Incretin action in the pancreas: Potential promise, possible perils, and pathological pitfalls

doi:10.2337/DB13-0822

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Incretin action in the pancreas: Potential promise, possible perils, and pathological pitfalls

Journal Article•DOI•

Incretin action in the pancreas: Potential promise, possible perils, and pathological pitfalls

Daniel J. Drucker¹•Institutions (1)

University of Toronto¹

01 Oct 2013-Diabetes (American Diabetes Association)-Vol. 62, Iss: 10, pp 3316-3323

TL;DR: Recent advances and controversies in incretin hormone action in the pancreas are reviewed and established mechanisms with areas of uncertainty are contrasted and methodological challenges and pitfalls are highlighted.

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Abstract: Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones that control the secretion of insulin, glucagon, and somatostatin to facilitate glucose disposal. The actions of incretin hormones are terminated via enzymatic cleavage by dipeptidyl peptidase-4 (DPP-4) and through renal clearance. GLP-1 and GIP promote β-cell proliferation and survival in rodents. DPP-4 inhibitors expand β-cell mass, reduce α-cell mass, and inhibit glucagon secretion in preclinical studies; however, whether incretin-based therapies sustain functional β-cell mass in human diabetic subjects remains unclear. GLP-1 and GIP exert their actions predominantly through unique G protein-coupled receptors expressed on β-cells and other pancreatic cell types. Accurate localization of incretin receptor expression in pancreatic ductal or acinar cells in normal or diabetic human pancreas is challenging because antisera used for detection of the GLP-1 receptor often are neither sufficiently sensitive nor specific to yield reliable data. This article reviews recent advances and controversies in incretin hormone action in the pancreas and contrasts established mechanisms with areas of uncertainty. Furthermore, methodological challenges and pitfalls are highlighted and key areas requiring additional scientific investigation are outlined.

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Journal Article•DOI•

Type 2 diabetes mellitus.

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Ralph A. DeFronzo¹, Ele Ferrannini, Leif Groop², Robert R. Henry³, William H. Herman⁴, Jens J. Holst⁵, Frank B. Hu⁶, C. Ronald Kahn⁶, Itamar Raz, Gerald I. Shulman⁷, Donald C. Simonson⁶, Marcia A. Testa⁶, Ram Weiss⁸ - Show less +9 more•Institutions (8)

University of Texas Health Science Center at San Antonio¹, Lund University², University of California, San Diego³, University of Michigan⁴, University of Copenhagen⁵, Harvard University⁶, Yale University⁷, Hebrew University of Jerusalem⁸

23 Jul 2015

TL;DR: The greatest need is for agents that enhance insulin sensitivity, halt the progressive pancreatic β-cell failure that is characteristic of T2DM and prevent or reverse the microvascular complications.

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Abstract: Type 2 diabetes mellitus (T2DM) is an expanding global health problem, closely linked to the epidemic of obesity. Individuals with T2DM are at high risk for both microvascular complications (including retinopathy, nephropathy and neuropathy) and macrovascular complications (such as cardiovascular comorbidities), owing to hyperglycaemia and individual components of the insulin resistance (metabolic) syndrome. Environmental factors (for example, obesity, an unhealthy diet and physical inactivity) and genetic factors contribute to the multiple pathophysiological disturbances that are responsible for impaired glucose homeostasis in T2DM. Insulin resistance and impaired insulin secretion remain the core defects in T2DM, but at least six other pathophysiological abnormalities contribute to the dysregulation of glucose metabolism. The multiple pathogenetic disturbances present in T2DM dictate that multiple antidiabetic agents, used in combination, will be required to maintain normoglycaemia. The treatment must not only be effective and safe but also improve the quality of life. Several novel medications are in development, but the greatest need is for agents that enhance insulin sensitivity, halt the progressive pancreatic β-cell failure that is characteristic of T2DM and prevent or reverse the microvascular complications. For an illustrated summary of this Primer, visit: http://go.nature.com/V2eGfN.

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1,757 citations

Journal Article•DOI•

Adipokines in health and disease

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Mathias Fasshauer¹, Matthias Blüher¹•Institutions (1)

Leipzig University¹

01 Jul 2015-Trends in Pharmacological Sciences

TL;DR: Secretion of adipokines, including leptin, adiponectin, fibroblast growth factor 21, retinol-binding protein 4 (RBP4), dipeptidyl peptidase 4 (DPP-4), bone morphogenetic protein (BMP)-4, BMP-7, vaspin, apelin, and progranulin, is altered in adipose tissue dysfunction and may contribute to a spectrum of obesity-associated diseases.

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705 citations

Journal Article•DOI•

Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1.

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Daniel J. Drucker¹•Institutions (1)

Lunenfeld-Tanenbaum Research Institute¹

03 Apr 2018-Cell Metabolism

TL;DR: This review highlights established and emerging concepts, unanswered questions, and future challenges for development and optimization of GLP-1R agonists in the treatment of metabolic disease.

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705 citations

Cites background or methods from "Incretin action in the pancreas: Po..."

...GLP-1R agonists improve the survival of human islets ex vivo, or following transplantation into animals (Campbell and Drucker, 2013)....
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...Extensive evidence demonstrates that GLP-1R agonism reduces food intake and promotes weight loss (Campbell and Drucker, 2013; Drucker and Nauck, 2006), and a single GLP1R agonist, liraglutide, has been approved for the treatment of obesity (Astrup et al., 2009)....
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...Several long-acting glucagon-GLP-1 co-agonists produce greater weight loss than GLP-1 alone in preclinical studies while improving glucose control via GLP-1R signaling (Sadry and Drucker, 2013)....
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...…acute and chronic pancreatitis in animals treated with the DPP-4 inhibitor sitagliptin, concurrent with clinical reports of pancreatitis in exenatide-treated subjects, and subsequent demonstrations of preneoplastic pancreatic ductal lesions in animals treated with GLP-1R agonists (Drucker, 2013)....
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...…reagents used to detect the GLP-1R revealed generalized problems with impaired sensitivity and specificity of multiple commercially available GLP-1R antisera, questioning the accuracy of reports of GLP-1R localization using these antisera (Drucker, 2013; Panjwani et al., 2013; Pyke et al., 2014)....
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Journal Article•DOI•

GLP-1 Receptor Localization in Monkey and Human Tissue: Novel Distribution Revealed With Extensively Validated Monoclonal Antibody

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Charles Pyke¹, R. Scott Heller¹, Rikke Kaae Kirk¹, Cathrine Ørskov¹, Steffen Reedtz-Runge¹, Peter Kaastrup¹, Anders Hvelplund¹, Linda Bardram, Dan Calatayud, Lotte Bjerre Knudsen¹ - Show less +6 more•Institutions (1)

Novo Nordisk¹

27 Jan 2014-Endocrinology

TL;DR: Results give important new insight into the molecular mode of action of GLP-1 analogs by identifying the exact cellular localization of GLp-1R.

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Abstract: Glucagon-like peptide 1 (GLP-1) analogs are increasingly being used in the treatment of type 2 diabetes. It is clear that these drugs lower blood glucose through an increase in insulin secretion and a lowering of glucagon secretion; in addition, they lower body weight and systolic blood pressure and increase heart rate. Using a new monoclonal antibody for immunohistochemistry, we detected GLP-1 receptor (GLP-1R) in important target organs in humans and monkeys. In the pancreas, GLP-1R was predominantly localized in β-cells with a markedly weaker expression in acinar cells. Pancreatic ductal epithelial cells did not express GLP-1R. In the kidney and lung, GLP-1R was exclusively expressed in smooth muscle cells in the walls of arteries and arterioles. In the heart, GLP-1R was localized in myocytes of the sinoatrial node. In the gastrointestinal tract, the highest GLP-1R expression was seen in the Brunner's gland in the duodenum, with lower level expression in parietal cells and smooth muscle cells in the mu...

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555 citations

Journal Article•DOI•

The Cardiovascular Biology of Glucagon-like Peptide-1.

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Daniel J. Drucker¹•Institutions (1)

Lunenfeld-Tanenbaum Research Institute¹

12 Jul 2016-Cell Metabolism

TL;DR: The risks and benefits of GLp-1R agonists are updated in light of recent data suggesting that GLP-1 R agonists favorably modify outcomes in diabetic subjects at high risk for cardiovascular events.

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417 citations

Cites background or methods from "Incretin action in the pancreas: Po..."

...to drug-induced pancreatic inflammation in preclinical studies (Drucker, 2013; Koehler et al., 2009)....
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...Diabetes and obesity are associated with increased cancer incidence rates; however, whether therapy with GLP-1R agonists modifies the risk of developing specific cancers remains uncertain, due to limitations in existing clinical data (Drucker, 2013, 2015)....
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...The putative mechanisms linking GLP-1R signaling to pancreatic inflammation remain unclear; GLP-1R agonists reduce experimental pancreatic inflammation and do not increase the susceptibility to drug-induced pancreatic inflammation in preclinical studies (Drucker, 2013; Koehler et al., 2009)....
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...…useful updates focused on incretin and EEC biology and control of metabolism, we refer the interested reader to the following resources for more general background information: Campbell and Drucker (2013), Drucker (2016), Gribble and Reimann (2016), Meier (2012), and Sandoval and D’Alessio (2015)....
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...…expression of the GLP-1R in human pancreatic and thyroid tumors have been modified by the realization that some of these studies employed non-specific GLP-1R antibodies with poor sensitivity (Campbell and Drucker, 2013; Drucker, 2013, 2015; Panjwani et al., 2013; Pyke and Knudsen, 2013)....
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References

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Journal Article•DOI•

The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes

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Daniel J. Drucker¹, Michael A. Nauck•Institutions (1)

University of Toronto¹

11 Nov 2006-The Lancet

TL;DR: Clinical trials with the incretin mimetic exenatide and liraglutide show reductions in fasting and postprandial glucose concentrations, and haemoglobin A1c (HbA1c) associated with weight loss, but long-term clinical studies are needed to determine the benefits of targeting the inc retin axis for the treatment of type 2 diabetes.

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3,497 citations

"Incretin action in the pancreas: Po..." refers background in this paper

...Potentiation of incretin action underlines two therapeutic classes of glucoselowering agents: GLP-1 receptor (GLP-1R) agonists and DPP-4 inhibitors (1)....
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Journal Article•DOI•

Pharmacology, physiology, and mechanisms of incretin hormone action

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Jonathan E. Campbell¹, Daniel J. Drucker¹•Institutions (1)

University of Toronto¹

04 Jun 2013-Cell Metabolism

TL;DR: Whether mechanisms identified in preclinical studies have potential translational relevance for the treatment of human disease and highlight controversies and uncertainties in incretin biology that require resolution in future studies are discussed.

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1,068 citations

"Incretin action in the pancreas: Po..." refers background or result in this paper

...Antiapoptotic actions of GLP-1R agonists have been demonstrated in rodent and human islets (2,32) and in preclinical studies of transplanted human islet cells....
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...Early experiments promoted the concept that GLP-1R agonists stimulated neogenesis of b-cells via activation of a ductal cell GLP-1R (2,32)....
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...Although the insulin-stimulating properties of GLP-1R agonists are preserved in experimental models of diabetes and human subjects with type 2 diabetes (T2D), the actions of GIP on the diabetic b-cell likely are attenuated because of downregulation of Gipr expression and/or attenuation of signaling pathways coupling GIP receptor activation to insulin secretion (2)....
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...In contrast to findings observed in hIAPP transgenic rats (64), islet amyloid deposition, ductal cell proliferation, and pancreatic mass were not increased by sitagliptin in hIAPP transgenic mice; however, b-cell mass was increased, consistent with the known actions of sitagliptin in mice (2)....
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...Original concepts of GIP and GLP-1 biology, which focused primarily on islet b-cells, have been expanded to include actions on other cell types within and outside the pancreas (2,3)....
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Journal Article•DOI•

Effects of bariatric surgery on cancer incidence in obese patients in Sweden (Swedish Obese Subjects Study): a prospective, controlled intervention trial

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Lars Sjöström¹, Lars Sjöström², Anders Gummesson², C. David Sjöström², Kristina Narbro, Markku Peltonen³, Hans Wedel, Calle Bengtsson², Claude Bouchard¹, Björn Carlsson², Sven Dahlgren⁴, Peter Jacobson², Kristjan Karason², Jan Karlsson², B Larsson², A K Lindroos⁵, Hans Lönroth², Ingmar Näslund⁶, Torsten Olbers², Kaj Stenlöf², Jarl S Torgerson, Lena M. S. Carlsson² - Show less +18 more•Institutions (6)

Pennington Biomedical Research Center¹, University of Gothenburg², National Institutes of Health³, Umeå University⁴, Medical Research Council⁵, Örebro University⁶

01 Jul 2009-Lancet Oncology

TL;DR: Bariatric surgery was associated with reduced cancer incidence in obese women but not in obese men, and after exclusion of all cancer cases during the first 3 years of the intervention.

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Abstract: Summary Background Obesity is a risk factor for cancer. Intentional weight loss in the obese might protect against malignancy, but evidence is limited. To our knowledge, the Swedish Obese Subjects (SOS) study is the first intervention trial in the obese population to provide prospective, controlled cancer-incidence data. Methods The SOS study started in 1987 and involved 2010 obese patients (body-mass index [BMI] ≥34 kg/m 2 in men, and ≥38 kg/m 2 in women) who underwent bariatric surgery and 2037 contemporaneously matched obese controls, who received conventional treatment. While the main endpoint of SOS was overall mortality, the main outcome of this exploratory report was cancer incidence until Dec 31, 2005. Cancer follow-up rate was 99·9% and the median follow-up time was 10·9 years (range 0–18·1 years). Findings Bariatric surgery resulted in a sustained mean weight reduction of 19·9 kg (SD 15·6 kg) over 10 years, whereas the mean weight change in controls was a gain of 1·3 kg (SD 13·7 kg). The number of first-time cancers after inclusion was lower in the surgery group (n=117) than in the control group (n=169; HR 0·67, 95% CI 0·53–0·85, p=0·0009). The sex–treatment interaction p value was 0·054. In women, the number of first-time cancers after inclusion was lower in the surgery group (n=79) than in the control group (n=130; HR 0·58, 0·44–0·77; p=0·0001), whereas there was no effect of surgery in men (38 in the surgery group vs 39 in the control group; HR 0·97, 0·62–1·52; p=0·90). Similar results were obtained after exclusion of all cancer cases during the first 3 years of the intervention. Interpretation Bariatric surgery was associated with reduced cancer incidence in obese women but not in obese men. Funding Swedish Research Council, Swedish Foundation for Strategic Research, Swedish Federal Government under the LUA/ALF agreement, Hoffmann La Roche, Cederoths, AstraZeneca, Sanofi-Aventis, Ethicon Endosurgery.

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680 citations

Journal Article•DOI•

Lower blood glucose, hyperglucagonemia, and pancreatic α cell hyperplasia in glucagon receptor knockout mice

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Richard W. Gelling¹, Xueliang Du², Darwin S. Dichmann¹, John Rømer¹, H. Huang, Lingguang Cui², Silvana Obici², B. Tang², Jens J. Holst³, Christian Fledelius¹, Peter B. Johansen¹, Luciano Rossetti², Linda A. Jelicks, Palle Serup¹, Erica Nishimura¹, Maureen J. Charron - Show less +12 more•Institutions (3)

Novo Nordisk¹, Yeshiva University², University of Copenhagen³

04 Feb 2003-Proceedings of the National Academy of Sciences of the United States of America

TL;DR: The data indicate that glucagon is essential for maintenance of normal glycemia and postnatal regulation of islet and α and δ cell numbers and the lean phenotype of Gcgr−/− mice suggests glucagon action may be involved in the regulation of whole body composition.

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Abstract: Glucagon, the counter-regulatory hormone to insulin, is secreted from pancreatic α cells in response to low blood glucose. To examine the role of glucagon in glucose homeostasis, mice were generated with a null mutation of the glucagon receptor (Gcgr−/−). These mice display lower blood glucose levels throughout the day and improved glucose tolerance but similar insulin levels compared with control animals. Gcgr−/− mice displayed supraphysiological glucagon levels associated with postnatal enlargement of the pancreas and hyperplasia of islets due predominantly to α cell, and to a lesser extent, δ cell proliferation. In addition, increased proglucagon expression and processing resulted in increased pancreatic glucogen-like peptide 1 (GLP-1) (1–37) and GLP-1 amide (1–36 amide) content and a 3- to 10-fold increase in circulating GLP-1 amide. Gcgr−/− mice also displayed reduced adiposity and leptin levels but normal body weight, food intake, and energy expenditure. These data indicate that glucagon is essential for maintenance of normal glycemia and postnatal regulation of islet and α and δ cell numbers. Furthermore, the lean phenotype of Gcgr−/− mice suggests glucagon action may be involved in the regulation of whole body composition.

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538 citations

"Incretin action in the pancreas: Po..." refers background or result in this paper

...Although Gcgr mice exhibit pancreatic enlargement, increased acinar or ductal cell proliferation has not been detected by multiple independent groups that have studied these animals (45,46,48,52)....
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...The assertion that Gcgr mice or humans with a Gcgr null mutation exhibit enhanced exocrine proliferation (5) is not supported by the published data (52,53) cited by the same authors....
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Journal Article•DOI•

Minireview: Glucagon-Like Peptides Regulate Cell Proliferation and Apoptosis in the Pancreas, Gut, and Central Nervous System

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Patricia L. Brubaker¹, Daniel J. Drucker², Daniel J. Drucker¹•Institutions (2)

Toronto General Hospital¹, University of Toronto²

01 Jun 2004-Endocrinology

TL;DR: This article showed that glucagon-like peptides (GLP-1 and GLP-2) directly regulate signaling pathways coupled to cell proliferation and apoptosis, which may be mediated by direct or indirect effects on target cells.

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Abstract: Gut peptides exert diverse effects regulating satiety, gastrointestinal motility and acid secretion, epithelial integrity, and both nutrient absorption and disposal. These actions are initiated by activation of specific G protein-coupled receptors and may be mediated by direct or indirect effects on target cells. More recent evidence demonstrates that gut peptides, exemplified by glucagon-like peptides-1 and 2 (GLP-1 and GLP-2), directly regulate signaling pathways coupled to cell proliferation and apoptosis. GLP-1 receptor activation enhances beta-cell proliferation and promotes islet neogenesis via activation of pdx-1 expression. The proliferative effects of GLP-1 appear to involve multiple intracellular pathways, including stimulation of Akt, activation of protein kinase Czeta, and transactivation of the epidermal growth factor receptor through the c-src kinase. GLP-1 receptor activation also promotes cell survival in beta-cells and neurons via increased levels of cAMP leading to cAMP response element binding protein activation, enhanced insulin receptor substrate-2 activity and, ultimately, activation of Akt. These actions of GLP-1 are reflected by expansion of beta-cell mass and enhanced resistance to beta-cell injury in experimental models of diabetes in vivo. GLP-2 also promotes intestinal cell proliferation and confers resistance to cellular injury in a variety of cell types. Administration of GLP-2 to animals with experimental intestinal injury promotes regeneration of the gastrointestinal epithelial mucosa and confers resistance to apoptosis in an indirect manner via yet-to-be identified GLP-2 receptor-dependent regulators of mucosal growth and cell survival. These proliferative and antiapoptotic actions of GLP-1 and GLP-2 may contribute to protective and regenerative actions of these peptides in human subjects with diabetes and intestinal disorders, respectively.

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535 citations

"Incretin action in the pancreas: Po..." refers background in this paper

...Multiple preclinical studies demonstrate proliferative and antiapoptotic actions of GLP-1, leading to the expansion of b-cell mass (32)....
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...Antiapoptotic actions of GLP-1R agonists have been demonstrated in rodent and human islets (2,32) and in preclinical studies of transplanted human islet cells....
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...Early experiments promoted the concept that GLP-1R agonists stimulated neogenesis of b-cells via activation of a ductal cell GLP-1R (2,32)....
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