34 research outputs found
Plasma glucose regulation and insulin secretion in hypertriglyceridemic mice
In this study, we examined glucose homeostasis and insulin secretion in transgenic mice overexpressing the human apolipoprotein CIII gene (apo CIII tg). These mice have elevated plasma levels of triglycerides, FFA and cholesterol compared to control mice. The body weight, plasma glucose, and insulin levels, glucose disappearance rates, areas under the ipGTT curve for adult (4-8 mo. old) and aged (20-24 mo. old) apo CIII tg mice and the determination of insulin during the ipGTT were riot different from those of control mice. However, an additional elevation of plasma FFA by treatment with heparin for 2-4h impaired the ipGTT responses in apo CIII tg mice compared to saline-treated mice. The glucose disappearance rate in heparin-treated transgenic mice was slightly lower than in heparin-treated controls. Glucose (22.2 mmol/l) stimulated insulin secretion in isolated islets to the same extent in saline-treated control and apo CIII tg mice. in islets from heparin-treated apo CIII tg mice, the insulin secretion at 2.8 and 22.2 mmol glucose/l was lower than in heparin-treated control mice. In conclusion, hypertriglyceridemia per se or a mild elevation in FFA did not affect insulin secretion or insulin resistance in adult or aged apo CIII tg mice. Nonetheless, an additional elevation of FFA induced by heparin in hypertriglyceridemic mice impaired the ipGTT by reducing insulin secretion.341212
Beta cell compensation for insulin resistance in Zucker fatty rats: increased lipolysis and fatty acid signalling.
Aims/hypothesis The aim of this study was to determine the role of fatty acid signalling in islet beta cell compensation for insulin resistance in the Zucker fatty fa/fa (ZF) rat, a genetic model of severe obesity, hyperlipidaemia and insulin resistance that does not develop diabetes. Materials and methods NEFA augmentation of insulin secretion and fatty acid metabolism were studied in isolated islets from ZF and Zucker lean (ZL) control rats. Results Exogenous palmitate markedly potentiated glucose-stimulated insulin secretion (GSIS) in ZF islets, allowing robust secretion at physiological glucose levels (5-8 mmol/l). Exogenous palmitate also synergised with glucagon-like peptide-1 and the cyclic AMP-raising agent forskolin to enhance GSIS in ZF islets only. In assessing islet fatty acid metabolism, we found increased glucose-responsive palmitate esterification and lipolysis processes in ZF islets, suggestive of enhanced triglyceride-fatty acid cycling. Interruption of glucose-stimulated lipolysis by the lipase inhibitor Orlistat (tetrahydrolipstatin) blunted palmitate-augmented GSIS in ZF islets. Fatty acid oxidation was also higher at intermediate glucose levels in ZF islets and steatotic triglyceride accumulation was absent. Conclusions/interpreation The results highlight the potential importance of NEFA and glucoincretin enhancement of insulin secretion in beta cell compensation for insulin resistance. We propose that coordinated glucose-responsive fatty acid esterification and lipolysis processes, suggestive of triglyceride-fatty acid cycling, play a role in the coupling mechanisms of glucose-induced insulin secretion as well as in beta cell compensation and the hypersecretion of insulin in obesity
Gene Expression Profiles of Beta-Cell Enriched Tissue Obtained by Laser Capture Microdissection from Subjects with Type 2 Diabetes
Background: Changes in gene expression in pancreatic beta-cells from type 2 diabetes (T2D) should provide insights into their abnormal insulin secretion and turnover. Methodology/Principal Findings: Frozen sections were obtained from cadaver pancreases of 10 control and 10 T2D human subjects. Beta-cell enriched samples were obtained by laser capture microdissection (LCM). RNA was extracted, amplified and subjected to microarray analysis. Further analysis was performed with DNA-Chip Analyzer (dChip) and Gene Set Enrichment Analysis (GSEA) software. There were changes in expression of genes linked to glucotoxicity. Evidence of oxidative stress was provided by upregulation of several metallothionein genes. There were few changes in the major genes associated with cell cycle, apoptosis or endoplasmic reticulum stress. There was differential expression of genes associated with pancreatic regeneration, most notably upregulation of members of the regenerating islet gene (REG) family and metalloproteinase 7 (MMP7). Some of the genes found in GWAS studies to be related to T2D were also found to be differentially expressed. IGF2BP2, TSPAN8, and HNF1B (TCF2) were upregulated while JAZF1 and SLC30A8 were downregulated. Conclusions/Significance: This study made possible by LCM has identified many novel changes in gene expression tha
Moderate calorie restriction to achieve normal weight reverses β-cell dysfunction in diet-induced obese mice: involvement of autophagy
High Passage MIN6 Cells Have Impaired Insulin Secretion with Impaired Glucose and Lipid Oxidation
Type 2 diabetes is a metabolic disorder characterized by the inability of beta-cells to secrete enough insulin to maintain glucose homeostasis. MIN6 cells secrete insulin in response to glucose and other secretagogues, but high passage (HP) MIN6 cells lose their ability to secrete insulin in response to glucose. We hypothesized that metabolism of glucose and lipids were defective in HP MIN6 cells causing impaired glucose stimulated insulin secretion (GSIS). HP MIN6 cells had no first phase and impaired second phase GSIS indicative of global functional impairment. This was coupled with a markedly reduced ATP content at basal and glucose stimulated states. Glucose uptake and oxidation were higher at basal glucose but ATP content failed to increase with glucose. HP MIN6 cells had decreased basal lipid oxidation. This was accompanied by reduced expressions of Glut1, Gck, Pfk, Srebp1c, Ucp2, Sirt3, Nampt. MIN6 cells represent an important model of beta cells which, as passage numbers increased lost first phase but retained partial second phase GSIS, similar to patients early in type 2 diabetes onset. We believe a number of gene expression changes occurred to produce this defect, with emphasis on Sirt3 and Nampt, two genes that have been implicated in maintenance of glucose homeostasis
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
Circulating lipids are lowered but pancreatic islet lipid metabolism and insulin secretion are unaltered in exercise-trained female rats.
Deteriorating islet beta-cell function is key in the progression of an impaired glucose tolerance state to overt type 2 diabetes (T2D), a transition that can be delayed by exercise. We have previously shown that trained rats are protected from heart ischemia-reperfusion injury in correlation with an increase in cardiac tissue fatty-acid oxidation. This trained metabolic phenotype, if induced in the islet, could also prevent beta-cell failure in the pathogenesis of T2D. To assess the effect of training on islet lipid metabolism and insulin secretion, female Sprague-Dawley rats were exercised on a treadmill for 90 min/d, 4 d/week, for 10 weeks. Islet fatty-acid oxidation, the expression of key lipid metabolism genes, and glucose-stimulated insulin secretion were determined in freshly isolated islets from trained and sedentary control rats after a 48 h rest period from the last exercise. Although this moderate training reduced plasma glycerol, free fatty acids, and triglyceride levels by about 40%, consistent with reduced lipolysis from adipose tissue, it did not alter islet fatty-acid oxidation, nor the islet expression of key transcription factors and enzymes of lipid metabolism. The training also had no effect on glucose-stimulated insulin secretion or its amplification by free fatty acids. In summary, chronic exercise training did not cause an intrinsic change in islet lipid metabolism. Training did, however, substantially reduce the exposure of islets to exogenous lipid, thereby providing a potential mechanism by which exercise can prevent islet beta-cell failure leading to T2D
Decreased insulin secretion in islets from rats fed a low protein diet is associated with a reduced PKA alpha 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 mumol 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 alpha catalytic subunit of protein kinase A (PKAalpha) was 35% lower in islets from LP rats than in islets from NP rats (P < 0.05). Moreover, PKAalpha 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 PKAalpha expression. These alterations in PKAalpha may be responsible in part for the decreased insulin secretion by islets from rats fed a low protein diet.1341636
A low protein diet alters gene expression in rat pancreatic islets
Insulin secretion is regulated mainly by circulating nutrients, particularly glucose, and is also modulated by hormonal and neuronal inputs. Nutritional alterations during fetal and early postnatal periods, induced by either low protein or energy-restricted diets, produce beta-cell dysfunction. As a consequence, insulin secretion in response to different secretagogues is reduced, as is the number of beta-cells and the size and vascularization of islets. In this study, we used a cDNA macroarray technique and RT-PCR to assess the pattern of gene expression in pancreatic islets from rats fed isocaloric low (6 g/100 g, LP) and normal (17 g/100 g, NP) protein diets, after weaning. Thirty-two genes related to metabolism, neurotransmitter receptors, protein trafficking and targeting, intracellular kinase network members and hormones had altered expression (up- or down-regulated). RT-PCR confirmed the macroarray results for five selected genes, i.e., clusterin, secretogranin II precursor, eukaryotic translation initiation factor 2, phospholipase A(2) and glucose transporter. Thus, cDNA macroarray analysis revealed significant changes in the gene expression pattern in rats fed a low protein diet after weaning. The range of proteins affected indicated that numerous mechanisms are involved in the intracellular alterations in the endocrine pancreas, including impaired glucose-induced insulin secretion.134232132
Prolactin-modulated gene expression profiles in pancreatic islets from adult female rats
The effects of prolactin (PRL) on transcript profile expression in 24 h cultured pancreatic adult rat islets were investigated by cDNA expression array analysis to identify possible candidate mRNA species that encode proteins involved in the maturation and growth of the endocrine pancreas. The expression of 54 out of 588 genes was altered by treatment with PRL. The differentially expressed transcripts identified were distributed in six main categories involved in cell proliferation and differentiation, namely, cell cycle regulation, signal transduction, transcription factors and coactivators, translational machinery, Ca2+-mediated exocytosis, and immuno-response. Treatment with PRL also reduced the expression of genes related to apoptosis. Several genes, whose expression was previously not known to be modulated by PRL were also identified including macrophage migration inhibitory factor and Ca2+/calmodulin-dependent protein kinase IV. These genes have recently been shown to play a crucial role in insulin secretion and insulin gene expression, respectively. Treatment with PRL also modified the expression of AKT2 and bone morphogenetic protein receptor 1A that control glucose homeostasis and directly affect the behavior of endocrine pancreas and/or the sensitivity of target tissues to insulin. In conclusion, PRL induces several patterns of gene expression in pancreatic islet cells. The analysis of these different patterns will be useful for understanding the complex mechanism of action of PRL in the maturation and differentiation of pancreatic islets. (C) 2004 Elsevier Ireland Ltd. All rights reserved.22041671415