Glucagon-like peptide-1 (GLP-1) receptor agonists, obesity and psoriasis: diabetes meets dermatology

Drucker, Daniel J.; Rosen, Cheryl F.

doi:10.1007/s00125-011-2297-z

Cited by 48 publications

(43 citation statements)

References 19 publications

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“…Of note, central blockade of GLP-1R signaling enhanced the pyrogenic effect of LPS (38), implying that endogenous GLP-1 exerts anti-inflammatory actions. Indeed, pharmacological administration of GLP-1R agonists has exerted anti-inflammatory actions in multiple studies through incompletely understood mechanisms (39). The current data extend previous observations by demonstrating that GLP-1 rapidly suppresses a proinflammatory cytokine program from activated intestinal IELs ex vivo, actions requiring a functional GLP-1R.…”

Section: Discussionsupporting

confidence: 80%

GLP-1R Agonists Modulate Enteric Immune Responses Through the Intestinal Intraepithelial Lymphocyte GLP-1R

et al. 2015

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Obesity and diabetes are characterized by increased inflammation reflecting disordered control of innate immunity. We reveal a local intestinal intraepithelial lymphocyte (IEL)-GLP-1 receptor (GLP-1R) signaling network that controls mucosal immune responses. Glp1r expression was enriched in intestinal IEL preparations and copurified with markers of Tαβ and Tγδ IELs, the two main subsets of intestinal IELs. Exendin-4 increased cAMP accumulation in purified IELs and reduced the production of cytokines from activated IELs but not from splenocytes ex vivo. These actions were mimicked by forskolin, absent in IELs from Glp1r−/− mice, and attenuated by the GLP-1R agonist exendin (9-39) consistent with a GLP-1R–dependent mechanism of action. Furthermore, Glp1r−/− mice exhibited dysregulated intestinal gene expression, an abnormal representation of microbial species in feces, and enhanced sensitivity to intestinal injury following administration of dextran sodium sulfate. Bone marrow transplantation using wild-type C57BL/6 donors normalized expression of multiple genes regulating immune function and epithelial integrity in Glp1r−/− recipient mice, whereas acute exendin-4 administration robustly induced the expression of genes encoding cytokines and chemokines in normal and injured intestine. Taken together, these findings define a local enteroendocrine-IEL axis linking energy availability, host microbial responses, and mucosal integrity to the control of innate immunity.

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Section: Discussionsupporting

confidence: 80%

GLP-1R Agonists Modulate Enteric Immune Responses Through the Intestinal Intraepithelial Lymphocyte GLP-1R

et al. 2015

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“…The results of present study are supported by Drucker DJ and Rosen CF [15] who demonstrated that exenatide and liraglutide which have an incretin like effect similar to sitagliptin given for control of diabetes result in improvement of PASI score in diabetic patients with plaque psoriasis. Our results disagree with Masvidal A. et al [16] who found that sitagliptin treatment for old diabetic woman produce un expected psoriasiform eruption on her trunk and both limbs after receiving six doses of drug, this can be explained as rare reaction to the drug and only one case study.…”

Section: Discussionsupporting

confidence: 80%

“…Exenatide and liraglutide have an incretin like effect similar to Sitagliptin given for control of diabetes result in improvement of PASI score in diabetic patients with plaque psoriasis [12]. In contrast Mas-Vidal A et.…”

Section: Introductionmentioning

confidence: 99%

Effect of Sitagliptin on glycemic profiles and their correlation with PASI score in patients with plaque psoriasis

Hadi¹,

Al‐Dhalimi²,

Harchan³

2016

AJBM

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Psoriatic patients with plaque psoriasis particularly those with high body mass index have increasing risk of developing a diabetes mellitus type 2 (DM). Since both conditions are associated with dysregulation in DPP-IV, DPP-IV inhibitors have been suggested as therapeutic drugs for both diseases. The role of enzyme in the diabetes pathogenesis is well-known; however information on psoriatic patients is conflicting. The objective of this study is to determine the effect of Sitagliptin on glycemic profiles and their correlation with PASI score in psoriatic patients with DM. The study was conducted on 50 diabetic patients with moderate to severe plaque psoriasis who were divided into two groups: Placebo group (n =25) Patients were administered placebo 100mg once daily plus dietary control and exercise for 3 months ; Sitagliptin group (n =25) Patients were administered Sitagliptin tablet 100mg once a day plus dietary control and exercise for 3 month. PASI score for all patients was assessed before and after 12 weeks of treatment. The blood samples were obtained from the patients in both groups at baseline and after 12 week of therapy were used to measure the concentration of serum fasting blood sugar and HbA1c. Compared with baseline in Sitagliptin group and control group after 12 week, the level of fasting blood sugar, HbA1c, were significantly reduced and correlated with PASI score after 12 week of sitagliptin treatment (P < 0.05). The current results reveal that sitagliptin improves psoriasis possibly via a reduction in glycemic profiles which were significantly correlated with PASI score.

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“…Rapid progress continues to emanate from efforts to develop more potent GLP-1R agonists, including coagonists, triagonists, and chimeric molecules enabling delivery of steroid hormones to GLP-1R + cell types. The incretin field has not been without controversy, enveloping topics spanning inflammation (60), medullary thyroid cancer, pancreatitis, pancreatic cancer, tachycardia, and the potential development of pancreatic endocrine tumors. In each instance, rigorous basic and clinical science has helped illuminate data that are correct and reproducible versus findings that may be limited in significance to specific models and species or that do not hold up to widespread scrutiny.…”

Section: The Future Of Incretin-based Sciencementioning

confidence: 99%

Deciphering Metabolic Messages From the Gut Drives Therapeutic Innovation: The 2014 Banting Lecture

Drucker

2015

Diabetes

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The Banting Medal for Scientific Achievement is the highest scientific award of the American Diabetes Association (ADA). Given in memory of Sir Frederick Banting, one of the key investigators in the discovery of insulin, the Banting Medal is awarded annually for scientific excellence, recognizing significant long-term contributions to the understanding, treatment, or prevention of diabetes. Daniel J. Drucker, MD, of the Department of Medicine, Mount Sinai Hospital and the Lunenfeld-Tanenbaum Research Institute in Toronto, Ontario, Canada, received the prestigious award at the ADA's 74th Scientific Sessions, 13–17 June 2014, in San Francisco, California. He presented the Banting Lecture, “Deciphering Metabolic Messages From the Gut Drives Therapeutic Innovation,” on Sunday, 15 June 2014. Gut peptides convey nutrient-regulated signals to the enteric nervous system and to distal organs, acting as circulating hormones secreted in the basal and postprandial state. Here I provide an overview of the actions of glucagon-like peptide (GLP)-1 and GLP-2, the two major enteroendocrine L-cell peptides. The endogenous physiological actions of GLP-1 have been delineated using antagonists and Glp1r−/− mice and include the control of islet hormone secretion in a glucose-dependent manner, leading to improvement of fasting and postprandial glucose homeostasis. GLP-1 receptors (GLP-1Rs) are also widely distributed in multiple extrapancreatic organs, providing a mechanistic explanation for the nonglycemic actions attributed to GLP-1. The multiple metabolic actions of GLP-1 enable reduction of glycemia and body weight in diabetic and obese subjects, providing the opportunity to reduce glycemia in human subjects with diabetes with a low risk of hypoglycemia. GLP-2 plays a key role in the control of energy absorption and in the integrity of the intestinal mucosa, and a GLP-2R agonist, teduglutide, is now used for augmentation of energy absorption in parenteral nutrition–dependent subjects with short bowel syndrome. GLP-1 and GLP-2 are both cleaved by dipeptidyl peptidase-4 (DPP-4); hence, inhibition of DPP-4 activity enables yet another pathway for potentiation of incretin action and the therapy for type 2 diabetes. Here I review our 30-year experience with the elucidation of gut hormone action and, wherever possible, highlight therapeutic implications of our preclinical studies and future opportunities for incretin research.

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Glucagon-like peptide-1 (GLP-1) receptor agonists, obesity and psoriasis: diabetes meets dermatology

Cited by 48 publications

References 19 publications

GLP-1R Agonists Modulate Enteric Immune Responses Through the Intestinal Intraepithelial Lymphocyte GLP-1R

GLP-1R Agonists Modulate Enteric Immune Responses Through the Intestinal Intraepithelial Lymphocyte GLP-1R

Effect of Sitagliptin on glycemic profiles and their correlation with PASI score in patients with plaque psoriasis

Deciphering Metabolic Messages From the Gut Drives Therapeutic Innovation: The 2014 Banting Lecture

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