Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In previous studies on the enteroinsular axis in Zucker rats, it was found that glucose-dependent insulinotropic polypeptide (GIP) levels were normal in obese animals, but the glucose threshold for the insulinotropic action of GIP in the perfused rat pancreas was reduced. Glucagon-like peptide I (GLP-I)(7-36) is also an important incretin, and in the current study, glucose, insulin, and immunoreactive (IR)-COOH-terminal GLP-I responses to oral glucose were compared in lean (Fa/?) and obese (fa/fa) rats. In addition, the concentration thresholds for stimulation and glucose dependence of perfused pancreases to GLP-I(7-36) were examined. Glucose responses to oral glucose were similar in fa/fa and Fa/? rats. Obese animals were hyperinsulinemic when fasting and after oral glucose. Significant increases in IR-GLP-I levels in response to glucose were only observed in fa/fa rats. Perfused pancreases from fa/fa rats hypersecreted insulin at all glucose concentrations. In the presence of 4.4 mmol/l glucose, GLP-I(7-36) increased insulin secretion in fa/fa pancreases approximately 25-fold, whereas there was only a 5-fold increase in Fa/? pancreases. Pancreases from fa/fa rats, perfused with a glucose gradient (2.8-11 mmol/l) in the presence of GLP-I(7-36), responded with an immediate increase in insulin secretion, i.e., at a glucose concentration of 2.8 mmol/l, whereas Fa/? pancreases required a minimum of 4.22 mmol/l glucose for stimulation. With high glucose (16.7 mmol/l), both fa/fa and Fa/? rat pancreases exhibited similar responsiveness to GLP-I(7-36), having thresholds of < 50 pmol/l.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Altered glucose dependence of glucagon-like peptide I(7-36)-induced insulin secretion from the Zucker (fa/fa) rat pancreas. 772 5

Glucagon-like peptide I (GLP-I) stimulates glucose-dependent insulin secretion and inhibits food intake in the central nervous system. Because leptin reduces food intake but inhibits insulin secretion, we examined leptin action in mice with a null mutation in the GLP-I receptor. Intracerebroventricular leptin administration inhibited food intake in both wild-type and GLP-I receptor (GLP-IR) -/- mice, and daily intraperitoneal administration of leptin for 2 weeks produced comparable reductions in food intake and body weight in control and GLP-IR -/- mice. Glucose tolerance was improved in both wild-type and GLP-IR -/- mice, whether pair fed or leptin treated; however, blood sugars were significantly lower in the leptin-treated GLP-IR -/- mice following oral glucose challenge (P < 0.01). Glucose-stimulated insulin was reduced in both pair-fed and leptin-treated mice (P < 0.01-0.001); however, insulin levels were significantly lower in leptin-treated versus pair-fed GLP-IR -/- mice (P < 0.01). A single leptin injection had no effect on glucose tolerance in GLP-IR -/- mice, but decreased hepatic PEPCK mRNA in both wild-type and GLP-IR -/- mice. The improvement in blood glucose excursion, despite lower levels of glucose-stimulated insulin in lean leptin-treated GLP-IR -/- mice, suggests that leptin may have beneficial effects on control of blood glucose in the absence of obesity. Furthermore, the greater effects of leptin on glucose and insulin in leptin-treated versus pair-fed GLP-IR -/- mice raises the possibility that disruption of GLP-I signaling modifies the sensitivity to leptin in vivo.
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PMID:Leptin sensitivity in nonobese glucagon-like peptide I receptor -/- mice. 939 91

Obese African-American (AA) subjects have higher resting and stimulated insulin concentrations than obese Caucasians (C), which could not be explained by the severity of obesity or the degree of insulin sensitivity. We investigated whether differences in glucagon-like peptide-1 (GLP-1), the most potent incretin that regulates insulin secretion, might explain racial differences in insulin response. Accordingly, we measured fasting and stimulated glucose, insulin, and GLP-1 levels during a 3-h oral glucose tolerance test (OGTT) in 26 obese C (age 38+/-2 y, body mass index 44+/-1 kg/m(2)) and 16 obese AA (age 36+/-2 y, BMI 46+/-2 kg/m(2)) subjects. Corrected insulin response (CIR(30)), a measure of beta-cell activity, whole body insulin sensitivity index (WBISI), and area under the curve (AUC) for insulin, GLP-1, and C-peptide/insulin ratio were computed from the OGTT. Glucose levels, fasting and during the OGTT, were similar between racial groups; 32% of the C and 31% of the AA subjects had impaired glucose tolerance. With a similar WBISI, AAs had significantly higher CIR(30) (2.3+/-0.4 vs 1.01+/-0.1), insulin response (IAUC: 23 974+/-4828 vs 14 478+/-1463), and lower insulin clearance (0.07+/-0.01 vs 0.11+/-0.01) than C (all, P<0.01). Obese AAs also had higher fasting GLP-1 (6.7+/-2.5 vs 4.5+/-1.1) and GLP-1AUC (1174.7+/-412 vs 822.4+/-191) than C (both, P<0.02). Our results indicate that obese AAs had higher concentrations of GLP-1 both at fasting and during the OGTT than obese C. The increased GLP-1 concentration could explain the greater insulin concentration and the increased prevalence of hyperinsulinemia-associated disorders including obesity and type 2 diabetes in AAs.
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PMID:Racial differences in glucagon-like peptide-1 (GLP-1) concentrations and insulin dynamics during oral glucose tolerance test in obese subjects. 1457 47

Exendin 4 (Ex4) is a glucagon-like peptide-1 receptor (GLP- 1R) agonist which is available as a short-acting injectable treatment for type 2 diabetes. Our aim was to characterize the long-term effects of elevated steady-state levels of Ex4 provided by in vivo gene therapy. We constructed a helper-dependent adenoviral (HDAd) vector for long-term expression of Ex4 in vivo. A high-fat diet (HFD)-induced obesity (DIO) mouse model was chosen to approximate the metabolic derangements seen in obese patients. Mice were treated with a single injection of HDAd-Ex4 and were monitored for 15 weeks. Both hepatic Ex4 RNA and plasma Ex4 were detectable at the end of the study. HDAd-Ex4 treatment improved glucose homeostasis without increasing insulin levels. However, there was evidence of enhanced insulin action and decreased gluconeogenic enzyme expression. HDAd-Ex4 caused decreased weight gain without detectable changes in food intake, in part, due to increases in energy expenditure (EE). HDAd-Ex4 DIO mice also had reduced hepatic fat and an improved adipokine profile. In the liver, there was decreased expression of genes that were involved in de novo fatty acid synthesis. These observations are important in considering the development of longer acting GLP-1R agonists for the treatment of type 2 diabetes.
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PMID:Gene therapy for diabetes: metabolic effects of helper-dependent adenoviral exendin 4 expression in a diet-induced obesity mouse model. 1878 Nov 41

A 62-year old woman with obesity, high blood pressure and type 2 diabetes mellitus (DM2) was referred to a Vascular Risk Unit of the Internal Medicine Department due to elevated HbA1C (8.1%) in spite of having taken metformin (850 mg/12h) and glipizide (10 mg/12 h) regularly. She tries to exercise daily (walking 30 min) and has lost weight (from 5 to 12 kg) several times, but always regains what she has lost. Furthermore, she monitors her glucose levels in fasting every two weeks and generally has between 120 and 160 mg/dL. Her high blood pressure is being treated with enalapril/HCTZ and she also takes aspirin 100mg/day and simvastatin 20 mg/day. It is seen in her family background that one brother died suddenly at 50 years of age. Her physical examination shows a BMI of 32.4 Kg/m(2), and she has no edemas in the lower limbs. Her BP is 154/82 mmHg and creatinine 0.9 mg/dL. She has no microalbuminuria and her liver function is normal. What treatment do you think would be the more appropriate? 1 - Add glitazones. 2 - Add incretin mimetics (GLP 1/ DPP-4). 3 - Slow acting insulin.
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PMID:[Therapeutic behavior to follow in the following clinical case: treatment of type 2 diabetes]. 2014 94

Central administration of glucagon-like peptide-1 (GLP-1) causes a dose-dependent reduction in food intake, but the role of endogenous CNS GLP-1 in the regulation of energy balance remains unclear. Here, we tested the hypothesis that CNS GLP-1 activity is required for normal energy balance by using two independent methods to achieve chronic CNS GLP-1 loss of function in rats. Specifically, lentiviral-mediated expression of RNA interference was used to knock down nucleus of the solitary tract (NTS) preproglucagon (PPG), and chronic intracerebroventricular (ICV) infusion of the GLP-1 receptor (GLP-1r) antagonist exendin (9-39) (Ex9) was used to block CNS GLP-1r. NTS PPG knockdown caused hyperphagia and exacerbated high-fat diet (HFD)-induced fat accumulation and glucose intolerance. Moreover, in control virus-treated rats fed the HFD, NTS PPG expression levels correlated positively with fat mass. Chronic ICV Ex9 also caused hyperphagia; however, increased fat accumulation and glucose intolerance occurred regardless of diet. Collectively, these data provide the strongest evidence to date that CNS GLP-1 plays a physiologic role in the long-term regulation of energy balance. Moreover, they suggest that this role is distinct from that of circulating GLP-1 as a short-term satiation signal. Therefore, it may be possible to tailor GLP-1-based therapies for the prevention and/or treatment of obesity.
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PMID:Hyperphagia and increased fat accumulation in two models of chronic CNS glucagon-like peptide-1 loss of function. 2138 45

Glucagon-like peptide-1 (GLP-1) functions as an incretin hormone with antidiabetogenic properties. However the role of GLP-1 in human bone marrow-derived mesenchymal stem cells (hMSCs), if any, remains unknown. The effects of GLP-lin hMSCs were tested with regard to cell proliferation, cytoprotection, and cell differentiation into adipocytes. The signalling pathways involved in these processes were also analyzed. Cells were characterized by biochemical and morphological approaches before and after being induce to differentiate into adipocytes. PCNA protein levels were used as an protein index, whereas cell apoptosis was studied by deprivation of fetal bovine serum. Isolated hMSCs expressed stem cell markers as well as mRNA and GLP-1 receptor protein. GLP-1 increased the proliferarion of hMSCs, which decreased when they were induced to differentiate into adipocytes.This process produced biochemical and morphological changes in cells expressing PPARgamma, C/EBPbeta, AP2, and LPL in a time-dependent pattern. Notably, GLP-1 significantly reduced the expression of PPARgamma, C/EBPbeta, and LPL. These effects were exerted at least through the MEK and PKC signaling pathways. In addition, GLP-1 significantly reduced cell apoptosis. Our data indicate that, in hMSCs, GLP-1 promotes cellular proliferation and cytoprotection and prevents cell differentiation into adipocytes. These latter findings underscore the potential therapeutic role of GLP-1 in preventing the adipocyte hyperplasia associated with obesity and, additionally, could bolster the maintenance of hMSC stores by promoting the proliferation and cytoprotection of undifferentiated hMSC. These data suggest that the GLP-1 may have some function during embryonic life. Thus, both the peptide and its receptor were identified early in the mouse development, as well as GLP-1 modified significantly gene expression in mouse undifferentiated pluripotent cells. These findings also suggest that the pathophysiological implications of GLP-1 imbalance in adulthood may have a counterpart during development.
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PMID:[Reception and signal transduction implied in the differentiation of stem cells from human bone marrow until adipocytes]. 2226 60

The prevalence of obesity and diabetes continues to rise in the US. Glucagon-like peptide-1 receptor agonist (GLP-1RA) is an effective treatment option for type 2 diabetes mellitus (T2DM) that promotes weight loss. Common and effective treatment options added to metformin therapy (basal insulin, sulfonylureas, and pioglitazone) contribute to weight gain, which makes the addition of GLP-1RAs advantageous. Exenatide was the first agent in this class and has recently been approved for use in combination with insulin glargine by the US Food and Drug Administration and the European Medicines Agency. Until recently, there was a lack of data examining basal insulin combined with these agents. The main purpose of this article is to review the prospective interventional data on the safety and efficacy of GLP-1RAs (exenatide, liraglutide, albiglutide, lixisenatide) combined with basal insulin therapy in nonpregnant adults with T2DM. Databases searched were PubMed, Cochrane Central Register of Controlled Trials and the Database of Systematic Reviews (inception to January 2012). Abstracts presented at relevant diabetes and endocrine meetings from 2009 to 2011 were also reviewed, as were reference lists of identified publications. A total of five studies met the criteria and were included in the review. Data from these studies demonstrated that this combination therapy offers advantages for the treatment of diabetes, such as additional lowering of A1c without major risk for hypoglycemia, lower basal insulin requirements, decreased postprandial glucose levels (with or without fasting plasma glucose decreases), and weight loss, or at the very least, less weight gain. However, the gastrointestinal side effects and high cost of these agents may limit their use. This review demonstrates that adding a GLP-1RA to an existing basal insulin regimen is a reasonable treatment strategy in nonpregnant adult patients with T2DM.
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PMID:Glucagon-like peptide-1 receptor agonists as add-on therapy to basal insulin in patients with type 2 diabetes: a systematic review. 2282 35

Recent work has demonstrated that the route of administration affects the pharmacokinetics and biological activity of peptides. For example, the physiological profile of insulin consists of basal and prandial components with a small-scale oscillatory element. Insulin is used more efficiently when the pharmacokinetic profile mimics features of physiological release. Noninvasive administration of insulin by oral, transdermal, nasal and pulmonary routes resembles the relatively sharp peak and short duration of exposure of prandial release. The route of administration per se, can affect the response by avoiding first-pass metabolism or perhaps altering the timing in which the peptide reaches different sets of receptors. GLP-I delivered by injection and inhalation produces different side effect profiles. Nonclinical studies on two potential treatments for obesity, oxyntomodulin and PYY 3-36, are also presented to illustrate the relationship between exposure and effect as functions of route of administration.
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PMID:Peptide therapeutics: it's all in the delivery. 2294 31

Glucagon like peptide-1 (GLP-1) is one of the gastrointestinal peptides implicated in glycaemic homeostasis. In non-obese individuals with normal glucose tolerance GLP-1 is secreted in response to nutrient intake. However, this GLP- 1 response is generally accepted to be significantly diminished in those with diabetes, obesity or both. Given that GLP-1 is secreted from enteroendocrine L cells in the intestine, it is not surprising that manipulation of the gastro- intestinal tract has been shown to alter GLP-1 secretion; particularly when this intestinal manipulation is designed to aid weight reduction. GLP-1 dynamics are altered by bariatric surgery, with an improved secretory response to nutrient intake. However, there remains debate on the mechanisms responsible for the alterations in GLP-1 dynamics. Here we review the evidence for GLP-1 dynamics after Roux-en-Y gastric bpyass (RYGB), adjustable gastric banding (AGB), biliopancreatic diversion (BPD) and sleeve gastrectomy (SG), and make comparisons between modalities. In addition, we review the potential mechanisms underlying these dynamics, other molecules that may add to the "incretin effect" and other possible roles for GLP-1 following bariatric surgery. Finally, we will offer our critique of the evidence base.
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PMID:Glucagon like peptide-1 (GLP-1) dynamics following bariatric surgery: a Signpost to a new frontier. 2323 Sep 96


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