GLP-1R Agonists Promote Normal and Neoplastic Intestinal Growth through Mechanisms Requiring Fgf7

Koehler, Jacqueline A.; Baggio, Laurie L.; Yusta, Bernardo; Longuet, Christine; Rowland, Katherine; Cao, Xiemin; Holland, Diane T.; Brubaker, Patricia L.; Drucker, Daniel J.

doi:10.1016/j.cmet.2015.02.005

Cited by 104 publications

(122 citation statements)

References 54 publications

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“…40 The effects of incretin therapy on colonic epithelia are not entirely clear: it was previously suggested that GLP-1RA and DPP4 inhibitors have the capacity to decrease growth and survival of colon cancer cells 74 ; however, more recent preclinical data indicate that GLP-1RA agonists may promote small and large bowel tumor growth. 41 Of interest, an increased risk of colorectal cancer has been reported after bariatric surgery, which has been proposed to be the result of increased incretin secretion. 75 As these incretin-based agents are increasingly used in the treatment of T2DM, their potential antineoplastic and procarcinogenic effects must be further addressed in clinical studies.…”

Section: Incretin-based Drugs and Cancermentioning

confidence: 99%

Type 2 Diabetes Mellitus and Cancer: The Role of Pharmacotherapy

Shlomai

Neel

LeRoith³

et al. 2016

JCO

181

153

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Type 2 diabetes mellitus (T2DM) is becoming increasingly prevalent worldwide. Epidemiologic data suggest that T2DM is associated with an increased incidence and mortality from many cancers. The purpose of this review is to discuss the links between diabetes and cancer, the effects of various antidiabetic medications on cancer incidence and mortality, and the effects of anticancer therapies on diabetes. DesignThis study is a review of preclinical and clinical data regarding the effects of antidiabetic medications on cancer incidence and mortality and the effects of anticancer therapies on glucose homeostasis. ResultsT2DM is associated with an increased risk and greater mortality from many cancer types. Metformin use has been associated with a decrease in cancer incidence and mortality, and there are many ongoing randomized trials investigating the effects of metformin on cancer-related outcomes. However, data regarding the association of other antidiabetes medications with cancer incidence and mortality are conflicting. Glucocorticoids, hormone-based therapies, inhibitors that target the phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin pathway, and insulin-like growth factor 1 receptor-targeted therapy have been associated with high rates of hyperglycemia. These agents mediate their deleterious metabolic effects by reducing insulin secretion and increasing insulin resistance in peripheral tissues. ConclusionStudies must be performed to optimize cancer screening strategies in individuals with T2DM. A greater understanding of the mechanisms that link diabetes and cancer are needed to identify targets for therapy in individuals with diabetes who develop cancer. Data from clinical studies are needed to further elucidate the effects of antidiabetic medications on cancer incidence and progression. As several anticancer therapies alter glucose homeostasis, physicians need to be aware of these potential effects. Careful patient screening and monitoring during treatment with these agents is necessary. J Clin Oncol 34:4261-4269. © 2016 by American Society of Clinical Oncology DIABETES MELLITUS AND CANCEREpidemiology Type 2 diabetes. Type 2 diabetes mellitus (T2DM) is a chronic progressive disease that is characterized by years of insulin resistance and hyperinsulinemia preceding the development of hyperglycemia. The prediabetes phase may predate the diagnosis of T2DM by up to 10 years. This potentially modifiable phase is frequently associated with the metabolic syndrome, a condition that comprises abdominal obesity, impaired glucose tolerance or impaired fasting glucose, dyslipidemia with elevated triglycerides (TGs) and low HDL cholesterol, and hypertension.1 The prevalence of T2DM and obesity has now reached epidemic proportions worldwide. A number of large-scale epidemiologic studies and meta-analyses, including a recent umbrella review of meta-analyses and observational studies, have shown a consistent increase in site-specific cancer incidence among patients with T2DM.2 This includes a two-to three-fol...

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Section: Incretin-based Drugs and Cancermentioning

confidence: 99%

Type 2 Diabetes Mellitus and Cancer: The Role of Pharmacotherapy

Shlomai

Neel

LeRoith³

et al. 2016

JCO

181

153

View full text Add to dashboard Cite

show abstract

“…Indeed, we now understand that GLP-1 controls inflammation (75), reduces experimental kidney injury (76), and like GLP-2, acts as a potent intestinal growth factor through mechanisms including stimulation of crypt fission (ref. 77 and Figure 6). Among the actions of GLP-1 that have engendered the most interest are its effects in the cardiovascular system.…”

Section: Challenges In Studies Of Glp-1 and In Development Of Glp-1r mentioning

confidence: 99%

Discovery, characterization, and clinical development of the glucagon-like peptides

Drucker

Habener

Holst

2017

Journal of Clinical Investigation

297

227

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“…Long-term safety concerns related to the induction of tachycardia (GLP-1 receptor agonists only), a potential risk of pancreatitis, pancreatic cancer, thyroid cancer, colon cancer, cholecystitis and heart failure (in a trial with saxagliptin) have been expressed [4,16]. Nevertheless, data available at this point in time still indicate a favourable risk-benefit ratio.…”

Section: Incretin-based Therapies: Dealing With Safety Concernsmentioning

confidence: 99%

Incretin-based therapies: where will we be 50 years from now?

Meier

Nauck

2015

Diabetologia

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The development of incretin-based therapies (glucagon-like peptide 1 [GLP-1] receptor agonists and dipeptidyl peptidase-4 [DPP-4] inhibitors) has changed the landscape of type 2 diabetes management over the past decade. Current developments include longer-acting GLP-1 receptor agonists, fixed-ratio combinations of GLP-1 analogues and basal insulin, as well as implantable osmotic minipumps for long-term delivery of GLP-1 receptor agonists. In longer terms, oral or inhaled GLP-1 analogues may become a reality. In addition, oral enhancers of GLP-1 secretion (e.g. via G-protein-coupled receptors, nuclear farnesoid-receptor X and the G-proteincoupled bile acid-activated receptor [TGR5]) are currently being explored in experimental studies. Combination of GLP-1 with other gut hormones (e.g. peptide YY, glucagon, gastrin, glucose-dependent insulinotropic polypeptide [GIP], secretin, cholecystokinin, vasoactive intestinal polypeptide and pituitary adenylate cyclase-activating polypeptide) may enhance the glucose-and weight-lowering effect of GLP-1 alone, and dual or triple hormone receptor agonists may even exploit the properties of different peptides with just one molecule. There is also an increasing interest in employing incretin-based therapies in other areas, such as type 1 diabetes, impaired glucose metabolism, obesity, polycystic ovary syndrome, non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), psoriasis or even neurodegeneration. Thus, incretin-based therapies may continue to broaden the therapeutic spectrum for type 2 diabetes and for various other indications in the coming years. This is one of a series of commentaries under the banner '50 years forward', giving personal opinions on future perspectives in diabetes, to celebrate the 50th anniversary of Diabetologia (1965Diabetologia ( -2015.Keywords GIP . GLP-1 . Gut hormones . Type 2 diabetes Where are we today and where have we come from?The development of incretin-based therapies is a splendid and unique example of the successful development of novel glucose-lowering medications based on basic research findings from academic researchers. Physiological experiments in human volunteers revealed different increments in insulin secretion after oral and intravenous glucose administration, which were subsequently attributed to the actions of the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) [1]. These peptide hormones were later synthesised and prepared for intravenous infusion in patients with type 2 diabetes. On this basis, the glucose-lowering activity of GLP-1 was first discovered by academic researchers. Later on, dipeptidyl peptidase-4 (DPP-4) inhibition was identified as an effective way of raising endogenous GLP-1 levels [2]. These clinical research findings have prompted the development of GLP-1 receptor

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GLP-1R Agonists Promote Normal and Neoplastic Intestinal Growth through Mechanisms Requiring Fgf7

Cited by 104 publications

References 54 publications

Type 2 Diabetes Mellitus and Cancer: The Role of Pharmacotherapy

Type 2 Diabetes Mellitus and Cancer: The Role of Pharmacotherapy

Discovery, characterization, and clinical development of the glucagon-like peptides

Incretin-based therapies: where will we be 50 years from now?

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