Novel extrapancreatic effects of incretin.
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ABSTRACT:
SUBMITTER: Yamada Y
PROVIDER: S-EPMC4854509 | biostudies-other | 2016 Apr
REPOSITORIES: biostudies-other
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Project description:BackgroundSepsis, a complex disorder characterized by a dysregulated immune response to an inciting infection, affects over one million Americans annually. Dysglycemia during sepsis hospitalization confers increased risk of organ dysfunction and death, and novel targets for the treatment of sepsis and maintenance of glucose homeostasis are needed. Incretin hormones are secreted by enteroendocrine cells in response to enteral nutrients and potentiate insulin release from pancreatic β cells in a glucose-dependent manner, thereby reducing the risk of insulin-induced hypoglycemia. Incretin hormones also reduce systemic inflammation in preclinical studies, but studies of incretins in the setting of sepsis are limited.MethodsIn this bench-to-bedside mini-review, we detail the evidence to support incretin hormones as a therapeutic target in patients with sepsis. We performed a PubMed search using the medical subject headings "incretins," "glucagon-like peptide-1," "gastric inhibitory peptide," "inflammation," and "sepsis."ResultsIncretin-based therapies decrease immune cell activation, inhibit proinflammatory cytokine release, and reduce organ dysfunction and mortality in preclinical models of sepsis. Several small clinical trials in critically ill patients have suggested potential benefit in glycemic control using exogenous incretin infusions, but these studies had limited power and were performed in mixed populations. Further clinical studies examining incretins specifically in septic populations are needed.ConclusionsTargeting the incretin hormone axis in sepsis may provide a means of not only promoting euglycemia in sepsis but also attenuating the proinflammatory response and improving clinical outcomes.
| S-EPMC6763279 | biostudies-literature
Project description:Type 2 diabetes is associated with a high prevalence of comorbidities resulting from hypertension, dyslipidemia, and hyperglycemia. Inadequate management of these risk factors will eventually result in detrimental health consequences. Thus, the effect of a drug on factors such as weight, cardiovascular (CV) risk factors, and adherence is important to consider. A review was undertaken of the recent medical literature describing the extraglycemic characteristics of the two classes of incretin-based therapies-glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 (DPP-4) inhibitors. PubMed searches were performed to identify published data on incretin therapies that describe their effects on CV risk factors, CV events, and factors related to medication adherence. The maintenance or loss of weight associated with the use of GLP-1RAs and DPP-4 inhibitors is well described in the medical literature. These agents also appear to be associated with a modest decrease in blood pressure and a reduced risk of CV events. In addition, several characteristics of incretin therapies may improve rates of medication adherence, such as generally favorable tolerability profiles (particularly with DPP-4 inhibitors), the availability of formulations that simplify treatment regimens, and a low risk for hypoglycemia. The literature on incretin therapies describes a number of clinical characteristics that are relevant to the management of extraglycemic risk factors. As part of a holistic treatment strategy, these properties constitute important considerations for tailoring therapy to individual patients with type 2 diabetes.
| S-EPMC3889321 | biostudies-literature
Project description:A recently published study by Butler et al. concluded that incretin treatment had adverse effects on the human type 2 diabetic pancreas including 'a marked expansion of the exocrine and endocrine pancreatic compartments, the former being accompanied by increased proliferation and dysplasia and the latter by α-cell hyperplasia with the potential for evolution into neuroendocrine tumours'. Incretin therapy has become widely used for type 2 diabetes, so these conclusions have instigated major concerns with regard to patient safety. We reassessed both the clinical case information and virtual microscopy images of the same 34 cases that were used in the Butler study as well as Network for Pancreatic Organ Donation (nPOD) cases that were not included. Whereas we would like to stress that it is important to investigate in depth any indication that incretin treatment may lead to inflammation or dysplasia in the pancreas, we find that the data presented in the Butler paper have serious methodological deficiencies that preclude any meaningful conclusions.
| S-EPMC5678976 | biostudies-literature
Project description:Type 2 diabetes and obesity are emerging pandemics in the 21st century creating worldwide urgency for the development of novel and safe therapies. We investigated trace amine-associated receptor 1 (TAAR1) as a novel target contributing to the control of glucose homeostasis and body weight.We investigated the peripheral human tissue distribution of TAAR1 by immunohistochemistry and tested the effect of a small molecule TAAR1 agonist on insulin secretion in vitro using INS1E cells and human islets and on glucose tolerance in C57Bl6, and db/db mice. Body weight effects were investigated in obese DIO mice.TAAR1 activation by a selective small molecule agonist increased glucose-dependent insulin secretion in INS1E cells and human islets and elevated plasma PYY and GLP-1 levels in mice. In diabetic db/db mice, the TAAR1 agonist normalized glucose excursion during an oral glucose tolerance test. Sub-chronic treatment of diet-induced obese (DIO) mice with the TAAR1 agonist resulted in reduced food intake and body weight. Furthermore insulin sensitivity was improved and plasma triglyceride levels and liver triglyceride content were lower than in controls.We have identified TAAR1 as a novel integrator of metabolic control, which acts on gastrointestinal and pancreatic islet hormone secretion. Thus TAAR1 qualifies as a novel and promising target for the treatment of type 2 diabetes and obesity.
| S-EPMC4703809 | biostudies-other
Project description:B-cell failure at the onset of type 2 diabetes is caused by a decline in ?-cell function in the postprandial state and loss of pancreatic ?-cell mass. Recently, we showed an association between increased insulin secretion and a single nucleotide polymorphism (SNP), SNP rs12686676, in the NR4A3 gene locus encoding the nuclear receptor Nor-1. Nor-1 is expressed in ?-cells, however, not much is known about its function with regard to insulin gene expression and insulin secretion. Nor-1 is induced in a glucose-/incretin-dependent manner via the PKA pathway and directly induces insulin gene expression. Additionally, it stimulates insulin secretion possibly via regulation of potentially important genes in insulin exocytosis. Moreover, we show that the minor allele of NR4A3 SNP rs12686676 fully rescues incretin resistance provoked by a well-described polymorphism in TCF7L2. Thus, Nor-1 represents a promising new target for pharmacological intervention to fight diabetes.
| S-EPMC3773820 | biostudies-literature
Project description:Purpose of reviewThe purpose of this review is to correlate predictions based on pre-clinical data with outcomes from clinical trials that examine the effects of incretin-based diabetes treatments on the kidney. The incretin-based treatments include agonists of the glucagon-like peptide 1 receptor (GLP-1R) and inhibitors of the enzyme, dipeptidyl peptidase-4 (DPP-4). In addition, what is known about the incretin-based therapies will be compared to what is known about the renal effects of SGLT2 inhibitors.Recent findingsLarge-scale clinical trials have shown that SGLT2 inhibitors reduce albuminuria and preserve estimated glomerular filtration rate (eGFR) in patients with diabetic nephropathy. A concise and plausible hemodynamic mechanism is supported by pre-clinical research on the physiology and pharmacology of SGLT2. Large-scale clinical trials have shown that incretin-based therapies mitigate albuminuria but have not shown beneficial effects on eGFR. Research on the incretin-based therapies has yielded a diverse array of direct effects throughout the body, which fuels speculation as to how these drugs might benefit the diabetic kidney and affect its function(s). But in vivo experiments have yet to confirm that the proposed mechanisms underlying emergent phenomena, such as proximal tubular fluid reabsorption, are the ones predicted by cell and molecular experiments. There may be salutary effects of incretin-based treatments on the diabetic kidney, but the system is complex and not amenable to simple explanation or prior prediction. This contrasts with the renal effects of SGLT2 inhibitors, which can be explained concisely.
| S-EPMC6426321 | biostudies-literature
Project description:Aims/introductionIt was reported that fetuses secrete endogenous incretin; however, the stimulants of fetal incretin secretion are not fully understood. To investigate the association between the passage of amniotic fluid through the intestinal tract and fetal secretion of incretin, we analyzed umbilical cord incretin levels of infants with duodenum atresia.Materials and methodsInfants born from July 2017 to July 2019 (infants with duodenum atresia and normal term or preterm infants) were enrolled. We measured and compared the concentrations of glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide/glucose-dependent insulinotropic polypeptide (GIP) in the umbilical vein and preprandial blood samples after birth.ResultsA total of 98 infants (47 term, 46 preterm and 5 with duodenum atresia) were included. In patients with duodenum atresia, umbilical vein GLP-1 and GIP levels were the same as those in normal infants. In postnatal samples, there were positive correlations between the amount of enteral feeding and preprandial serum concentrations of GLP-1 (r = 0.47) or GIP (r = 0.49).ConclusionsOur results show that enteral feeding is important for secretion of GLP-1 and GIP in postnatal infants, whereas the passage of amniotic fluid is not important for fetal secretion of GLP-1 and GIP. The effect of ingested material passing through the digestive tract on incretin secretion might change before and after birth. Other factors might stimulate secretion of GLP-1 and GIP during the fetal period.
| S-EPMC8169361 | biostudies-literature
Project description:AIMS/HYPOTHESIS:The mechanisms for improved glycemic control after bariatric surgery in subjects with type 2 diabetes (T2D) are not fully known. We hypothesized that dynamic hepatic blood responses to a mixed-meal are changed after bariatric surgery in parallel with an improvement in glucose tolerance. METHODS:A total of ten morbidly obese subjects with T2D were recruited to receive a mixed-meal and a glucose-dependent insulinotropic polypeptide (GIP) infusion before and early after (within a median of less than three months) bariatric surgery, and hepatic blood flow and volume (HBV) were measured repeatedly with combined positron emission tomography/MRI. Ten lean non-diabetic individuals served as controls. RESULTS:Bariatric surgery leads to a significant decrease in weight, accompanied with an improved β-cell function and glucagon-like peptide 1 (GLP-1) secretion, and a reduction in liver volume. Blood flow in portal vein (PV) was increased by 1.65-fold (P = 0.026) in response to a mixed-meal in subjects after surgery, while HBV decreased in all groups (P < 0.001). When the effect of GIP infusion was tested separately, no change in hepatic arterial and PV flow was observed, but HBV decreased as seen during the mixed-meal test. CONCLUSIONS/INTERPRETATION:Early after bariatric surgery, PV flow response to a mixed-meal is augmented, improving digestion and nutrient absorption. GIP influences the post-prandial reduction in HBV thereby diverting blood to the extrahepatic sites.
| S-EPMC6063878 | biostudies-literature
Project description:Although newer treatments for type 2 diabetes (T2D) patients have produced continual improvements in outcome, a large and growing population with prediabetes remains under-treated. In the last few years, incretin-based therapies have become an important treatment option for patients with T2D. There are two classes of incretin agents: the dipeptidyl peptidase-4 (DPP-4) inhibitors and the glucagon like peptide 1 (GLP-1) receptor agonists. The ultimate goal of agents within both of these classes is to increase GLP-1 signaling, which results in augmented glucose-induced insulin secretion, inhibition of glucagon secretion, and decreased appetite. This should result in improved regulation of glucose homeostasis. GLP-1 receptor agonists enable patients to achieve significant weight loss. In contrast, DPP-4 inhibitors result in a less dramatic increase in GLP-1 levels; therefore, they are weight neutral. Incretin therapies are currently recommended for use early in the treatment algorithm for T2D patients whose disease is not manageable by diet and exercise alone, but the potential for these agents may be farther reaching. Current studies are evaluating the potential benefits of combining incretin therapies with basal insulin to provide continuous glucose control before and after meals. In addition, these agents may be promising for patients with prediabetes since they effectively reduce glycosylated hemoglobin levels and fasting plasma glucose levels, enable weight control, and have the potential to preserve β-cell function. Clearly, all of these properties are desirable for patients with prediabetes.
| S-EPMC3280666 | biostudies-literature
Project description:Attention deficit/hyperactivity disorder (ADHD) is the most common childhood neurodevelopmental disorder. Single nucleotide polymorphisms (SNPs) in the Adhesion G Protein-Coupled Receptor L3 (ADGRL3) gene are associated with increased susceptibility to developing ADHD worldwide. However, the effect of ADGRL3 non-synonymous SNPs (nsSNPs) on the ADGRL3 protein function is vastly unknown. Using several bioinformatics tools to evaluate the impact of mutations, we found that nsSNPs rs35106420, rs61747658, and rs734644, previously reported to be associated and in linkage with ADHD in disparate populations from the world over, are predicted as pathogenic variants. Docking analysis of rs35106420, harbored in the ADGLR3-hormone receptor domain (HRM, a common extracellular domain of the secretin-like GPCRs family), showed that HRM interacts with the Glucose-dependent insulinotropic polypeptide (GIP), part of the incretin hormones family. GIP has been linked to the pathogenesis of diabetes mellitus, and our analyses suggest a potential link to ADHD. Overall, the comprehensive application of bioinformatics tools showed that functional mutations in the ADGLR3 gene disrupt the standard and wild ADGRL3 structure, most likely affecting its metabolic regulation. Further in vitro experiments are granted to evaluate these in silico predictions of the ADGRL3-GIP interaction and dissect the complexity underlying the development of ADHD.
| S-EPMC9508192 | biostudies-literature