Increased plasma pancreastatin-like levels in gestational diabetes: correlation with catecholamine levels.

Sánchez-Margalet, Vı́ctor; Lobón, J A; Gonzalez, Andrea Gerard; Fernández-Soto, María Luisa; Escobar-Jiménez, Fernándo; Goberna, R.

doi:10.2337/diacare.21.11.1951

Cited by 37 publications

(23 citation statements)

References 2 publications

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“…It seems the PLC-b3 isoform is specifically activated by pancreastatin receptors and mediated by Ga 11 [44]. Increased circulating pancreastatin concentrations have been found in patients with Type II diabetes [25], gestational diabetes [45] and in hypertensive patients [26]. These data suggest that pancreastatin could have a role in the insulin resistance syndrome.…”

Section: Discussionmentioning

confidence: 67%

“…Moreover, we have recently found that plasma pancreastatin-like immunorreactivity correlates with plasma norepinephrine in essential hypertension [28] and gestational diabetes [45]. Since insulin resistance and the sympathoadrenal system are involved in the metabolic abnormalities associated with hypertension [46] we proposed that pancreastatin might contribute to the counterregulatory effect of catecholamines in pathophysiological conditions, when catecholamines concentrations are increased.…”

Section: Discussionmentioning

confidence: 99%

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Modulation of insulin receptor signalling by pancreastatin in HTC hepatoma cells

Sánchez-Margalet

1999

Diabetologia

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Pancreastatin [1], a chromogranin A-derived neuropeptide [2] that was isolated first from the porcine pancreas is widely distributed throughout the neuroendocrine system [3±6]. In islets, it appears to be localized to the insulin-containing beta cells, somatostatin containing delta cells [4] and glucagon containing alpha cells [5,6]. Post-secretory processing of chromogranin A also occurs [7,8]. A pancreastatinlike sequence, homologous to porcine pancreastatin has been found in rat chromogranin A cDNA [9±11].Pancreastatin has a number of effects in a variety of cell targets [12]. Thus, we have found a glycogenolytic effect [13±15] and a counterregulatory effect to insulin in the rat liver [16]. We have shown that its action in the liver is mediated by a specific receptor [17,18] coupled to GTP binding proteins in the plasma membrane [17±19]. This receptor activates Ga q/11 in rat liver membranes [20] resulting in activation of Diabetologia (1999) Summary Pancreastatin, a neuropeptide derived from chromogranin A, has a glycogenolytic and counterregulatory effect to insulin in the rat liver. This effect is mediated by calcium and protein kinase C activity. Our aim was to study the possible cross-talk between pancreastatin and the insulin signalling system, by using the well-studied insulin sensitive rat hepatoma HTC cells. First, we checked the counterregulatory effect of pancreastatin on insulin action. Pancreastatin dose-dependently inhibited insulin stimulated glycogen synthesis. This effect was not due to competition for insulin receptors. Moreover, when protein kinase C activation was blocked with staurosporine, this effect of pancreastatin was not observed. Next, we found a dose-dependent inhibition of insulin receptor autophosphorylation by pancreastatin. In addition, phosphorylation of the major substrates of insulin receptor in HTC, i. e. insulin-receptor substrate (IRS)-1/IRS-2 and p62 was also blunted and so was its association with p85 regulatory subunit of phosphatidylinositol-3-kinase. Moreover, the insulin activation of S6 kinase was also blocked by pancreastatin. Again, all these inhibitory effects of pancreastatin were prevented by staurosporine. Furthermore, pancreastatin produced Ser/Thr phosphorylation of insulin receptor by a staurosporine-sensitive mechanism. Finally, we checked the pancreastatin activation of protein kinase C in HTC cells and found that a ªclas-sicalº isoform of this protein is translocated to the plasma membrane. These findings suggest that pancreastatin could exert its anti-insulin effect in the hepatocyte by interrupting the stimulation of early insulin receptor signalling as a result of phosphorylation. This interaction might have a role in the mechanisms of insulin resistance. [Diabetologia (1999) Corresponding author: V. Sµnchez-Margalet, Department Medical Biochemistry and Molecular Biology, School of Medicine, Av. Sanchez Pizjuan 4, E-41 009 Seville, Spain Abbreviations: IRS-1, Insulin receptor substrate 1; IRS-2, insulin receptor substrate 2; PI3K, phosphatidyli...

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Modulation of insulin receptor signalling by pancreastatin in HTC hepatoma cells

Sánchez-Margalet

1999

Diabetologia

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“…Sánchez-Margalet és mtsai [26] a pancreastatin emelkedett szintjét fi gyelték meg gestatiós diabetesesekben kontrollegyénekhez képest. Ugyanebben a vizsgálatban pozitív korrelációt mutattak ki a pancrestatin és egyes katecholaminok (epinefrin és norepinefrin) szintje kö-zött.…”

Section: A Kromogranin-a éS Hasításából Keletkező Fehérjék Extracelluunclassified

“…A különböző endokrin szö-vetekben proteolitikus módosításokat követően alakul át extracellulárisan működő biológiailag aktív peptidformákká. A CgA-ból kialakuló fehérjék, mint a pancreastatin, a vasostatin, a WE-14 és további formák jelentős és specifi kus biológiai hatással rendelkeznek (1. táblázat) [26,27,28,29,30,34,35,45,47,48,49,50,51,52].…”

Section: Következtetésekunclassified

The role of chromogranin-A and its derived peptide, WE-14 in the development of type 1 diabetes mellitus

et al. 2015

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A kromogranin-A a granincsaládba tartozó fehérje, amelyet neuroendokrin sejtek termelnek és ezek szekréciós granulumaiból származik. A kromogranin-A-ból számos, mind ez idáig kevésbé tisztázott funkciójú fehérje képződik. Jelenleg a kromogranin-A vérben mérhető szintjének meghatározását elsősorban neuroendokrin daganatok laboratóriumi diagnosztikájában használják. A legfrissebb kutatások alapján azonban úgy tűnik, a kromogranin-A-ból szár-mazó WE-14 nevű fehérjének szerepe lehet az 1-es típusú cukorbetegség kialakulásában is. A WE-14 fehérje autoantigénként viselkedik a β-sejtek elpusztításában részt vevő T-sejtek számára. Ezt a mechanizmust eddig specifi kusan a nem obes diabetogén egerekben fi gyelték meg. Újabb eredmények alapján a WE-14 a diabeteses egerek mellett az újonnan diagnosztizált 1-es típusú cukorbetegeknél is az autoreaktív sejtek célpontjaként szolgál, amely reakció szö-veti transzglutamináz enzimmel fokozható. A szerzők jelen összefoglalójukban áttekintik a kromogranin-A bioszintézisét, biokémiai jellegzetességeit, szervezetbeli funkcióit, valamint ismertetik a cukorbetegség patomechanizmusá-ban betöltött szerepére vonatkozó jelen ismereteket. Orv. Hetil., 2015, 156(5), 163-170. Kulcsszavak: kromogranin-A, diabetes mellitus, tumormarker, WE-14The role of chromogranin-A and its derived peptide, WE-14 in the development of type 1 diabetes mellitus Chromogranin-A is a member of the granine protein family. It is produced in neuroendocrine cells via secretory granules. Many cleavage proteins are formed from chromogranin-A, from which some have well known biological activity, while the function of others is not yet fully known. Serum chromogranin-A levels are used in neuroendocrine tumour diagnostics. Recent studies showed that one of its cleavage protein, WE-14 may also play a role in the development of type 1 diabetes. WE-14 may function as an autoantigen for T-cells involved in the destruction of β-cells. This mechanism was previously observed only in non-obese diabetic mice. Novel results show that WE-14 also serves as a target for autoreactive cells in newly diagnosed type 1 diabetic patients as well, which reaction can be increased with transglutaminase. In this paper the authors summarize the recent knowledge about chromogranin-A and its potential role in the pathomechanism of type 1 diabetes mellitus.Keywords: chromogranin-A, diabetes mellitus, tumour marker, Z., Nagy, P., Patócs, A., Somogyi, A. [The role of chromogranin-A and its derived peptide, WE-14 in the development of type 1 diabetes mellitus]. Orv. Hetil., 2015, 156(5), 163-170.

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“…This hypothesis was substantiated by the data on the effect of PKC inhibition abrogating the inhibitory action of PST on insulin-stimulated tyrosine phosphorylation, PI3K activity, and GLUT4 translocation. Enhanced serine kinase activity has been described in insulin resistance (64), and PST may contribute to this pathophysiological feature along with other counterregulatory hormones, such as catecholamines, whose circulating levels correlate with those of PST (49)(50)(51).…”

Section: Pancreastatin Modulates Insulin Signalingmentioning

confidence: 99%

Pancreastatin modulates insulin signaling in rat adipocytes: mechanisms of cross-talk.

González-Yanes

Sánchez-Margalet

2000

Diabetes

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Pancreastatin (PST), a chromogranin A-derived peptide, has counterregulatory effects on insulin in the hepatocyte and the adipocyte, suggesting a possible role in insulin resistance. The mechanism of PST action on glucose and lipid metabolism is typical of a calcium-mobilizing hormone and involves a receptor G q /11 protein-phospholipase C (PLC)-␤ pathway. In the rat adipocyte, PST inhibits insulin-mediated glucose transport, glucose utilization, and lipid synthesis, and it has a lipolytic effect but stimulates basal and insulinstimulated protein synthesis. We have also recently studied the PST receptor-effector system in adipocyte membranes. To further investigate the mechanisms of PST effect on insulin action, we studied the cross-talk of PST with insulin signaling in the rat adipocyte. We found that PST inhibits insulin-stimulated GLUT4 translocation to the membrane, which may explain the reported inhibition of glucose transport. Tyrosine phosphorylation of the activated insulin receptor, insulin receptor substrate (IRS)-1, and p60-70 was also blunted, preventing their association with p85 phosphatidylinositol 3-kinase (PI3K) and their activity. The mechanism of this inhibition involves the activation of the "classical" protein kinase C isoforms and the serine phosphorylation of insulin receptor and IRS-1. On the other hand, PST activates the mitogen-activated protein kinase (MAPK) signaling module and enhances the effect of insulin. This pathway may account for the described effect of PST on protein synthesis. In conclusion, PST seems to inhibit the insulin-stimulated PI3K pathway in the adipocyte, whereas it activates the MAPK pathway. These data provide some clues to the PST cross-talk with insulin signaling that may explain the PST effects on glucose metabolism and protein synthesis. Diabetes 49:1288-1294, 2000 P ancreastatin (PST) is a chromogranin A-derived peptide (1,2) widely distributed throughout the neuroendocrine system (3-6). In islets, PST is present in ␤-, ␣-, and ␦-cells (4-6). PST may be secreted from the neuroendocrine cells after the precursor glycoprotein chromogranin A is processed (7,8). Postsecretory processing of chromogranin A also occurs (9,10). A PSTlike sequence has been found in different species, including the rat (11-13).PST was named after its first described effect inhibiting insulin secretion (1). However, many other different biologic effects have been reported (14). The best characterized effect of PST was studied in the rat liver (15), in which it has a glycogenolytic effect (16-18) and a counterregulatory effect to insulin (19). PST action in the liver is mediated by a specific G protein-coupled receptor (20-22), activating G␣ q/11 , which then activates PLC-␤3 in the plasma membrane (23). This signaling pathway leads to an increase in intracellular calcium concentration ([Ca 2+ ] i ) and activation of protein kinase C (PKC), which may finally mediate PST action (24,25). Recently, we found that PST also has metabolic effects in rat adipocytes (26). Thus, PST has a li...

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Increased plasma pancreastatin-like levels in gestational diabetes: correlation with catecholamine levels.

Abstract: Catecholamine and pancreastatin-like levels were found elevated in gestational diabetic subjects. These counterregulatory hormones may play a role in the insulin resistance syndrome of gestational diabetes.

Cited by 37 publications

References 2 publications

Modulation of insulin receptor signalling by pancreastatin in HTC hepatoma cells

Modulation of insulin receptor signalling by pancreastatin in HTC hepatoma cells

The role of chromogranin-A and its derived peptide, WE-14 in the development of type 1 diabetes mellitus

Pancreastatin modulates insulin signaling in rat adipocytes: mechanisms of cross-talk.

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