Decreased Insulin Secretion In Islets From Rats Fed A Low Protein Diet Is Associated With A Reduced Pkaα Expression

A low protein diet has been shown to affect the amount and activity of several enzymes and to decrease insulin secretion by islets isolated from rats fed such a diet. To understand the mechanisms involved in this phenomenon, we investigated the effects of forskolin, a stimulator of adenylyl cyclase, on insulin secretion by pancreatic islets from rats fed a normal (17%; NP) or low (6%; LP) protein diet for 8 wk. Isolated islets were incubated for 1 h in Krebs-bicarbonate solution containing 8.3 mmol glucose/L, with or without 10 μmol forskolin/L. The forskolin-induced insulin secretion was higher in islets from NP rats than in those from LP rats (P < 0.05). Western blotting revealed that the amount of the α catalytic subunit of protein kinase A (PKAα) was 35% lower in islets from LP rats than in islets from NP rats (P < 0.05). Moreover, PKAα mRNA expression was reduced by 30% in islets from LP rats (P < 0.05). Our results indicated a possible relationship between a low protein diet and a reduction in PKAα expression. These alterations in PKAα may be responsible in part for the decreased insulin secretion by islets from rats fed a low protein diet.13416367Cleator, J., Wilding, J., Obesity and diabetes (2003) Nurs. Times, 99, pp. 54-55Ferreira, F., Filiputti, E., Arantes, V.C., Stoppiglia, L.F., Araujo, E.P., Delghingaro-Augusto, V., Latorraca, M.Q., Carneiro, E.M., Decreased cholinergic stimulation of insulin secretion by islets from rats fed a low protein diet is associated with reduced protein kinaseα expression (2003) J. Nutr., 133, pp. 695-699Reis, M.A., Carneiro, E.M., Mello, M.A., Boschero, A.C., Saad, M.J., Velloso, L.A., Glucose-induced insulin secretion is impaired and insulin-induced phosphorylation of the insulin receptor and insulin receptor substrate-1 are increased in protein-deficient rats (1997) J. Nutr., 127, pp. 403-410Latorraca, M.Q., Reis, M.A., Carneiro, E.M., Mello, M.A., Velloso, L.A., Saad, M.J.A., Boschero, A.C., Protein deficiency and nutritional recovery modulate insulin secretion and the early steps of insulin action in rats (1998) J. Nutr., 128, pp. 1643-1649Swenne, I., Crace, C.J., Milner, R.D., Persistent impairment of insulin secretory response to glucose in adult rats after limited period of protein-calorie malnutrition early in life (1987) Diabetes, 36, pp. 454-458Escriva, F., Rodriguez, C., Cacho, J., Alvarez, C., Portha, B., Pascual-Leone, A.M., Glucose utilization and insulin action in adult rats submitted to prolonged food restriction (1992) Am. J. Physiol., 263, pp. E1-E7Okitolonda, W., Brichard, S.M., Henquin, J.C., Repercussions of chronic protein-calorie malnutrition on glucose homeostasis in the rat (1987) Diabetologia, 30, pp. 946-951Picarel-Blanchot, F., Alvarez, C., Bailbe, D., Pascual-Leone, A.M., Portha, B., Changes in insulin action and insulin secretion in the rat after dietary restriction early in life: Influence of food restriction versus low-protein food restriction (1995) Metabolism, 44, pp. 1519-1526Escriva, F., Kergoat, M., Bailbe, D., Pascual-Leone, A.M., Portha, B., Increased insulin action in the rat after protein malnutrition early in life (1991) Diabetologia, 34, pp. 559-564Levine, L.S., Wright, P.G., Marcus, F., Failure to secrete immunoreactive insulin by rats fed a low protein diet (1983) Acta Endocrinol., 102, pp. 240-245Swenne, I., Borg, L.A., Crace, C.J., Schnell Landstrom, A., Persistent reduction of pancreatic beta-cell mass after a limited period of protein-energy malnutrition in the young rat (1992) Diabetologia, 35, pp. 939-945Cherif, H., Reusens, B., Dahri, S., Remacle, C., A protein-restricted diet during pregnancy alters in vitro insulin secretion from islets of fetal Wistar rats (2001) J. Nutr., 131, pp. 1555-1559Araujo, E.P., Amaral, M.E., Souza, C.T., Bordin, S., Ferreira, F., Saad, M.J., Boschero, A.C., Velloso, L.A., Blockade of IRS1 in isolated rat pancreatic islets improves glucose-induced insulin secretion (2002) FEBS Lett., 531, pp. 437-442Satin, L.S., Kinard, T.A., Neurotransmitters and their receptors in the islets of Langerhans of the pancreas: What messages do acetylcholine, glutamate, and GABA transmit? (1998) Endocrine, 8, pp. 213-223Nesher, R., Anteby, E., Yedovizky, M., Warwar, N., Kaiser, N., Cerasi, E., Beta-cell protein kinases and the dynamics of the insulin response to glucose (2002) Diabetes, 51 (SUPPL. 1), pp. S68-S73Krebs, E.G., Beavo, J.A., Phosphorylation-dephosphorylation of enzymes (1979) Annu. Rev. Biochem., 48, pp. 923-959Meinkoth, J.L., Ji, Y., Taylor, S.S., Feramisco, J.R., Dynamics of the distribution of cyclic AMP-dependent protein kinase in living cells (1990) Proc. Natl. Acad. Sci. U.S.A., 87, pp. 9595-9599Takahashi, N., Kadowaki, T., Yazaki, Y., Miyashita, Y., Kasai, H., Multiple exocytotic pathways in pancreatic beta cells (1997) J. Cell. Biol., 138, pp. 55-64Griffioen, G., Thevelein, J.M., Molecular mechanisms controlling the localisation of protein kinase A (2002) Curr. Genet., 41, pp. 199-207Szecowka, J., Grill, V., Sandberg, E., Efendic, S., Effect of GIP on the secretion of insulin and somatostatin and the accumulation of cyclic AMP in vitro in the rat (1982) Acta Endocrinol., 99, pp. 416-421Thorens, B., GLP-1 and the control of insulin secretion (1994) J. Annu. Diabetol. Hotel Dieu, pp. 33-46Doyle, M.E., Egan, J.M., Pharmacological agents that directly modulate insulin secretion (2003) Pharmacol. Rev., 55, pp. 105-131Morgan, L.M., Hampton, S.M., Tredger, J.A., Cramb, R., Marks, V., Modifications of gastric inhibitory polypeptide (GIP) secretion in man by a high-fat diet (1988) Br. J. Nutr., 59, pp. 373-380O'Brien, L.J., Levac, K.D., Nagy, L.E., Moderate dietary protein and energy restriction modulate cAMP-dependent protein kinase activity in rat liver (1998) J. Nutr., 128, pp. 927-933Dumas, B.T., Watson, W.A., Biggs, H.G., Albumin standards and the measurement of serum albumin with bromocresol green (1997) Clin. Chim. Acta, 258, pp. 21-30Heard, C.R., Frangi, S.M., Wright, P.M., Biochemical characteristics of different forms of protein-energy malnutrition in rats (1973) Proc. Nutr. Soc., 32, pp. 47A. , absWeinkove, C., Weinkove, E.A., Pimstone, B.L., Glucose tolerance and insulin release in malnourished rats (1976) Clin. Sci. Mol. Med., 50, pp. 153-163Bordin, S., Boschero, A.C., Carneiro, E.M., Atwater, I., Ionic mechanisms involved in the regulation of insulin secretion by muscarinic agonists (1995) J. Membr. Biol., 148, pp. 177-184Scott, A.M., Atwater, I., Rojas, E., A method for the simultaneous measurement of insulin release and B cell membrane potential in single mouse islets of Langerhans (1981) Diabetologia, 21, pp. 470-475Amaral, M.E., Ueno, M., Carvalheira, J.B., Carneiro, E.M., Velloso, L.A., Saad, M.J., Boschero, A.C., Prolactin-signal transduction in neonatal rat pancreatic islets and interaction with the insulin-signaling pathway (2003) Horm. Metab. Res., 35, pp. 282-289Kelley, G.G., Zawalich, K.C., Zawalich, W.S., Synergistic interaction of glucose and neurohumoral agonists to stimulate islet phosphoinositide hydrolysis (1995) Am. J. Physiol., 269, pp. E575-E582Verspohl, E.J., Tacke, R., Mutschler, E., Lambrecht, G., Muscarinic receptor subtypes in rat pancreatic islets: Binding and functional studies (1990) Eur. J. Pharmacol., 178, pp. 303-311Bradford, M.M., A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding (1976) Anal. Biochem., 72, pp. 248-254Eickhoff, B., Korn, B., Schick, M., Poustka, A., Van Der Bosch, J., Normalization of array hybridization experiments in differential gene expression analysis (1999) Nucleic Acids Res., 27, pp. e33. , absHeard, C.R., The effects of protein-energy malnutrition on blood glucose homeostasis (1978) World Rev. Nutr. Diet., 30, pp. 107-147Claeyssens, S., Lavoinne, A., Vaillant, C., Rakotomanga, J.A., Bois-Joyeux, B., Peret, J., Metabolic changes during early starvation in rats fed a low-protein diet in the postweaning growth period (1992) Metabolism, 41, pp. 722-727Srinivasan, M., Aalinkeel, R., Song, F., Lee, B., Laychock, S.G., Patel, M.S., Adaptive changes in insulin secretion by islets from neonatal rats raised on a high-carbohydrate formula (2000) Am. J. Physiol., 279, pp. E1347-E1357Jones, P.M., Persaud, S.J., Protein kinases, protein phosphorylation, and the regulation of insulin secretion from pancreatic beta-cells (1998) Endocr. Rev., 19, pp. 429-461Wang, X., Zhou, J., Doyle, M.E., Egan, J.M., Glucagon-like peptide-1 causes pancreatic duodenal homeobox-1 protein translocation from the cytoplasm to the nucleus of pancreatic beta-cells by a cyclic adenosine monophosphate/protein kinase A-dependent mechanism (2001) Endocrinology, 142, pp. 1820-1827Yamazaki, T., Komuro, I., Zou, Y., Kudoh, S., Mizuno, T., Hiroi, Y., Shiojima, I., Yazaki, Y., Protein kinase A and protein kinase C synergistically activate the Raf-1 kinase/mitogen-activated protein kinase cascade in neonatal rat cardiomyocytes (1997) J. Mol. Cell. Cardiol., 29, pp. 2491-2501Huang, C.J., Feltkamp, D., Nilsson, S., Gustafsson, J.A., Synergistic activation of RLD-1 by agents triggering PKA and PKC dependent signalling (1998) Biochem. Biophys. Res. Commun., 243, pp. 657-663Wei, Y., Tae, N., Tatsuya, F., Hiroyoshi, H., Takao, S., Yasuharu, S., Ighiro, N., Synergism of protein kinase A, protein kinase C, and myosin light-chain kinase in the secretory cascade of the pancreatic B-cell (2000) Diabetes, 49, pp. 945-952Simonsson, E., Karlsson, S., Ahren, B., The cyclic AMP-protein kinase A pathway restrains islet phospholipase A2 activation (2000) Biochem. Biophys. Res. Commun., 269, pp. 242-246Ammon, H.P., Muller, A.B., Effect of forskolin on islet cyclic AMP, insulin secretion, blood glucose and intravenous glucose tolerance in rats (1984) Naunyn-Schmiedebergs Arch. Pharmakol., 326, pp. 364-367Stephen, L.L., Nagy, L.E., Very low protein diets induce a rapid decrease in hepatic cAMP-dependent protein kinase followed by a lower increase in adenylyl cyclase activity in rats (1996) J. Nutr., 126, pp. 1799-1807Bruhat, A., Jousse, C., Fafournoux, P., Amino acid limitation regulates gene expression (1999) Proc. Nutr. Soc., 58, pp. 625-632Jousse, C., Bruhat, A., Fafournoux, P., Amino acid regulation of gene expression (1999) Curr. Opin. Clin. Nutr. Metab. Care, 2, pp. 297-301Jousse, C., Bruhat, A., Ferrara, M., Fafournoux, P., Evidence for multiple signaling pathways in the regulation of gene expression by amino acids in human cell lines (2000) J. Nutr., 130, pp. 1555-1560Harrison, A.P., Tivey, D.R., Clausen, T., Duchamp, C., Dauncey, M.J., Role of thyroid hormones in early postnatal development of skeletal muscle and its implications for undernutrition (1996) Br. J. Nutr., 76, pp. 841-855Jahnsen, T., Lohmann, S.M., Walter, U., Hedin, L., Richards, J.S., Purification and characterization of hormone-regulated isoforms of the regulatory subunit of type II cAMP-dependent protein kinase from rat ovaries (1985) J. Biol. Chem., 260, pp. 15980-15987Oyen, O., Sandberg, M., Eskild, W., Levy, F.O., Knutsen, G., Beebe, S., Hansson, V., Jahnsen, T., Differential regulation of messenger ribonucleic acids for specific subunits of cyclic adenosine 3′, 5′-monophosphate (cAMP)-dependent protein kinase by cAMP in rat Sertoli cells (1988) Endocrinology, 122, pp. 2658-2666Levy, F.O., Ree, A.H., Eikvar, L., Govindan, M.V., Jahnsen, T., Hansson, V., Glucocorticoid receptors and glucocorticoid effects in rat Sertoli cells (1989) Endocrinology, 124, pp. 430-436Tasken, K.A., Knutsen, H.K., Eikvar, L., Tasken, K., Eskild, W., Jahnsen, T., Hansson, V., Protein kinase C activation by 12-O-tetradecanoyl-phorbol 13-acetate modulates messenger ribonucleic acid levels for two of the regulatory subunits of 3′, 5′-cyclic adenosine monophosphate-dependent protein kinases (RII beta and RI alpha) via multiple and distinct mechanisms (1992) Endocrinology, 130, pp. 1271-1280Tasken, K., Kvale, D., Hansson, V., Jahnsen, T., Protein kinase C activation selectively increases mRNA levels for one of the regulatory subunits (RI alpha) of cAMP-dependent protein kinases in HT-29 cells (1990) Biochem. Biophys. Res. Commun., 172, pp. 409-414Reeves, P.G., Nielsen, F.H., Fahey Jr., C.G., AIN-93 purified diets for laboratory rodents: Report of the American Institute of Nutrition ad hoc working committee on the reformulation of the AIN-76 rodent diet (1993) J. Nutr., 123, pp. 1939-195