incretins and Pancreatic-Diseases

Pancreatic α-cell hyperplasia (ACH) was once an esoteric pathological entity, but it has become an important differential diagnosis of hyperglucagonemia after inactivating glucagon receptor (GCGR) genomic mutations were found in patients with ACH. Recently, the controversy over the pancreatic effects of incretins has stimulated much discussion of ACH that often includes inaccurate statements not supported by the literature.. Literature related to ACH was reviewed.. ACH is defined as a diffuse and specific increase in the number of α-cells. A dozen cases have been reported and fall into three clinical types: reactive, functional, and nonfunctional. Characterized by remarkable hyperglucagonemia without glucagonoma syndrome, reactive ACH is caused by inactivating GCGR mutations, and its main clinical significance is pancreatic neuroendocrine tumors diagnosed at middle age. The Gcgr(-/-) mice, a model of reactive ACH, exhibit a multistage tumorigenesis in their pancreata. Pharmacological agents that inhibit glucagon signaling also cause reactive ACH in animals and possibly in humans as well. The pancreata of incretin-treated humans and those of reactive ACH murine models share similarities. Functional ACH features hyperglucagonemia with glucagonoma syndrome. Nonfunctional ACH is associated with normal glucagon levels. The causes of functional and nonfunctional ACH are unknown as yet.. ACH is a histological diagnosis and clinically heterogeneous. Caused by GCGR mutations, reactive ACH is a preneoplastic lesion giving rise to slow-developing pancreatic neuroendocrine tumors. The effects of treatments targeting glucagon signaling in this regard remain controversial. The strong negative feedback control of glucagon signaling conserved in all mammals studied, including humans, makes long-term pancreatic tumor surveillance advisable for the glucagon signaling-targeting therapies.

Topics: Animals; Diabetes Mellitus; Disease Models, Animal; Glucagon-Secreting Cells; Humans; Hyperplasia; Incretins; Mice; Mice, Knockout; Pancreatic Diseases; Receptors, Glucagon

Type 3c diabetes mellitus (T3cDM) is a clinically relevant condition with a prevalence of 5-10% among all diabetic subjects in Western populations. Its prevalence and clinical importance have been underestimated and underappreciated so far. In contrast to the management of type 1 or type 2 diabetes, the endocrinopathy in T3cDM is very complex and complicated by additional present comorbidities such as maldigestion and concommitant qualitative malnutrition. The failure to correctly diagnose T3cDM leads to failure to implement an appropriate medical therapy of these patients. Physicians should screen for important and easily reversable pathological conditions such as exocrine insufficiency, lack of fat-soluble vitamins (especially vitamin D) and impairment of fat hydrolysis and incretin secretion which are found very commonly in T3cDM. Since most patients with T3cDM suffer from chronic pancreatitis, physicians must additionally be aware of the elevated risk of pancreatic cancer in this subset of patients.

Topics: Diabetes Mellitus; Diagnostic Errors; Early Diagnosis; Humans; Incretins; Malnutrition; Pancreas, Exocrine; Pancreatic Diseases; Prevalence; Risk Factors; Vitamins

A lot of contradictory data regarding the serious side effects of incretin-based therapies are currently available, with more being prepared or published every month. Considering the widespread use of these drugs it should be considered a priority to establish both short- and long-term risks connected with incretin treatment. We performed an extensive literature search of the PubMed database looking for articles dealing with connections between incretin-based therapies and pancreatitis, pancreatic cancer, thyroid cancer and other neoplasms. Data obtained indicate that GLP-1 agonists and DPPIV inhibitors could increase the risk of pancreatitis and pancreatic cancer, possibly due to their capacity to increase ductal cell turnover, which has previously been found to be up-regulated in patients with obesity and T2DM. GLP-1 analogues exenatide and liraglutide seem to be connected with medullary thyroid carcinoma in rat models and, surprisingly, GLP-1 receptors have been found in papillary thyroid carcinoma, currently the most common neoplasm of the thyroid gland in humans. Changes in expression of DPPIV have been described in ovarian carcinoma, melanoma, endometrial adenocarcinoma, prostate cancer, non-small cell lung cancer and in certain haematological malignancies. In most cases loss of DPPIV activity is connected with a higher grading scale, more aggressive tumour behaviour and higher metastatic potential. In conclusion animal and human studies indicate that there could be a connection between incretin-based therapies and pancreatitis, pancreatic cancer, thyroid cancer and other neoplasms. Therefore whenever such therapy is started it would be wise to proceed with caution, especially if personal history of neoplasms is present.

Topics: Animals; Cell Proliferation; Diabetes Mellitus, Type 2; Drug-Related Side Effects and Adverse Reactions; Gastric Inhibitory Polypeptide; Gastrointestinal Agents; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Models, Animal; Neoplasms; Outcome Assessment, Health Care; Pancreas; Pancreatic Diseases; Randomized Controlled Trials as Topic; Rats; Risk Factors

Type 2 diabetes is a heterogeneous, polygenic disorder in which dysfunction in a number of important metabolic pathways appears to play roles. Although it remains unclear exactly which event triggers the disorder, beta-cell dysfunction is a key element in the underlyingpathophysiology. Both impaired insulin secretion and insulin resistance contribute to the hyperglycemic state that causes the devastating cardiovascular, neurologic, and renal effects characteristic of type 2 diabetes. To prevent these complications, the American Diabetes Association recommends maintaining A1C levels below 7%. A1C has long been the target of diabetes therapy, and while this remains true in those with A1C levels above 8.4%, it is now apparent that in those with mild to moderate diabetes, postprandial glucose excursions may be of greater importance. Postprandial hyperglycemia occurs in 74% of those diagnosed with diabetes and 39% of those with optimal A1C levels. Involvement of impaired alpha-cell function has recently been recognized in the pathophysiology of type 2 diabetes. As a result of this dysfunction, glucagon and hepatic glucose levels that rise during fasting are not suppressed with a meal. Given inadequate levels of insulin and increased insulin resistance, hyperglycemia results. The incretins are important gut mediators of insulin release, and in the case of GLP-1, of glucagon suppression. Although GIP activity is impaired in those with type 2 diabetes, GLP-1 insulinotropic effects are preserved, and thus GLP-1 represents a potentially beneficial therapeutic option. However, like GIP, GLP-1 is rapidly inactivated by DPP-IV in vivo. Two therapeutic approaches to this problem have been developed: GLP-1 analogs with increased half-lives, and DPP-IV inhibitors, which prevent the breakdown of endogenous GLP-1 as well as GIP. Both classes of agent have shown promise, with potential not only to normalize fasting and postprandial glucose levels but also to improve beta-cell functioning and mass.

Topics: Diabetes Mellitus, Type 2; Disease Progression; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Incretins; Insulin-Secreting Cells; Pancreatic Diseases; Postprandial Period

Glucocorticoids impair glucose tolerance by inducing insulin resistance. We investigated the dose-dependent effects of glucocorticoid treatment on islet-cell function in healthy males and studied the role of the autonomic nervous system.. A randomized, placebo-controlled, double-blind, dose-response intervention study was conducted in 32 healthy males (age: 21±2years; BMI: 21.9±1.7kg/m(2)). Participants were allocated to prednisolone 7.5mg once daily (n=12), prednisolone 30mg once daily (n=12), or placebo (n=8) for two weeks. Beta-cell function was measured by hyperglycemic clamp with arginine stimulation, glucagon levels were measured following a standardized meal test.. We found that prednisolone treatment dose-dependently reduced C-peptide secretion following arginine stimulation on top of hyperglycemia (ASI-iAUCCP): -2.8 (-5.2;0.2) and -3.1 (-8.8; -1.0) nmolL(-1)min(-1) for prednisolone 7.5mg and prednisolone 30mg, respectively (P=0.035 vs. placebo). Fasting glucagon levels increased dose-dependently (vs. placebo; P=0.001), whereas postprandial glucagon levels were only increased by prednisolone 30mg. Changes in parasympathetic activity related with changes in fasting glucose levels (r=-0.407; P=0.03) and showed a trend towards correlation with fasting glucagon concentrations (r=-0.337; P=0.07). The change in sympathovagal balance was inversely related to ASI-iAUCCP (r=-0.365; P=0.05).. We conclude that in addition to inducing insulin resistance, prednisolone treatment dose-dependently impaired islet-cell function. Altered sympathovagal balance may be related to these effects.

Topics: Adolescent; Adult; Anthropometry; Arginine; Blood Glucose; Dose-Response Relationship, Drug; Double-Blind Method; Glucagon; Glucocorticoids; Glucose Clamp Technique; Heart Rate; Humans; Hyperglycemia; Incretins; Islets of Langerhans; Male; Pancreatic Diseases; Pancreatic Function Tests; Prednisolone; Stimulation, Chemical; Sympathetic Nervous System; Vagus Nerve; Young Adult

In people with metformin-treated diabetes, to evaluate the risk of acute pancreatitis, pancreatic cancer and other diseases of the pancreas post second-line anti-hyperglycaemic agent initiation.. People with Type 2 diabetes diagnosed after 2004 who received metformin plus a dipeptidyl peptidase-4 inhibitor (DPP-4i, n = 50 095), glucagon-like peptide-1 receptor agonist (GLP-1RA, n = 12 654), sulfonylurea (n = 110 747), thiazolidinedione (n = 17 597) or insulin (n = 34 805) for at least 3 months were identified in the US Centricity Electronic Medical Records. Time to developing acute pancreatitis, other diseases of the pancreas and pancreatic cancer was estimated, balancing and adjusting anti-hyperglycaemic drug groups for appropriate confounders.. In the DPP-4i group, the adjusted mean time to acute pancreatitis was 2.63 [95% confidence intervals (CI) 2.38, 2.88] years; time to pancreatic cancer was 2.70 (2.19, 3.21) years; and time to other diseases of the pancreas was 2.73 (2.33, 3.12) years. Compared with DPP-4i, the insulin group developed acute pancreatitis 0.48 years (P < 0.01) earlier and the GLP-1RA group developed pancreatic cancer 3 years later (P < 0.01). However, with the constraint of no event within 6 months of insulin initiation, the risk of acute pancreatitis in the insulin group was insignificant. No other significant differences were observed between groups.. No significant differences in the risk of developing pancreatic diseases in those treated with various anti-hyperglycaemic drug classes were found.

Topics: Acute Disease; Aged; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin; Male; Metformin; Middle Aged; Pancreatic Diseases; Pancreatic Neoplasms; Pancreatitis

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

Incretin-based therapies either increase endogenous levels of glucagon-like peptide-1 by prolonging its half-life (DPP-4 inhibitors) or directly stimulate its receptor (glucagon-like peptide-1 analogues; GLP-1 RA). They are currently widely used for the treatment of patients with type 2 diabetes mellitus owing to good antidiabetic efficacy, low risk of hypoglycemia, and relatively few other side effects. They also offer potential additional benefits such as weight neutrality or weight loss, positive effects on blood pressure and lipid levels, and potential cardio- and neuroprotectivity. Some experimental and clinical studies have raised concerns with respect to potential cardiovascular and pancreatic side effects of these therapies such as increased risk of heart failure with DPP-4 inhibitors as well as acute pancreatitis and pancreatic cancer with both classes. The available data are at present not robust enough to enable firm conclusions regarding these potential associations. Nevertheless, some recent data suggest a possibility of slightly increased risk of acute pancreatitis with GLP-1 RAs while they do not indicate increased risk of pancreatic cancer. Ongoing cardiovascular outcome trials will shed more light on the possible cardioprotective effects of incretin-based therapies as well as on the possible interconnection of DPP-4 inhibitors and heart failure.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug-Related Side Effects and Adverse Reactions; Humans; Hypoglycemic Agents; Incretins; Pancreatic Diseases; Risk Assessment

Topics: Diabetes Mellitus; Drug Industry; Europe; Glucagon-Like Peptide 1; Humans; Incretins; Pancreatic Diseases

Topics: Diabetes Mellitus; Drug Industry; Glucagon-Like Peptide 1; Humans; Incretins; Pancreatic Diseases

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Information Dissemination; Male; Mass Media; Pancreatic Diseases; Receptors, Glucagon; Risk Assessment; Television

The 'Second Giessen International Workshop on Interactions of Exocrine and Endocrine Pancreatic Diseases' was organized in order to reflect and discuss recent developments in the field, especially the progress that has been achieved since the first meeting in March 2005. About thirty international specialists were invited to share their experience and thoughts covering the main topics of: A) pancreatic diabetes (type 3c); B) chronic inflammation of the pancreas. The presentations of session A covered an overview about the frequency of exocrine dysfunction in diabetes mellitus, the relation between diabetes, celiac disease and the exocrine pancreas, the prevalence of type 3c diabetes, damage to the pancreas caused by genes, the role of incretins in type 2 and type 3 diabetes, the role of exocrine tissue in beta cell homeostasis, peculiarities in the treatment of type 3c diabetes and a lecture on incretins: from concept to treatment. Session B included presentations about the frequency of chronic inflammation of the pancreas and therapeutical implications, the role of ACE in the pancreas, genomics and the metabolic hypothesis of chronic pancreatitis, nutritional aspects of pancreatic diseases, the stellate cell concept, autoimmunity, genetic background of chronic pancreatitis and the hypothesis of chronic obstruction induced by gallstone disease. The meeting resulted in several new projects that will be started by the participants in the near future.

Topics: Aged; Alcohol Drinking; Cell Differentiation; Chronic Disease; Comorbidity; Cystic Fibrosis Transmembrane Conductance Regulator; Diabetes Mellitus; Diet Therapy; Female; Genetic Predisposition to Disease; Germany; Hepatocyte Nuclear Factor 1-beta; Humans; Hypoglycemic Agents; Incretins; Islets of Langerhans; Japan; Lipase; Male; Middle Aged; Mutation; Nutritional Support; Pancreas, Exocrine; Pancreatic Diseases; Prevalence; Renin-Angiotensin System; Risk Factors; United States