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1
Ye, Ji-Ming, Miguel A. Iglesias, David G. Watson, Bronwyn Ellis, Leonie Wood, Per Bo Jensen, Rikke Veggerby Sørensen, et al. "PPARα/γ ragaglitazar eliminates fatty liver and enhances insulin action in fat-fed rats in the absence of hepatomegaly." American Journal of Physiology-Endocrinology and Metabolism 284, no. 3 (March 1, 2003): E531—E540. http://dx.doi.org/10.1152/ajpendo.00299.2002.
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Peroxisome proliferator-activated receptor (PPAR)α and PPARγ agonists lower lipid accumulation in muscle and liver by different mechanisms. We investigated whether benefits could be achieved on insulin sensitivity and lipid metabolism by the dual PPARα/γ agonist ragaglitazar in high fat-fed rats. Ragaglitazar completely eliminated high-fat feeding-induced liver triglyceride accumulation and visceral adiposity, like the PPARα agonist Wy-14643 but without causing hepatomegaly. In contrast, the PPARγ agonist rosiglitazone only slightly lessened liver triglyceride without affecting visceral adiposity. Compared with rosiglitazone or Wy-14643, ragaglitazar showed a much greater effect (79%, P< 0.05) to enhance insulin's suppression of hepatic glucose output. Whereas all three PPAR agonists lowered plasma triglyceride levels and lessened muscle long-chain acyl-CoAs, ragaglitazar and rosiglitazone had greater insulin-sensitizing action in muscle than Wy-14643, associated with a threefold increase in plasma adiponectin levels. There was a significant correlation of lipid content and insulin action in liver and particularly muscle with adiponectin levels ( P < 0.01). We conclude that the PPARα/γ agonist ragaglitazar has a therapeutic potential for insulin-resistant states as a PPARγ ligand, with possible involvement of adiponectin. Additionally, it can counteract fatty liver, hepatic insulin resistance, and visceral adiposity generally associated with PPARα activation, but without hepatomegaly.
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Yajima, Ken, Hiroshi Hirose, Haruhisa Fujita, Yoshiko Seto, Hiroshi Fujita, Kaname Ukeda, Kiichi Miyashita, et al. "Combination therapy with PPARγ and PPARα agonists increases glucose-stimulated insulin secretion in db/dbmice." American Journal of Physiology-Endocrinology and Metabolism 284, no. 5 (May 1, 2003): E966—E971. http://dx.doi.org/10.1152/ajpendo.00149.2002.
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Although peroxisome proliferator-activated receptor (PPAR)γ agonists ameliorate insulin resistance, they sometimes cause body weight gain, and the effect of PPAR agonists on insulin secretion is unclear. We evaluated the effects of combination therapy with a PPARγ agonist, pioglitazone, and a PPARα agonist, bezafibrate, and a dual agonist, KRP-297, for 4 wk in male C57BL/6J mice and db/db mice, and we investigated glucose-stimulated insulin secretion (GSIS) by in situ pancreatic perfusion. Body weight gain in db/db mice was less with KRP-297 treatment than with pioglitazone or pioglitazone + bezafibrate treatment. Plasma glucose, insulin, triglyceride, and nonesterified fatty acid levels were elevated in untreated db/db mice compared with untreated C57BL/6J mice, and these parameters were significantly ameliorated in the PPARγ agonist-treated groups. Also, PPARγ agonists ameliorated the diminished GSIS and insulin content, and they preserved insulin and GLUT2 staining in db/db mice. GSIS was further increased by PPARγ and -α agonists. We conclude that combination therapy with PPARγ and PPARα agonists may be more useful with respect to body weight and pancreatic GSIS in type 2 diabetes with obesity.
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Kim Jun, Jeany. "Focus on New Diabetes Treatment Options with Cardiovascular Benefits." Journal of Contemporary Pharmacy Practice 66, no. 3 (September 1, 2019): 34–40. http://dx.doi.org/10.37901/jcphp18-00029.
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The landscape of diabetes treatment options has changed due to new diabetes drug approvals, changes in the Food and Drug Administration indications based on cardiovascular (CV) outcomes studies, as well as the approval of follow-on biologic insulins. Two new drugs were approved for type 2 diabetes mellitus including ertugliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and semaglutide, a glucagon-like peptide-1 (GLP1) receptor agonist joining a number of other drugs in these classes. In addition, follow-on biologic insulins, such as long-acting Basaglar (insulin glargine), and rapid-acting insulins Admelog (insulin lispro) and Fiasp (insulin aspart), were also approved. Furthermore, the CV outcome trial for dapagliflozin was published in November 2018 showing CV benefits. Finally, the 2018 joint American Diabetes Association (ADA) and European Association for the Study of Diabetes statement on the management of type 2 diabetes and the 2019 ADA Standards of Care for Diabetes made several recommendations. They encourage the use of agents with CV benefit in those with established atherosclerotic cardiovascular disease (ASCVD) or heart failure and to consider GLP1 receptor agonists as the first injectable agent, even before basal insulin, in certain patients. The purpose of this review is to discuss recently approved agents for type 2 diabetes comparing the available cardiovascular findings of SGLT2 inhibitors and GLP1 receptor agonists and outline key take-home points when recommending additional treatment for patients with type 2 diabetes after metformin.
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Cresser, Justin, Arend Bonen, Adrian Chabowski, Leslie E. Stefanyk, Roberto Gulli, Ian Ritchie, and David J. Dyck. "Oral administration of a PPAR-δ agonist to rodents worsens, not improves, maximal insulin-stimulated glucose transport in skeletal muscle of different fibers." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 299, no. 2 (August 2010): R470—R479. http://dx.doi.org/10.1152/ajpregu.00431.2009.
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Agonists targeting the nuclear receptor peroxisome proliferator-activated receptors (PPAR)-δ may be potential therapeutic agents for insulin-resistant related conditions, as they may be able to stimulate fatty acid (FA) oxidation and attenuate the accumulation of harmful lipid species in skeletal muscle. Several reports have demonstrated that PPAR-δ agonists improve whole body insulin sensitivity. However, whether these agonists exert their direct effects on glucose and FA metabolism in skeletal muscle, and specifically with different fiber types, is unknown. This study was undertaken to determine the effects of oral treatment with the PPAR-δ agonist, GW 501516, in conjunction with the administration of a high-saturated-fat diet on insulin-stimulated glucose transport in isolated oxidative (soleus) and glycolytic (epitrochlearis) rodent skeletal muscle in vitro. High-fat feeding significantly decreased maximal insulin-stimulated glucose transport in soleus, but not epitrochlearis muscle, and was associated with increased skeletal muscle diacylglycerol and ceramide content. Unexpectedly, treatment with the PPAR-δ agonist significantly reduced insulin-stimulated glucose transport in both soleus and epitrochlearis muscles, regardless of dietary fat content. The reduction in insulin-stimulated glucose transport induced by the agonist was associated with large increases in total muscle fatty acid translocase (FAT)/CD36protein content, but not diacylglycerol or ceramide contents. Agonist treatment did not alter the protein content of PPAR-δ, GLUT4, or insulin-signaling proteins (IRS-1, p85 PI3-K, Akt). Agonist treatment led to a small, but significant increase, in the oxidative capacity of glycolytic but not oxidative muscle. We propose that chronic treatment with the PPAR-δ agonist GW 501516 may induce or worsen insulin resistance in rodent skeletal muscle by increasing the capacity for FA transport across the sarcolemma without a sufficient compensatory increase in FA oxidation. However, an accumulation of diacylglycerol and ceramide, while associated with diet-induced insulin resistance, does not appear to be responsible for the agonist-induced reduction in insulin-stimulated glucose transport.
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Zhang, Xianyang, Tengjiao Cui, Jinlin He, Haibo Wang, Renzhi Cai, Petra Popovics, Irving Vidaurre, et al. "Beneficial effects of growth hormone-releasing hormone agonists on rat INS-1 cells and on streptozotocin-induced NOD/SCID mice." Proceedings of the National Academy of Sciences 112, no. 44 (October 16, 2015): 13651–56. http://dx.doi.org/10.1073/pnas.1518540112.
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Agonists of growth hormone-releasing hormone (GHRH) have been previously reported to promote growth, function, and engraftment of islet cells following transplantation. Here we evaluated recently synthesized GHRH agonists on the proliferation and biological functions of rat pancreatic β-cell line (INS-1) and islets. In vitro treatment of INS-1 cells with GHRH agonists increased cell proliferation, the expression of cellular insulin, insulin-like growth factor-1 (IGF1), and GHRH receptor, and also stimulated insulin secretion in response to glucose challenge. Exposure of INS-1 cells to GHRH agonists, MR-356 and MR-409, induced activation of ERK and AKT pathways. Agonist MR-409 also significantly increased the levels of cellular cAMP and the phosphorylation of cAMP response element binding protein (CREB) in INS-1 cells. Treatment of rat islets with agonist, MR-409 significantly increased cell proliferation, islet size, and the expression of insulin. In vivo daily s.c. administration of 10 μg MR-409 for 3 wk dramatically reduced the severity of streptozotocin (STZ)-induced diabetes in nonobese diabetic severe combined immunodeficiency (NOD/SCID) mice. The maximal therapeutic benefits with respect to the efficiency of engraftment, ability to reach normoglycemia, gain in body weight, response to high glucose challenge, and induction of higher levels of serum insulin and IGF1 were observed when diabetic mice were transplanted with rat islets preconditioned with GHRH agonist, MR-409, and received additional treatment with MR-409 posttransplantation. This study provides an improved approach to the therapeutic use of GHRH agonists in the treatment of diabetes mellitus.
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Cariou, Bertrand, Narimène Belhatem, Esteban Jodar, Stewart Harris, Elmar Jaeckel, Ildiko Lingvay, keval Chandrana, Trine Abrahamsen, and Christopher Sorli. "Impact de l’IMC sur la réduction de l’HbA 1c sous IDegLira chez des diabétiques de type 2 insuffisamment contrôlés sous sulfamides, agonistes des récepteurs au GLP-1 ou insuline Glargine U100 : analyses d’études de phase IIIb." Diabetes & Metabolism 43, no. 2 (March 2017): A114. http://dx.doi.org/10.1016/s1262-3636(17)30437-8.
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Chang, Feng, Linda A. Jaber, Helen D. Berlie, and Mary Beth O'Connell. "Evolution of Peroxisome Proliferator-Activated Receptor Agonists." Annals of Pharmacotherapy 41, no. 6 (June 2007): 973–83. http://dx.doi.org/10.1345/aph.1k013.
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OBJECTIVE: To discuss the evolution of peroxisome proliferator-activated receptor (PPAR) agonists from single site to multiple subtype or partial agonists for the treatment of type 2 diabetes, dyslipidemia, obesity, and the metabolic syndrome. DATA SOURCES: Information was obtained from MEDLINE (1966-March 2007) using search terms peroxisome proliferator-activated receptor agonist, PPAR dual agonist, PPAR α/γ agonist, PPAR pan agonist, partial PPAR, and the specific compound names. Other sources included pharmaceutical companies, the Internet, and the American Diabetes Association 64th-66th Scientific Sessions abstract books. STUDY SELECTION AND DATA EXTRACTION: Animal data, abstracts, clinical trials, and review articles were reviewed and summarized. DATA SYNTHESIS: PPAR α, γ, and δ receptors play an important role in lipid metabolism, regulation of adipocyte proliferation and differentiation, and insulin sensitivity. The PPAR dual agonists were developed to combine the triglyceride lowering and high-density lipoprotein cholesterol elevation from the PPAR-α agonists (fibrates) with the insulin sensitivity improvement from the PPAR-γ agonists (thiazolidinediones). Although the dual agonists reduced hemoglobin A1C(A1C) and improved the lipid profile, adverse effects led to discontinued development. Currently, PPAR-γ agonists (GW501516 in Phase I trials), partial PPAR-γ agonists (metaglidasen in Phase II and III trials), and pan agonists (α, γ, δ netoglitazone in Phase II and III trials) with improved cell and tissue selectivity are undergoing investigation to address multiple aspects of the metabolic syndrome with a single medication. By decreasing both A1C and triglycerides, metaglidasen did improve multiple aspects of the metabolic syndrome with fewer adverse effects than compared with placebo. Metaglidasen is now being compared with pioglitazone. CONCLUSIONS: Influencing the various PPARs results in improved glucose, lipid, and weight management, with effects dependent on full or partial agonist activity at single or multiple receptors. Although the dual PPAR compounds have been associated with unacceptable toxicities, new PPAR agonist medications continue to be developed and investigated to discover a safe drug with benefits in multiple disease states.
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Porskjær Christensen, Lars, and Rime Bahij El-Houri. "Development of an In Vitro Screening Platform for the Identification of Partial PPARγ Agonists as a Source for Antidiabetic Lead Compounds." Molecules 23, no. 10 (September 22, 2018): 2431. http://dx.doi.org/10.3390/molecules23102431.
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Type 2 diabetes (T2D) is a metabolic disorder where insulin-sensitive tissues show reduced sensitivity towards insulin and a decreased glucose uptake (GU), which leads to hyperglycaemia. Peroxisome proliferator-activated receptor (PPAR)γ plays an important role in lipid and glucose homeostasis and is one of the targets in the discovery of drugs against T2D. Activation of PPARγ by agonists leads to a conformational change in the ligand-binding domain, a process that alters the transcription of several target genes involved in glucose and lipid metabolism. Depending on the ligands, they can induce different sets of genes that depends of their recruitment of coactivators. The activation of PPARγ by full agonists such as the thiazolidinediones leads to improved insulin sensitivity but also to severe side effects probably due to their behavior as full agonists. Partial PPARγ agonists are compounds with diminished agonist efficacy compared to full agonist that may exhibit the same antidiabetic effect as full agonists without inducing the same magnitude of side effects. In this review, we describe a screening platform for the identification of partial PPARγ agonists from plant extracts that could be promising lead compounds for the development of antidiabetic drugs. The screening platform includes a series of in vitro bioassays, such as GU in adipocytes, PPARγ-mediated transactivation, adipocyte differentiation and gene expression as well as in silico docking for partial PPARγ agonism.
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Montessuit, Christophe, Irène Papageorgiou, and René Lerch. "Nuclear Receptor Agonists Improve Insulin Responsiveness in Cultured Cardiomyocytes through Enhanced Signaling and Preserved Cytoskeletal Architecture." Endocrinology 149, no. 3 (December 6, 2007): 1064–74. http://dx.doi.org/10.1210/en.2007-0656.
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Insulin resistance is the failure of insulin to stimulate the transport of glucose into its target cells. A highly regulatable supply of glucose is important for cardiomyocytes to cope with situations of metabolic stress. We recently observed that isolated adult rat cardiomyocytes become insulin resistant in vitro. Insulin resistance is combated at the whole body level with agonists of the nuclear receptor complex peroxisome proliferator-activated receptor γ (PPARγ)/retinoid X receptor (RXR). We investigated the effects of PPARγ/RXR agonists on the insulin-stimulated glucose transport and on insulin signaling in insulin-resistant adult rat cardiomyocytes. Treatment of cardiomyocytes with ciglitazone, a PPARγ agonist, or 9-cis retinoic acid (RA), a RXR agonist, increased insulin- and metabolic stress-stimulated glucose transport, whereas agonists of PPARα or PPARβ/δ had no effect. Stimulation of glucose transport in response to insulin requires the phosphorylation of the signaling intermediate Akt on the residues Thr308 and Ser473 and, downstream of Akt, AS160 on several Thr and Ser residues. Phosphorylation of Akt and AS160 in response to insulin was lower in insulin-resistant cardiomyocytes. However, treatment with 9-cis RA markedly increased phosphorylation of both proteins. Treatment with 9-cis RA also led to better preservation of microtubules in cultured cardiomyocytes. Disruption of microtubules in insulin-responsive cardiomyocytes abolished insulin-stimulated glucose transport and reduced phosphorylation of AS160 but not Akt. Metabolic stress-stimulated glucose transport also involved AS160 phosphorylation in a microtubule-dependent manner. Thus, the stimulation of glucose uptake in response to insulin or metabolic stress is dependent in cardiomyocytes on the presence of intact microtubules.
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Balakumar, Pitchai, Nanjaian Mahadevan, and Ramanathan Sambathkumar. "A Contemporary Overview of PPARα/γ Dual Agonists for the Management of Diabetic Dyslipidemia." Current Molecular Pharmacology 12, no. 3 (July 29, 2019): 195–201. http://dx.doi.org/10.2174/1874467212666190111165015.
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Background: Diabetes mellitus and concomitant dyslipidemia, being referred to as ‘diabetic dyslipidemia’, are the foremost detrimental factors documented to play a pivotal role in cardiovascular illness. Diabetic dyslipidemia is associated with insulin resistance, high plasma triglyceride levels, low HDL-cholesterol concentration and elevated small dense LDL-cholesterol particles. Maintaining an optimal glucose and lipid levels in patients afflicted with diabetic dyslipidemia could be a major task that might require a well-planned diet-management system and regular physical activity, or otherwise an intake of combined antidiabetic and antihyperlipidemic medications. Synchronized treatment which efficiently controls insulin resistance-associated diabetes mellitus and co-existing dyslipidemia could indeed be a fascinating therapeutic option in the management of diabetic dyslipidemia. Peroxisome proliferator-activated receptors α/γ (PPARα/γ) dual agonists are such kind of drugs which possess therapeutic potentials to treat diabetic dyslipidemia. Nevertheless, PPARα/γ dual agonists like muraglitazar, naveglitazar, tesaglitazar, ragaglitazar and aleglitazar have been reported to have undesirable adverse effects, and their developments have been halted at various stages. On the other hand, a recently introduced PPARα/γ dual agonist, saroglitazar is an emerging therapeutic agent of glitazar class approved in India for the management of diabetic dyslipidemia, and its treatment has been reported to be generally safe and well tolerated. Conclusion: Some additional and new compounds, at initial and preclinical stages, have been recently reported to possess PPARα/γ dual agonistic potentials with considerable therapeutic efficacy and reduced adverse profile. This review sheds light on the current status of various PPARα/γ dual agonists for the management of diabetic dyslipidemia.
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Shafi, Sana, Pawan Gupta, Gopal Lal Khatik, and Jeena Gupta. "PPARγ: Potential Therapeutic Target for Ailments Beyond Diabetes and its Natural Agonism." Current Drug Targets 20, no. 12 (August 22, 2019): 1281–94. http://dx.doi.org/10.2174/1389450120666190527115538.
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Intense research interests have been observed in establishing PPAR gamma as a therapeutic target for diabetes. However, PPARγ is also emerging as an important therapeutic target for varied disease states other than type 2 diabetes like neurodegenerative disorders, cancer, spinal cord injury, asthma, and cardiovascular problems. Furthermore, glitazones, the synthetic thiazolidinediones, also known as insulin sensitizers, are the largely studied PPARγ agonists and the only ones approved for the treatment of type 2 diabetes. However, they are loaded with side effects like fluid retention, obesity, hepatic failure, bone fractures, and cardiac failure; which restrict their clinical application. Medicinal plants used traditionally are the sources of bioactive compounds to be used for the development of successful drugs and many structurally diverse natural molecules are already established as PPARγ agonists. These natural partial agonists when compared to full agonist synthetic thiazolidinediones led to weaker PPARγ activation with lesser side effects but are not thoroughly investigated. Their thorough characterization and elucidation of mechanistic activity might prove beneficial for counteracting diseases by modulating PPARγ activity through dietary changes. We aim to review the therapeutic significance of PPARγ for ailments other than diabetes and highlight natural molecules with potential PPARγ agonistic activity.
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Finn, Patricia D., David Rodriguez, Jill Kohler, Zhengfeng Jiang, Sindy Wan, Erick Blanco, Andrew J. King, et al. "Intestinal TGR5 agonism improves hepatic steatosis and insulin sensitivity in Western diet-fed mice." American Journal of Physiology-Gastrointestinal and Liver Physiology 316, no. 3 (March 1, 2019): G412—G424. http://dx.doi.org/10.1152/ajpgi.00300.2018.
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Takeda G protein-coupled receptor 5 (TGR5) agonists induce systemic release of glucagon-like peptides (GLPs) from intestinal L cells, a potentially therapeutic action against metabolic diseases such as nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and Type 2 diabetes. Historically, TGR5 agonist use has been hindered by side effects, including inhibition of gallbladder emptying. Here, we characterize RDX8940, a novel, orally administered TGR5 agonist designed to have minimal systemic effects and investigate its activity in mice fed a Western diet, a model of NAFLD and mild insulin resistance. Agonist activity, binding selectivity, toxicity, solubility, and permeability of RDX8940 were characterized in standard in vitro models. RDX8940 pharmacokinetics and effects on GLP secretion, insulin sensitivity, and liver steatosis were assessed in C57BL/6 mice fed normal or Western diet chow and given single or repeated doses of RDX8940 or vehicle, with or without dipeptidyl peptidase-4 (DPP4) inhibitors. Gallbladder effects were assessed in CD-1 mice fed normal chow and given RDX8940 or a systemic TGR5 agonist or vehicle. Our results showed that RDX8940 is minimally systemic, potent, and selective, and induces incretin (GLP-1, GLP-2, and peptide YY) secretion. RDX8940-induced increases in plasma active GLP-1 (aGLP-1) levels were enhanced by repeated dosing and by coadministration of DPP4 inhibitors. RDX8940 increased hepatic exposure to aGLP-1 without requiring coadministration of a DPP4 inhibitor. In mice fed a Western diet, RDX8940 improved liver steatosis and insulin sensitivity. Unlike systemic TGR5 agonists, RDX8940 did not inhibit gallbladder emptying. These results indicate that RDX8940 may have therapeutic potential in patients with NAFLD/NASH. NEW & NOTEWORTHY Takeda G protein-coupled receptor 5 (TGR5) agonists have potential as a treatment for nonalcoholic steatohepatitis and nonalcoholic fatty liver disease (NAFLD) but have until now been associated with undesirable side effects associated with systemic TGR5 agonism, including blockade of gallbladder emptying. We demonstrate that RDX8940, a potent, selective, minimally systemic oral TGR5 agonist, improves liver steatosis and insulin sensitivity in a mouse model of NAFLD and does not inhibit gallbladder emptying in mice.
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Meade, Lisa T., and Morgan L. Mannka. "The Effect of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter-2 Inhibitors in Patients Prescribed Regular U-500 Insulin." Annals of Pharmacotherapy 53, no. 11 (June 19, 2019): 1111–16. http://dx.doi.org/10.1177/1060028019857557.
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Background: Only 2 small studies have examined the use of glucagon-like peptide-1 (GLP-1) receptor agonists with U-500 insulin, with mixed results. Moreover, there are no studies to our knowledge that have investigated use of sodium-glucose cotransporter-2 (SGLT-2) inhibitors with U-500 insulin therapy. Objective: This research was designed to determine the effectiveness of GLP-1 agonists and SGLT-2 inhibitors in patients already taking U-500 insulin. Methods: A retrospective chart review was conducted on patients using U-500 insulin to which a GLP-1 agonist or SGLT-2 inhibitor was added as their treatment protocol. The primary outcome measure was change in glycosylated hemoglobin (A1C) after 3 to 6 months on the additional therapy. Secondary outcomes included A1C change at 12 months, changes in total daily dose (TDD) of U-500 insulin, body mass index (BMI) and body weight from baseline, and episodes of hypoglycemia. Results: A total of 17 patients were included in the review. The combination of a GLP-1 agonist and/or SGLT-2 inhibitor with U-500 insulin resulted in significant reductions in A1C (0.84%, P = 0.004) and TDD of U-500 insulin (33.5 units, P = 0.031) at the 3- to 6-month interval. Furthermore, statistically significant decreases in mean BMI and body weight were observed 12 months postbaseline. Hypoglycemia occurred in the majority of patients (64.7%). Conclusion and Relevance: This is the first study to examine SGLT-2 inhibitors in combination with U-500 insulin therapy. Clinically, the addition of a GLP-1 agonist and/or SGLT-2 inhibitor can improve A1C and decrease TDD, BMI, and body weight.
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Wake, Deborah J., Roland H. Stimson, Garry D. Tan, Natalie Z. M. Homer, Ruth Andrew, Fredrik Karpe, and Brian R. Walker. "Effects of Peroxisome Proliferator-Activated Receptor-α and -γ Agonists on 11β-Hydroxysteroid Dehydrogenase Type 1 in Subcutaneous Adipose Tissue in Men." Journal of Clinical Endocrinology & Metabolism 92, no. 5 (May 1, 2007): 1848–56. http://dx.doi.org/10.1210/jc.2006-2713.
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Abstract Context: In animals, peroxisome proliferator-activated receptor-α (PPARα) and PPARγ agonists down-regulate 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) mRNA and activity in liver and adipose tissue, respectively, and PPARγ agonists reduce ACTH secretion from corticotrope cells. Objective: Our objective was to test whether PPAR agonists alter cortisol secretion and peripheral regeneration by 11β-HSD1 in humans and whether reduced cortisol action contributes to metabolic effects of PPARγ agonists. Design and Setting: Three randomized placebo-controlled crossover studies were conducted at a clinical research facility. Patients and Participants: Healthy men and patients with type 2 diabetes participated. Interventions, Outcome Measures, and Results: In nine healthy men, 7 d of PPARα agonist (fenofibrate) or PPARγ agonist (rosiglitazone) had no effect on cortisol secretion, hepatic cortisol generation after oral cortisone administration, or tracer kinetics during 9,11,12,12-[2H]4-cortisol infusion, although rosiglitazone marginally reduced cortisol generation in sc adipose tissue measured by in vivo microdialysis. In 12 healthy men, 4–5 wk of rosiglitazone increased insulin sensitivity during insulin infusion but did not change 11β-HSD1 mRNA or activity in sc adipose tissue, and insulin sensitization was unaffected by glucocorticoid blockade with a combination of metyrapone and RU38486. In 12 men with type 2 diabetes 12 wk of rosiglitazone reduced arteriovenous cortisone extraction across abdominal sc adipose tissue and reduced 11β-HSD1 mRNA in sc adipose tissue but increased plasma cortisol concentrations. Conclusions: Neither PPARα nor PPARγ agonists down-regulate 11β-HSD1 or cortisol secretion acutely in humans. The early insulin-sensitizing effect of rosiglitazone is not dependent on reducing intracellular glucocorticoid concentrations. Reduced adipose 11β-HSD1 expression and increased plasma cortisol during longer therapy with rosiglitazone probably reflect indirect effects, e.g. mediated by changes in body fat.
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Vikulova, O. K., Z. T. Zuraeva, O. V. Michaleva, L. V. Nikankina, M. Sh Shamkhalova, M. V. Shestakova, and I. I. Dedov. "Renal effects of glucagon-like peptide receptor agonists in patients with type 1 diabetes mellitus." Terapevticheskii arkhiv 90, no. 6 (June 15, 2018): 59–64. http://dx.doi.org/10.26442/terarkh201890659-64.
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The purpose of our study is to assess the effects of glucagon-like peptide-1 receptor agonists (GLP-1R agonists) on early markers of kidney damage in patients with type 1 diabetes mellitus (DM). Materials and methods. The study included 27 patients with type 1 diabetes with normo- (n=16) and microalbuminuria (n=11) on intensive insulin injection regimen with insulin analogs. Patients were divided into two groups: 15 patients continued insulin therapy throughout the follow-up period, 12 patients were given 1.2 mg GLP-1R agonist (Liraglutide) once a day in addition to the insulin therapy for 6 months. HbA1c, lipid profile, classic markers of kidney damage (albuminuria, creatinine, glomerular filtration rate); plazma (neutrophilic gelatinase-associated lipoxalin - NGAL, molecule renal damage of type 1 - KIM-1, cystatin C, osteopontin) and urinary kidney biomarkers (nephrin, podocyne, uromodulin, NGAL, KIM-1, collagen type IV, cystatin C) were evaluated prior and in dynamics at 6 months. Kidney biomarkers levels were assessed by the enzyme-linked immunosorbent assay (ELISA). Results. We observed a significant decrease in the urinary excretion of type IV collagen, cystatin C, increased uromodulin excretion and decrease in the plasma levels of osteopontin, NGAL and cystatin C in the group of combined insulin and GLP-1R agonist therapy. Conclusions. Changes in the level of sensitive kidney biomarkers indicate a possible renoprotective effect of GLP-1R agonist therapy in patients with type 1 diabetes at an early stages of kidney damage.
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Gorski, Judith N., Michele J. Pachanski, Joel Mane, Christopher W. Plummer, Sarah Souza, Brande S. Thomas-Fowlkes, Aimie M. Ogawa, et al. "GPR40 reduces food intake and body weight through GLP-1." American Journal of Physiology-Endocrinology and Metabolism 313, no. 1 (July 1, 2017): E37—E47. http://dx.doi.org/10.1152/ajpendo.00435.2016.
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G protein-coupled receptor 40 (GPR40) partial agonists lower glucose through the potentiation of glucose-stimulated insulin secretion, which is believed to provide significant glucose lowering without the weight gain or hypoglycemic risk associated with exogenous insulin or glucose-independent insulin secretagogues. The class of small-molecule GPR40 modulators, known as AgoPAMs (agonist also capable of acting as positive allosteric modulators), differentiate from partial agonists, binding to a distinct site and functioning as full agonists to stimulate the secretion of both insulin and glucagon-like peptide-1 (GLP-1). Here we show that GPR40 AgoPAMs significantly increase active GLP-1 levels and reduce acute and chronic food intake and body weight in diet-induced obese (DIO) mice. These effects of AgoPAM treatment on food intake are novel and required both GPR40 and GLP-1 receptor signaling pathways, as demonstrated in GPR40 and GLP-1 receptor-null mice. Furthermore, weight loss associated with GPR40 AgoPAMs was accompanied by a significant reduction in gastric motility in these DIO mice. Chronic treatment with a GPR40 AgoPAM, in combination with a dipeptidyl peptidase IV inhibitor, synergistically decreased food intake and body weight in the mouse. The effect of GPR40 AgoPAMs on GLP-1 secretion was recapitulated in lean, healthy rhesus macaque demonstrating that the putative mechanism mediating weight loss translates to higher species. Together, our data indicate effects of AgoPAMs that go beyond glucose lowering previously observed with GPR40 partial agonist treatment with additional potential for weight loss.
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Nofziger, Charity, Kathleen K. Brown, Chari D. Smith, Wallace Harrington, David Murray, John Bisi, Thalia T. Ashton, et al. "PPARγ agonists inhibit vasopressin-mediated anion transport in the MDCK-C7 cell line." American Journal of Physiology-Renal Physiology 297, no. 1 (July 2009): F55—F62. http://dx.doi.org/10.1152/ajprenal.00090.2009.
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PPARγ agonists are synthetic ligands for the peroxisome proliferator-activated receptor-γ (PPARγ). These agents have insulin-sensitizing properties but can cause fluid retention, thereby limiting their usefulness in patients at risk for cardiovascular disease. The side effect etiology is unknown, but the nature of presentation suggests modulation of renal salt and water homeostasis. In a well-characterized cell culture model of the principal cell type [Madin-Darby canine kidney (MDCK)-C7], PPARγ agonists inhibit vasopressin-stimulated Cl− secretion with agonist dose-response relationships that mirror receptor transactivation profiles. Analyses of the components of the vasopressin-stimulated intracellular signaling pathway indicated no PPARγ agonist-induced changes in basolateral membrane conductances, intracellular cAMP, protein kinase A, or total cellular adenine nucleotides. The PPARγ agonist-induced decrease in anion secretion is the result of decreased mRNA of the final effector in the pathway, the apically located cystic fibrosis transmembrane regulator (CFTR). These data showing that CFTR is a target for PPARγ agonists may provide new insights into the physiology of PPARγ agonist-induced fluid retention.
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Hegarty, Bronwyn D., Stuart M. Furler, Nicholas D. Oakes, Edward W. Kraegen, and Gregory J. Cooney. "Peroxisome Proliferator-Activated Receptor (PPAR) Activation Induces Tissue-Specific Effects on Fatty Acid Uptake and Metabolism in Vivo—A Study Using the Novel PPARα/γ Agonist Tesaglitazar." Endocrinology 145, no. 7 (July 1, 2004): 3158–64. http://dx.doi.org/10.1210/en.2004-0260.
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Abstract Agonists of peroxisome proliferator-activated receptors (PPARs) have emerged as important pharmacological agents for improving insulin action. A major mechanism of action of PPAR agonists is thought to involve the alteration of the tissue distribution of nonesterified fatty acid (NEFA) uptake and utilization. To test this hypothesis directly, we examined the effect of the novel PPARα/γ agonist tesaglitazar on whole-body insulin sensitivity and NEFA clearance into epididymal white adipose tissue (WAT), red gastrocnemius muscle, and liver in rats with dietary-induced insulin resistance. Wistar rats were fed a high-fat diet (59% of calories as fat) for 3 wk with or without treatment with tesaglitazar (1 μmol·kg−1·d−1, 7 d). NEFA clearance was measured using the partially metabolizable NEFA tracer, 3H-R-bromopalmitate, administered under conditions of basal or elevated NEFA availability. Tesaglitazar improved the insulin sensitivity of high-fat-fed rats, indicated by an increase in the glucose infusion rate during hyperinsulinemic-euglycemic clamp (P < 0.01). This improvement in insulin action was associated with decreased diglyceride (P < 0.05) and long chain acyl coenzyme A (P < 0.05) in skeletal muscle. NEFA clearance into WAT of high-fat-fed rats was increased 52% by tesaglitazar under basal conditions (P < 0.001). In addition the PPARα/γ agonist moderately increased hepatic and muscle NEFA utilization and reduced hepatic triglyceride accumulation (P < 0.05). This study shows that tesaglitazar is an effective insulin-sensitizing agent in a mild dietary model of insulin resistance. Furthermore, we provide the first direct in vivo evidence that an agonist of both PPARα and PPARγ increases the ability of WAT, liver, and skeletal muscle to use fatty acids in association with its beneficial effects on insulin action in this model.
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Lacey, R. J., N. S. Berrow, N. J. M. London, S. P. Lake, R. F. James, J. H. B. Scarpello, and N. G. Morgan. "Differential effects of β-adrenergic agonists on insulin secretion from pancreatic islets isolated from rat and man." Journal of Molecular Endocrinology 5, no. 1 (August 1990): 49–54. http://dx.doi.org/10.1677/jme.0.0050049.
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ABSTRACT The selective β2-adrenergic agonist clenbuterol was ineffective as a stimulus for insulin secretion when isolated rat pancreatic islets were incubated with glucose at concentrations between 4 and 20 mM. Inclusion of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine led to potentiation of glucose-induced insulin secretion, but did not facilitate stimulation by clenbuterol. Furthermore, maintenance of isolated rat islets for up to 3 days in tissue culture also failed to result in the appearance of a secretory response to β-agonists. By contrast, clenbuterol induced a dose-dependent increase in insulin release from isolated human islets incubated with 20 mm glucose. Clenbuterol did not increase the basal rate of insulin secretion (4 mm glucose) in human islets. Under perifusion conditions, the secretory response of human islets to clenbuterol was rapid, of similar magnitude to that seen under static incubation conditions and could be sustained for at least 30 min. The increase in insulin secretion induced by clenbuterol was inhibited by propranolol, indicating that the response was mediated by activation of β-receptors. In support of this, a similar enhancement of glucose-induced insulin secretion was elicited by a different β2-agonist, salbutamol, in human islets. The results indicate that the B cells of isolated rat islets are unresponsive to β-agonists, whereas those of human islets are equipped with functional β-receptors which can directly influence the rate of insulin secretion.
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Chu, Zhi-Liang, Robert M. Jones, Hongmei He, Chris Carroll, Veronica Gutierrez, Annette Lucman, Molly Moloney, et al. "A Role for β-Cell-Expressed G Protein-Coupled Receptor 119 in Glycemic Control by Enhancing Glucose-Dependent Insulin Release." Endocrinology 148, no. 6 (June 1, 2007): 2601–9. http://dx.doi.org/10.1210/en.2006-1608.
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Pancreatic β-cell dysfunction is a hallmark event in the pathogenesis of type 2 diabetes. Injectable peptide agonists of the glucagon-like peptide 1 (GLP-1) receptor have shown significant promise as antidiabetic agents by virtue of their ability to amplify glucose-dependent insulin release and preserve pancreatic β-cell mass. These effects are mediated via stimulation of cAMP through β-cell GLP-1 receptors. We report that the Gαs-coupled receptor GPR119 is largely restricted to insulin-producing β-cells of pancreatic islets. Additionally, we show here that GPR119 functions as a glucose-dependent insulinotropic receptor. Unlike receptors for GLP-1 and other peptides that mediate enhanced glucose-dependent insulin release, GPR119 was suitable for the development of potent, orally active, small-molecule agonists. The GPR119-specific agonist AR231453 significantly increased cAMP accumulation and insulin release in both HIT-T15 cells and rodent islets. In both cases, loss of GPR119 rendered AR231453 inactive. AR231453 also enhanced glucose-dependent insulin release in vivo and improved oral glucose tolerance in wild-type mice but not in GPR119-deficient mice. Diabetic KK/Ay mice were also highly responsive to AR231453. Orally active GPR119 agonists may offer significant promise as novel antihyperglycemic agents acting in a glucose-dependent fashion.
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Downing, S. E., and J. C. Lee. "Enhanced adrenergic sensitivity of the diabetic neonatal heart." American Journal of Physiology-Heart and Circulatory Physiology 248, no. 1 (January 1, 1985): H125—H131. http://dx.doi.org/10.1152/ajpheart.1985.248.1.h125.
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We have previously shown that insulin reduces inotropic responses to norepinephrine (NE) in isolated cardiac muscle and intact hearts. This inhibition also occurs in vascular smooth muscle. The present study was designed to examine inotropic sensitivity of insulin-deficient diabetic (D) hearts to mixed (NE) and pure beta 1 (isoproterenol, Iso) adrenergic agonists. Lambs were given alloxan (150 mg/kg) and studied 2 days later (glucose, 392 mg/dl). Results from eight controls (C) were compared. All animals were prepared for measurements of ventricular performance and coronary flow (CF) under conditions of constant arterial pressure, aortic flow, and heart rate (paced). Dose-response dP/dtmax curves were obtained by stepped increases of agonist infusion (iv). Iso (40 ng X min-1 X kg-1) caused a 30% increase of CF in both C and D, but no change occurred with NE (0.4 micrograms X min-1 X kg-1). Myocardial O2 consumption did not differ among groups and was unaltered by either agonist. Initial values for heart rate and dP/dt did not differ between C and D. NE dose-response curves were consistently higher in D and the slopes significantly steeper than C. However, Iso curves did not differ. Insulin (10 U/kg) was given to both groups, and the studies were repeated. Dose-response curves in C did not differ significantly with either NE or Iso after insulin. In contrast, curves with both agonists were lower following insulin replacement in the diabetic animals. It is concluded that coronary resistance is reduced by beta-activation but unchanged by NE, which is also an alpha-agonist.(ABSTRACT TRUNCATED AT 250 WORDS)
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Zheng, Shanqing, Hilton Chiu, Jeffrey Boudreau, Tony Papanicolaou, William Bendena, and Ian Chin-Sang. "A functional study of all 40 Caenorhabditis elegans insulin-like peptides." Journal of Biological Chemistry 293, no. 43 (September 11, 2018): 16912–22. http://dx.doi.org/10.1074/jbc.ra118.004542.
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The human genome encodes 10 insulin-like genes, whereas the Caenorhabditis elegans genome remarkably encodes 40 insulin-like genes. Knockout strategies to determine the roles of all the insulin/insulin-like peptide ligands (INS) in C. elegans has been challenging due to functional redundancy. Here, we individually overexpressed each of the 40 ins genes pan-neuronally, and monitored multiple phenotypes including: L1 arrest life span, neuroblast divisions under L1 arrest, dauer formation, and fat accumulation, as readouts to characterize the functions of each INS in vivo. Of the 40 INS peptides, we found functions for 35 INS peptides and functionally categorized each as agonists, antagonists, or of pleiotropic function. In particular, we found that 9 of 16 agonistic INS peptides shortened L1 arrest life span and promoted neuroblast divisions during L1 arrest. Our study revealed that a subset of β-class INS peptides that contain a distinct F peptide sequence are agonists. Our work is the first to categorize the structures of INS peptides and relate these structures to the functions of all 40 INS peptides in vivo. Our findings will promote the study of insulin function on development, metabolism, and aging-related diseases.
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Rico, Elizabeth, Jian Zhao, Mi Chen, Ana Karin Kusnetzow, Yun Fei Zhu, and Stephen F. Betz. "Selective Somatostatin 5 (SST5) and Somatostatin 2 (SST2) Nonpeptide Agonists Potently Suppress Glucose- and Tolbutamide-Stimulated Dynamic Insulin Secretion From Isolated Human Islets." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A325. http://dx.doi.org/10.1210/jendso/bvab048.663.
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Abstract Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in newborns and infants and arises from dysregulated insulin secretion. Rapid recognition and treatment are vital to prevent seizures, permanent developmental delays, coma, or even death. Very few medical options exist to treat congenital HI patients: the KATP channel activator diazoxide, the injectable somatostatin receptor peptide agonists octreotide and lanreotide, or chronic glucose infusions. However, side effects and/or limited efficacy render these therapies inadequate for many patients. Somatostatin is a 14-amino acid peptide hormone with a broad spectrum of biological actions, which are regulated through five somatostatin receptor subtypes (SST1-SST5). Somatostatin’s common physiological role is to down-regulate secretion of other hormones in various tissues. Its role in the maintenance of euglycemia is to regulate insulin and glucagon secretion from pancreatic β- and α-cells, respectively. Somatostatin regulates insulin secretion by decreasing the intracellular levels of cAMP, inhibition of voltage-gated calcium channels (VGCC), activation of the G protein-activated inward rectifier K+ channel (GIRK), and direct inhibition of insulin exocytosis. Several studies have evaluated the effect of somatostatin, somatostatin peptide analogs, and a limited number of nonpeptide somatostatin receptor agonists on insulin secretion in static assays using isolated human islets. However, the lack of highly selective agonists has made the interpretation of the contribution of SST receptor sub-types difficult to discern. Our programs for the treatment of hyperinsulinism, acromegaly, and other indications have led to the development of selective nonpeptide SST2, SST3, SST4, and SST5 agonists, possessing EC50s < 1 nM in cell-based assays of receptor activation and selectivity > 130 times over the other members of the family. The ability of these selective nonpeptide agonists to regulate glucose- and tolbutamide-stimulated dynamic insulin secretion from human islets was evaluated using a perifusion system (Biorep, FL). We found that selective SST2 and SST5 agonists potently suppressed dynamic insulin secretion in contrast to SST3 or SST4 selective agonists. Importantly, SST5 agonists were shown to have a greater effect than selective SST2 agonists or diazoxide, demonstrating their potential utility in human conditions such as congenital HI. In addition, SST5 activation is also known to have a smaller effect on glucagon secretion and is also less prone to agonist-driven desensitization than SST2 activation. Taken together, these studies support our program to identify, characterize, and develop potent, nonpeptide, orally-bioavailable, selective SST5 agonists with appropriate pharmaceutical and safety characteristics for the treatment of congenital HI.
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Tyurenkov, Ivan N., Denis V. Kurkin, Dmitry A. Bakulin, Elena V. Volotova, Aleksej V. Smirnov, Dmitry S. Mednikov, and Mikhail A. Shafeev. "Influence of novel GPR119 receptor agonist on plasma glucose and insulin level, as well as structural changes of pancreas islets in rats with experimental type 2 diabetes." Problems of Endocrinology 62, no. 4 (June 10, 2016): 32–37. http://dx.doi.org/10.14341/probl201662432-37.
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Background. GPR119 receptor is a promising target for novel antidiabetic drugs development because of its agonists in addition to hypoglycemic effects have cytoprotective effect on beta cells.Aim — to assess the effect of the novel GPR119 receptor agonist and sitagliptin on carbohydrate metabolism and morphological structure of the pancreas in animals with experimental type 2 diabetes.Material and methods. The study was performed in Wistar rats with streptozotocin-nicotinamide-induced diabetes. Serum insulin was determined by ELISA (Rat Insulin, (INS) ELISA Kit, 96 CSB). Immunohistochemical studies were performed using mouse monoclonal antibodies to insulin (clone 1G4, GeneTex) with determination of the absolute and relative area of immunopositive material (beta-cells) of the pancreatic islets.Results. 28-day treatment of animals with diabetes by GPR119 receptor agonist — ZB-16 (dipiaron) (1 mg/kg, per os, daily) and an inhibitor of the DPP-4 (sitagliptin) led to a reduction of fasting hyperglycemia and improve its glucose tolerance and enhance basal and stimulated insulin secretion relative to the control without treatment. Morphometric assessment of islets revealed that animals treated with the ZB-16 and sitagliptin have significantly higher absolute and relative islets area, as well as the perimeter of the insulin-positive material compared to islets of rats without treatment.Conclusion. Course administration of GPR119 receptor agonist to animals with streptozotocin-nicotinamide-induced diabetes has a pronounced antidiabetic effect consists in reducing fasting plasma glucose, improve glucose utilization, increase basal and stimulated insulin secretion, as well as increasing the area of the insulin-positive material in islets. Antidiabetic action of novel GPR119 receptor agonist, was comparable to that of sitagliptin.
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Hu, Xinran, David Friedman, Salisha Hill, Richard Caprioli, Wendell Nicholson, Alvin C. Powers, Lawrence Hunter, and Lee E. Limbird. "Proteomic exploration of pancreatic islets in mice null for the α2A adrenergic receptor." Journal of Molecular Endocrinology 35, no. 1 (August 2005): 73–88. http://dx.doi.org/10.1677/jme.1.01764.
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The present studies extend recent findings that mice null for the α2A adrenergic receptor (α2A AR KO mice) lack suppression of exogenous secretagogue-stimulated insulin secretion in response to α2 AR agonists by evaluating the endogenous secretagogue, glucose, ex vivo, and providing in vivo data that baseline insulin levels are elevated and baseline glucose levels are decreased in α2A AR KO mice. These latter findings reveal that the α2A AR subtype regulates glucose-stimulated insulin release in response to endogenous catecholamines in vivo. The changes in α2A AR responsiveness and resultant changes in insulin/glucose homeostasis encouraged us to utilize proteomics strategies to identify possible α2A AR downstream signaling molecules or other resultant changes due to perturbation of α2A AR expression. Although agonist stimulation of islets from wild type (WT) mice did not significantly alter islet protein profiles, several proteins were enriched in islets from α2A AR KO mice when compared with those from WT mice, including an enzyme participating in insulin protein processing. The present studies document the important role of the α2A AR subtype in tonic suppression of insulin release in response to endogenous catecholamines as well as exogenous α2 agonists and provide insights into pleiotropic changes that result from loss of α2A AR expression and tonic suppression of insulin release.
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Ropero, Ana B., Pablo Juan-Picó, Alex Rafacho, Esther Fuentes, F. Javier Bermúdez-Silva, Enrique Roche, Ivan Quesada, Fernando Rodríguez de Fonseca, and Angel Nadal. "Rapid non-genomic regulation of Ca2+ signals and insulin secretion by PPARα ligands in mouse pancreatic islets of Langerhans." Journal of Endocrinology 200, no. 2 (November 17, 2008): 127–38. http://dx.doi.org/10.1677/joe-08-0397.
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PPARα is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. PPARα is involved in the regulation of in vivo triglyceride levels, presumably through its effects on fatty acid and lipoprotein metabolism. Some nuclear receptors have been involved in rapid effects mediated by non-genomic mechanisms. In this paper, we report the rapid non-genomic effects of PPARα ligands on the intracellular calcium concentration ([Ca2+]i), mitochondrial function, reactive oxygen species (ROS) generation, and secretion of insulin in freshly isolated mouse islets of Langerhans. The hypolipidemic fibrate PPARα agonist WY-14 643 decreased the glucose-induced calcium oscillations in intact islets. This effect was mimicked by the synthetic agonist GW7647 and the endogenous agonist oleylethanolamide. The WY-14 643 action was rapid in onset (5 min) and was still produced in the presence of protein and mRNA synthesis inhibitors, cycloheximide, and actinomycin-d. This suggests that it is independent of gene transcription. In addition, WY-14 623 impaired mitochondrial function, increased ROS formation and decreased insulin release. PPARα is present in β-cells, mainly in the cytosol and nucleus, with a small subpopulation localized in the plasma membrane. However, the presence of the PPARα ligand effects in mice bearing a disrupted Pparα gene raises the possibility that the rapid effects of the agonists in pancreatic β-cells are independent of the receptor. We conclude that PPARα agonists produce a decrease in glucose-induced [Ca2+]i signals and insulin secretion in β-cells through a rapid, non-genomic mechanism.
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Carpéné, C., E. Chalaux, M. Lizarbe, A. Estrada, C. Mora, M. Palacin, A. Zorzano, M. Lafontan, and X. Testar. "β 3-adrenergic receptors are responsible for the adrenergic inhibition of insulin-stimulated glucose transport in rat adipocytes." Biochemical Journal 296, no. 1 (November 15, 1993): 99–105. http://dx.doi.org/10.1042/bj2960099.
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The inhibition of insulin-stimulated glucose transport by isoprenaline, a mixed beta-adrenergic-receptor (AR) agonist, is well documented in rat adipocytes. Since it has been described that rat adipocytes possess not only beta 1- and beta 2- but also beta 3-ARs, the influence of various subtype-selective beta-AR agonists and antagonists on 2-deoxyglucose (2-DG) transport was assessed in order to characterize the beta-AR subtype involved in the adrenergic counter-regulation of the insulin effect. The stimulation of 2-DG transport by insulin was counteracted, in a dose-dependent manner, by all the beta-AR agonists tested, and the magnitude of the inhibition followed the rank order: BRL 37344 > isoprenaline = noradrenaline >> dobutamine = procaterol. The same rank order of potency was obtained for lipolysis activation. This is not in accordance with the pharmacological definition of a beta 1- or a beta 2-adrenergic effect, but agrees with the pharmacological pattern of a beta 3-adrenergic effect. The inhibitory effect of the beta 3-agonist BRL 37344 on insulin-stimulated 2-DG transport was not reversed by either the selective beta 1-antagonist ICI 89406 or the beta 2-antagonist ICI 118551. In addition, neither of these beta-antagonists was able to block the isoprenaline and noradrenaline effects, supporting major beta 3-adrenoceptor-subtype involvement in the adrenergic inhibition of insulin-stimulated 2-DG transport. Like isoprenaline, BRL 37344 inhibited (60% inhibition) insulin-stimulated glucose transport only when adenosine deaminase was present in the assay. Furthermore, the maximal inhibitory effects of isoprenaline and BRL 37344 were not additive, and were both dependent on albumin concentration in the incubation medium: they increased when the albumin concentration decreased in the medium from 3.5 to 1%. To conclude, the similarities between isoprenaline and BRL 37344 action on insulin-stimulated 2-DG transport, the poor efficacy of the beta 1-/beta 2-agonists and the lack of effect of selective beta 1- and beta 2-antagonists are compelling arguments to support the important role of beta 3-adrenoceptors in the adrenergic inhibition of glucose transport in rat adipocytes.
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Farese, R. V., M. L. Standaert, A. J. Francois, K. Ways, T. P. Arnold, H. Hernandez, and D. R. Cooper. "Effects of insulin and phorbol esters on subcellular distribution of protein kinase C isoforms in rat adipocytes." Biochemical Journal 288, no. 1 (November 15, 1992): 319–23. http://dx.doi.org/10.1042/bj2880319.
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Effects of insulin and phorbol esters on subcellular distribution of protein kinase C (PKC) isoforms were examined in rat adipocytes. Both agonists provoked rapid decreases in cytosolic, and/or increases in membrane, immunoreactive PKC-alpha, PKC-beta, PKC-gamma, and PKC-epsilon. Effects of phorbol esters on PKC-alpha redistribution to the plasma membrane, however, were much greater than those of insulin. In contrast, insulin, but not phorbol esters, stimulated the translocation of PKC-beta to the plasma membrane, and provoked changes in PKC-zeta redistribution. Neither agonist altered subcellular distribution of PKC-delta, which was detected only in membrane fractions. Our findings indicate that insulin and phorbol esters have overlapping and distinctly different effects on the subcellular redistribution of specific PKC isoforms.
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Berthiaume, Magalie, Henrike Sell, Josée Lalonde, Yves Gélinas, André Tchernof, Denis Richard, and Yves Deshaies. "Actions of PPARγ agonism on adipose tissue remodeling, insulin sensitivity, and lipemia in absence of glucocorticoids." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 287, no. 5 (November 2004): R1116—R1123. http://dx.doi.org/10.1152/ajpregu.00339.2004.
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Peroxisome proliferator-activated receptor γ (PPARγ) agonists improve insulin sensitivity and lipemia partly through enhancing adipose tissue proliferation and capacity for lipid retention. The agonists also reduce local adipose glucocorticoid production, which may in turn contribute to their metabolic actions. This study assessed the effects of a PPARγ agonist in the absence of glucocorticoids (adrenalectomy, ADX). Intact, ADX, and intact pair-fed (PF) rats were treated with the PPARγ agonist rosiglitazone (RSG) for 2 wk. RSG increased inguinal (subcutaneous) white (50%) and brown adipose tissue (6-fold) weight but not that of retroperitoneal (visceral) white adipose tissue. ADX but not PF reduced fat accretion in both inguinal and retroperitoneal adipose depots but did not affect brown adipose mass. RSG no longer increased inguinal weight in ADX and PF rats but increased brown adipose mass, albeit less so than in intact rats. RSG increased cell proliferation in white (3-fold) and brown adipose tissue (6-fold), as assessed microscopically and by total DNA, an effect that was attenuated but not abrogated by ADX. RSG reduced the expression of the glucocorticoid-activating enzyme 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) in all adipose depots. RSG improved insulin sensitivity (reduction in fasting insulin and homeostasis model assessment of insulin resistance, both −50%) and triacylglycerolemia (−75%) regardless of the glucocorticoid status, these effects being fully additive to those of ADX and PF. In conclusion, RSG partially retained its ability to induce white and brown adipose cell proliferation and brown adipose fat accretion and further improved insulin sensitivity and lipemia in ADX rats, such effects being therefore independent from the PPARγ-mediated modulation of glucocorticoids.
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Cong, Li, Ke Chen, Ji Li, Ping Gao, Qiang Li, Shuhua Mi, Xin Wu, and Allan Z. Zhao. "Regulation of adiponectin and leptin secretion and expression by insulin through a PI3K-PDE3B dependent mechanism in rat primary adipocytes." Biochemical Journal 403, no. 3 (April 12, 2007): 519–25. http://dx.doi.org/10.1042/bj20061478.
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Adiponectin is intimately involved in the regulation of insulin sensitivity, carbohydrate and lipid metabolism, and cardiovascular functions. The circulating concentration of adiponectin is decreased in obesity and Type 2 diabetes. The present study attempts to elucidate the mechanisms underlying the regulation of adiponectin secretion and expression in rat primary adipocytes. The β-agonist, isoprenaline, decreased adiponectin secretion and expression in a dose-dependent manner in primary adipocytes. Importantly, such an inhibitory effect could be blocked by insulin. The opposing effects of isoprenaline and insulin could be explained by differential regulation of intracellular cAMP levels, since cAMP analogues suppressed adiponectin secretion and expression in a fashion similar to isoprenaline, and insulin blocked the inhibitory effects of the cAMP analogue hydrolysable by PDE (phosphodiesterase). A specific PDE3 inhibitor, milrinone, and PI3K (phosphoinositide 3-kinase) inhibitors abolished the effects of insulin on adiponectin secretion and expression. In the same studies, leptin secretion and expression displayed a similar pattern of regulation to adiponectin. We conclude that insulin and β-agonists act directly at the adipocytes in opposing fashions to regulate the production of adiponectin and leptin, and that a PI3K-PDE3B-cAMP pathway mediates the effects of insulin to restore β-agonist/cAMP-suppressed secretion and expression of these two adipokines.
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Kim, Hyunsook, Patricia A. Pennisi, Oksana Gavrilova, Stephanie Pack, William Jou, Jennifer Setser-Portas, Joyce East-Palmer, Yan Tang, Vincent C. Manganiello, and Derek LeRoith. "Effect of adipocyte β3-adrenergic receptor activation on the type 2 diabetic MKR mice." American Journal of Physiology-Endocrinology and Metabolism 290, no. 6 (June 2006): E1227—E1236. http://dx.doi.org/10.1152/ajpendo.00344.2005.
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The antiobesity and antidiabetic effects of the β3-adrenergic agonists were investigated on nonobese type 2 diabetic MKR mice after injection with a β3-adrenergic agonist, CL-316243. An intact response to acute CL-316243 treatment was observed in MKR mice. Chronic intraperitoneal CL-316243 treatment of MKR mice reduced blood glucose and serum insulin levels. Hyperinsulinemic euglycemic clamps exhibited improvement of the whole body insulin sensitivity and glucose homeostasis concurrently with enhanced insulin action in liver and adipose tissue. Treating MKR mice with CL-316243 significantly lowered serum and hepatic lipid levels, in part due to increased whole body triglyceride clearance and fatty acid oxidation in adipocytes. A significant reduction in total body fat content and epididymal fat weight was observed along with enhanced metabolic rate in both wild-type and MKR mice after treatment. These data demonstrate that β3-adrenergic activation improves the diabetic state of nonobese diabetic MKR mice by potentiation of free fatty acid oxidation by adipose tissue, suggesting a potential therapeutic role for β3-adrenergic agonists in nonobese diabetic subjects.
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Asrih, Mohamed, René Lerch, Irène Papageorgiou, Corinne Pellieux, and Christophe Montessuit. "Differential regulation of stimulated glucose transport by free fatty acids and PPARα or -δ agonists in cardiac myocytes." American Journal of Physiology-Endocrinology and Metabolism 302, no. 7 (April 1, 2012): E872—E884. http://dx.doi.org/10.1152/ajpendo.00427.2011.
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Stimulation of glucose transport in response to insulin or metabolic stress is an important determinant of cardiac myocyte function and survival, particularly during ischemia-reperfusion episodes. The impact of dyslipidemia and its consequence PPAR activation on stimulated glucose transport in cardiac myocytes remains unknown. Isolated adult rat cardiac myocytes were chronically exposed to free fatty acids (FFA) or PPAR agonists. Insulin- (ISGT) and oligomycin-stimulated glucose transport (OSGT) and related cell signaling were analyzed. Exposure of cardiac myocytes to FFA reduced both ISGT and OSGT. Exposure to either PPARα or PPARδ agonists, but not to a PPARγ agonist, reduced ISGT but not OSGT and increased fatty acid oxidation (FAO). The reduction in ISGT was associated with impaired insulin signaling and, in the case of PPAR stimulation, overexpression of SOCS-3, a protein known to hinder proximal insulin signaling. In contrast, the reduction of OSGT could not be explained by a reduced activity of the cellular energy-sensing system, as assessed from the maintained phosphorylation state of AMPK. Inhibition of FAO at the level of mitochondrial acylcarnitine uptake restored OSGT but not ISGT. Seemingly paradoxically, further stimulation of FAO with PPARα or PPARδ agonists also restored OSGT but not ISGT. Together, these results suggest that inhibition of OSGT occurs downstream of energy gauging and is caused by some intermediate(s) of fatty acid oxidation, which does not appear to be acylcarnitines. The results indicate that the mechanisms underlying FFA-mediated inhibition of ISGT and OSGT differ remarkably.
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Ou, Horng-Yih, Hung-Tsung Wu, Hao-Chang Hung, Yi-Ching Yang, Jin-Shang Wu, and Chih-Jen Chang. "Multiple mechanisms of GW-9508, a selective G protein-coupled receptor 40 agonist, in the regulation of glucose homeostasis and insulin sensitivity." American Journal of Physiology-Endocrinology and Metabolism 304, no. 6 (March 15, 2013): E668—E676. http://dx.doi.org/10.1152/ajpendo.00419.2012.
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Activation of G protein-coupled receptor 40 (GPR40) by agonists increases insulin release in isolated islets, whereas it is inconclusive whether GPR40 antagonists decrease blood glucose and increase insulin sensitivity. Although some clinical trials indicated that administration of a GPR40 agonist shows benefits in the regulation of blood glucose homeostasis, the pharmacological mechanisms of this receptor in the improvement of glycemic control remain unclear. Therefore, we used a selective GPR40 agonist, GW-9508, to clarify the role of GPR40 in the regulation of blood glucose. Bolus intraperitoneal injection of GW-9508 in mice showed a slight decrease in blood glucose, with an increase in plasma insulin levels under glucose stimuli. However, long-term treatment with low doses of GW-9508 in high-fat diet-induced (HFD) diabetic mice decreased blood glucose with decreased plasma insulin significantly and improved glucose intolerance and insulin resistance. Using small interfering ribonucleic acid to delete GPR40 in HepG2 cells, we demonstrated that GW-9508 reversed palmitate-induced insulin signaling impairment through a GPR40-dependent pathway. We also found that GW-9508 activates the Akt/GSK-3β pathway to increase glycogen levels in HepG2 cells. Furthermore, administration of GW-9508 decreased the hepatic expression of fetuin-A in HFD mice significantly and regulated high-glucose- or palmitate-induced fetuin-A expression to increase insulin sensitivity through a GPR40/PLC/PKC pathway in HepG2 cells. Taken together, GW-9508 exerts a partial agonist effect to regulate blood glucose through multiple mechanisms. Investigation of chemicals that act on GPR40 might be a new strategy for the treatment of diabetes.
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Ackeifi, Courtney, Peng Wang, Esra Karakose, Jocelyn E. Manning Fox, Bryan J. González, Hongtao Liu, Jessica Wilson, et al. "GLP-1 receptor agonists synergize with DYRK1A inhibitors to potentiate functional human β cell regeneration." Science Translational Medicine 12, no. 530 (February 12, 2020): eaaw9996. http://dx.doi.org/10.1126/scitranslmed.aaw9996.
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Glucagon-like peptide-1 receptor (GLP1R) agonists and dipeptidyl peptidase 4 inhibitors are widely prescribed diabetes drugs due to their ability to stimulate insulin secretion from remaining β cells and to reduce caloric intake. Unfortunately, they fail to increase human β cell proliferation. Small-molecule inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) are able to induce adult human β cell proliferation, but rates are modest (~2%), and their specificity to β cells is limited. Here, we provide evidence that combining any member of the GLP1R agonist class with any member of the DYRK1A inhibitor class induces a synergistic increase in human β cell replication (5 to 6%) accompanied by an actual increase in numbers of human β cells. GLP1R agonist–DYRK1A inhibitor synergy required combined inhibition of DYRK1A and an increase in cAMP and did not lead to β cell dedifferentiation. These beneficial effects on proliferation were seen in both normal human β cells and β cells derived from individuals with type 2 diabetes. The ability of the GLP1R agonist–DYRK1A inhibitor combination to enhance human β cell proliferation, human insulin secretion, and blood glucose control extended in vivo to studies of human islets transplanted into euglycemic and streptozotocin-diabetic immunodeficient mice. No adverse events were observed in the mouse studies during a 1-week period. Because of the relative β cell specificity of GLP1R agonists, the combination provides an improved, although not complete, degree of human β cell specificity.
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Gregoire, Francine M., Fang Zhang, Holly J. Clarke, Thomas A. Gustafson, Dorothy D. Sears, Svetlana Favelyukis, James Lenhard, et al. "MBX-102/JNJ39659100, a Novel Peroxisome Proliferator Activated Receptor-γ Ligand with Weak Transactivation Activity Retains Full Anti-Diabetic Properties in the Absence of Side Effects." Endocrine Reviews 30, no. 4 (June 1, 2009): 414. http://dx.doi.org/10.1210/edrv.30.4.9988.
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ABSTRACT MBX-102/JNJ39659100 (MBX-102) is in clinical development as an oral glucose lowering agent for the treatment of type 2 diabetes. MBX-102 is a non-thiazolidinedione (TZD) selective partial agonist of PPAR-γ that is differentiated from the TZDs structurally, mechanistically, pre-clinically and clinically. In diabetic rodent models, MBX-102 has insulin sensitizing and glucose lowering properties comparable to TZDs without dose-dependent increases in body weight. In vitro, in contrast with full PPAR-γ agonist treatment, MBX-102 fails to drive human and murine adipocyte differentiation and selectively modulates the expression of a subset of PPAR-γ target genes in mature adipocytes. Moreover, MBX-102 does not inhibit oteoblastogenesis of murine mesenchymal cells. Compared to full PPAR-γ agonists, MBX-102 displays differential interactions with the PPAR-γ ligand binding domain (LBD) and possesses reduced ability to recruit coactivators. Interestingly, in primary mouse macrophages, MBX-102 displays enhanced anti-inflammatory properties compared to other PPAR-γ or α/γ agonists suggesting that MBX-102 has more potent transrepression activity. In summary, MBX-102 is a selective PPAR-γ modulator with weak transactivation but robust transrepression activity. MBX-102 exhibits full therapeutic activity without the classical PPAR-γ side effects and may represent the next generation insulin sensitizer.
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Gregoire, Francine M., Fang Zhang, Holly J. Clarke, Thomas A. Gustafson, Dorothy D. Sears, Svetlana Favelyukis, James Lenhard, et al. "MBX-102/JNJ39659100, a Novel Peroxisome Proliferator-Activated Receptor-Ligand with Weak Transactivation Activity Retains Antidiabetic Properties in the Absence of Weight Gain and Edema." Molecular Endocrinology 23, no. 7 (July 1, 2009): 975–88. http://dx.doi.org/10.1210/me.2008-0473.
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Abstract MBX-102/JNJ39659100 (MBX-102) is in clinical development as an oral glucose-lowering agent for the treatment of type 2 diabetes. MBX-102 is a nonthiazolidinedione (TZD) selective partial agonist of peroxisome proliferator-activated receptor (PPAR)-γ that is differentiated from the TZDs structurally, mechanistically, preclinically and clinically. In diabetic rodent models, MBX-102 has insulin-sensitizing and glucose-lowering properties comparable to TZDs without dose-dependent increases in body weight. In vitro, in contrast with full PPAR-γ agonist treatment, MBX-102 fails to drive human and murine adipocyte differentiation and selectively modulates the expression of a subset of PPAR-γ target genes in mature adipocytes. Moreover, MBX-102 does not inhibit osteoblastogenesis of murine mesenchymal cells. Compared with full PPAR-γ agonists, MBX-102 displays differential interactions with the PPAR-γ ligand binding domain and possesses reduced ability to recruit coactivators. Interestingly, in primary mouse macrophages, MBX-102 displays enhanced antiinflammatory properties compared with other PPAR-γ or α/γ agonists, suggesting that MBX-102 has more potent transrepression activity. In summary, MBX-102 is a selective PPAR-γ modulator with weak transactivation but robust transrepression activity. MBX-102 exhibits full therapeutic activity without the classical PPAR-γ side effects and may represent the next generation insulin sensitizer.
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Iannotti, Fabio Arturo, Fabrizia De Maio, Elisabetta Panza, Giovanni Appendino, Orazio Taglialatela-Scafati, Luciano De Petrocellis, Pietro Amodeo, and Rosa Maria Vitale. "Identification and Characterization of Cannabimovone, a Cannabinoid from Cannabis sativa, as a Novel PPARγ Agonist via a Combined Computational and Functional Study." Molecules 25, no. 5 (March 3, 2020): 1119. http://dx.doi.org/10.3390/molecules25051119.
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Phytocannabinoids (pCBs) are a large family of meroterpenoids isolated from the plant Cannabis sativa. Δ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the best investigated phytocannabinoids due to their relative abundance and interesting bioactivity profiles. In addition to various targets, THC and CBD are also well-known agonists of peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor involved in energy homeostasis and lipid metabolism. In the search of new pCBs potentially acting as PPARγ agonists, we identified cannabimovone (CBM), a structurally unique abeo-menthane pCB, as a novel PPARγ modulator via a combined computational and experimental approach. The ability of CBM to act as dual PPARγ/α agonist was also evaluated. Computational studies suggested a different binding mode toward the two isoforms, with the compound able to recapitulate the pattern of H-bonds of a canonical agonist only in the case of PPARγ. Luciferase assays confirmed the computational results, showing a selective activation of PPARγ by CBM in the low micromolar range. CBM promoted the expression of PPARγ target genes regulating the adipocyte differentiation and prevented palmitate-induced insulin signaling impairment. Altogether, these results candidate CBM as a novel bioactive compound potentially useful for the treatment of insulin resistance-related disorders.
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Yang, Tianrui, B. Tate Cutshall, Alexandra Tatara, and Melanie Ruegger. "Combined Insulin and GLP-1 Receptor Agonists: Simplifying Treatment or Adding Obstacles?" Journal of Pharmacy Practice 32, no. 4 (October 1, 2018): 447–49. http://dx.doi.org/10.1177/0897190017753041.
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The US Food and Drug Administration recently approved 2 combination products containing a basal insulin and a glucagon-like peptide 1 receptor agonist: insulin glargine/lixisenatide and insulin degludec/liraglutide. These agents were shown to be noninferior in lowering hemoglobin A1c compared to basal insulin and are indicated for patients inadequately controlled on basal insulin or glucagon-like peptide 1 receptor agonists alone. The clinical implications of these agents are unclear due to limitations in the clinical trials and limited recommendations in current guidelines. While these agents may provide financial and adherence benefits, their role is likely limited to the outpatient setting. With the availability of these agents, concerns with transitions of care arise due to multiple vulnerabilities in reconciling these agents throughout the inpatient admission and discharge process. Provider awareness of the availability and dosing of insulin glargine/lixisenatide and insulin degludec/liraglutide is essential to reduce errors in the medication reconciliation process.
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Riis-Vestergaard, Mette Ji, Bjørn Richelsen, Jens Meldgaard Bruun, Wei Li, Jacob B. Hansen, and Steen Bønløkke Pedersen. "Beta-1 and Not Beta-3 Adrenergic Receptors May Be the Primary Regulator of Human Brown Adipocyte Metabolism." Journal of Clinical Endocrinology & Metabolism 105, no. 4 (December 26, 2019): e994-e1005. http://dx.doi.org/10.1210/clinem/dgz298.
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Abstract Purpose Brown adipose tissue (BAT) activation in humans has gained interest as a potential target for treatment of obesity and insulin resistance. In rodents, BAT is primarily induced through beta-3 adrenergic receptor (ADRB3) stimulation, whereas the primary beta adrenergic receptors (ADRBs) involved in human BAT activation are debated. We evaluated the importance of different ADRB subtypes for uncoupling protein 1 (UCP1) induction in human brown adipocytes. Methods A human BAT cell model (TERT-hBA) was investigated for subtype-specific ADRB agonists and receptor knockdown on UCP1 mRNA levels and lipolysis (glycerol release). In addition, fresh human BAT biopsies and TERT-hBA were evaluated for expression of ADRB1, ADRB2, and ADRB3 using RT-qPCR. Results The predominant ADRB subtype in TERT-hBA adipocytes and BAT biopsies was ADRB1. In TERT-hBA, UCP1 mRNA expression was stimulated 11.0-fold by dibutyryl cAMP (dbcAMP), 8.0-fold to 8.4-fold by isoproterenol (ISO; a pan-ADRB agonist), and 6.1-fold to 12.7-fold by dobutamine (ADRB1 agonist), whereas neither procaterol (ADRB2 agonist), CL314.432, or Mirabegron (ADRB3 agonists) affected UCP1. Similarly, dbcAMP, ISO, and dobutamine stimulated glycerol release, whereas lipolysis was unaffected by ADRB2 and ADRB3 agonists. Selective knockdown of ADRB1 significantly attenuated ISO-induced UCP1 expression. Conclusion The adrenergic stimulation of UCP1 and lipolysis may mainly be mediated through ADRB1. Moreover, ADRB1 is the predominant ADRB in both TERT-hBA and human BAT biopsies. Thus, UCP1 expression in human BAT may, unlike in rodents, primarily be regulated by ADRB1. These findings may have implications for ADRB agonists as future therapeutic compounds for human BAT activation.
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Sahay, Rakesh, and V. Nagesh. "Type 1 diabetes and fasting during Ramzan." Journal of Social Health and Diabetes 04, no. 01 (June 2016): 011–16. http://dx.doi.org/10.4103/2321-0656.176571.
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AbstractFasting is one of the five pillars of Islam, and consequently, even the Muslims with diabetes prefer to fast fast during Ramadan, irrespective of the healthcare implications. However, this fast can be very difficult to manage in patients of Type 1 diabetes (T1DM), who are on insulin therapy. Risks of diabetic ketoacidosis, severe hypoglycaemia, hyperglycemia, dehydration and thrombotic episodes are increased. Lack of proper pre-fast assessment, management and diabetes education have been stumbling blocks in facilitating Ramadan fasting in type 1 diabetes patients. Recent developments like the use of insulin pumps and analogs and recognition of the importance of structured diabetes education and assessment to select the patients best suited for the rigors of fasting, have wrought a sea change in the usually negative approach of doctors towards Ramadan fasting in patients with T1DM. Sophisticated therapeutic options like smart insulins, can provide safer and more convenient options for management of Type 1 diabetes during Ramadan, a few years down the line. More studies are also needed to explore other options like GLP-1 agonists, alpha glycosides inhibitors and DDP-4 agonists, as adjuncts to insulin therapy.
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Panse, Madhura, Felicia Gerst, Gabriele Kaiser, Charlott-Amélie Teutsch, Rebecca Dölker, Robert Wagner, Hans-Ulrich Häring, and Susanne Ullrich. "Activation of Extracellular Signal-Regulated Protein Kinases 1 and 2 (ERK1/2) by Free Fatty Acid Receptor 1 (FFAR1/GPR40) Protects from Palmitate-Induced Beta Cell Death, but Plays no Role in Insulin Secretion." Cellular Physiology and Biochemistry 35, no. 4 (2015): 1537–45. http://dx.doi.org/10.1159/000373969.
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Aims: GPR40/FFAR1 mediates palmitate-induced stimulation of insulin secretion but its involvement in lipotoxicity is controversial. Our previous observations suggest that FFAR1/GPR40 agonists protect against lipotoxicity although the underlying mechanism remains elusive. The present study examines the role of ERK1/2 and GPR40/FFAR1 in palmitate-induced stimulation of insulin secretion and beta cell death. Methods: Insulin secretion of INS-1E cells was measured by radioimmunoassay. Protein phosphorylation was examined on Western blots. Apoptosis was assessed by TUNEL staining. Results: Palmitate and the GPR40/FFAR1 agonist TUG-469 increased phosphorylation of ERK1/2 at low (2.8 mmol/L) and high (12 mmol/L) glucose but stimulated insulin secretion only at high glucose. The MEK1 inhibitor PD98059 significantly reduced phosphorylation of ERK1/2 but did not reverse the stimulation of secretion induced by glucose, palmitate or TUG-469. PD98059 rather augmented glucose-induced secretion. Prolonged exposure to palmitate stimulated apoptosis, an effect counteracted by TUG-469. PD98059 accentuated palmitate-induced apoptosis and reversed TUG-469-mediated inhibition of cell death. Conclusions: Activation of ERK1/2 by palmitate and GPR40/FFAR1 agonist correlates neither with stimulation of insulin secretion nor with induction of apoptosis. The results suggest a significant anti-apoptotic role of ERK1/2 under conditions of lipotoxicity.
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MOREAU, FRANCOIS, BRUNA BRANDAO, CARLY CEDERQUIST, THIAGO M. BATISTA, RICHARD DIMARCHI, EMRAH ALTINDIS, and C. RONALD KAHN. "1725-P: Viral Insulins as Agonists and Antagonists on Insulin/IGF-1 Receptors." Diabetes 69, Supplement 1 (June 2020): 1725—P. http://dx.doi.org/10.2337/db20-1725-p.
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Inman, Taylor R., Erika Plyushko, Nicholas P. Austin, and Jeremy L. Johnson. "The role of basal insulin and GLP-1 receptor agonist combination products in the management of type 2 diabetes." Therapeutic Advances in Endocrinology and Metabolism 9, no. 5 (April 23, 2018): 151–55. http://dx.doi.org/10.1177/2042018818763698.
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The prevalence of type 2 diabetes necessitates the development of new treatment options to individualize therapy. Basal insulin has been a standard treatment option for years, while glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have grown in use over the past decade due to glucose-lowering efficacy and weight loss potential. There are two new combination injectable products that have recently been approved combining basal insulins with GLP-1 RAs in single pen-injector devices. United States guidelines recently emphasize the option to use combination injectable therapy with GLP-1 RAs and basal insulin once the basal insulin has been optimally titrated as a second- or third-line agent in addition to metformin without reaching the goal A1c. Insulin glargine/lixisenatide 100/33 (IGlarLixi) can be dosed between 15 and 60 units once daily from a single pen-injector device. Insulin degludec/liraglutide 100/3.6 (IDegLira) can be dosed between 10 and 50 units once daily, also from a single pen-injector device. Maximum doses, while measured in units, correspond to limits defined by each individual GLP-1 RA. The dual use of basal insulin plus GLP-1 RA is non-inferior compared with basal insulin plus a single injection of prandial insulin at the largest meal and compared with twice daily-dosed premixed insulins; and this combination is associated with weight loss and less hypoglycemia. These new combination products could help providers effectively and efficiently follow clinical practice guidelines while enhancing patient adherence with injectable medications.
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Milgram, S. L., J. K. McDonald, and B. D. Noe. "Neuronal influence on hormone release from anglerfish islet cells." American Journal of Physiology-Endocrinology and Metabolism 261, no. 4 (October 1, 1991): E444—E456. http://dx.doi.org/10.1152/ajpendo.1991.261.4.e444.
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Pancreatic islets in anglerfish (AF) are macroscopic collections of nearly pure endocrine cells that are densely innervated. Immunohistochemical staining for neurotransmitter biosynthetic enzymes revealed noradrenergic and cholinergic innervation of AF islets. An in vitro preparation of perifused dispersed AF islet cells was developed to study nutrient and neural control of islet hormone secretion. Glucose stimulated insulin and somatostatin-14 (SS-14) secretion in a dose-dependent manner, and 16.7 mM glucose inhibited glucagon secretion. In 2 mM glucose, norepinephrine and isoproterenol stimulated glucagon and SS-14 release. Isoproterenol stimulated insulin secretion, and norepinephrine stimulated or inhibited insulin release, depending on the concentration. Clonidine potently inhibited glucose-stimulated insulin secretion but stimulated glucagon release. Methacholine, a muscarinic cholinergic agonist, stimulated insulin, glucagon, and SS-14 release. The control of AF hormone release by neurotransmitter agonists in vitro was similar to that in higher vertebrate species. Therefore we used this tissue preparation to study postsynaptic interactions between glucose and neurotransmitters in islets.
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Vilches-Flores, Alonso, Astrid C. Hauge-Evans, Peter M. Jones, and Shanta J. Persaud. "Chronic activation of cannabinoid receptors in vitro does not compromise mouse islet function." Clinical Science 124, no. 7 (December 7, 2012): 467–78. http://dx.doi.org/10.1042/cs20120447.
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We have demonstrated previously that mouse and human islets express ECS (endocannabinoid system) elements, and that short-term activation of islet cannabinoid CB1r and CB2r (cannabinoid type 1 and 2 receptors respectively) stimulates insulin secretion in vitro. There is evidence that the ECS is overactive in Type 2 diabetes, impairing glucose homoeostasis, but little is known about whether it is implicated in islet dysfunction. Therefore the aim of the present study was to investigate the effect of chronic exposure of isolated mouse islets to cannabinoid receptor agonists on islet gene expression and function. Quantitative RT–PCR (reverse transcription–PCR) indicated that mRNAs encoding synthesis [NAPE-PLD (N-acyl-phosphatidyl ethanolamide-hydrolysing phospholipase D)] and degradation [FAAH (fatty acid amide hydrolase)] of the endocannabinoid AEA (anandamide) were the most abundant ECS elements in mouse islets, with much lower levels of CB1r, CB2r, DAGL (diacylglycerol lipase) and MAGL (monoacylglycerol lipase) mRNAs. Maintenance of islets for up to 7 days in the presence of the CB1r agonist ACEA [N-(2-chloroethyl)-5Z,8Z,11Z,14Z-eiscosatetraenamide] or the CB2r agonist JWH015 [(2-methyl-1propyl-1H-indol3-yl)-1-napthalenylmethanone] did not compromise islet viability, as assessed by islet morphology and caspase activities, but there were some changes in mRNAs encoding ECS components. Neither glucose-stimulated insulin secretion nor acute insulin secretory responses to ACEA or JWH015 at 16 mM glucose were substantially modified by a 48 h or 7 day pre-exposure to these cannabinoid receptor agonists, but the stimulation of secretion at 3 mM glucose by 100 nM ACEA was significantly reduced after prolonged treatment with ACEA. Despite JWH015-induced reductions in islet glucagon content at 48 h and 7 days, there were no reductions in arginine-induced glucagon secretion from islets pre-exposed to JWH015 or ACEA. These data indicate that treatment of islets with agonists of CB1r and CB2r for up to 7 days does not have any major impact on islet function, suggesting that the impairments in glucose homoeostasis observed following overactivation of the ECS should be sought in relation to insulin resistance rather than β-cell dysfunction.
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Sato, Tetsuhiko, Emi Ohara, Chikafumi Ozone, Mikako Okazaki, Sachiho Fuse, Rie Sasaki, and Yoshinori Azuma. "A Possible Advantage of Glucagon-Like Peptide 1 Receptor Agonist in Kidney Transplant Recipients With Type 2 Diabetes." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A405—A406. http://dx.doi.org/10.1210/jendso/bvab048.826.
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Abstract Diabetic kidney disease (DKD), a devastating complication of diabetes, is one of the leading causes of end stage kidney disease (ESKD). Kidney transplantation provides superior outcomes for ESKD patients with type 2 diabetes, giving opportunities to be free from dialysis, but needs lifetime immunosuppressive medications to avoid graft kidney rejection. Post-transplant hyperglycemia, however, remains to be unsolved, because immunosuppressive agents, including glucocorticoids and calcineurin inhibitors, may result in impaired insulin secretion and sensitivity. Safe and promising anti-diabetic strategy is long-awaited among kidney transplant recipients (KTRs) with type 2 diabetes. Enormous evidence has accumulated that Glucagon-like peptide 1 (GLP-1) receptor agonists have potential to maintain kidney function as well as improve glucose tolerance in patients with DKD. The present study was designed to elucidate the association between GLP-1 receptor agonist use and better graft kidney function in KTRs with type 2 diabetes. Among KTRs with type 2 diabetes between 2012 and 2019, 73 with GLP-1 receptor agonist use and 73 without GLP-1 receptor use were identified in our center. After propensity matching, 50 KTRs were newly initiated with GLP-1 receptor agonist use or other antidiabetic medications. Baseline characteristics were well-balanced in the 2 groups. KTRs with GLP-1 receptor agonist use had greater kidney function 12 months after initiation of GLP-1 receptor agonists, compared to their counterpart KTRs without GLP-1 receptor agonists, according to estimated glomerular filtration ratio (p=0.01). Interestingly, transient decrease of body mass index was observed in KTRs with GLP-1 receptor agonist use during the 12 months. All GLP-1 receptor agonist-initiated KTRs were followed up through December 31, 2019. In conclusion, GLP-1 receptor agonist treatment was associated with better graft kidney function in KTRs with type 2 diabetes. Pharmacological GLP-1 receptor activation showed favorable tolerability and may alleviate graft kidney damage in KTRs with type 2 diabetes.
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Maida, Adriano, Julie A. Lovshin, Laurie L. Baggio, and Daniel J. Drucker. "The Glucagon-Like Peptide-1 Receptor Agonist Oxyntomodulin Enhances β-Cell Function but Does Not Inhibit Gastric Emptying in Mice." Endocrinology 149, no. 11 (July 31, 2008): 5670–78. http://dx.doi.org/10.1210/en.2008-0336.
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The proglucagon gene gives rise to multiple peptides that play diverse roles in the control of energy intake, gut motility, and nutrient disposal. Glucagon-like peptide-1 (GLP-1), a 30-amino-acid peptide regulates glucose homeostasis via control of insulin and glucagon secretion and by inhibition of gastric emptying and food intake. Oxyntomodulin (OXM) a 37-amino-acid peptide also derived from the proglucagon gene, binds to both the glucagon and GLP-1 receptor (GLP-1R); however, a separate OXM receptor has not yet been identified. Here we show that OXM, like other GLP-1R agonists, stimulates cAMP formation and lowers blood glucose after both oral and ip glucose administration, actions that require a functional GLP-1R. OXM also directly stimulates insulin secretion from murine islets and INS-1 cells in a glucose- and GLP-1R-dependent manner. Moreover, OXM ameliorates hyperglycemia and significantly reduces apoptosis in murine β-cells after streptozotocin administration and directly reduces apoptosis in thapsigargin-treated INS-1 cells. Unexpectedly, OXM, but not the GLP-1R agonist exendin-4, increased plasma levels of insulin after oral glucose administration. Moreover, OXM administered at doses that potently lower blood glucose had no effect on inhibition of gastric emptying but reduced food intake in WT mice. Taken together, these findings illustrate that although structurally distinct proglucagon-derived peptides such as GLP-1 and OXM engage the GLP-1R, OXM mimics some but not all of the actions of GLP-1R agonists in vivo. These findings may have implications for therapeutic efforts using OXM as a long-acting GLP-1R agonist for the treatment of metabolic disorders.
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Ruz-Maldonado, Inmaculada, Patricio Atanes, Guo Cai Huang, Bo Liu, and Shanta J. Persaud. "Direct Stimulatory Effects of the CB2 Ligand JTE 907 in Human and Mouse Islets." Cells 10, no. 3 (March 22, 2021): 700. http://dx.doi.org/10.3390/cells10030700.
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Aims: The endocannabinoid system is a complex cell-signaling network through which endogenous cannabinoid ligands regulate cell function by interaction with CB1 and CB2 cannabinoid receptors, and with the novel cannabinoid receptor GPR55. CB1, CB2, and GPR55 are expressed by islet β-cells where they modulate insulin secretion. We have previously shown that administration of the putative CB2 antagonist/inverse agonist JTE 907 to human islets did not affect the insulinotropic actions of CB2 agonists and it unexpectedly stimulated insulin secretion on its own. In this study, we evaluated whether the lack of antagonism could be related to the ability of JTE 907 to act as a GPR55 agonist. Materials and Methods: We used islets isolated from human donors and from Gpr55+/+ and Gpr55−/− mice and quantified the effects of incubation with 10 μM JTE 907 on dynamic insulin secretion, apoptosis, and β-cell proliferation by radioimmunoassay, luminescence caspase 3/7 activity, and immunofluorescence, respectively. We also measured islet IP1 and cAMP accumulation using fluorescence assays, and monitored [Ca2+]i elevations by Fura-2 single cell microfluorometry. Results: JTE 907 significantly stimulated insulin secretion from islets isolated from human donors and islets from Gpr55+/+ and Gpr55−/− mice. These stimulatory effects were accompanied by significant elevations of IP1 and [Ca2+]i, but there were no changes in cAMP generation. JTE 907 also significantly reduced cytokine-induced apoptosis in human and mouse islets and promoted human β-cell proliferation. Conclusion: Our observations show for the first time that JTE 907 acts as a Gq-coupled agonist in islets to stimulate insulin secretion and maintain β-cell mass in a GPR55-independent fashion.
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Lacey, R. J., H. C. Cable, R. F. L. James, N. J. M. London, J. H. B. Scarpello, and N. G. Morgan. "Concentration-dependent effects of adrenaline on the profile of insulin secretion from isolated human islets of Langerhans." Journal of Endocrinology 138, no. 3 (September 1993): 555–63. http://dx.doi.org/10.1677/joe.0.1380555.
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ABSTRACT The effects of the mixed α/β-agonist adrenaline on insulin secretion from isolated human islets of Langerhans were studied. In static incubation experiments, adrenaline (0·1 nmol/l to 10 μmol/l) caused a concentration-dependent inhibition of glucose-induced insulin secretion from isolated human islets. However, perifusion experiments revealed that the time-course of the secretory changes induced by adrenaline was complex. When employed at a high concentration (1 μmol/l), adrenaline caused a sustained inhibition of glucose-induced insulin secretion, which could be relieved by the addition of the α2-antagonist yohimbine (10 μmol/l). By contrast, infusion of adrenaline at a lower concentration (10 nmol/l), produced a large initial potentiation of glucose-induced insulin secretion. This response was, however, short-lived and followed by sustained inhibition of secretion, which could be relieved by yohimbine (10 μmol/l). The initial stimulation of insulin secretion provoked by 10 nmol adrenaline/l was abolished when islets were incubated in the presence of the β-antagonist, propranolol (1 μmol/l), consistent with activation of β-adrenoceptors. In support of this, treatment of human islets with the selective β2-agonist clenbuterol, was also associated with marked stimulation of insulin secretion. By contrast, each of two selective β3-agonists tested failed to alter insulin secretion from human islets. The results indicate that human pancreatic B-cells are equipped with both α2-and β2-adrenoceptors which can affect insulin secretion. Adrenaline interacts with both of these but the α2-response is predominant and can overcome the tendency of β2-adrenoceptors to potentiate insulin release. Journal of Endocrinology (1993) 138, 555–563
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Viby, Niels-Erik, Marie S. Isidor, Katrine B. Buggeskov, Steen S. Poulsen, Jacob B. Hansen, and Hannelouise Kissow. "Glucagon-Like Peptide-1 (GLP-1) Reduces Mortality and Improves Lung Function in a Model of Experimental Obstructive Lung Disease in Female Mice." Endocrinology 154, no. 12 (December 1, 2013): 4503–11. http://dx.doi.org/10.1210/en.2013-1666.
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The incretin hormone glucagon-like peptide-1 (GLP-1) is an important insulin secretagogue and GLP-1 analogs are used for the treatment of type 2 diabetes. GLP-1 displays antiinflammatory and surfactant-releasing effects. Thus, we hypothesize that treatment with GLP-1 analogs will improve pulmonary function in a mouse model of obstructive lung disease. Female mice were sensitized with injected ovalbumin and treated with GLP-1 receptor (GLP-1R) agonists. Exacerbation was induced with inhalations of ovalbumin and lipopolysaccharide. Lung function was evaluated with a measurement of enhanced pause in a whole-body plethysmograph. mRNA levels of GLP-1R, surfactants (SFTPs), and a number of inflammatory markers were measured. GLP-1R was highly expressed in lung tissue. Mice treated with GLP-1R agonists had a noticeably better clinical appearance than the control group. Enhanced pause increased dramatically at day 17 in all control mice, but the increase was significantly less in the groups of GLP-1R agonist-treated mice (P < .001). Survival proportions were significantly increased in GLP-1R agonist-treated mice (P < .01). SFTPB and SFTPA were down-regulated and the expression of inflammatory cytokines were increased in mice with obstructive lung disease, but levels were largely unaffected by GLP-1R agonist treatment. These results show that GLP-1R agonists have potential therapeutic potential in the treatment of obstructive pulmonary diseases, such as chronic obstructive pulmonary disease, by decreasing the severity of acute exacerbations. The mechanism of action does not seem to be the modulation of inflammation and SFTP expression.