DPP-4 is expressed in human pancreatic beta cells and its direct inhibition improves beta cell function and survival in type 2 diabetes

Bugliani, Marco; Syed, Farooq; Paula, Flávia M.; Omar, Bilal; Suleiman, Mara; Mossuto, Sandra; Grano, Francesca; Cardarelli, Francesco; Boggi, Ugo; Vistoli, Fabio; Filipponi, Franco; Simone, Paolo De; Marselli, Lorella; Tata, Vincenzo De; Åhrén, Bo; Eizirik, Décio L.; Marchetti, Piero

doi:10.1016/j.mce.2018.01.019

Cited by 55 publications

(51 citation statements)

References 51 publications

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“…As well as influencing glucose homeostasis through its more widespread systemic effects, as discussed above, there is some evidence to suggest that DPP-4 may have local actions in the endocrine pancreas. Reports that DPP-4 may be associated with glucagon in the secretory granules of the pancreatic α-cell first emerged in 1993, when positive staining in pig islets was shown using immunohistochemical and enzyme histochemical techniques (96), but the pancreatic localization of DPP-4 has also been unequivocally demonstrated more recently using molecular biological techniques (97–99). It has also been suggested that DPP-4 might be secreted into the interstitial spaces within the islets (100) and, accordingly, DPP-4 activity can be measured in the media of human islet incubations (101), but whether this is simple shedding of membrane-associated DPP-4 or regulated secretion is not known.…”

Section: Pancreatic Dpp-4mentioning

confidence: 99%

“…The situation in human islets is less clear. The majority of studies have found DPP-4 to be associated primarily with the α-cell (97, 99, 102, 103), and to be present in only a subset of human β-cells (99), although one study reported that it was the β-cell which was the predominant site of expression (98). Moreover, its expression appears to be influenced by metabolic stress, with it being increased in islets from diet-induced obese mice compared to normal weight animals (104), but lower in human islets from diabetic compared to non-diabetic donors (98, 99, 104).…”

Section: Pancreatic Dpp-4mentioning

confidence: 99%

“…Nevertheless, when taken together, these studies do raise the possibility that pancreatic DPP-4 may be able to influence islet function by modulating the activity of locally produced GLP-1. Accordingly, culturing human islets in the presence of a DPP-4 inhibitor resulted in increased levels of intact GLP-1 (98, 101, 104), increased insulin secretion (98, 99, 101, 104), and improved β-cell survival (99, 101). However, there is also a possibility that some of the effect may be independent of GLP-1, because DPP-4 inhibition still reduced β-cell apoptosis in human islets cultured in the presence of exendin 9-39 (99), suggesting that other mediators might be involved, but it was also suggested that an anti-inflammatory action could have played a role (99).…”

Section: Pancreatic Dpp-4mentioning

confidence: 99%

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Physiology and Pharmacology of DPP-4 in Glucose Homeostasis and the Treatment of Type 2 Diabetes

2019

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Dipeptidyl peptidase-4 (DPP-4), also known as the T-cell antigen CD26, is a multi-functional protein which, besides its catalytic activity, also functions as a binding protein and a ligand for a variety of extracellular molecules. It is an integral membrane protein expressed on cells throughout the body, but is also shed from the membrane and circulates as a soluble protein in the plasma. A large number of bioactive molecules can be cleaved by DPP-4 in vitro , but only a few of these have been demonstrated to be physiological substrates. One of these is the incretin hormone, glucagon-like peptide-1 (GLP-1), which plays an important role in the maintenance of normal glucose homeostasis, and DPP-4 has been shown to be the key enzyme regulating its biological activity. This pathway has been targeted pharmacologically through the development of DPP-4 inhibitors, and these are now a successful class of anti-hyperglycaemic agents used to treat type 2 diabetes (T2DM). DPP-4 may additionally influence metabolic control via its proteolytic effect on other regulatory peptides, but it has also been reported to affect insulin sensitivity, potentially mediated through its non-enzymatic interactions with other membrane proteins. Given that altered expression and activity of DPP-4 are associated with increasing body mass index and hyperglycaemia, DPP-4 has been proposed to play a role in linking obesity and the pathogenesis of T2DM by functioning as a local mediator of inflammation and insulin resistance in adipose and hepatic tissue. As well as these broader systemic effects, it has also been suggested that DPP-4 may be able to modulate β-cell function as part of a paracrine system involving GLP-1 produced locally within the pancreatic islets. However, while it is evident that DPP-4 has the potential to influence glycaemic control, its overall significance for the normal physiological regulation of glucose homeostasis in humans and its role in the pathogenesis of metabolic disease remain to be established.

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Section: Pancreatic Dpp-4mentioning

confidence: 99%

Section: Pancreatic Dpp-4mentioning

confidence: 99%

Section: Pancreatic Dpp-4mentioning

confidence: 99%

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Physiology and Pharmacology of DPP-4 in Glucose Homeostasis and the Treatment of Type 2 Diabetes

2019

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“…Briefly, islets were incubated at a density of 1 islet per 10 µl of media. For GLP-1 secretion studies, the DPP4 inhibitor (Millipore) was added to the media to prevent GLP-1 degradation 54 . A membrane permeable cAMP analog (8-CPT-cAMP, referred to as cAMP) was used to stimulate CCK secretion as previously described 4 .…”

Section: Methodsmentioning

confidence: 99%

Intra-islet GLP-1, but not CCK, is necessary for β-cell function in mouse and human islets

Souza

Tang

Yadev

et al. 2020

Sci Rep

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Glucagon-like peptide 1 (GLP-1) and cholecystokinin (CCK) are gut-derived peptide hormones known to play important roles in the regulation of gastrointestinal motility and secretion, appetite, and food intake. We have previously demonstrated that both GLP-1 and CCK are produced in the endocrine pancreas of obese mice. Interestingly, while GLP-1 is well known to stimulate insulin secretion by the pancreatic β-cells, direct evidence of CCK promoting insulin release in human islets remains to be determined. Here, we tested whether islet-derived GLP-1 or CCK is necessary for the full stimulation of insulin secretion. We confirm that mouse pancreatic islets secrete GLP-1 and CCK, but only GLP-1 acts locally within the islet to promote insulin release ex vivo. GLP-1 is exclusively produced in approximately 50% of α-cells in lean mouse islets and 70% of α-cells in human islets, suggesting a paracrine α to β-cell signaling through the β-cell GLP-1 receptor. Additionally, we provide evidence that islet CCK expression is regulated by glucose, but its receptor signaling is not required during glucose-stimulated insulin secretion (GSIS). We also see no increase in GSIS in response to CCK peptides. Importantly, all these findings were confirmed in islets from non-diabetic human donors. In summary, our data suggest no direct role for CCK in stimulating insulin secretion and highlight the critical role of intra-islet GLP-1 signaling in the regulation of human β-cell function.The precise control of blood glucose is dependent on the islets of Langerhans located within the pancreas. Pancreatic islets are complex structures consisting of several types of cells, including insulin-producing β-cells, glucagon-producing α-cells, and somatostatin-producing α-cells. After feeding, nutrients stimulate insulin release by the β-cell and the circulating hormone acts on peripheral tissues lowering blood glucose. The full stimulation of insulin secretion after food intake depends on the incretin effect of gut-derived peptide hormones and paracrine signaling within the islet 1 .We and others discovered that two classic gut hormones, glucagon-like peptide 1 (GLP-1) and cholecystokinin (CCK), are also produced by pancreatic islets 2-5 . GLP-1 is a peptide hormone mainly secreted by intestinal L-cells and is known to decrease blood glucose levels by enhancing β-cell insulin secretion 6 . CCK is a peptide hormone mainly secreted by intestinal I-cells and is involved in the digestion of nutrients 7 and regulation of food intake 8 . The production of both GLP-1 and CCK in the islet has been associated with β-cell expansion and survival in response to metabolic stress 5,9 . While each of these gut-derived hormones can contribute to improvements in glucose homeostasis 10,11 , it is unclear whether their local production in the islet contributes to β-cell function. Moreover, it is unknown whether CCK stimulates insulin release in human islets. Here, we describe experiments with GLP-1 and CCK receptor antagonists in isolated mouse and human islets to ass...

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“…A further factor which might contribute to the relative lack of effect on downstream responses to biased GLP-1, GIP and GCG analogues during prolonged incubations is enzymatic peptide degradation, for example by neutral endopeptidase 24.11 (NEP 24.11), found on pancreatic beta cell membranes and capable of hydrolysing GLP-1, GCG, and to a lesser extent, GIP [52], or endothelin converting enzyme-1 [53] situated predominantly in endosomal compartments. DPP-4, also expressed by beta cells [54], is also likely to contribute, although the modified N-termini of the ligands tested may confer some resistance to its action. Sequence optimisation to increase proteolytic stability during our extended in vitro studies may be required to maintain adequate ligand concentration to fully manifest consequences of signal bias.…”

Section: Responses To Biased Gcg Analogues In the Hepatocyte Contextmentioning

confidence: 99%

Signal bias at glucagon family receptors: rationale and downstream impacts

Jones

Fang

et al. 2020

Preprint

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AbbreviationscAMP Cyclic adenosine monophosphate DERET Diffusion-enhanced resonance energy transfer DPP-4 Dipeptidyl dipeptidase-4 GCG Glucagon GCGR Glucagon receptor GIP Glucose-dependent insulinotropic polypeptide GIPR Glucose-dependent insulinotropic polypeptide receptor GLP-1 Glucagon-like peptide-1 GLP-1R Glucagon-like peptide-1 receptor NEP24.11 Neutral endopeptidase T2D Type 2 diabetes TR-FRET Time-resolved Förster resonance energy transfer AbstractReceptors for the peptide hormones glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon (GCG) are important regulators of insulin secretion and energy metabolism. Here we sought to investigate how signal bias between cyclic AMP and βarrestin-2 recruitment can modulate the effects of prolonged agonist stimulation at each of these receptors. We generated analogues of GLP-1, GCG and GIP which in some cases showed selective reduction in β-arrestin-2 recruitment versus cAMP signalling compared to the parent peptide. Despite reduced acute signalling potency and/or efficacy, some biased GLP-1 and GIP analogues increased maximal sustained insulin secretion, although only at high agonist concentrations. Biased GCG analogues did not affect maximal insulin release from beta cells, or glucose output in hepatocytes.

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DPP-4 is expressed in human pancreatic beta cells and its direct inhibition improves beta cell function and survival in type 2 diabetes

Cited by 55 publications

References 51 publications

Physiology and Pharmacology of DPP-4 in Glucose Homeostasis and the Treatment of Type 2 Diabetes

Physiology and Pharmacology of DPP-4 in Glucose Homeostasis and the Treatment of Type 2 Diabetes

Intra-islet GLP-1, but not CCK, is necessary for β-cell function in mouse and human islets

Signal bias at glucagon family receptors: rationale and downstream impacts

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