Endoproteolysis of Glucagon-like Peptide (GLP)-1(7–36) amide by Ectopeptidases in RINm5F Cells

Hupe-Sodmann, K.; Göke, Rüdiger; Göke, Burkhard; Thole, Hubert; Zimmermann, Bodo; Voigt, Karlheinz; McGregor, G.P.

doi:10.1016/s0196-9781(97)00123-x

Cited by 70 publications

(60 citation statements)

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“…We therefore sought to determine whether neprilysin is present and active in islets and whether changes in neprilysin activity are associated with amyloid deposition. To our knowledge, this is the first report describing production as well as activity of the amyloid-degrading enzyme neprilysin in pancreatic islets, although previously neprilysin activity was detected in a pancreatic ␤-cell line (27). Our work confirms neprilysin expression in ␤-cells and shows that neprilysin also exists in non-␤-cells of the islet, consistent with the fact that it has previously been detected in a wide range of cells/tissues (39).…”

Section: Discussionsupporting

confidence: 88%

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Identification of the Amyloid-Degrading Enzyme Neprilysin in Mouse Islets and Potential Role in Islet Amyloidogenesis

et al. 2007

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Islet amyloid contributes to loss of ␤-cell mass and function in type 2 diabetes. It is poorly understood how the building block of amyloid, islet amyloid polypeptide (IAPP), misfolds and accumulates within the islet to contribute to cellular dysfunction. We sought to determine whether neprilysin, an amyloid-degrading enzyme, is present in islets and plays a role in the accumulation of amyloid fibrils. Human IAPP (hIAPP) transgenic mice, a model of islet amyloid in which primarily male mice develop amyloid by 12 months of age, were studied at 10 weeks and 6 months of age, enabling investigation of islet changes before and during early amyloidogenesis. Neprilysin was present in islets, including ␤-cells, and islet neprilysin mRNA and activity were found to decline with age in nontransgenic mice as well as in hIAPP transgenic female mice. In contrast, neprilysin mRNA and activity did not decrease in amyloid-prone hIAPP transgenic male mice at 6 months compared with nontransgenic mice and female hIAPP transgenic mice. Islet amyloid was detected in 43% of the 6-month-old hIAPP transgenic male mice only, suggesting the sustained elevation of islet neprilysin in these mice was a compensatory mechanism aimed at preventing amyloid accumulation. In keeping with amyloid formation, the proportion of insulin-positive area to islet area was significantly reduced in 6-month-old hIAPP transgenic male mice, which also displayed mild fasting hyperglycemia compared with age-matched transgenic female and nontransgenic mice. Together, these findings demonstrate that neprilysin is a factor associated with islet amyloid accumulation and subsequent deterioration of ␤-cell function in hIAPP transgenic male mice. Diabetes 56:304 -310, 2007 I slet amyloid is a pathological characteristic of the endocrine pancreas in type 2 diabetes thought to contribute to reduced ␤-cell mass and function (1,2). The unique peptide component of islet amyloid is islet amyloid polypeptide (IAPP), or amylin (3,4), which is a normal product of the ␤-cell that is cosecreted with insulin in response to nutrient stimulation (5). The human IAPP (hIAPP) molecule, unlike rodent IAPP, is capable of forming amyloid fibrils because of species-specific differences in the amino acid sequence (6 -8). Using hIAPP transgenic models of islet amyloid formation, we and others (9 -16) have shown that hIAPP expression and/or amyloid deposition is associated with both impaired ␤-cell function (manifest primarily as hyperglycemia) and reduced ␤-cell mass.The regulation of IAPP production and secretion has long been studied and shown to closely mirror that of insulin. Thus, in conditions associated with insulin resistance, and specifically hyperinsulinemia, IAPP levels are elevated (17)(18)(19). In the face of ␤-cell dysfunction, this can potentially lead to aggregation and fibril formation (20). A factor that may further accelerate amyloidogenesis is reduced IAPP and/or amyloid degradation. Studies by Bennett et al. (21,22) have demonstrated that insulindegrading enzyme degrades ...

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Section: Discussionsupporting

confidence: 88%

“…There is, however, one study where neprilysin activity was detected in RINm5F plasma cell membranes (27). RINm5F cells are derived from a rat insulinoma and are commonly used as a pancreatic ␤-cell model.…”

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confidence: 99%

Identification of the Amyloid-Degrading Enzyme Neprilysin in Mouse Islets and Potential Role in Islet Amyloidogenesis

et al. 2007

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“…The metabolite is also cleared rapidly, mainly in the kidneys, with a half-life of 4 -5 min (182,309). It has been established that GLP-1 is also a substrate for the enzyme, neutral endopeptidase 24.11 (134), and recent studies have shown that inhibition of this enzyme will enhance survival of both endogenous and exogenous GLP-1 in vivo (242). However, the enhanced survival will only be apparent if the NH 2 -terminal degradation by DDP-IV has been prevented.…”

Section: Measurement Release and Metabolismmentioning

confidence: 99%

The Physiology of Glucagon-like Peptide 1

Holst¹

2007

Physiological Reviews

2,650

2,385

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Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, the gene which is expressed in these cells. The current knowledge regarding regulation of proglucagon gene expression in the gut and in the brain and mechanisms responsible for the posttranslational processing are reviewed. GLP-1 is released in response to meal intake, and the stimuli and molecular mechanisms involved are discussed. GLP-1 is extremely rapidly metabolized and inactivated by the enzyme dipeptidyl peptidase IV even before the hormone has left the gut, raising the possibility that the actions of GLP-1 are transmitted via sensory neurons in the intestine and the liver expressing the GLP-1 receptor. Because of this, it is important to distinguish between measurements of the intact hormone (responsible for endocrine actions) or the sum of the intact hormone and its metabolites, reflecting the total L-cell secretion and therefore also the possible neural actions. The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin hormone) and to inhibit glucagon secretion, thereby contributing to limit postprandial glucose excursions. It also inhibits gastrointestinal motility and secretion and thus acts as an enterogastrone and part of the “ileal brake” mechanism. GLP-1 also appears to be a physiological regulator of appetite and food intake. Because of these actions, GLP-1 or GLP-1 receptor agonists are currently being evaluated for the therapy of type 2 diabetes. Decreased secretion of GLP-1 may contribute to the development of obesity, and exaggerated secretion may be responsible for postprandial reactive hypoglycemia.

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“…PACAP acts at very low concentrations on cultured islets cells (Yada et al, 1994Filipsson et al, 1998b;Davalli et al, 1999;Filipsson et al, 1999), and its stimulatory effect on insulin secretion is mediated through activation of PAC1-R and VPAC2-R coupled to the AC pathway (Jamen et al, 2000a(Jamen et al, , 2002bAsnicar et al, 2002;Persson and Ahrén, 2002). Furthermore, pancreatic ␤-cells express cell-surface ectopeptidases capable of degrading PACAP (Hupe-Sodmann et al, 1997), indicating that the action of PACAP on insulin secretion is finely regulated. The amplitude and kinetics of the PACAP-evoked stimulation of insulin release depends on glucose concentration in the incubation medium (Yokota et al, 1993;Bertrand et al, 1996;Edwards et al, 1997).…”

Section: H Effects Of Pituitary Adenylate Cyclase-activating Polypepmentioning

confidence: 99%

Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: 20 Years after the Discovery

et al. 2009

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Endoproteolysis of Glucagon-like Peptide (GLP)-1(7–36) amide by Ectopeptidases in RINm5F Cells

Cited by 70 publications

References 20 publications

Identification of the Amyloid-Degrading Enzyme Neprilysin in Mouse Islets and Potential Role in Islet Amyloidogenesis

Identification of the Amyloid-Degrading Enzyme Neprilysin in Mouse Islets and Potential Role in Islet Amyloidogenesis

The Physiology of Glucagon-like Peptide 1

Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: 20 Years after the Discovery

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