 administered as iv-infusions and saline (control) during a glycaemic clamp at fasting plasma glucose (FPG) levels. Patients were investigated on a third occasion with GLP-1 infusions after an over-night normalisation of PG using adjustable insulin infusions. From these experiments we were able to conclude that GLP-1-induced glucagon inhibition is dose-dependent, but surprisingly GLP-1 suppressed the alpha cell equally potently in patients and controls - and the suppression was independent of PG level. Therefore we concluded that the paradoxical glucagon response to orally ingested glucose is not caused by decreased potency of GLP-1 with respect to glucagon suppression. It may be due to the decreased secretion of this hormone reported in earlier studies. My second protocol aimed towards quantifying the glucose-lowering effect of GLP-1-induced glucagon inhibition seen in patients with T2DM. The glucose-lowering effect of GLP-1 is due to both insulin stimulation leading to peripheral glucose disposal and glucagon inhibition resulting in decreased stimulation of hepatic glucose production. With a five-day protocol including both glycaemic and pancreatic clamps in ten patients with T2DM we were able to isolate the contribution of glucagon suppression to

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin; Male

Severe obesity is associated with type 2 diabetes mellitus, and both resolve with weight loss after bariatric operations. Intestinal hormones have been identified which are stimulated by rapid nutrient delivery to the lower small bowel after certain weight-loss operations. These incretins stimulate secretion and hypertrophy of the pancreatic beta cells. Surgical procedures are now being performed to treat diabetes in adults of lesser weight, and the importance of ruling out latent autoimmune diabetes in the adult (a variety of type 1) is suggested, before experimenting with these procedures.

Topics: Adult; Bariatric Surgery; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Obesity; Weight Loss

Encapsulating pancreatic islets in a semipermeable poly(ethylene glycol) (PEG) hydrogel membrane holds potential as an immuno-isolation barrier for the treatment of type 1 diabetes mellitus. The semipermeable PEG hydrogel not only permits free diffusion of nutrients, metabolic waste, and insulin produced from the encapsulated beta-cells, but also provides a size-exclusion effect to prevent direct contact of entrapped islets to host immune cells and antibodies. However, the use of unmodified PEG hydrogels for islet encapsulation is not ideal, as there is no bioactive cue to promote the long-term survival and function of the encapsulated cells. Herein, we report the synthesis and characterization of a bioactive glucagon-like peptide 1 (GLP-1) analog, namely, GLP-1-cysteine or GLP-1C, and the fabrication of functional GLP-1 immobilized PEG hydrogels via a facile thiol-acrylate photopolymerization. The immobilization of bioactive GLP-1C within PEG hydrogels is efficient and does not alter the bulk hydrogel properties. Further, the GLP-1 immobilized PEG hydrogels enhance the survival and insulin secretion of encapsulated islets. Overall, this study demonstrates a strategy to modify PEG hydrogels with bioactive peptide moieties that can significantly enhance the efficacy of islet encapsulation.

Topics: Capsules; Cell Survival; Diabetes Mellitus, Type 1; Glucagon-Like Peptide 1; Humans; Hydrogels; Insulin; Insulin Secretion; Insulin-Secreting Cells; Polyethylene Glycols

The aim of this study was to investigate whether insulin deficiency and increased catabolism may have a role in the regulation of plasma glucagon-like peptide (GLP)-1 and GLP-2 levels in children with diabetic ketoacidosis (DKA) and whether insulin treatment may affect the levels of these polypeptides.. Plasma GLP-1 and -2 levels were measured in 24 patients with DKA aged 8 to 14 years before insulin infusion (time 0), when ketonemia and acidosis disappeared (time 1), and when weight gain started (time 2). Eighteen healthy children aged 8 to 14 years constituted the control group.. At time 0, mean plasma GLP-1 and GLP-2 levels were significantly elevated in the patients compared with the control group (p<0.05 and p<0.01, respectively). At time 1 when ketonemia and acidosis disappeared, GLP-1 and GLP-2 levels decreased significantly from the initial levels (p<0.05 and p<0.01, respectively). At this time, while GLP-1 level was not different from that of the controls, GLP-2 level was higher than that of the controls (p<0.05). GLP-1 and-2 levels did not show any significant differences between the patients and controls when weight gain started (time 2).. Our results show that DKA is associated with increased plasma GLP-1 and -2 concentrations. Effective fluid and insulin treatment resulted in a significant decrease in plasma GLP-1 and -2 levels. This may be due to the negative feedback effect of insulin on the production of these polypeptides.

Topics: Adolescent; Case-Control Studies; Child; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Humans; Hypoglycemic Agents; Insulin; Male

Glucagon-like peptide-1 (GLP-1) and gastrin promote pancreatic beta-cell function, survival, and growth. Here, we investigated whether GLP-1 and gastrin can restore the beta-cell mass and reverse hyperglycemia in NOD mice with autoimmune diabetes.. Acutely diabetic NOD mice were treated with GLP-1 and gastrin, separately or together, twice daily for 3 weeks. Blood glucose was measured weekly and for a further 5 weeks after treatments, after which pancreatic insulin content and beta-cell mass, proliferation, neogenesis, and apoptosis were measured. Insulin autoantibodies were measured, and adoptive transfer of diabetes and syngeneic islet transplant studies were done to evaluate the effects of GLP-1 and gastrin treatment on autoimmunity.. Combination therapy with GLP-1 and gastrin, but not with GLP-1 or gastrin alone, restored normoglycemia in diabetic NOD mice. The GLP-1 and gastrin combination increased pancreatic insulin content, beta-cell mass, and insulin-positive cells in pancreatic ducts, and beta-cell apoptosis was decreased. Insulin autoantibodies were reduced in GLP-1- and gastrin-treated NOD mice, and splenocytes from these mice delayed adoptive transfer of diabetes in NOD-scid mice. Syngeneic islet grafts in GLP-1 -and gastrin-treated NOD mice were infiltrated by leukocytes with a shift in cytokine expression from interferon-gamma to transforming growth factor-beta1, and beta-cells were protected from apoptosis.. Combination therapy with GLP-1 and gastrin restores normoglycemia in diabetic NOD mice by increasing the pancreatic beta-cell mass and downregulating the autoimmune response.

Topics: Animals; Apoptosis; Autoantibodies; Blood Glucose; Cell Division; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Gastrins; Glucagon-Like Peptide 1; Injections, Intraperitoneal; Insulin Antibodies; Insulin-Secreting Cells; Islets of Langerhans; Islets of Langerhans Transplantation; Mice; Mice, Inbred NOD; Reference Values

The first antidiabetic agent was a hormone--insulin--and ever since, all therapeutic strategies have been based on the synthesis of chemical compounds to bind its receptors or transcription factors, or to trigger its intracellular mechanisms. Eighty years on, new therapeutic molecules are available for the treatment of diabetes and, again, are based on a hormone--glucagon-like peptide-1 (GLP-1). Whereas the theoretical benefit of insulin is based on normalization of functional physiology, therapeutic strategies based on GLP-1 aim to increase the circulating concentration of a natural component--the hormone GLP-1. There are two strategies for increasing GLP-1 plasma concentrations: replace the hormone with a long-acting analogue or molecule with a longer half-life; and prevent its degradation by inhibiting its natural protease, dipeptidyl peptidase IV (DPPIV). Although numerous clinical trials have been carried out and vast amounts of data are available, the mechanisms through which GLP-1-based therapy reduces blood glucose in diabetic patients remain unclear. Thus, it is essential to ask the right questions and to design appropriate clinical trials and experiments to increase our understanding of the mode of action of GLP-1-based therapy. For this reason, in the spring of 2008, expert scientists and clinicians in the field of GLP-1 got together for an intensive debate on the subject at the first meeting of the European Club for the study of GLP-1, held in Marseille. The subject of the round table discussions was: what is known, new and controversial about GLP-1? During these discussions, numerous facts and controversies were reevaluated, and revealed that several long-held, dogmatic beliefs have never been fully and scientifically established. These points are detailed here in these minutes of the landmark meeting.

Topics: Animals; Cell Differentiation; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; France; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; L Cells; Mice

Recent clinical trials have shown that the loss of insulin production that characterizes progressive type 1 diabetes mellitus can be attenuated by treatment with non-FcR binding anti-CD3 monoclonal antibody (mAb). This approach is a first step towards the ultimate goals of treatment: to improve and maintain insulin production. However, additional interventions will be needed because, with time, there is progressive loss of insulin production after treatment with a single course of anti-CD3 mAb. The basis for the long-term loss of insulin production after immune therapy is not known because animal models have not been informative about the mechanisms, and there are not biomarkers of autoimmunity that can be used to monitor the process. Therefore, strategies for clinical testing might involve both beta cell and immunological therapies. Examples of the former include agents such as GLP1 receptor agonists or DPPIV inhibitors which increase beta cell insulin content. Preclinical data suggest that co-administration of antigen with anti-CD3 mAb can induce a tolerogenic response to the antigen that may then be administered to maintain tolerance. In addition, other immunological approaches as well as interventions earlier in the disease process may be successful in maintaining greater beta cell function for extended periods.

Topics: Animals; Antibodies, Monoclonal; Autoimmunity; B-Lymphocytes; CD3 Complex; CD8-Positive T-Lymphocytes; Diabetes Mellitus, Type 1; Glucagon-Like Peptide 1; Humans; Immune Tolerance; Immunologic Factors; Immunosuppression Therapy; Immunotherapy; Insulin; Insulin-Secreting Cells; Mice; Mice, Inbred NOD; T-Lymphocytes, Regulatory

Topics: Adult; Bezoars; Diabetes Mellitus, Type 1; Endoscopy, Gastrointestinal; Exenatide; Female; Gastroparesis; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Islets of Langerhans Transplantation; Kidney Transplantation; Peptides; Venoms

Glucagon-like peptide 1 (GLP-1) and its analogue exendin-4 (Ex4) have displayed potent glucose homeostasis-modulating characteristics in type 2 diabetes (T2D). However, there are few reports of effectiveness in type 1 diabetes (T1D) therapy, where there is massive loss of beta cells. We previously described a novel GLP-1 analogue consisting of the fusion of active GLP-1 and IgG heavy chain constant regions (GLP-1/IgG-Fc), and showed that in vivo expression of the protein, via electroporation-enhanced intramuscular plasmid-based gene transfer, normalized blood glucose levels in T2D-prone db/db mice. In the present study, GLP-1/IgG-Fc and Ex4/IgG-Fc were independently tested in multiple low-dose streptozotocin-induced T1D. Both GLP-1/IgG-Fc and Ex4/IgG-Fc effectively reduced fed blood glucose levels in treated mice and ameliorated diabetes symptoms, where as control IgG-Fc had no effect. Treatment with GLP-1/IgG-Fc or Ex4/IgG-Fc improved glucose tolerance and increased circulating insulin and GLP-1 levels. It also significantly enhanced islet beta-cell mass, which is likely a major factor in the amelioration of diabetes. This suggests that GLP-1/IgG-Fc gene therapy may be applicable to diseases where there is either acute or chronic beta-cell injury.

Topics: Animals; Blood Glucose; Cell Size; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Electroporation; Exenatide; Gene Expression; Genetic Therapy; Glucagon-Like Peptide 1; Glucose Tolerance Test; Immunoglobulin Fc Fragments; Immunoglobulin G; Injections, Intramuscular; Insulin; Insulin-Secreting Cells; Mice; Mice, Inbred Strains; Peptides; Recombinant Fusion Proteins; Venoms

Gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (DM2) are suggested to be caused by the same metabolic disorder. Defects in gut hormone-dependent regulation of beta-cell function (entero-insular axis) have been proposed to contribute to the pathogenesis of DM2. The aim of study was to evaluate whether an impaired secretion of glucagon-like peptide-1 (GLP-1) and/or glucose-dependent insulinotropic polypeptide (GIP) could play a role in the development of carbohydrate disorders during pregnancy.. The study group (GDM) consisted of 13 gestational women with diabetes mellitus in whom GDM was diagnosed according to the World Health Organization criteria (75-g oral glucose tolerance test (OGTT)). The control group consisted of 13 pregnant women with normal glucose tolerance (NGT), matched according to age and duration of pregnancy. For all patients, plasma glucose, insulin, GLP-1 and GIP concentrations were evaluated after an OGTT, i.e. at 0, 30, 60, 90 and 120 min after glucose load.. Fasting plasma glucose concentrations were similar in both groups, but the 0-120 min area under the curve (AUC) for glucose was significantly greater in the GDM group than in the NGT group (p < 0.0005). Fasting insulin concentration was higher (p < 0.05) and the 2-h insulin response (AUCtotal) was significantly greater (p = 0.01) in the GDM group than in the NGT group. Insulin resistance was significantly higher in GDM compared with control women (homeostasis model assessment, p = 0.003). Fasting GLP-1 concentrations were higher in the GDM group (p = 0.05), but no differences were observed in GLP-1 response (AUC) between the studied groups. Fasting and stimulated GIP response did not differ between groups at any time of the study (p > 0.05). Positive correlations were observed between fasting GLP-1 and insulin concentration (r = 0.56, p < 0.004) and between fasting GLP-1 and insulin resistance (r = 0.43, p < 0.029).. An impaired secretion of GLP-1 and GIP does not seem to play a major role in the pathogenesis of GDM.

Topics: Adult; Blood Glucose; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetes, Gestational; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin; Pregnancy

The role of glucagon in hyperglycemia in type 1 diabetes is unresolved, and in vitro studies suggest that increasing blood glucose might stimulate glucagon secretion.. Our objective was to investigate the relationship between postprandial glucose and glucagon level during the first 12 months after diagnosis of childhood type 1 diabetes.. We conducted a prospective, noninterventional, 12-month follow-up study conducted in 22 centers in 18 countries.. Patients included 257 children and adolescents less than 16 yr old with newly diagnosed type 1 diabetes; 204 completed the 12-month follow-up.. The study was conducted at pediatric outpatient clinics.. We assessed residual beta-cell function (C-peptide), glycosylated hemoglobin (HbA(1c)), blood glucose, glucagon, and glucagon-like peptide-1 (GLP-1) release in response to a 90-min meal stimulation (Boost) at 1, 6, and 12 months after diagnosis.. Compound symmetric repeated-measurements models including all three visits showed that postprandial glucagon increased by 17% during follow-up (P = 0.001). Glucagon levels were highly associated with postprandial blood glucose levels because a 10 mmol/liter increase in blood glucose corresponded to a 20% increase in glucagon release (P = 0.0003). Glucagon levels were also associated with GLP-1 release because a 10% increase in GLP-1 corresponded to a 2% increase in glucagon release (P = 0.0003). Glucagon levels were not associated (coefficient -0.21, P = 0.07) with HbA(1c), adjusted for insulin dose. Immunohistochemical staining confirmed the presence of Kir6.2/SUR1 in human alpha-cells.. Our study supports the recent in vitro data showing a stimulation of glucagon secretion by high glucose levels. Postprandial glucagon levels were not associated with HbA(1c), adjusted for insulin dose, during the first year after onset of childhood type 1 diabetes.

Topics: Adolescent; ATP-Binding Cassette Transporters; Blood Glucose; C-Peptide; Child; Cohort Studies; Diabetes Mellitus, Type 1; Eating; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Glycated Hemoglobin; Humans; Immunohistochemistry; Insulin-Secreting Cells; Male; Postprandial Period; Potassium Channels; Potassium Channels, Inwardly Rectifying; Receptors, Drug; Sulfonylurea Receptors

The ATP-dependent K+-channel (K(ATP)) is critical for glucose sensing and normal glucagon and insulin secretion from pancreatic endocrine alpha- and beta-cells. Gastrointestinal endocrine L- and K-cells are also glucose-sensing cells secreting glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotrophic polypeptide (GIP) respectively. The aims of this study were to 1) investigate the expression and co-localisation of the K(ATP) channel subunits, Kir6.2 and SUR1, in human L- and K-cells and 2) investigate if a common hyperactive variant of the Kir6.2 subunit, Glu23Lys, exerts a functional impact on glucose-sensing tissues in vivo that may affect the overall glycaemic control in children with new-onset type 1 diabetes.. Western blot and immunohistochemical analyses were performed for expression and co-localisation studies. Meal-stimulated C-peptide test was carried out in 257 children at 1, 6 and 12 months after diagnosis. Genotyping for the Glu23Lys variant was by PCR-restriction fragment length polymorphism.. Kir6.2 and SUR1 co-localise with GLP-1 in L-cells and with GIP in K-cells in human ileum tissue. Children with type 1 diabetes carrying the hyperactive Glu23Lys variant had higher HbA1C at diagnosis (coefficient = 0.61%, P = 0.02) and 1 month after initial insulin therapy (coefficient = 0.30%, P = 0.05), but later disappeared. However, when adjusting HbA1C for the given dose of exogenous insulin, the dose-adjusted HbA1C remained higher throughout the 12 month study period (coefficient = 0.42%, P = 0.03).. Kir6.2 and SUR1 co-localise in the gastrointestinal endocrine L- and K-cells. The hyperactive Glu23Lys variant of the K(ATP) channel subunit Kir6.2 may cause defective glucose sensing in several tissues and impaired glycaemic control in children with type 1 diabetes.

Topics: Adolescent; ATP-Binding Cassette Transporters; Blotting, Western; C-Peptide; Child; Diabetes Mellitus, Type 1; Eating; Female; Gastric Inhibitory Polypeptide; Genotype; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Ileum; Immunohistochemistry; Insulin; Islets of Langerhans; Male; Polymorphism, Restriction Fragment Length; Potassium Channels; Potassium Channels, Inwardly Rectifying; Receptors, Drug; Sulfonylurea Receptors

We examined the effect of glucagon-like peptide-1 (GLP-1) on the development of diabetes and islet morphology in NOD mice by administering GLP-1 to prediabetic mice.. Eight-week-old female NOD mice were infused subcutaneously with human GLP-1 via a mini-osmotic pump for 4 or 8 weeks. In mice treated with GLP-1 for 4 weeks, blood glucose levels and body weight were measured. An intraperitoneal glucose tolerance test (IPGTT) and evaluation of insulitis score were also performed. Beta cell area, proliferation, apoptosis, neogenesis from ducts and subcellular localisation of forkhead box O1 (FOXO1) were examined by histomorphometrical, BrdU-labelling, TUNEL, insulin/cytokeratin and FOXO1/insulin double-immunostaining methods, respectively.. Mice treated with human GLP-1 for 4 weeks had lower blood glucose levels until 2 weeks after completion of treatment, showing improved IPGTT data and insulitis score. This effect continued even after cessation of the treatment. In addition to the increase of beta cell neogenesis, BrdU labelling index was elevated (0.24 vs 0.13%, p < 0.001), while apoptosis was suppressed by 54.2% (p < 0.001) in beta cells. Beta cell area was increased in parallel with the translocation of FOXO1 from the nucleus to the cytoplasm. The onset of diabetes was delayed in mice treated with GLP-1 for 4 weeks, while mice treated with GLP-1 for 8 weeks did not develop diabetes by age 21 weeks compared with a 60% diabetes incidence in control mice at this age.. Continuous infusion of human GLP-1 to prediabetic NOD mice not only induces beta cell proliferation and neogenesis, but also suppresses beta cell apoptosis and delays the onset of type 1 diabetes.

Topics: Animals; Blood Glucose; Cell Division; Diabetes Mellitus, Type 1; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Immunohistochemistry; Insulin-Secreting Cells; Mice; Mice, Inbred NOD; Pancreas; Peptide Fragments

Topics: Blood Glucose; C-Peptide; Child; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Glycated Hemoglobin; Humans; Hyperglycemia; Insulin; Postprandial Period; Potassium Channel Blockers; Potassium Channels, Inwardly Rectifying; Sulfonylurea Compounds

Topics: Animals; Antibodies; CD3 Complex; Combined Modality Therapy; Diabetes Mellitus, Type 1; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Immunotherapy; Mice; Mice, Inbred NOD; Models, Biological; Peptides; Receptors, Glucagon; Treatment Outcome; Venoms

Topics: Blood Glucose; Diabetes Complications; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Forecasting; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin-Secreting Cells

We examined whether free fatty acids (FFAs) promote glucagon-like peptide-1 (GLP-1) secretion when administered into the intestinal tract. We found that an unsaturated long-chain FFA, alpha-linolenic acid (alpha-LA), resulted in increased plasma GLP-1 and insulin levels when administered into the colon. Such stimulatory effects were not apparent with either vehicle or a saturated middle-chain FFA, octanoic acid (OA). Concomitant with GLP-1 secretion, the administration of alpha-LA, but not vehicle or OA, also resulted in a significant increase in the population of pERK positive cells within the GLP-1 positive cells of the colonic mucosa. Moreover, colonic administration of alpha-LA into normal C3H/He mice caused a reduction in plasma glucose levels, as well as in type 2 diabetic model NSY mice. Our results indicate that the in vivo colonic administration of alpha-LA promotes secretion of incretin GLP-1 by activating the ERK pathway in L-cells and thereby enhances the secretion of insulin.

Topics: Animals; Colon; Diabetes Mellitus, Type 1; Enteral Nutrition; Fatty Acids, Nonesterified; Glucagon-Like Peptide 1; Insulin; Insulin Secretion; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL

Islet transplantation can improve glycemic control in patients with type 1 diabetes and reduce or eliminate the need for insulin. Glucagon-like peptide-1 (GLP-1) is an intestinal insulinotropic hormone that augments glucose induced insulin secretion, and has a trophic effect on beta-cells. We evaluated the effect of GLP-1 on insulin secretion after islet transplantation. Patients underwent hyperglycemic glucose clamp studies 1 month after their last transplant. GLP-1 was infused during the second hour of the hyperglycemic clamp. Results were compared to normal control subjects and patients with type 2 diabetes who underwent an identical hyperglycemic clamp. First phase insulin release was absent in patients, while second phase insulin was not significantly reduced (control: 118+/-29 pM; type 2 diabetes: 68+/-20 pM; transplant: 99+/-18 pM, p=ns for all). GLP-1 had a significant incretin effect on transplanted islets but the response was less than controls (control: 2108+/-344 pM; type 2 diabetes: 929+/-331 pM; transplant: 329+/-112 pM, p<0.0001 control versus transplant). Islet transplant patients had no evidence of resistance to insulin mediated glucose disposal. We conclude that transplanted islets retain the ability to respond to GLP-1.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 1; Diet, Diabetic; Female; Glucagon-Like Peptide 1; Glucose Clamp Technique; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Islets of Langerhans Transplantation; Male; Middle Aged; Peptide Fragments; Peptides

Recent studies in adult patients with type 1 diabetes mellitus (T1DM) and T2DM have examined the potential utility, benefits, and side effects of agents that augment insulin secretion after oral ingestion of nutrients in comparison with intravenous nutrient delivery, the so-called incretins. Two families of incretin-like substances are now approved for use in adults. Glucagon-like peptide-1 (GLP-1) or agents that bind to its receptor (exenatide, Byetta) or agents that inhibit its destruction [dipeptidyl peptidase-IV (DPP-IV) inhibitors, Vildagliptin] improve insulin secretion, delay gastric emptying, and suppress glucagon secretion while decreasing food intake without increasing hypoglycemia. Pramlintide, a synthetic amylin analog, also decreases glucagon secretion and delays gastric emptying, improves hemoglobin A1c (HbA1C), and facilitates weight reduction without causing hypoglycemia. We review the historical discovery of these agents, their physiology [corrected] and their current applications. Remarkably, only one or two studies have been reported in children. Pediatricians caring for children with T1DM and T2DM should become familiar with these agents and investigate their applicability, as they seem likely to enhance our therapeutic armamentarium to treat children with diabetes mellitus.

Topics: Amyloid; Child; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diet, Diabetic; Energy Intake; Glucagon-Like Peptide 1; Humans; Islet Amyloid Polypeptide

Type 1 diabetes (T1D) is an autoimmune disease in which the pancreatic beta-cells are destroyed in an immune-mediated process. In one mouse model of T1D, the co-expression of the costimulatory molecule, B7-1, and the pro-inflammatory cytokine, tumor necrosis factor (TNF)-alpha, on the beta-cells leads to massive insulitis and loss of beta-cells, resulting in T1D. Here, we have investigated whether the specific loss of beta-cells is due to an intrinsic defect in the beta-cells or is a direct consequence of B7-1 expression. We show that transgenic mice expressing TNF-alpha on the beta-cells and B7-1 on the alpha-cells are resistant to the development of diabetes despite B7-1-dependent loss of alpha-cells and a massive islet inflammation consisting of T cells, B cells, macrophages and dendritic cells. Furthermore, islets with alpha-cell expression of B7-1 develop alpha-cell destruction and heavy infiltration, but maintain functional beta-cells when they are engrafted into diabetic mice that co-express TNF-alpha and B7-1 on the beta-cells. Thus, our results show that the beta-cells are able to survive in a severely inflamed organ where the neighboring alpha-cells are destroyed, suggesting that in this model B7-1 expression on the target cells is the primary determinant for the loss of islet cells.

Topics: Animals; B7-1 Antigen; Cell Death; Crosses, Genetic; Diabetes Mellitus, Type 1; Glucagon; Glucagon-Like Peptide 1; Immunohistochemistry; Insulin; Islets of Langerhans; Islets of Langerhans Transplantation; Mice; Mice, Inbred C57BL; Mice, Transgenic; Peptide Fragments; Protein Precursors; Reverse Transcriptase Polymerase Chain Reaction; Statistics, Nonparametric; Tumor Necrosis Factor-alpha

Glucagon-like peptide-1 (GLP-1) is the most insulinogenic of the glucagon-like peptides secreted mainly by L cells in the small and large intestine in response to the ingestion of nutrients. It binds to a specific GLP-1 receptor (GLP-1R) on beta-cells and can increase islet neogenesis and beta-cell mass. It is not clear whether the transmission of information from the gut to islet beta-cells by messengers such as GLP-1 is different in individuals who develop autoimmune diabetes. In the present study the expression of bioactive GLP-1 protein in the gut and its receptor in the pancreas was examined in diabetes-prone BioBreeding (BBdp) rats in the period before overt diabetes and in age-matched control, non-diabetes-prone BB (BBc) rats. An N-terminal directed antibody specific for the bioactive forms of GLP-1 (GLP-1(7-37) and GLP-1(7-36amide)) was used to mea-sure GLP-1 by radioimmunoassay in proximal, median, and distal gut. Pancreas GLP-1R area fraction, GLP-1R gene expression, and insulin content were analyzed, as were plasma GLP-1, glucose, and insulin. The concentration of GLP-1 protein in the jejunum and ileum of BBdp rats was lower than in BBc rats. Although these animals maintained normal blood glucose, there was impaired pancreatic endocrine function, characterized by low baseline insulin concentration in plasma and pancreas. GLP-1R mRNA expression was threefold less in islets isolated from BBdp rats, and GLP-1R+ islet area fraction in pancreas sections was decreased. When injected iv with GLP-1, BBdp rats displayed lower second-phase insulin response (and insulin/glucose ratios) compared with BBc rats. Thus, young BBdp rats displayed decreased concentrations of bioactive GLP-1 in jejunum and ileum, reduced GLP-1R in islets, and lower second-phase insulin response to iv GLP-1 than controls. The decrease in insulinogenic and islet beta-cell mass-promoting signal from GLP-1 in BBdp rats may contribute to impaired glucoregulation and ineffective maintenance of normal islet mass that shifts islet homeostasis in favor of development of diabetes.

Topics: Animals; Blood Glucose; Blotting, Northern; Diabetes Mellitus, Type 1; Female; Gastrointestinal Tract; Gene Expression; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Immunohistochemistry; Insulin; Male; Pancreas; Peptide Fragments; Protein Precursors; Rats; Rats, Inbred BB; Receptors, Glucagon

Abnormal nutrient-related small-intestinal feedback may contribute to disordered gastric motility and upper gastrointestinal symptoms in patients with diabetes.. To evaluate the motor, sensory and incretin responses to intraduodenal nutrients in patients with type 1 diabetes and in controls.. Eight type 1 diabetes patients (two with autonomic neuropathy) and nine controls were studied during euglycaemia. A manometric catheter was positioned across the pylorus, and nutrient was infused intraduodenally (90 kcal over 30 min). Blood glucose and plasma glucagon-like peptide 1 and gastric inhibitory polypeptide were measured, and sensations were assessed with visual analogue questionnaires.. During nutrient infusion, neither the number of antral waves nor the stimulation of phasic or basal pyloric pressures differed between patients and controls. Upper gut sensations and areas under the plasma incretin peptide curves did not differ between the groups.. During euglycaemia, the upper gastrointestinal motor, sensory and incretin peptide responses to small-intestinal nutrient are comparable in patients with relatively uncomplicated type 1 diabetes and in healthy subjects.

Topics: Adult; Autonomic Nervous System; Blood Glucose; Diabetes Mellitus, Type 1; Duodenum; Eating; Female; Gastric Emptying; Gastric Inhibitory Polypeptide; Gastrointestinal Motility; Glucagon; Glucagon-Like Peptide 1; Humans; Hunger; Male; Manometry; Middle Aged; Parenteral Nutrition; Peptide Fragments; Pressure; Protein Precursors; Pyloric Antrum

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones secreted in response to meal ingestion, thereby enhancing postprandial insulin secretion. Therefore, an attenuated incretin response could contribute to the impaired insulin responses in patients with diabetes mellitus. The aim of the present investigation was to investigate incretin secretion, in obesity and type 1 and type 2 diabetes mellitus, and its dependence on the magnitude of the meal stimulus. Plasma concentrations of incretin hormones (total, reflecting secretion and intact, reflecting potential action) were measured during two meal tests (260 kcal and 520 kcal) in eight type 1 diabetic patients, eight lean healthy subjects, eight obese type 2 diabetic patients, and eight obese healthy subjects. Both in diabetic patients and in healthy subjects, significant increases in GLP-1 and GIP concentrations were seen after ingestion of both meals. The incretin responses were significantly higher in all groups after the large meal, compared with the small meal, with correspondingly higher C-peptide responses. Both type 1 and type 2 diabetic patients had normal GIP responses, compared with healthy subjects, whereas decreased GLP-1 responses were seen in type 2 diabetic patients, compared with matched obese healthy subjects. Incremental GLP-1 responses were normal in type 1 diabetic patients. Increased fasting concentrations of GIP and an early enhanced postprandial GIP response were seen in obese, compared with lean healthy subjects, whereas GLP-1 responses were the same in the two groups. beta-cell sensitivity to glucose, evaluated as the slope of insulin secretion rates vs. plasma glucose concentration, tended to increase in both type 2 diabetic patients (29%, P = 0.19) and obese healthy subjects (22% P = 0.04) during the large meal, compared with the small meal, perhaps reflecting the increased incretin response. We conclude: 1) that a decreased GLP-1 secretion may contribute to impaired insulin secretion in type 2 diabetes mellitus, whereas GIP and GLP-1 secretion is normal in type 1 diabetic patients; and 2) that it is possible to modulate the beta-cell sensitivity to glucose in obese healthy subjects, and possibly also in type 2 diabetic patients, by giving them a large meal, compared with a small meal.

Topics: Adult; Aged; Blood Glucose; Body Weight; C-Peptide; Case-Control Studies; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Feeding Behavior; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Male; Middle Aged; Obesity; Peptide Fragments; Protein Precursors; Random Allocation

Topics: Adult; Amyloid; Blood Glucose; Diabetes Mellitus, Type 1; Female; Glucagon; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemic Agents; Islet Amyloid Polypeptide; Male; Peptide Fragments; Protein Precursors

Glucagon-like peptide-1 ameliorates the symptoms of diabetes through stimulation of insulin secretion and enhancement of beta-cell mass. We have therefore investigated the effects of glucagon-like peptide-1 on the development of diabetes, using db/db mice as a model of Type II diabetes.. The potent glucagon-like peptide-1 analogue Exendin-4 or vehicle (control) was administered (i.p.; 1 nmol/kg) to obese 6-week old db/db mice daily for 14 days ( n=10).. By 8 weeks of age, control db/db mice developed hyperglycaemia (fasting: 10.4+/-0.5 mmol/l), hyperinsulinaemia and impaired glucose tolerance. However, Exendin-4 treatment prevented hyperglycaemia (fasting: 6.1+/-1.0 mmol/l, p<0.01), with reduced plasma insulin concentrations ( p<0.001) and improved glucose tolerance ( p<0.05). Peripheral insulin sensitivity was not affected. However, insulin release in vivo and in vitro from the perfused pancreas was improved by Exendin-4, as were pancreatic insulin concentrations (0.54+/-0.02 vs 0.32+/-0.01 micro g/mg protein, p<0.05). These changes occurred in conjunction with increased beta-cell mass (3.01+/-0.31 vs 2.22+/-0.22 mg, p<0.05) and proliferation (BrdU(+) beta-cells: 1.08+/-0.20 vs 0.47+/-0.11%, p<0.05), as well as decreased apoptosis (Tunel (+) beta-cells: 0.37+/-0.06 vs 1.20+/-0.21%). Western blot demonstrated increased expression of Akt1 (by fivefold, p<0.01) and p44 MAP kinase (by sixfold, p<0.01), and decreased activation of caspase-3 (by 30%, p<0.05).. Our results suggest that Ex4 treatment delays the onset of diabetes in 6-8 week old db/db mice, through a mechanism involving Akt1 and expansion of the functional beta-cell mass.

Topics: Animals; Apoptosis; Blood Glucose; Cell Division; Diabetes Mellitus; Diabetes Mellitus, Type 1; Exenatide; Female; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Hyperglycemia; Insulin; Islets of Langerhans; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Peptide Fragments; Peptides; Protein Precursors; Venoms

Glucagon-like peptide 1 (GLP-1) content of the intestinal tract was recently found to be lower in diabetesprone BioBreeding (BBdp) rats than in the corresponding control animals (BBc rats), a finding compatible with the idea that an inflammatory intestinal state precedes insulitis in these diabetes-prone animals. This study aimed at measuring GLP-1 content of the intestinal tract both in another animal model of type 1 diabetes and in an animal model of type 2 diabetes. GLP-1 content of the jejunum, ileum, colon, and cecum was measured in male and female adult control rats and animals injected with streptozotocin (STZ) either during the neonatal period or 7 d before sacrifice. GLP-1 content of the intestinal tract was higher in type 1 diabetic rats than in control animals. Such was not the case in the type 2 diabetic rats. The findings recorded in the rats injected with STZ either during the neonatal period or later in life indicate that hyperglycemia and/or insulin deficiency do not cause a decrease in GLP-1 content of the intestinal tract. On the contrary, such a content may increase when the glucose intolerance and hypoinsulinemia are sufficiently pronounced, as was the case in the type 1 diabetic rats. These findings are thus compatible with the view that the decreased GLP-1 content of the intestinal tract in BBdp rats may result from intestinal inflammation.

Topics: Animals; Animals, Newborn; Blood Glucose; Body Weight; Cecum; Colon; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glucagon; Glucagon-Like Peptide 1; Ileum; Insulin; Intestines; Jejunum; Male; Pancreas; Peptide Fragments; Protein Precursors; Proteins; Rats; Rats, Inbred BB; Rats, Wistar; Streptozocin

In vitro studies indicate that glucagon-like peptide-1(7-36)-amide (GLP-1) can enhance hepatic glucose uptake. To determine whether GLP-1 increases splanchnic glucose uptake in humans, we studied seven subjects with type 1 diabetes on two occasions. On both occasions, glucose was maintained at approximately 5.5 mmo/l during the night using a variable insulin infusion. On the morning of the study, a somatostatin, glucagon, and growth hormone infusion was started to maintain basal hormone levels. Glucose (containing [3H]glucose) was infused via an intraduodenal tube at a rate of 20 micromol.kg(-1).min(-1). Insulin concentrations were increased to approximately 500 pmol/l while glucose was clamped at approximately 8.8 mmol/l for the next 4 h by means of a variable intravenous glucose infusion labeled with [6,6-2H2]glucose. Surprisingly, the systemic appearance of intraduodenally infused glucose was higher (P = 0.01) during GLP-1 infusion than saline infusion, indicating a lower (P < 0.05) rate of initial splanchnic glucose uptake (1.4 +/- 1.5 vs. 4.8 +/- 0.8 micromol.kg(-1).min(-1)). On the other hand, flux through the hepatic uridine-diphosphate- glucose pool did not differ between study days (14.2 +/- 5.5 vs. 13.0 +/- 4.2 micromol.kg(-1).min(-1)), implying equivalent rates of glycogen synthesis. GLP-1 also impaired (P < 0.05) insulin-induced suppression of endogenous glucose production (6.9 +/- 2.9 vs. 1.3 +/- 1.4 micromol.kg(-1).min(-1)), but caused a time-dependent increase (P < 0.01) in glucose disappearance (93.7 +/- 10.0 vs. 69.3 +/- 6.3 micromol.kg(-1).min(-1); P < 0.01) that was evident only during the final hour of study. We conclude that in the presence of hyperglycemia, hyperinsulinemia, and enterally delivered glucose, GLP-1 increases total body but not splanchnic glucose uptake in humans with type 1 diabetes.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Duodenum; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose; Human Growth Hormone; Hydrocortisone; Hypoglycemic Agents; Insulin; Intubation; Osmolar Concentration; Peptide Fragments; Viscera

Glucagon-like peptide-1 (G LP-1) is an incretin with glucose-dependent insulinotropic and insulin-independent antidiabetic properties that exerts insulin-like effects on glucose metabolism in rat liver, skeletal muscle, and fat. This study aimed to search for the effect of a prolonged treatment, 3 ds, with GLP-1 on glucotransporter GLUT2 expression in liver, and on that of GLUT4 in skeletal muscle and fat, in rats. Normal rats and streptozotocin-induced type 1 and type 2 diabetic models were used; diabetic rats were also treated with insulin for comparison. In normal rats, GLP-1 treatment reduced in the three tissues the corresponding glucotransporter protein level, without modifying their mRNA. In the type 2 diabetic model, GLP-1, like insulin, stimulated in liver and fat only the glucotransporter translational process, while in the muscle an effect at the GLUT4 transcriptional level was also observed. In the type 1 diabetic model, GLP-1 apparently exerted in the liver only a posttranslational effect on GLUT2 expression; in muscle and fat, while insulin was shown to have an action on GLUT4 at both transcriptional and translational levels, the effect of GLP-1 was restricted to glucotransporter translation. In normal and diabetic rats, exogenous GLP-1 controlled the glucotransporter expression in extrapancreatic tissues participating in the overall glucose homeostasis-liver, muscle, and fat-where the effect of the peptide seems to be exerted only at the translational and/or posttranslational level; in muscle and fat, the presence of insulin seems to be required for GLP-1 to activate the transcriptional process. The stimulating action of GLP-1 on GLUT2 and GLUT4 expression, mRNA or protein, could be a mechanism by which, at least in part, the peptide exerts its lowering effect on blood glucose.

Topics: Adipose Tissue; Animals; Blotting, Northern; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Gene Expression; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Transporter Type 2; Glucose Transporter Type 4; Liver; Male; Monosaccharide Transport Proteins; Muscle Proteins; Muscle, Skeletal; Peptide Fragments; Protein Precursors; Rats; Rats, Wistar; RNA, Messenger

GLP-1 (glucagon-like peptide 1), proposed as a possible tool for Type 2 diabetes therapy, has insulin-like effects upon glucose metabolism in extrapancreatic tissues, whose plasma membranes contain specific receptors for the peptide, being those, at least in liver and muscle, not associated to the adenylate cyclase/cAMP system. GLP-1, as insulin, modulates the content of glycosylphosphatidylinositols (GPIs)--precursors of inositolphosphoglycans (IPGs), considered mediators of insulin action--in several extrapancreatic cell lines and in normal rat hepatocytes and adipocytes. In the present paper, we document that in a streptozotocin-induced Type 2 diabetic rat model, GLP-1, as insulin, provokes a rapid decrease of the [myo-3H-inositol]GPI content in isolated adipocytes--indicative of its hydrolysis and immediate short-lived generation of IPG--as that previously observed in normal animals; in hepatocytes, GLP-1, but not insulin, induced a reduction in the cellular GPI, although delayed in relation to normal rats. In adipocytes from streptozotocin-induced Type 1 diabetic rats, GLP-1, as insulin, seems to induce a reduction in the cellular GPI content, which was smaller and occurred later than that provoked in the Type 2 diabetic model; in the hepatocytes, GLP-1 and insulin failed to affect the control GPI content at any time tested. In Type 2 diabetic rat, the hepatocyte retains its response capability to GLP-1, but not to insulin, suggesting that the peptide could be bypassing possible defective steps in the insulin signaling pathway in the liver of this diabetic model.

Topics: Adipocytes; Animals; Blood Glucose; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucagon; Glucagon-Like Peptide 1; Glycosylphosphatidylinositols; Hepatocytes; Hypoglycemic Agents; Inositol Phosphates; Insulin; Liver; Male; Oligosaccharides; Pancreas; Peptide Fragments; Polysaccharides; Protein Precursors; Rats; Rats, Wistar

A pharmacological concentration of glucagon-like peptide-1 (GLP-1) in the insulin-deficient state clearly decreases the blood glucose level. Therefore, this study was designed to evaluate a putatively relevant effect of the gastrointestinal peptide as an adjuvant to insulin replacement therapy. GLP-1 (GLP-1(7-36) amide 10 pmol x kg(-1) x min(-1)) was infused intravenously over 8 hours in nine fasting, C-peptide-negative diabetic dogs. The animals were under normoglycemic control by glucose-controlled insulin infusion (GCII) during the night before and during GLP-1 administration. During the paired control tests, the animals received saline infusion instead of GLP-1. In addition to the insulin infusion rates required to maintain normoglycemia, hormones, metabolites, and the turnover rates for glucose (6-3H-glucose), alanine (U-14C-alanine), and urea (15N2-urea) were measured during the final 2 hours of GLP-1 administration. Circulating plasma GLP-1 levels increased from 3+/-1 to 17+/-7 pmol/L. There was no significant difference in the insulin infusion rate between the experimental and control groups (0.43+/-0.05 v. 0.40+/-0.05 mU x kg(-1) x h(-1), average over the entire interval). Glycemia was maintained at a practically identical level (4.9+/-0.3 v. 4.8+/-0.4 mmol/L). Also, the concentration of plasma insulin-which was not hyperinsulinemic--and pancreatic glucagon remained unaltered. We found no appreciable effect of GLP-1 on glucose production and metabolic clearance, alanine turnover and the formation of glucose from alanine (1.8+/-0.2 v. 1.4+/-0.2 micromol x kg(-1) x min(-1), or the urea production rate as a measure of overall amino acid catabolism (4.1+/-0.4 v. 4.1+/-0.4 micromol x kg(-1) x min(-1)). Thus, no conclusive adjuvant effect of GLP-1 was ascertained in insulin-treated diabetic dogs under normoglycemic control.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 1; Dogs; Female; Glucagon; Glucagon-Like Peptide 1; Insulin; Male; Peptide Fragments; Protein Precursors

Hyperglycaemia slows gastric emptying in both normal subjects and patients with diabetes mellitus. The mechanisms mediating this effect, particularly the potential role of insulin, are uncertain. Hyperinsulinaemia has been reported to slow gastric emptying in normal subjects during euglycaemia. The purpose of this study was to evaluate the effect of euglycaemic hyperinsulinaemia on gastric emptying in Type I (insulin-dependent) and Type II (noninsulin-dependent) diabetes mellitus. In six patients with uncomplicated Type I and eight patients with uncomplicated Type II diabetes mellitus, measurements of gastric emptying were done on 2 separate days. No patients had gastrointestinal symptoms or cardiovascular autonomic neuropathy. The insulin infusion rate was 40 mU x m(-2) x min(-1) on one day and 80 mU x m(-2) x min(-1) on the other. Gastric emptying and intragastric meal distribution were measured using a scintigraphic technique for 3 h after ingestion of a mixed solid/liquid meal and results compared with a range established in normal volunteers. In both Type I and Type II patients the serum insulin concentration had no effect on gastric emptying or intragastric meal distribution of solids or liquids. When gastric emptying during insulin infusion rates of 40 mU x m(-2) x min(-1) and 80 mU x m(-2) x min(-1) were compared the solid T50 was 137.8+/-24.6 min vs. 128.7+/-24.3 min and liquid T50 was 36.7+/-19.4 min vs. 40.4+/-15.7 min in the Type I patients; the solid T50 was 94.9+/-19.1 vs. 86.1+/-10.7 min and liquid T50 was 21.8+/-6.9 min vs. 21.8+/-5.9 min in the Type II patients. We conclude that hyperinsulinaemia during euglycaemia has no notable effect on gastric emptying in patients with uncomplicated Type I and Type II diabetes; any effect of insulin on gastric emptying in patients with diabetes is likely to be minimal.

Topics: Adult; Amyloid; Blood Glucose; C-Peptide; Cholecystokinin; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Gastric Emptying; Glucagon; Glucagon-Like Peptide 1; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Hyperinsulinism; Hypoglycemic Agents; Infusions, Intravenous; Insulin; Islet Amyloid Polypeptide; Male; Peptide Fragments; Protein Precursors

To elucidate the question of whether production of the insulinotropic gut hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) is altered by a diabetic metabolic state, their intestinal expression pattern was evaluated. Two rodent models for diabetes mellitus were used, non-obese diabetic (NOD) mice as a model for insulin-dependent diabetes and Zucker diabetic fatty (ZDF) rats for non-insulin-dependent diabetes mellitus (NIDDM). Expression of both incretin hormones followed typical patterns, which were similar in both animals and unaltered by the diabetic state. The GIP gene was greatly expressed in the duodenum, jejunum, and ileum, with a continuous decrease from the upper to lower intestines. This pattern was observed in both NOD mice and ZDF rats regardless of the diabetic state. This expression data was corroborated by radioimmunoassay (RIA) analysis of the gene product GIP. Expression of the proglucagon gene encoding GLP-1 had an opposite appearance. The highest expression was seen in the large bowel and the ileum. RIA analysis of the gene product GLP-1 mirrored these data. Although the distribution pattern was similar in both animal models, in contrast to diabetic NOD mice, a regulated expression was found in diabetic ZDF rats. Compared with lean nondiabetic controls, fatty hyperglycemic animals showed an increased expression of the proglucagon gene in the colon and a concomitant reduction in the small intestine. This was mirrored by the GLP-1 content of the colon and ileum. Overall, basal GLP-1 plasma levels were increased in ZDF rats (17.0 +/- 2.8 pmol) compared with lean Zucker rats (12.4 +/- 1.8 pmol). In conclusion, incretin hormone expression (GIP and GLP-1) follows specific patterns throughout the gut and is unaltered by the diabetic state. In ZDF rats, regulation of proglucagon expression occurs mainly in the large intestine.

Topics: Animals; Blotting, Northern; Colon; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Disease Models, Animal; Gastric Inhibitory Polypeptide; Gene Expression; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Intestinal Mucosa; Intestine, Small; Intestines; Mice; Mice, Inbred NOD; Peptide Fragments; Proglucagon; Protein Precursors; Rats; Rats, Zucker; Rectum; RNA, Messenger; Tissue Distribution

To establish potential effects of glucagon-like peptide I (GLP-I) on blood glucose control in insulin-deficient states, GLP-I [GLP-I(7-36) amide; 10 pmol x kg(-1) x min(-1)] was infused intravenously in six fasting, canine C-peptide-negative, chronically diabetic dogs for 8 h. Blood samples were saved for the analysis of hormones, metabolites, and turnover rates of glucose (6-(3)H-glucose), alanine (U-(14)C-alanine), and urea ((15)N(2)-urea) starting 22 h after the last subcutaneous dose of exogenous insulin. Circulating plasma GLP-I levels rose under infusion from 2.9 +/- 0.8 to 41.4 +/- 10.1 pmol/l. This was efficient to significantly reduce the preexisting diabetic hyperglucagonemia. Since in the utilized model functioning pancreatic beta-cells are lacking, GLP-I had no insulinogenic effect. Compared with control experiments in the same animals receiving saline infusion, glycemia dropped from 20.8 +/- 1.9 to 16.2 +/- 1.0 mmol/l (P < 0.05). This was in parallel to the infusion of GLP-I and was most likely caused by a decrease of elevated glucose production since overall glucose turnover decreased with no alteration in glucose metabolic clearance. Alanine turnover was significantly reduced, obviously reflecting a decline in alanine production in relation to changed muscle glucose uptake under conditions of lower glycemia and overall glucose turnover. There was, however, neither an effect of GLP-I on alanine conversion into circulating glucose nor an effect on urea production rate, indicating unchanged gluconeogenesis from amino acid precursors. We conclude that the blood glucose-lowering effect of GLP-I in an animal model of insulinopenia was shown to be due to a reduction in hepatic glucose output, possibly secondary to reduction in glucagon concentrations leading to decreased glycogenolysis. Whether GLP-I might be therapeutically useful in clinical insulin-deficient diabetes needs to be verified.

Topics: Alanine; Animals; Blood Glucose; Diabetes Mellitus, Type 1; Dogs; Female; Glucagon; Glucagon-Like Peptide 1; Insulin; Male; Peptide Fragments; Protein Precursors; Urea

Weaning onto chow diets causes the highest incidence of diabetes in the BB rat. Changes in gut development and absorption of nutrients in the diabetes prone rat and the subsequent effect on pancreatic function may play a role in the ultimate development of the disease. BB diabetes prone (dp) and BB normal (n) dams were fed chow diets. Pups were killed at various ages ranging from 7 to 30 days. BBdp rats had higher small intestine and colon weights expressed per body weight at all ages (p < 0.0001). RNA content (mg/g) in the jejunum, ileum and colon was higher in the BBdp rats beginning at the critical period at 21 days and maintained at 24 days and 30 days (p < 0.0001). Proglucagon message decreased with age in both BBdp and BBn animals (p < 0.0001). Levels of proglucagon mRNA were higher in BBdp compared to BBn animals only in the ileum at 10 days (p < 0.01). Adjusting for total ileal and colonic RNA content resulted in BBdp animals having higher total colonic proglucagon mRNA at 21, 24 and 30 days (p < 0.0001). Plasma GLP-1(7-36) amide was more than doubled in BBdp compared to BBn animals (p < 0.0005) at 30 days. Expressing sodium-dependent D-glucose co-transporter (SGLT-1), GLUT2 and GLUT5 mRNA per total jejunal RNA shows increased transporter mRNA in BBdp compared to BBn rats at weaning (21 days) (p < 0.05). Radical differences exist between BBdp and BBn animals at 'critical periods' in both proglucagon and glucose transporter gene expression. These differences may help explain altered growth and diseases incidence between these two strains.

Topics: Age Factors; Animals; Blood Glucose; Colon; Diabetes Mellitus, Type 1; Diet; Female; Gene Expression Regulation, Developmental; Glucagon; Glucagon-Like Peptide 1; Glucose Transporter Type 1; Glucose Transporter Type 2; Intestine, Small; Male; Membrane Glycoproteins; Monosaccharide Transport Proteins; Peptide Fragments; Proglucagon; Protein Precursors; Rats; Rats, Inbred BB; RNA, Messenger; Sodium-Glucose Transporter 1

Effects of human glucagon-like peptide I (GLP-I)(7-36)amide were examined in volunteers having insulin-dependent diabetes mellitus (IDDM) with residual C-peptide (CP) secretion (n = 8, 7 men and 1 woman; age, 31 +/- 1.4 years; body mass index, 24.7 +/- 0.7 kg/m2; duration of diabetes, 3.2 +/- 0.8 years; insulin dose, 0.41 +/- 0.05 U.kg-1.day-1; meal-stimulated CP, 1.0 +/- 0.2 nmol/l [means +/- SE]). After a mixed meal (Sustacal, 30 kJ/kg body wt), intravenous injection of GLP-I, 1.2 pmol.kg-1.min-1 through 120 min, virtually abolished increments of plasma glucose, CP, pancreatic polypeptide (PP), and glucagon concentrations, with no significant effect on plasma gastrin levels during the infusions. At reduced dosage (0.75 pmol.kg-1.min-1), GLP-I had lesser effects on plasma glucose and CP levels. On cessation of intravenous GLP-I infusions after the meals, plasma glucose, CP, PP, and glucagon concentrations rebounded toward control levels by 180 min, and the response of plasma gastrin was prolonged. These rebound responses are consistent with intestinal delivery of food retained in the stomach on escape from inhibition of gastric emptying by GLP-I. Infusion of 1.2 pmol.kg-1.min-1 GLP-I with 20 g glucose (10% dextrose in water) injected intravenously over 60 min enhanced plasma responses of immunoreactive CP; the mean incremental areas under concentration curves (0-60 min) increased sixfold, but the glycemic excursion was not affected. Thus, in CP-positive IDDM, pharmacological doses of GLP-I reduce glycemic excursions after meals by a mechanism(s) not dependent on stimulation of insulin secretion, presumably involving delayed gastric emptying.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Eating; Female; Glucagon; Glucagon-Like Peptide 1; Humans; Infusions, Intravenous; Insulin; Male; Peptide Fragments; Protein Precursors

Insulin secretion is stimulated better by oral than by intravenous glucose (incretin effect). The contribution of the autonomic nervous system to the incretin effect after oral glucose in humans is unclear. We therefore examined nine type 1 diabetic (insulin-dependent) patients with end-stage nephropathy, studied after combined heterotopic pancreas and kidney transplantation, and 7 non-diabetic kidney recipients (matched for creatinine clearance and immunosuppressive medication). The release of gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) immunoreactivity and B cell secretory responses (IR insulin and C-peptide) to oral (50 g) and "isoglycaemic" intravenous glucose (identical glycaemic profile) were measured by radioimmunoassay. The difference in B cell responses between the two tests represents the contribution of the enteroinsular axis to the response after oral glucose (incretin effect). Insulin responses after the oral glucose challenge were similar in the two patient groups despite systemic venous drainage of the pancreas graft in the pancreas-kidney-transplanted group. In both groups GIP and GLP-1 increased after oral but not after intravenous glucose, and B cell secretory responses were significantly smaller (by 55.2 +/- 7.7% and 46.5 +/- 12.5%, respectively) with "isoglycaemic" intravenous glucose infusions. The lack of reduction in the incretin effect in pancreas-kidney-transplanted patients, whose functioning pancreas is denervated, indicates a lesser role for the nervous system and a more important contribution of circulating incretin hormones in mediating the enteroinsular axis in man.

Topics: Adult; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Insulin; Insulin Secretion; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Pancreas Transplantation; Peptide Fragments; Protein Precursors; Radioimmunoassay; Reference Values; Transplantation, Heterotopic

Glucagon-like peptide-1 (7-36) amide (glucagon-like insulinotropic peptide, or GLIP) is a gastrointestinal peptide that potentiates the release of insulin in physiologic concentrations. Its effects in patients with diabetes mellitus are not known.. We compared the effect of an infusion of GLIP that raised plasma concentrations of GLIP twofold with the effect of an infusion of saline, on the meal-related release of insulin, glucagon, and somatostatin in eight normal subjects, nine obese patients with non-insulin-dependent diabetes mellitus (NIDDM), and eight patients with insulin-dependent diabetes mellitus (IDDM). The blood glucose concentrations in the patients with diabetes were controlled by a closed-loop insulin-infusion system (artificial pancreas) during the infusion of each agent, allowing measurement of the meal-related requirement for exogenous insulin. In the patients with IDDM, normoglycemic-clamp studies were performed during the infusions of GLIP and saline to determine the effect of GLIP on insulin sensitivity.. In the normal subjects, the infusion of GLIP significantly lowered the meal-related increases in the blood glucose concentration (P less than 0.01) and the plasma concentrations of insulin and glucagon (P less than 0.05 for both comparisons). The insulinogenic index (the ratio of insulin to glucose) increased almost 10-fold, indicating that GLIP had an insulinotropic effect. In the patients with NIDDM, the infusion of GLIP reduced the mean (+/- SE) calculated isoglycemic meal-related requirement for insulin from 17.4 +/- 2.8 to 2.0 +/- 0.5 U (P less than 0.001), so that the integrated area under the curve for plasma free insulin was decreased (P less than 0.05) in spite of the stimulation of insulin release. In the patients with IDDM, the GLIP infusion decreased the calculated isoglycemic meal-related insulin requirement from 9.4 +/- 1.5 to 4.7 +/- 1.4 U. The peptide decreased glucagon and somatostatin release in both groups of patients. In the normoglycemic-clamp studies in the patients with IDDM, the GLIP infusion significantly increased glucose utilization (saline vs. GLIP, 7.2 +/- 0.5 vs. 8.6 +/- 0.4 mg per kilogram of body weight per minute; P less than 0.01).. GLIP has an antidiabetogenic effect, and it may therefore be useful in the treatment of patients with NIDDM:

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Eating; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Insulin; Insulin Infusion Systems; Insulin Secretion; Male; Middle Aged; Obesity; Peptide Fragments; Peptides; Somatostatin

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Insulin; Insulin Secretion; Peptide Fragments; Peptides