glucagon-like-peptide-1 and Pancreatitis

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

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

The glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide , is a widely used drug for the treatment of type 2 diabetes. Liraglutide is one of several incretin-based agents that have been suggested to be associated with pancreatitis and pancreas cancer. The suspicion accelerated after publication of an autopsy study claiming increased incidences of several pathological changes in pancreata from patients with diabetes treated with incretin-based drugs.. The aim of the present review is to give an overview of the pharmacology of liraglutide and provide a review of adverse reactions associated with liraglutide with a focus on the risk of pancreatitis and pancreas cancer.. When comprehensively reviewing the available literature, no clear and significant associations between liraglutide and pancreatitis and/or pancreas cancer seem evident. However, a recently published analysis suggests a trend toward a slightly elevated risk of pancreatitis with GLP-1 receptor agonists (including liraglutide), which may become statistical significant as more data become available. Well-established side effects are of gastrointestinal origin, typical mild-to-moderate and of transient character. The risk of hypoglycemia associated with liraglutide treatment is low.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Pancreatic Neoplasms; Pancreatitis; Receptors, Glucagon

Several randomized trials with metabolic outcomes have reported that glucagon like peptide-1 receptor agonists (GLP-1 RA) could be associated with an increased risk of pancreatitis. The present meta-analysis aimed to examine this hypothesis.. An extensive Medline, Embase, and Cochrane Database search for "exenatide", "liraglutide", "albiglutide", "taspoglutide", "dulaglutide", "lixisenatide", and "semaglutide" was performed up to March 31st, 2013.. (i) randomized trials, (ii) duration ≥12 weeks; (iii) on type 2 diabetes; and (iv) comparison of GLP-1RA with placebo or active drugs. Mantel-Haenszel odds ratio with 95% confidence interval (MH-OR) was calculated for pancreatitis.. 80 eligible trials were identified. Of these, 39 had not disclosed their findings or did not report any information on pancreatitis. The remaining 41 trials enrolled 14,972 patients, with a total exposure of 14,333 patient × years (8353 and 5980 patient × years for GLP-1 receptor agonists and comparators, respectively). The overall risk of pancreatitis was not different between GLP-1RA and comparators (MH-OR: 1.01[0.37; 2.76]; p = 0.99).. The present meta-analysis does not suggest any increase in the risk of pancreatitis with the use of GLP-1RA. However, it should be recognized that the number of observed cases of incident pancreatitis is very small and the confidence intervals of risk estimates are wide.

Topics: Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Pancreatitis; Peptides; Randomized Controlled Trials as Topic; Receptors, Glucagon; Venoms

Although rodent models provide insight into the mechanisms underlying type 2 diabetes mellitus (T2DM), they are limited in their translatability to humans. The nonhuman primate (NHP) shares important metabolic similarities with the human, making it an ideal model for the investigation of type 2 diabetes and use in preclinical trials. This review highlights the key contributions in the field over the last year using the NHP model.. The NHP has not only provided novel insight into the normal and pathological processes that occur within the islet, but has also allowed for the preclinical testing of novel pharmaceutical targets for obesity and T2DM. Particularly, administration of fibroblast growth factor-21 in the NHP resulted in weight loss and improvements in metabolic health, supporting rodent studies and recent clinical trials. In addition, the NHP was used to demonstrate that a novel melanocortin-4 receptor agonist did not cause adverse cardiovascular effects. Finally, this model has been used to provide evidence that glucagon-like peptide-1-based therapies do not induce pancreatitis in the healthy NHP.. The insight gained from studies using the NHP model has allowed for a better understanding of the processes driving T2DM and has promoted the development of well tolerated and effective treatments.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Female; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin-Secreting Cells; Macaca mulatta; Male; Pancreatitis; Weight Loss

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

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

Topics: Animals; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Pancreatic Neoplasms; Pancreatitis; Risk Factors; Thyroid Neoplasms

Recent suggestions that glucagon-like peptide-1 (GLP-1)-based therapies could cause pancreatitis, and even pancreatic cancer, are based on:. The worrying histological changes are not reproduced in all studies and are unexpectedly variable with different GLP-1-based therapies.. Singh's findings that pancreatitis is doubled with GLP-1-based therapies could relate to their use in obese patients who are prone to pancreatitis risk factors--gallstones and hypertriglyceridaemia. The other observational studies do not find an association between GLP-1-based therapies and pancreatitis.. The increased reports of pancreatitis and pancreatic cancer are likely to be attributable to 'notoriety bias'.. Butler's findings for those on GLP-1-based therapies vs. those not, could have other explanations. Meanwhile: META ANALYSIS: Randomized control trials with GLP-1-based therapies do not find increased pancreatitis risk. Meta-analysis of 53 randomized controlled trials including 20 212 dipeptidyl peptidase-4 inhibitor-treated patients found a significantly reduced risk of major adverse cardiovascular events [odds ratio 0.689 (0.528-0.899), P = 0.006] for dipeptidyl peptidase-4 inhibitors compared with control subjects.. The evidence suggests that there is more than a possibility that some of the GLP-1 receptor agonists, and possibly also some dipeptidyl peptidase-4 inhibitors, may be associated with reduced cardiovascular events. Eight ongoing long-term cardiovascular randomized controlled trials will report from September 2013 onwards. These trials should resolve the issue of pancreatitis risk and substantiate the extent of benefit.. Whilst we should remain vigilant, currently the balance of evidence is strongly in support of GLP-1-based therapy, with benefits far outweighing potential risks.

Topics: Adverse Drug Reaction Reporting Systems; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Liraglutide; Male; Pancreatic Neoplasms; Pancreatitis; Patient Selection; Peptides; Randomized Controlled Trials as Topic; Receptors, Glucagon; Risk Assessment; Risk Factors; Venoms

Within recent years, glucagon-like peptide 1 receptor agonists (GLP-1-RA) have emerged as a new treatment option for type 2 diabetes. The GLP-1-RA are administered subcutaneously and differ substantially in pharmacokinetic profiles.. This review describes the pharmacokinetics and safety aspects of the currently available GLP-1 receptor agonists, liraglutide (based on the structure of native GLP-1), exenatide twice daily and exenatide once weekly (based on exendin-4) in relation to the kinetics and toxicology of native GLP-1. The review is based on electronic literature searches and legal documents in the form of assessment reports from the European Medicines Agency and the United States Food and Drug Administration.. GLP-1-based therapy combines several unique mechanisms of action and have the potential to gain widespread use in the fight against diabetes and obesity. The difference in chemical structure have strong implications for key pharmacokinetic parameters such as absorption and clearance, and eventually the safety and efficacy of the individual GLP-1-RA. The main safety concerns are pancreatitis and neoplasms, for which there are no identifiable differences in risk between the available agents. Antibody formation and injection site reactions are more frequent with the exendin-4-based compounds. The efficacy with regard to Hb(A1c) reduction is superior with the longer-acting agonists, whereas the shorter-acting GLP-1-RA seems to provide greater postprandial glucose control and lower tolerability as a possible consequence of less induction of tachyphylaxis. The future place of these agents will depend on the added safety and efficacy data in the several ongoing cardiovascular outcome trials.

Topics: Animals; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Liraglutide; Pancreatitis; Peptides; Tachyphylaxis; Venoms

The association between GLP-1 agonists, acute pancreatitis (AP), any cancer and thyroid cancer is discussed. This meta-analysis was aimed at evaluating the risk of those serious adverse events associated with GLP-1 agonists in patients with type 2 diabetes.. Medline, EMBASE, Cochrane Library and clinicaltrials.gov were searched in order to identify longitudinal studies evaluating exenatide or liraglutide use and reporting data on AP or cancer. Odds ratios (ORs) were pooled using a random-effects model. I(2) statistics assessed heterogeneity.. Twenty-five studies were included. Neither exenatide (OR 0.84 [95% CI 0.58-1.22], I(2) = 30%) nor liraglutide (OR 0.97 [95% CI 0.21-4.39], I(2) = 0%) were associated with an increased risk of AP, independent of baseline comparator. The pooled OR for cancer associated with exenatide was 0.86 (95% CI 0.29, 2.60, I(2) = 0%) and for liraglutide was 1.35 (95% CI 0.70, 2.59, I(2) = 0%). Liraglutide was not associated with an increased risk for thyroid cancer (OR 1.54 [95% CI 0.40-6.02], I(2) = 0%). For exenatide, no thyroid malignancies were reported.. Current available published evidence is insufficient to support an increased risk of AP or cancer associated with GLP-1 agonists. These rare and long-term adverse events deserve properly monitoring in future studies evaluating GLP-1 agonists.

Topics: Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Liraglutide; Neoplasms; Pancreatitis; Peptides; Venoms

To review the evidence surrounding a potential association between liraglutide and pancreatitis.. A literature search was conducted in MEDLINE (1948-July 12, 2012) and EMBASE (1974-week 27, 2012) using the search terms pancreatitis, liraglutide, and glucagon-like peptide 1/adverse effects. Reference citations from identified publications were reviewed. The manufacturer was contacted and regulatory documents from the Food and Drug Administration website were reviewed for unpublished data related to cases of pancreatitis associated with liraglutide use.. All identified sources that were published in English were considered for inclusion.. Eleven cases of pancreatitis have been reported in patients taking liraglutide. Seven were from the LEAD (Liraglutide Effect and Action in Diabetes) studies, 1 was reported in the extension of a clinical trial, and 1 was in an unpublished obesity trial. Two were published postmarketing case reports. Nine of the cases reported were diagnosed as acute pancreatitis, while 2 were classified as chronic pancreatitis. The mean age of the patients was 57.5 years and mean body mass index was 33.92 kg/m(2). Six of the 11 cases occurred in male patients. Nine of the patients were white and 1 was African American. In 7 of the cases, onset occurred at liraglutide doses at or above 1.8 mg daily. Common comorbidities included history of pancreatitis, cholelithiasis, and diabetes. One case was fatal.. Pancreatitis is a potential complication with liraglutide therapy. Liraglutide should be used cautiously in patients at risk of pancreatitis (eg, alcohol abuse, history of pancreatitis, cholelithiasis).

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

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

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

To review the possible association between glucagon-like peptide-1 (GLP-1) agonist use and pancreatitis in patients with type 2 diabetes mellitus.. A MEDLINE search (1950-January 2010) identified key clinical trials delineating adverse effects associated with GLP-1 agonist use. Key search terms included type 2 diabetes mellitus, pancreatitis, incretins, exenatide, liraglutide, albiglutide, and taspoglutide. Review of references listed in the articles identified was also performed. The Food and Drug Administration (FDA) Web site and Amylin Pharmaceuticals file data were utilized to extract case report information and unpublished clinical development data related to GLP-1 agonist use and pancreatitis.. Phase 2 and 3 clinical trials evaluating exenatide, liraglutide, albiglutide, and taspoglutide that discussed treatmentrelated adverse effects as well as FDA-reviewed case reports of pancreatitis in patients taking these same therapies were included. One study evaluating type 2 diabetes as a risk factor for development of acute pancreatitis was also included. Exenatide case reports and clinical development data were also included.. Currently there have been 8 cases during clinical development and 36 postmarketing reports of acute pancreatitis in exenatide-treated patients. Four patients have developed acute (n = 3) or chronic (1) pancreatitis during liraglutide clinical trials. There have been no reports to date of development of acute pancreatitis in patients taking albiglutide or taspoglutide.. Observational reports and clinical trial data suggest an association between GLP-1 agonist use and acute pancreatitis; however, additional clinical trial data and in-depth case report analysis are needed to further evaluate and verify this finding.

Topics: Acute Disease; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Pancreatitis

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

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

Topics: Adipose Tissue; Amino Acid Sequence; Animals; Diabetes Mellitus; Gastric Acid; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Diseases; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose; Humans; Insulin; Pancreatitis; Pepsin A; Peptide Fragments; Peptides; Proinsulin; Radioimmunoassay; Salivation; Splanchnic Circulation

This report from the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial describes baseline lipase and amylase activity in type 2 diabetic subjects without acute pancreatitis symptoms before randomization to the glucagonlike peptide analog liraglutide or placebo.. The LEADER is an international randomized placebo-controlled trial evaluating the cardiovascular safety of liraglutide in 9340 type 2 diabetic patients at high cardiovascular risk. Fasting lipase and amylase activity was assessed at baseline, before receiving liraglutide or placebo, using a commercial assay (Roche) with upper limit of normal values of 63 U/L for lipase and 100 U/L for amylase.. Either or both enzymes were above the upper limit of normal in 22.7% of subjects; 16.6% (n = 1540) had an elevated lipase level (including 1.2% >3-fold elevated), and 11.8% (n = 1094) had an elevated amylase level (including 0.2% >3-fold elevated). In multivariable regression models, severely reduced kidney function was associated with the largest effect on increasing activity of both. However, even among subjects with normal kidney function, 12.2% and 7.7% had elevated lipase and amylase levels.. In this large study of type 2 diabetic patients, nearly 25% had elevated lipase or amylase levels without symptoms of acute pancreatitis. The clinician must take these data into account when evaluating abdominal symptoms in type 2 diabetic patients.

Topics: Acute Disease; Aged; Amylases; Biomarkers; Diabetes Mellitus, Type 2; Double-Blind Method; Fasting; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Kidney; Lipase; Liraglutide; Male; Middle Aged; Pancreatitis

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

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

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

Diabetes mellitus secondary to chronic pancreatitis is characterized by a progressive destruction of the pancreas, including loss of the islet cells, leading to a form of diabetes that can mimic both type 1 and type 2 diabetes. Glucagon-like peptide 1(7-36)amide (GLP-1), an intestinally derived insulinotropic hormone, represents a potential therapeutic agent for type 2 diabetes, because exogenous GLP-1 has been shown to increase the insulin and reduce the glucagon concentrations in these patients, and thus induce lower blood glucose, but without causing hypoglycemia. Ten patients with diabetes mellitus secondary to chronic pancreatitis and five normal subjects were studied. Nine patients were treated with insulin and one patient with sulfonylurea. In the fasting state, saline or GLP-1 in doses of 0.4 or 1.2 pmol/min/kg body weight were infused intravenously for 4 hours. Blood glucose was reduced in all patients with both doses of GLP-1; plasma C-peptide increased (p<0.02), and plasma glucagon decreased (p<0.02) compared with basal levels, also in three patients with normoglycemia and high levels of presumably exogenous insulin. Similar results were obtained in the normal subjects. In conclusion, GLP-1 treatment may be considered in patients with diabetes mellitus secondary to chronic pancreatitis, provided that a certain amount of alpha- and beta-cell secretory capacity is still present.

Topics: Aged; Blood Glucose; C-Peptide; Chronic Disease; Diabetes Mellitus; Drug Therapy, Combination; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Middle Aged; Pancreatitis; Peptide Fragments

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have significantly improved clinical effects on glycemic control. However, real-world data concerning the difference in gastrointestinal adverse events (AEs) among different GLP-1 RAs are still lacking. Our study aimed to characterize and compare gastrointestinal AEs among different marketed GLP-1 RAs (exenatide, liraglutide, dulaglutide, lixisenatide, and semaglutide) based on real-world data.. Disproportionality analysis was used to evaluate the association between GLP-1 RAs and gastrointestinal adverse events. Data were extracted from the US FDA Adverse Event Reporting System (FAERS) database between January 2018 and September 2022. Clinical characteristics, the time-to-onset, and the severe proportion of GLP-1 RAs-associated gastrointestinal AEs were further analyzed.. A total of 21,281 reports of gastrointestinal toxicity were analyzed out of 81,752 adverse event reports, and the median age of the included patients was 62 (interquartile range [IQR] 54-70) years old. Overall GLP-1 RAs were associated with increased risk of gastrointestinal system disorders (ROR, 1.46; 95% CI, 1.44-1.49), which were further attributed to liraglutide (ROR, 2.39; 95% CI, 2.28-2.51), dulaglutide (ROR, 1.39; 95% CI, 1.36-1.42), and semaglutide (ROR, 3.00; 95% CI, 2.89-3.11). Adverse events uncovered in the labels included gastroesophageal reflux disease, gastritis, bezoar, breath odor, intra-abdominal hematoma, etc. Furthermore, it was observed that semaglutide had the greatest risk of nausea (ROR, 7.41; 95% CI, 7.10-7.74), diarrhea (ROR, 3.55; 95% CI, 3.35-3.77), vomiting (ROR, 6.67; 95% CI, 6.32-7.05), and constipation (ROR, 6.17; 95% CI, 5.72-6.66); liraglutide had the greatest risk of abdominal pain upper (ROR, 4.63; 95% CI, 4.12-5.21) and pancreatitis (ROR, 32.67; 95% CI, 29.44-36.25). Most gastrointestinal AEs tended to occur within one month. Liraglutide had the highest severe rate of gastrointestinal AEs (23.31%), while dulaglutide had the lowest, with a severe rate of 12.29%.. GLP-1 RA were significantly associated with gastrointestinal AEs, and the association was further attributed to liraglutide, dulaglutide, and semaglutide. In addition, semaglutide had the greatest risk of nausea, diarrhea, vomiting, constipation, and pancreatitis, while liraglutide had the greatest risk of upper abdominal pain. Our study provided valuable evidence for selecting appropriate GLP-1 RAs to avoid the occurrence of GLP-1 RA-induced gastrointestinal AEs.

Topics: Abdominal Pain; Adverse Drug Reaction Reporting Systems; Aged; Constipation; Databases, Factual; Diabetes Mellitus, Type 2; Diarrhea; Gastrointestinal Diseases; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Middle Aged; Nausea; Pancreatitis; United States; United States Food and Drug Administration; Vomiting

/Objectives: The pathogenesis of hyperglycemia during acute pancreatitis (AP) remains unknown due to inaccessibility of human tissues and lack of animal models. We aimed to develop an animal model to study the mechanisms of hyperglycemia and impaired glucose tolerance in AP.. We injected ferrets with intraperitoneal cerulein (50 μg/kg, 9 hourly injections) or saline. Blood samples were collected for glucose (0, 4, 8, 12, 24h); TNF-α, IL-6 (6h); amylase, lipase, insulin, glucagon, pancreatic polypeptide (PP), glucagon-like peptide-1 (GLP-1), and gastric inhibitory polypeptide (GIP) (24h). Animals underwent oral glucose tolerance test (OGTT), mixed meal tolerance test (MMTT) at 24h or 3 months, followed by harvesting pancreas for histopathology and immunostaining.. Cerulein-injected ferrets exhibited mild pancreatic edema, neutrophil infiltration, and elevations in serum amylase, lipase, TNF-α, IL-6, consistent with AP. Plasma glucose was significantly higher in ferrets with AP at all time points. Plasma glucagon, GLP-1 and PP were significantly higher in cerulein-injected animals, while plasma insulin was significantly lower compared to controls. OGTT and MMTT showed abnormal glycemic responses with higher area under the curve. The hypoglycemic response to insulin injection was completely lost, suggestive of insulin resistance. OGTT showed low plasma insulin; MMTT confirmed low insulin and GIP; abnormal OGTT and MMTT responses returned to normal 3 months after cerulein injection.. Acute cerulein injection causes mild acute pancreatitis in ferrets and hyperglycemia related to transient islet cell dysfunction and insulin resistance. The ferret cerulein model may contribute to the understanding of hyperglycemia in acute pancreatitis.

Topics: Acute Disease; Amylases; Animals; Blood Glucose; Ceruletide; Ferrets; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Insulin; Insulin Resistance; Interleukin-6; Lipase; Pancreatitis; Tumor Necrosis Factor-alpha

The study was aimed to investigate gut hormone responses to mixed meal test in individuals with new-onset prediabetes or diabetes after acute pancreatitis (cases) compared with healthy controls, and the effect of body fat parameters. A total of 29 cases and 29 age- and sex-matched healthy controls were recruited. All participants were given standard mixed meal drink and blood samples were collected to measure dipeptidyl peptidase IV, gastric inhibitory peptide, glucagon like peptide-1, insulin, oxyntomodulin, and peptide YY. Body fat parameters were measured using magnetic resonance imaging. Repeated measures and linear regression analyses were conducted in unadjusted and adjusted models. Gastric inhibitory peptide levels were significantly higher whereas oxyntomodulin levels were significantly lower in cases compared with controls in both the unadjusted (p<0.001 and p<0.001, respectively) and adjusted (p<0.001 and p<0.001, respectively) models. In cases, liver fat % contributed up to 13.4% (vs. 2.9% in controls) to variance in circulating levels of gastric inhibitory peptide whereas body mass index - up to 20.8% (vs. 9.9% in controls) in circulating levels of oxyntomodulin. New-onset prediabetes/diabetes after acute pancreatitis is characterised by increased levels of gastric inhibitory peptide and decreased levels of oxyntomodulin. Further, liver fat % and body mass index appear to be the body fat parameters that contribute most significantly to gastric inhibitory peptide and oxyntomodulin levels, respectively.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Female; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Magnetic Resonance Imaging; Male; Meals; Middle Aged; Oxyntomodulin; Pancreatitis; Peptide YY; Postprandial Period; Prediabetic State; Subcutaneous Fat

Incretin therapy is one of the most potential approaches in the treatment of diabetes. In contrast to markedly available drugs, the herbal incretin modulators have lesser side effects with low economic cost. The main aim of this work was to analyze the potential of previously reported DPPIV inhibitor, aqueous extract of Pueraria tuberosa tubers (PTY-2) as incretin hormones receptor agonist against streptozotocin (STZ)-induced diabetes.. Chronic diabetes was induced with STZ (65mg/kg bw) in rats for 60days and grouped into diabetic control and PTY-2. Expression of genes was assessed by PCR, IHC, and ELISA. Morphological analysis of tissue was observed using H & E stain. In silico molecular docking approach has been used to see the interaction of active phytochemicals of PTY-2 on the basis of their binding energy [kcal/mol] and dissociation constant [pM] using YASARA software. Interactive visualization was done using Discovery studio 3.0.. In comparison to diabetic control, the size and number of islet cells along with the plasma level of GLP-1, GIP, and pancreatic expressions of GLP-1R, GIP-R, Bcl2, and insulin were enhanced significantly after PTY-2 treatment. Through in silico molecular docking, tuberostan showed the best interaction for GLP-1R with binding energy at 8.15kcal/mol and dissociation constant at 1061624.125 pM. Puererone showed the best interaction for GIP-R with binding energy at 8.31kcal/mol and dissociation constant at 810381 pM.. In addition to previously studied DPPIV inhibitor, PTY-2 also acts as incretin receptors agonist and protects against STZ-induced diabetes by down regulating β cells apoptosis.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Glucagon-Like Peptide 1; Hypoglycemic Agents; Incretins; Insulin; Male; Molecular Docking Simulation; Pancreatitis; Plant Extracts; Protein Binding; Pueraria; Rats; Signal Transduction

Glucagon is believed to be a pancreas-specific hormone, and hyperglucagonemia has been shown to contribute significantly to the hyperglycemic state of patients with diabetes. This hyperglucagonemia has been thought to arise from α-cell insensitivity to suppressive effects of glucose and insulin combined with reduced insulin secretion. We hypothesized that postabsorptive hyperglucagonemia represents a gut-dependent phenomenon and subjected 10 totally pancreatectomized patients and 10 healthy control subjects to a 75-g oral glucose tolerance test and a corresponding isoglycemic intravenous glucose infusion. We applied novel analytical methods of plasma glucagon (sandwich ELISA and mass spectrometry-based proteomics) and show that 29-amino acid glucagon circulates in patients without a pancreas and that glucose stimulation of the gastrointestinal tract elicits significant hyperglucagonemia in these patients. These findings emphasize the existence of extrapancreatic glucagon (perhaps originating from the gut) in man and suggest that it may play a role in diabetes secondary to total pancreatectomy.

Topics: Aged; Blood Glucose; Case-Control Studies; Cholecystokinin; Chromatography, Liquid; Enzyme-Linked Immunosorbent Assay; Female; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Tract; Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Glucose; Glucose Tolerance Test; Humans; Male; Middle Aged; Pancreatectomy; Pancreatic Neoplasms; Pancreatitis; Peptide Fragments; Proteomics; Radioimmunoassay; Tandem Mass Spectrometry

The association between incretin-based drugs, such as dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) agonists, and acute pancreatitis is controversial.. To determine whether the use of incretin-based drugs, compared with the use of 2 or more other oral antidiabetic drugs, is associated with an increased risk of acute pancreatitis.. A large, international, multicenter, population-based cohort study was conducted using combined health records from 7 participating sites in Canada, the United States, and the United Kingdom. An overall cohort of 1 532 513 patients with type 2 diabetes initiating the use of antidiabetic drugs between January 1, 2007, and June 30, 2013, was included, with follow-up until June 30, 2014.. Current use of incretin-based drugs compared with current use of at least 2 oral antidiabetic drugs.. Nested case-control analyses were conducted including hospitalized patients with acute pancreatitis matched with up to 20 controls on sex, age, cohort entry date, duration of treated diabetes, and follow-up duration. Hazard ratios (HRs) and 95% CIs for hospitalized acute pancreatitis were estimated and compared current use of incretin-based drugs with current use of 2 or more oral antidiabetic drugs. Secondary analyses were performed to assess whether the risk varied by class of drug (DPP-4 inhibitors and GLP-1 agonists) or by duration of use. Site-specific HRs were pooled using random-effects models.. Of 1 532 513 patients included in the analysis, 781 567 (51.0%) were male; mean age was 56.6 years. During 3 464 659 person-years of follow-up, 5165 patients were hospitalized for acute pancreatitis (incidence rate, 1.49 per 1000 person-years). Compared with current use of 2 or more oral antidiabetic drugs, current use of incretin-based drugs was not associated with an increased risk of acute pancreatitis (pooled adjusted HR, 1.03; 95% CI, 0.87-1.22). Similarly, the risk did not vary by drug class (DPP-4 inhibitors: pooled adjusted HR, 1.09; 95% CI, 0.86-1.22; GLP-1 agonists: pooled adjusted HR, 1.04; 95% CI, 0.81-1.35) and there was no evidence of a duration-response association.. In this large population-based study, use of incretin-based drugs was not associated with an increased risk of acute pancreatitis compared with other oral antidiabetic drugs.

Topics: Adolescent; Adult; Aged; Canada; Case-Control Studies; Cohort Studies; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Male; Middle Aged; Pancreatitis; United Kingdom; United States; Young Adult

Incretin-based therapies are widely used for type 2 diabetes and now also for obesity, but they are associated with elevated plasma levels of pancreatic enzymes and perhaps a modestly increased risk of acute pancreatitis. However, little is known about the effects of the incretin hormone glucagon-like peptide 1 (GLP-1) on the exocrine pancreas. Here, we identify GLP-1 receptors on pancreatic acini and analyze the impact of receptor activation in humans, rodents, isolated acini, and cell lines from the exocrine pancreas. GLP-1 did not directly stimulate amylase or lipase release. However, we saw that GLP-1 induces phosphorylation of the epidermal growth factor receptor and activation of Foxo1, resulting in cell growth with concomitant enzyme release. Our work uncovers GLP-1-induced signaling pathways in the exocrine pancreas and suggests that increases in amylase and lipase levels in subjects treated with GLP-1 receptor agonists reflect adaptive growth rather than early-stage pancreatitis.

Topics: Acinar Cells; Amylases; Animals; Cell Line; Cell Proliferation; Diabetes Mellitus, Type 2; Forkhead Box Protein O1; Gene Expression Regulation, Enzymologic; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Lipase; Pancreas; Pancreatitis; Signal Transduction

To investigate whether the use of incretin-based drugs (GLP-1 receptor agonists and dipeptidyl peptidase 4 [DPP4] inhibitors) is associated with acute pancreatitis.. The study was a nationwide population-based case-control study using medical databases in Denmark. Participants were 12,868 patients with a first-time hospitalization for acute pancreatitis between 2005 and 2012 and a population of 128,680 matched control subjects. The main outcome measure was the odds ratio (OR) for acute pancreatitis associated with different antihyperglycemic drugs. We adjusted for history of gallstones, alcoholism, obesity, and other pancreatitis-associated comorbidities and medications.. A total of 89 pancreatitis patients (0.69%) and 684 control subjects (0.53%) were ever users of incretins. The crude OR for acute pancreatitis among incretin users was 1.36 (95% CI 1.08-1.69), while it was 1.44 (95% CI 1.34-1.54) among users of other antihyperglycemic drugs. After confounder adjustment, the risk of acute pancreatitis was not increased among incretin users (OR 0.95 [95% CI 0.75-1.21]), including DPP4 inhibitor users (OR 1.04 [95% CI 0.80-1.37]) or GLP-1 receptor agonist users (OR 0.82 [95% CI 0.54-1.23]), or among nonincretin antihyperglycemic drug users (OR 1.05 [95% CI 0.98-1.13]), compared with nonusers of any antihyperglycemic drugs. Findings were similar in current versus ever drug users and in patients with pancreatitis risk factors. The adjusted OR comparing incretin-based therapy with other antihyperglycemic therapy internally while also adjusting for diabetes duration and complications was 0.97 (95% CI 0.76-1.23).. Our findings suggest that the use of incretin-based drugs appears not to be associated with an increased risk of acute pancreatitis.

Topics: Acute Disease; Adolescent; Adult; Aged; Databases, Factual; Denmark; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Epidemiologic Methods; Female; Glucagon-Like Peptide 1; Hospitalization; Humans; Hypoglycemic Agents; Incretins; Male; Middle Aged; Pancreatitis; Young Adult

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Male; Pancreatitis

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Male; Pancreatitis

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Male; Pancreatitis

We evaluated the relationship between liraglutide and acute pancreatitis or pancreatic cancer in an ongoing post-marketing safety assessment programme.. Initiators of liraglutide, exenatide, metformin, pioglitazone or groups containing initiators of dipeptidyl peptidase-4 inhibitors or sulfonylureas were identified in a US commercial health insurance claims database (1 February 2010 to 31 March 2013) and followed for a median of 15 months. We estimated incidence rates (IR/100 000 person-years), rate ratio (RR) and 95% confidence intervals (CI) of new insurance claims with diagnoses of primary inpatient acute pancreatitis or pancreatic cancer from Poisson regression models.. The IR for acute pancreatitis for liraglutide was 187.5 compared with 154.4 for all non-glucagon-like peptide-1 (GLP-1)-based therapies (adjusted RR 1.10; CI 0.81-1.49). The IR for pancreatic cancer was 19.9 for liraglutide compared with 33.0 for all non-GLP-1-based therapies (adjusted RR 0.65; 95% CI 0.26-1.60).. We did not observe excess risk of either outcome associated with liraglutide relative to individual or pooled comparator drugs.

Topics: Databases, Factual; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insurance Claim Reporting; Insurance, Health; Liraglutide; Male; Metformin; Pancreatic Neoplasms; Pancreatitis; Prospective Studies; Risk Assessment; Sulfonylurea Compounds; United States

Glucagon-like peptide 1-based therapies, collectively described as incretins, produce glycemic benefits in the treatment of type 2 diabetes. Recent publications raised concern for a potential increased risk of pancreatitis and pancreatic cancer with incretins based in part on findings from a small number of rodents. However, extensive toxicology assessments in a substantial number of animals dosed up to 2 years at high multiples of human exposure do not support these concerns. We hypothesized that the lesions being attributed to incretins are commonly observed background findings and endeavored to characterize the incidence of spontaneous pancreatic lesions in three rat strains (Sprague-Dawley [S-D] rats, Zucker diabetic fatty [ZDF] rats, and rats expressing human islet amyloid polypeptide [HIP]; n = 36/group) on a normal or high-fat diet over 4 months. Pancreatic findings in all groups included focal exocrine degeneration, atrophy, inflammation, ductular cell proliferation, and/or observations in large pancreatic ducts similar to those described in the literature, with an incidence of exocrine atrophy/inflammation seen in S-D (42-72%), HIP (39%), and ZDF (6%) rats. These data indicate that the pancreatic findings attributed to incretins are common background findings, observed without drug treatment and independent of diet or glycemic status, suggesting a need to exercise caution when interpreting the relevance of some recent reports regarding human safety.

Topics: Animals; Diabetes Mellitus; Diet, High-Fat; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Incretins; Pancreas; Pancreatic Diseases; Pancreatitis; Rats; Rats, Sprague-Dawley; Rats, Zucker; Weight Gain

In the recent past, concerns have raised regarding the potential risk of acute pancreatitis among type 2 diabetic patients using incretin-based drugs such as glucagon-like peptide 1 (GLP-1) analogs and dipeptidyl peptidase 4 (DPP-4) inhibitors. The aim of this study is to investigate the association between exposure to incretin-based drugs and the occurrence of pancreatitis reported in the French Pharmacovigilance Database. The case/non-case method was performed from serious adverse drug reactions (ADRs) involving antihyperglycemic agents (except insulin alone) reported to the French pharmacovigilance system between March 2008 (first marketing of an incretin-based drug in France) and March 2013. Cases were defined as reports of pancreatitis, and all other serious ADRs were considered non-cases. Disproportionality was assessed by calculating reporting odds ratios (ROR) adjusted for age, gender, history of pancreatitis, other antihyperglycemic drugs and other drugs associated with a higher risk of pancreatitis. Among 3,109 serious ADRs, 147 (4.7 %) reports of pancreatitis were identified as cases and 2,962 reports (95.3 %) of other ADRs as non-cases. Among the cases, 122 (83.0 %) involved incretin-based drugs. Disproportionality was found for all incretin-based drugs (adjusted ROR: 15.7 [95 % CI 9.8-24.9]), all GLP-1 analogs (29.4 [16.0-53.8]), exenatide (28.3 [12.8-62.3]), liraglutide (30.4 [15.4-60.0]), all DPP-4 inhibitors (12.1 [7.3-20.0]), sitagliptin (12.4 [7.3-21.0]), saxagliptin (15.1 [4.3-52.7]), and vildagliptin (7.4 [3.1-17.6]). Temporal analysis found disproportionality for incretin-based drugs since their first year of marketing in France. Compared with other antihyperglycemic agents, use of incretin-based drugs is associated with an increased risk of reported pancreatitis in France.

Topics: Adult; Aged; Aged, 80 and over; Case-Control Studies; Databases, Factual; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; France; Glucagon-Like Peptide 1; Humans; Male; Middle Aged; Pancreatitis; Pharmacovigilance

Previous studies have suggested a link between glucagon-like peptide 1 (GLP-1)-based therapies and acute pancreatitis, while other studies have found no association. Because differences in diabetes severity may confound this relationship, a self-controlled case series (SCCS) analysis has been suggested as a means to control for individual-level confounding.. We evaluated the relationship between GLP-1-based therapies and pancreatitis by SCCS method using a large observational database. We calculated the incidence density ratio of pancreatitis for exposure versus non-exposure to each drug. To examine the robustness of our findings, we performed sensitivity analyses by varying risk windows, using two pancreatitis definitions and including incident pancreatitis or all occurrences.. From dispensing data on 1.2 million patients, we found 7992 sitagliptin-exposed patients and 3552 exenatide-exposed patients between 2004 and 2009. Using an ICD9/CPT-based case definition of pancreatitis, we identified 207 sitagliptin and 82 exenatide cases. Augmenting this definition with laboratory criteria increased our cohort to 245 sitagliptin and 96 exenatide cases. For sitagliptin and exenatide cases, respectively, the mean duration of observation was 5.2 and 5.5 years, and the mean duration of drug exposure was 0.7 and 0.5 years. For all analyses (including different pancreatitis definitions, risk periods, and incident or recurrent events), the incidence density ratios for development of pancreatitis during exposure versus non-exposure ranged from 0.68 to 1.46, with all having 95% confidence intervals containing 1.. We found no association between the use of GLP-1-based therapies and pancreatitis using SCCS analysis in a large observational database.

Topics: Adult; Aged; Cohort Studies; Databases, Factual; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Male; Middle Aged; Pancreatitis; Peptides; Pyrazines; Risk Factors; Sitagliptin Phosphate; Triazoles; Venoms; Young Adult

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Male; Pancreatitis

To determine whether the use of incretin based drugs, compared with sulfonylureas, is associated with an increased risk of acute pancreatitis.. Population based cohort study.. 680 general practices in the United Kingdom contributing to the Clinical Practice Research Datalink.. From 1 January 2007 to 31 March 2012, 20 748 new users of incretin based drugs were compared with 51 712 users of sulfonylureas and followed up until 31 March 2013.. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals for acute pancreatitis in users of incretin based drugs compared with users of sulfonylureas. Models were adjusted for tenths of high dimensional propensity score (hdPS).. The crude incidence rate for acute pancreatitis was 1.45 per 1000 patients per year (95% confidence interval 0.99 to 2.11) for incretin based drug users and 1.47 (1.23 to 1.76) for sulfonylurea users. The rate of acute pancreatitis associated with the use of incretin based drugs was not increased (hdPS adjusted hazard ratio: 1.00, 95% confidence interval 0.59 to 1.70) relative to sulfonylurea use.. Compared with use of sulfonylureas, the use of incretin based drugs is not associated with an increased risk of acute pancreatitis. While this study is reassuring, it does not preclude a modest increased risk, and thus additional studies are needed to confirm these findings.

Topics: Acute Disease; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Kaplan-Meier Estimate; Male; Middle Aged; Pancreatitis; Sulfonylurea Compounds

An obese lady of 51 year with Type 2 Diabetes Mellitus for 13 years was prescribed Liraglutide, a glucagon like peptide (GLP-1) analogue (Victoza) for glycaemic control and reduction of weight. She was on gliclazide and Insulin prior to initiation of Liraglutide. Eight weeks after initiation of GLP -1 analogue, she developed severe abdominal pain, nausea and vomiting. She was admitted to a private hospital and evaluated. Biochemical tests and CT scan revealed presence of pancreatitis and she was treated for acute pancreatitis. Liraglutide was withdrawn and symptoms subsided. Subsequent follow-up showed that pancreatic enzyme levels were normal.

Topics: Acute Disease; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Liraglutide; Middle Aged; Pancreatitis

Acute pancreatitis has significant morbidity and mortality. Previous studies have raised the possibility that glucagonlike peptide 1 (GLP-1)-based therapies, including a GLP-1 mimetic (exenatide) and a dipeptidyl peptidase 4 inhibitor (sitagliptin phosphate), may increase the risk of acute pancreatitis.. To test whether GLP-1-based therapies such as exenatide and sitagliptin are associated with an increased risk of acute pancreatitis. We used conditional logistic regression to analyze the data.. Population-based case-control study.. A large administrative database in the United States from February 1, 2005, through December 31, 2008.. Adults with type 2 diabetes mellitus aged 18 to 64 years. We identified 1269 hospitalized cases with acute pancreatitis using a validated algorithm and 1269 control subjects matched for age category, sex, enrollment pattern, and diabetes complications.. Hospitalization for acute pancreatitis.. The mean age of included individuals was 52 years, and 57.45% were male. Cases were significantly more likely than controls to have hypertriglyceridemia (12.92% vs 8.35%), alcohol use (3.23% vs 0.24%), gallstones (9.06% vs 1.34), tobacco abuse (16.39% vs 5.52%), obesity (19.62% vs 9.77%), biliary and pancreatic cancer (2.84% vs 0%), cystic fibrosis (0.79% vs 0%), and any neoplasm (29.94% vs 18.05%). After adjusting for available confounders and metformin hydrochloride use, current use of GLP-1-based therapies within 30 days (adjusted odds ratio, 2.24 [95% CI, 1.36-3.68]) and recent use past 30 days and less than 2 years (2.01 [1.37-3.18]) were associated with significantly increased odds of acute pancreatitis relative to the odds in nonusers.. In this administrative database study of US adults with type 2 diabetes mellitus, treatment with the GLP-1-based therapies sitagliptin and exenatide was associated with increased odds of hospitalization for acute pancreatitis.

Topics: Acute Disease; Adolescent; Adult; Case-Control Studies; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Female; Glucagon-Like Peptide 1; Hospitalization; Humans; Logistic Models; Male; Middle Aged; Pancreatitis; Peptides; Pyrazines; Risk Factors; Sitagliptin Phosphate; Triazoles; Venoms

Topics: Acute Disease; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Metaphor; Pancreatitis; Peptides; Pyrazines; Sitagliptin Phosphate; Treatment Outcome; Triazoles; Venoms

Topics: Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Hospitalization; Humans; Male; Pancreatitis

Topics: Acute Disease; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Pancreatitis

Topics: Databases, Factual; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Pancreatic Neoplasms; Pancreatitis; Precancerous Conditions; Risk Assessment; United States; United States Food and Drug Administration

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hyperplasia; Incretins; Metaplasia; Pancreas; Pancreatic Neoplasms; Pancreatitis

Topics: Adamantane; Diabetes Mellitus; Dipeptides; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Linagliptin; Pancreatitis; Purines; Pyrazines; Quinazolines; Sitagliptin Phosphate; Triazoles; United States

Topics: Adverse Drug Reaction Reporting Systems; Animals; Disclosure; Drug Industry; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Mass Media; Pancreatic Neoplasms; Pancreatitis; Risk Assessment; Sulfonylurea Compounds

Topics: Acute Disease; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Pancreas; Pancreatitis

Topics: Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Hospitalization; Humans; Male; Pancreatitis

Topics: Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Hospitalization; Humans; Male; Pancreatitis

Topics: Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Hospitalization; Humans; Male; Pancreatitis

Topics: Animals; Breast Neoplasms; Calcitonin; Carcinoma, Medullary; Clinical Trials as Topic; Comorbidity; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Disease Susceptibility; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Infections; Liraglutide; Pancreatitis; Pharmacovigilance; Pioglitazone; Pyrazines; Risk Assessment; Safety-Based Drug Withdrawals; Sitagliptin Phosphate; Species Specificity; Thiazolidinediones; Thyroid Neoplasms; Triazoles; Urinary Bladder Neoplasms

Glucagon-like peptide (GLP)-1 analogs have been implicated as a risk factor for pancreatitis in humans. We investigated whether liraglutide, the once-daily human GLP-1 analog, induces pancreatitis in rats, mice, and monkeys. Pancreata from mice, rats, and nonhuman primates were examined macro- and microscopically. Evaluation of preneoplastic proliferative lesions in the pancreata from nonhuman primates was performed. After 2 years of treatment, 3 of 79 male mice in the control group and 2, 1, 1, and 1 mice in the different liraglutide groups (of 67-79 mice per group) had pancreatitis based on microscopic criteria. For females, the numbers were 0 of 79 mice in the control group and 3 mice in all the liraglutide groups (of 66-76 mice per group). Pancreatitis was not the cause of death in any animals. There were no cases of pancreatitis, macroscopically or microscopically, in 400 rats. Neither pancreatitis nor preneoplastic proliferative lesions was found in monkeys dosed for 87 weeks, with plasma liraglutide exposure 60-fold higher than that observed in humans at the maximal clinical dose. In conclusion, liraglutide did not induce pancreatitis in mice, rats, or monkeys when dosed for up to 2 years and at exposure levels up to 60 times higher than in humans.

Topics: Animals; Drug Administration Schedule; Female; Glucagon-Like Peptide 1; Humans; Liraglutide; Macaca fascicularis; Male; Mice; Pancreas; Pancreatitis; Rats; Rats, Sprague-Dawley

A case of acute pancreatitis associated with liraglutide is reported.. A 53-year-old African-American man (height, 185.4 cm; weight, 108.6 kg) with type 2 diabetes mellitus arrived at the emergency department (ED) with new-onset intolerable abdominal pain in the right upper quadrant and left upper quadrant that had appeared suddenly and lasted two to three hours. He had nausea but no vomiting, with tenderness in the epigastric region. In the ED, his serum amylase concentration was found to be extremely elevated (3,963 units/L), as was his serum lipase concentration (>15,000 units/L). In addition to type 2 diabetes, his medical history included hyperlipidemia, hypertension, peripheral neuropathy, erectile dysfunction, and obesity. His home medications included aspirin 81 mg orally daily, metformin 1000 mg orally every morning and 1500 mg every evening, simvastatin 80 mg orally daily at bedtime, tadalafil 20 mg orally as needed, glimepiride 4 mg orally twice daily, and liraglutide 1.2 mg subcutaneously daily. Two months before his arrival to the ED, the patient's dosage of liraglutide was increased from 0.6 to 1.2 mg subcutaneously daily. Radiographic data were obtained, and acute pancreatitis was diagnosed. Liraglutide was discontinued indefinitely after ruling out elevated triglycerides as the cause of pancreatitis. The patient was initiated on standard therapy for acute pancreatitis and discharged eight days later with complete resolution of symptoms and normal laboratory test values.. A 53-year-old man with type 2 diabetes mellitus developed a probable case of liraglutide-induced acute pancreatitis after receiving the drug for approximately two months.

Topics: Acute Disease; Amylases; Diabetes Mellitus, Type 2; Emergency Service, Hospital; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Lipase; Liraglutide; Male; Middle Aged; Pancreatitis

Topics: Animals; Exenatide; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Male; Pancreas; Pancreatic Ducts; Pancreatitis; Peptides; Proto-Oncogene Proteins p21(ras); Receptors, Glucagon; Venoms

Topics: Animals; Exenatide; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Male; Pancreas; Pancreatic Ducts; Pancreatitis; Peptides; Proto-Oncogene Proteins p21(ras); Receptors, Glucagon; Venoms

A possible association between glucagon-like peptide-1 (GLP-1) analogs and incidences of pancreatitis has been suggested based on clinical studies. In male and female diabetic Zucker diabetic fatty (ZDF) rats, we investigated the effects of continuous administration of liraglutide and exenatide on biochemical [lipase, pancreatic amylase (P-amylase)] and histopathological markers of pancreatitis. Male and female ZDF rats were dosed for 13 wk with liraglutide (0.4 or 1.0 mg·kg(-1)·day(-1) sc once daily) or exenatide (0.25 mg·kg(-1)·day(-1) sc, Alzet osmotic minipumps). P-amylase and lipase plasma activity were measured, and an extended histopathological and stereological (specific cell mass and proliferation rate) evaluation of the exocrine and the endocrine pancreas was performed. Expectedly, liraglutide and exenatide lowered blood glucose and Hb A(1c) in male and female ZDF rats, whereas β-cell mass and proliferation rate were increased with greatly improved blood glucose control. Whereas neither analog affected lipase activity, small increases in P-amylase activity were observed in animals treated with liraglutide and exenatide. However, concurrent or permanent increases in lipase and P-amylase activity were never observed. Triglycerides were lowered by both GLP-1 analogs. The qualitative histopathological findings did not reveal adverse effects of liraglutide. The findings were mainly minimal in severity and focal in distribution. Similarly, the quantitative stereological analyses revealed no effects of liraglutide or exenatide on overall pancreas weight or exocrine and duct cell mass or proliferation. The present study demonstrates that, in overtly diabetic male and female ZDF rats, prolonged exposure to GLP-1 receptor agonists does not affect biochemical or histopathological markers of pancreatitis, and whereas both exenatide and liraglutide increase β-cell mass, they have no effect on the exocrine pancreas. However, clinical outcome studies and studies using primate tissues and/or studies in nonhuman primates are needed to further assess human risk.

Topics: Animals; Blood Glucose; Cell Proliferation; Exenatide; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Hypoglycemic Agents; Lipase; Liraglutide; Male; Pancreas; Pancreatic alpha-Amylases; Pancreatitis; Peptides; Rats; Rats, Zucker; Venoms

Topics: Acute Disease; Aged; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Liraglutide; Male; Pancreatitis

We herein report two cases of pancreatitis associated with incretin-based therapies in end-stage renal disease (ESRD) patients undergoing dialysis. A 75-year-old woman with a history of liraglutide use and a 68-year-old man with a history of vildagliptin use both presented with nausea. They showed elevated levels of pancreatic enzymes and pancreatic tail swelling on CT. Their symptoms improved after discontinuing the drugs. In the absence of any obvious secondary causes of pancreatitis, we believe that the pancreatitis observed in these cases was associated with the incretin-based therapies. Few reports have been published on the safety and efficacy of incretin-based therapies in ESRD patients, and it remains uncertain whether the changes in the pancreas observed in the present cases are characteristic of ESRD patients.

Topics: Adamantane; Aged; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Glucagon-Like Peptide 1; Humans; Incretins; Kidney Failure, Chronic; Liraglutide; Magnetic Resonance Imaging; Male; Nitriles; Pancreatitis; Pyrrolidines; Renal Dialysis; Tomography, X-Ray Computed; Vildagliptin

To report what is, to our knowledge, the first postmarketing case of acute pancreatitis associated with liraglutide.. A 60-year-old female with type 2 diabetes presented with a 16-hour history of mid-epigastric pain 3 weeks after treatment was changed from exenatide 10 μg twice daily, which she had taken for 4 years, to liraglutide 1.8 mg daily. Her serum lipase level was elevated (478 units/L) at admission, and other laboratory values were within normal limits. Liraglutide was discontinued at admission. Standard therapy for pancreatitis resulted in symptom resolution and a significant decrease in serum lipase (131 units/L) by hospital day 4; she was discharged on hospital day 5.. Based on the Naranjo scale, this case represents a probable adverse drug reaction. Eight cases of pancreatitis were observed in liraglutide-treated patients in premarketing clinical trials. Extensive literature describing exenatide-related pancreatitis and premarketing reports of liraglutide-related pancreatitis, along with the temporal relationship between the initiation of liraglutide and the onset of this patient's symptoms, suggest that the episode of pancreatitis was induced by liraglutide.. Liraglutide should be used cautiously in patients with a history of pancreatitis, and clinicians should have a high index of suspicion for this rare, but potentially serious, adverse effect.

Topics: Acute Disease; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Lipase; Liraglutide; Middle Aged; Pancreatitis; Peptides; Venoms

Topics: Female; Glucagon-Like Peptide 1; Humans; Pancreatitis

The incretin system plays an important role in glucose homeostasis, largely through the actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Unlike GIP, the actions of GLP-1 are preserved in patients with type 2 diabetes mellitus, which has led to the development of injectable GLP-1 receptor (GLP-1R) agonists and oral dipeptidyl peptidase-4 (DPP-4) inhibitors. GLP-1R agonists-which can be dosed to pharmacologic levels-act directly upon the GLP-1R. In contrast, DPP-4 inhibitors work indirectly by inhibiting the enzymatic inactivation of native GLP-1, resulting in a modest increase in endogenous GLP-1 levels. GLP-1R agonists generally lower the fasting and postprandial glucose levels more than DPP-4 inhibitors, resulting in a greater mean reduction in glycated hemoglobin level with GLP-1R agonists (0.4%-1.7%) compared with DPP-4 inhibitors (0.4%-1.0%). GLP-1R agonists also promote satiety and reduce total caloric intake, generally resulting in a mean weight loss of 1 to 4 kg over several months in most patients, whereas DPP-4 inhbitors are weight-neutral overall. GLP-1R agonists and DPP-4 inhibitors are generally safe and well tolerated. The glucose-dependent manner of stimulation of insulin release and inhibition of glucagon secretion by both GLP-1R agonists and DPP-4 inhibitors contribute to the low incidence of hypoglycemia. Although transient nausea occurs in 26% to 28% of patients treated with GLP-1R agonists but not DPP-4 inhibitors, this can be reduced by using a dose-escalation strategy. Other adverse events (AEs) associated with GLP-1R agonists include diarrhea, headache, and dizziness. The main AEs associated with DPP-4 inhibitors include upper respiratory tract infection, nasopharyngitis, and headache. Overall, compared with other therapies for type 2 diabetes mellitus with similar efficacy, incretin-based agents have low risk of hypoglycemia and weight gain. However, GLP-1R agonists demonstrate greater comparative efficacy and weight benefit than DPP-4 inhibitors.

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Hypersensitivity; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Homeostasis; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Pancreatitis; Peptides; Receptors, Glucagon; Venoms

Topics: Animals; Disease Models, Animal; Glucagon-Like Peptide 1; Humans; Hyperplasia; Pancreas, Exocrine; Pancreatic Ducts; Pancreatitis; Pancreatitis, Chronic; Rats; United States; United States Food and Drug Administration

Topics: Animals; Biomarkers; Calcitonin; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Approval; Drug Therapy, Combination; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Liraglutide; Pancreatitis; Risk Factors; Rodentia; Thyroid Neoplasms; United States; United States Food and Drug Administration

Topics: Acute Disease; Adult; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Male; Pancreatitis; Risk; Young Adult

Clinical reports link use of the glucagon-like peptide-1 receptor (GLP-1R) agonists exenatide and liraglutide to pancreatitis. However, whether these agents act on the exocrine pancreas is poorly understood.. We assessed whether the antidiabetic agents exendin (Ex)-4, liraglutide, the dipeptidyl peptidase-4 inhibitor sitagliptin, or the biguanide metformin were associated with changes in expression of genes associated with the development of experimental pancreatitis. The effects of Ex-4 when administered before or after the initiation of caerulein-induced experimental pancreatitis were determined. The importance of endogenous GLP-1R signaling for gene expression in the exocrine pancreas and the severity of pancreatitis was assessed in Glp1r(-/-) mice.. Acute administration of Ex-4 increased expression of egr-1 and c-fos in the exocrine pancreas. Administration of Ex-4 or liraglutide for 1 week increased pancreas weight and induced expression of mRNA transcripts encoding the anti-inflammatory proteins pancreatitis-associated protein (PAP) (RegIIIbeta) and RegIIIalpha. Chronic Ex-4 treatment of high-fat-fed mice increased expression of PAP and reduced pancreatic expression of mRNA transcripts encoding for the proinflammatory monocyte chemotactic protein-1, tumor necrosis factor-alpha, and signal transducer and activator of transcription-3. Sitagliptin and metformin did not significantly change pancreatic gene expression profiles. Ex-4 administered before or after caerulein did not modify the severity of experimental pancreatitis, and levels of pancreatic edema and serum amylase were comparable in caerulein-treated Glp1r(-/-) versus Glp1r(+/+) mice.. These findings demonstrate that GLP-1 receptor activation increases pancreatic mass and selectively modulates the expression of genes associated with pancreatitis. However, activation or genetic elimination of GLP-1R signaling does not modify the severity of experimental pancreatitis in mice.

Topics: Animals; Ceruletide; Dietary Fats; Disease Models, Animal; Early Growth Response Protein 1; Exenatide; Gene Expression; Genes, fos; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Liraglutide; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Pancreas, Exocrine; Pancreatitis; Pancreatitis-Associated Proteins; Peptides; Receptors, Glucagon; Severity of Illness Index; Signal Transduction; Venoms

Topics: Adult; Aged; Animals; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Lizards; Male; Middle Aged; Pancreatitis; Peptides; Venoms

The purpose of the present study was to evaluate plasma glucagon-like peptide-1 (GLP-1) responses after oral glucose ingestion in patients with chronic pancreatitis and to clarify how GLP-1 secretion relates to pancreatic diabetes.. An oral glucose tolerance test (OGTT) was performed in 17 patients with chronic pancreatitis. Plasma glucose, immunoreactive insulin (IRI), C-peptide, glucagon, and GLP-1 levels at each time point during OGTT were measured. The diagnosis of chronic pancreatitis was made by the findings of endoscopic retrograde pancreatography (ERP): evident dilation of the main pancreatic duct with or without pancreatolithiasis.. The patients were divided into three groups according to the World Health Organization classification of diabetes based on plasma glucose levels after OGTT. The groups were: normal (three patients), impaired glucose tolerant (IGT) (six patients), and diabetic (DM) (eight patients). In the DM group, IRI and C-peptide response levels after oral glucose ingestion were significantly reduced as compared with those of the normal and IGT groups. No significant glucagon responses to oral glucose ingestion were found in the three groups. In contrast, plasma GLP-1 levels were significantly elevated after oral glucose ingestion in the DM groups as compared with normal and IGT groups.. The present study affords evidence that plasma GLP-1 levels become elevated with development of pancreatic diabetes, although the precise mechanism of this elevation remains undetermined.

Topics: C-Peptide; Case-Control Studies; Chronic Disease; Diabetes Mellitus; Female; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin; Male; Middle Aged; Pancreatitis; Peptide Fragments; Protein Precursors; Time Factors

To study GIP and insulin release after a test meal in patients with chronic pancreatitis with and without secondary diabetes mellitus.. 28 patients with chronic pancreatitis were classified in groups I and II according to the presence or absence of secondary diabetes mellitus. Twelve healthy subjects were included as controls. After a test meal plasma GIP levels and serum insulin levels were determined at 0, 30, 60, 120 and 180 min.. A significant diminished GIP response was found in the groups of patients with respect to the control group. No association could be detected with severity of pancreatic insufficiency. Higher values of GIP were demonstrated at 60 and 120 min in patients without diabetes than in patients with it.. An abnormal GIP response is present in cases of chronic pancreatitis irrespective of the presence or severity of pancreatic insufficiency. This response is further affected if secondary diabetes mellitus is present.

Topics: Adult; Age Factors; Diabetes Mellitus; Digestion; Exocrine Pancreatic Insufficiency; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Insulin; Male; Middle Aged; Pancreatitis; Peptide Fragments; Postprandial Period; Sex Factors