Altered glucose homeostasis and hepatic function in obese mice deficient for both kinin receptor genes

The Kallikrein-Kinin System (KKS) has been implicated in several aspects of metabolism, including the regulation of glucose homeostasis and adiposity. Kinins and des-Arg-kinins are the major effectors of this system and promote their effects by binding to two different receptors, the kinin B2 and B1 receptors, respectively. To understand the influence of the KKS on the pathophysiology of obesity and type 2 diabetes (T2DM), we generated an animal model deficient for both kinin receptor genes and leptin (obB1B2KO). Six-month-old obB1B2KO mice showed increased blood glucose levels. Isolated islets of the transgenic animals were more responsive to glucose stimulation releasing greater amounts of insulin, mainly in 3-month-old mice, which was corroborated by elevated serum C-peptide concentrations. Furthermore, they presented hepatomegaly, pronounced steatosis, and increased levels of circulating transaminases. This mouse also demonstrated exacerbated gluconeogenesis during the pyruvate challenge test. The hepatic abnormalities were accompanied by changes in the gene expression of factors linked to glucose and lipid metabolisms in the liver. Thus, we conclude that kinin receptors are important for modulation of insulin secretion and for the preservation of normal glucose levels and hepatic functions in obese mice, suggesting a protective role of the KKS regarding complications associated with obesity and T2DM

Taurine Supplementation: Involvement Of Cholinergic/phospholipase C And Protein Kinase A Pathways In Potentiation Of Insulin Secretion And Ca 2+ Handling In Mouse Pancreatic Islets

Taurine (TAU) supplementation increases insulin secretion in response to high glucose concentrations in rodent islets. This effect is probably due to an increase in Ca2+ handling by the islet cells. Here, we investigated the possible involvement of the cholinergic/phospholipase C (PLC) and protein kinase (PK) A pathways in this process. Adult mice were fed with 2% TAU in drinking water for 30d. The mice were killed and pancreatic islets isolated by the collagenase method. Islets from TAU-supplemented mice showed higher insulin secretion in the presence of 83mm-glucose, 100μm-carbachol (Cch) and 1mm-3-isobutyl-1-methyl-xanthine (IBMX), respectively. The increase in insulin secretion in response to Cch in TAU islets was accompanied by a higher intracellular Ca2+ mobilisation and PLCβ2 protein expression. The Ca2+ uptake was higher in TAU islets in the presence of 83mm-glucose, but similar when the islets were challenged by glucose plus IBMX. TAU islets also showed an increase in the expression of PKA protein. This protein may play a role in cation accumulation, since the amount of Ca 2+ in these islets was significantly reduced by the PKA inhibitors: N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinoline sulfonamide (H89) and PK inhibitor-(6-22)-amide (PKI). In conclusion, TAU supplementation increases insulin secretion in response to glucose, favouring both influx and internal mobilisation of Ca2+, and these effects seem to involve the activation of both PLC-inositol-1,4,5-trisphosphate and cAMP-PKA pathways. © The Authors 2010.104811481155Jones, P.M., Persaud, S.J., Protein kinases, protein phosphorylation, and the regulation of insulin secretion from pancreatic β-cells (1998) Endocr Rev, 19, pp. 429-461Tengholm, A., Gylfe, E., Oscillatory control of insulin secretion (2009) Mol Cell Endocrinol, 297, pp. 58-72Rorsman, P., Renström, E., Insulin granule dynamics in pancreatic b cells (2003) Diabetologia, 46, pp. 1029-1045Gromada, J., Høy, M., Renström, E., CaM kinase II-dependent mobilization of secretory granules underlies acetylcholine-induced stimulation of exocytosis in mouse pancreatic B-cells (1999) J Physiol, 518, pp. 745-759Leech, C.A., Castonguay, M.A., Habener, J.F., Expression of adenylyl cyclase subtypes in pancreatic β-cells (1999) Biochem Biophys Res Commun, 254, pp. 703-706Delmeire, D., Flamez, D., Hinke, S.A., Type VIII adenylyl cyclase in rat b cells: Coincidence signal detector/generator for glucose and GLP-1 (2003) Diabetologia, 46, pp. 1383-1393Rhee, S.G., Regulation of phosphoinositide-specific phospholipase C (2001) Annu Rev Biochem, 70, pp. 281-312Thore, S., Dyachok, O., Gylfe, E., Feedback activation of phospholipase C via intracellular mobilization and storeoperated influx of Ca2+ in insulin-secreting β-cells (2005) J Cell Sci, 118, pp. 4463-4471Thore, S., Wuttke, A., Tengholm, A., Rapid turnover of phosphatidylinositol-4,5-bisphosphate in insulin-secreting cells mediated by Ca2+ and the ATP-to-ADP ratio (2007) Diabetes, 56, pp. 818-826Liu, Y.J., Gylfe, E., Store-operated Ca2+ entry in insulinreleasing pancreatic β-cells (1997) Cell Calcium, 22, pp. 277-286Berridge, M.J., Bootman, M.D., Roderick, H.L., Calcium signalling: Dynamics, homeostasis and remodelling (2003) Nat Rev Mol Cell Biol, 4, pp. 517-529Ammala, C., Eliasson, L., Bokvist, K., Exocytosis elicited by action potentials and voltage-clamp calcium currents in individual mouse pancreatic B-cells (1993) J Physiol, 472, pp. 665-688Leiser, M., Fleischer, N., CAMP-dependent phosphorylation of the cardiac-type a1 subunit of the voltage-dependent Ca2+ channel in a murine pancreatic β-cell line (1996) Diabetes, 45, pp. 1412-1418Gao, T., Yatani, A., Dell'Acqua, M.L., CAMPdependent regulation of cardiac L-type Ca2+ channels requires membrane targeting of PKA and phosphorylation of channel subunits (1997) Neuron, 19, pp. 185-196Dyachok, O., Gylfe, E., Ca2+-induced Ca2+ release via inositol 1,4,5-trisphosphate receptors is amplified by protein kinase A and triggers exocytosis in pancreatic β-cells (2004) J Biol Chem, 279, pp. 45455-45461Grapengiesser, E., Gylfe, E., Hellman, B., Cyclic AMP as a determinant for glucose induction of fast Ca2+ oscillations in isolated pancreatic β-cells (1991) J Biol Chem, 266, pp. 12207-12210Seino, S., Shibasaki, T., PKA-dependent and PKAindependent pathways for cAMP-regulated exocytosis (2005) Physiol Rev, 85, pp. 1303-1342Hatakeyama, H., Kishimoto, T., Nemoto, T., Rapid glucose sensing by protein kinase A for insulin exocytosis in mouse pancreatic islets (2006) J Physiol, 570, pp. 271-282Schaffer, S., Takahashi, K., Azuma, J., Role of osmoregulation in the actions of taurine (2000) Amino Acids, 19, pp. 527-546Satoh, H., Cardiac actions of taurine as a modulator of the ion channels (1998) Adv Exp Med Biol, 442, pp. 121-128Satoh, H., Sperelakis, N., Review of some actions of taurine on ion channels of cardiac muscle cells and others (1998) Gen Pharmacol, 30, pp. 451-463Palmi, M., Youmbi, G.T., Fusi, F., Potentiation of mitochondrial Ca2+ sequestration by taurine (1999) Biochem Pharmacol, 58, pp. 1123-1131Lee, S.H., Lee, H.Y., Kim, S.Y., Enhancing effect of taurine on glucose response in UCP2-overexpressing β cells (2004) Diabetes Res Clin Pract, 66 (SUPPL. 1), pp. S69-S74Park, E.J., Bae, J.H., Kim, S.Y., Inhibition of ATPsensitive K+ channels by taurine through a benzamido-binding site on sulfonylurea receptor 1 (2004) Biochem Pharmacol, 67, pp. 1089-1096Cherif, H., Reusens, B., Dahri, S., Stimulatory effects of taurine on insulin secretion by fetal rat islets cultured in vitro (1996) J Endocrinol, 151, pp. 501-506Carneiro, E.M., Latorraca, M.Q., Araujo, E., Taurine supplementation modulates glucose homeostasis and islet function (2009) J Nutr. Biochem, 20, pp. 503-511Ribeiro, R.A., Bonfleur, M.L., Amaral, A.G., Taurine supplementation enhances nutrient-induced insulin secretion in pancreatic mice islets (2009) Diabetes Metab Res Rev, 25, pp. 370-379Loizzo, A., Carta, S., Bennardini, F., Neonatal taurine administration modifies metabolic programming in male mice (2007) Early Hum Dev, 83, pp. 693-696Dyachok, O., Idevall-Hagren, O., Sagetorp, J., Glucose-induced cyclic AMP oscillations regulate pulsatile insulin secretion (2008) Cell Metab, 8, pp. 26-37Scott, 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. 470-475Bidlingmeyer, B.A., Cohen, S.A., Tarvin, T.L., A new, rapid, high-sensitivity analysis of amino acids in food type samples (1987) J Assoc Off Anal Chem, 70, pp. 241-247Bradford, 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. 248-254Bustamante, J., Lobo, M.V., Alonso, F.J., An osmoticsensitive taurine pool is localized in rat pancreatic islet cells containing glucagon and somatostatin (2001) Am J Physiol Endocrinol Metab, 281, pp. E1275-E1285Niwa, T., Matsukawa, Y., Senda, T., Acetylcholine activates intracellular movement of insulin granules in pancreatic β-cells via inositol trisphosphate-dependent [correction of triphosphate-dependent] mobilization of intracellular Ca2+ (1998) Diabetes, 47, pp. 1699-1706Dyachok, O., Isakov, Y., Sagetorp, J., Oscillations of cyclic AMP in hormone-stimulated insulin-secreting β-cells (2006) Nature, 439, pp. 349-352Rajan, A.S., Hill, R.S., Boyd III, A.E., Effect of rise in cAMP levels on Ca2+ influx through voltage-dependent Ca2+ channels in HIT cells second-messenger synarchy in β-cells (1989) Diabetes, 38, pp. 874-880Mundina-Weilenmann, C., Chang, C.F., Gutierrez, L.M., Demonstration of the phosphorylation of dihydropyridine- sensitive calcium channels in chick skeletal muscle and the resultant activation of the channels after reconstitution (1991) J Biol Chem, 266, pp. 4067-4073Bourinet, E., Charnet, P., Tomlinson, W.J., Voltagedependent facilitation of a neuronal a1C L-type calcium channel (1994) Embo J, 13, pp. 5032-5039Kamp, T.J., Hell, J.W., Regulation of cardiac L-type calcium channels by protein kinase A and protein kinase C (2000) Circ Res, 87, pp. 1095-110

Physical Exercise Introduced After Weaning Enhances Pancreatic Islet Responsiveness To Glucose And Potentiating Agents In Adult Msg-obese Rats

Physical exercise represents an alternative way to prevent and/or ameliorate chronic metabolic diseases. Disruption of sympathetic nervous system (SNS) activity contributes to adiposity in obese subjects. Here, we verified the preventive effect of swimming training upon adiposity, adrenal catecholamine storage, and pancreatic islet function in obese monosodium glutamate (MSG)-treated rats. Male neonatal Wistar rats received MSG (4 mg/g body weight) during the first 5 days of life and, at weaning, half of the rats were submitted to swimming training, 30 min/day, 3 days a week, until 90 days of age (exercised rats: MSGex). Half of the rats were used as controls (sedentary group, MSGsd). Exercise training (ET) decreased insulinemia and fat deposition in MSGex, and increased adrenal catecholamine content, compared with MSGsd rats. Insulinemia during the ivGTT was lower in MSGex rats, despite a lack of difference in glycemia. Swimming training enhanced insulin release in islets challenged by 2.8-8.3 mmol/l glucose, whereas, at supraphysiological glucose concentrations (11.1-16.7 mmol/l), MSGex islets secreted less insulin than MSGsd. No differences in insulin secretion were observed following l-arginine (Arg) or K+ stimuli. In contrast, islets from MSGex rats secreted more insulin when exposed to carbachol (100 μmol/l), forskolin (10 μmol/l), or IBMX (1 mmol/l) at 8.3 mmol/l glucose. Additionally, MSGex islets presented a better epinephrine inhibition upon insulin release. These results demonstrate that ET prevented the onset of obesity in MSG rats, probably by enhancing adrenal catecholamine levels. ET ameliorates islet responsiveness to several compounds, as well as insulin peripheral action. © Georg Thieme Verlag KG Stuttgart · New York.469609614Arrone, L.J., Mackintosh, R., Rosenbaum, M., Leibel, R.L., Hirsch, J., Cardiac autonomic nervous system activity in obese and never-obese young men (1997) Obes Res, 5, pp. 354-359Kahn, S.E., Prigeon, R.L., Schwartz, R.S., Fujimoto, W.Y., Knopp, R.H., Brunzell, J.D., Porte Jr., D., Obesity, body fat distribution, insulin sensitivity and Islet beta-cell function as explanations for metabolic diversity (2001) J Nutr, 131, pp. 354S-360SKahn, S.E., The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes (2003) Diabetologia, 46, pp. 3-19Bray, G.A., York, D.A., Hypothalamic and genetic obesity in experimental animals: An autonomic and endocrine hypothesis (1979) Physiol Rev, 59, pp. 719-809Bray, G.A., York, D.A., The MONA LISA hypothesis in the time of leptin (1998) Recent Prog Horm Res, 53, pp. 95-117. , discussion 117-118Scomparin, D.X., Gomes, R.M., Grassiolli, S., Rinaldi, W., Martins, A.G., De Oliveira, J.C., Gravena, C., De Freitas Mathias, P.C., Autonomic activity and glycemic homeostasis are maintained by precocious and low intensity training exercises in MSG-programmed obese mice (2009) Endocrine, 36, pp. 510-517Atef, N., Ktorza, A., Picon, L., Penicaud, L., Increased islet blood flow in obese rats: Role of the autonomic nervous system (1992) Am J Physiol, 262, pp. E736-E740Leigh, F.S., Kaufman, L.N., Young, J.B., Diminished epinephrine excretion in genetically obese (ob/ob) mice and monosodium glutamate-treated rats (1992) Int J Obes Relat Metab Disord, 16, pp. 597-604Weyer, C., Salbe, A.D., Lindsay, R.S., Pratley, R.E., Bogardus, C., Tataranni, P.A., Exaggerated pancreatic polypeptide secretion in Pima Indians: Can an increased parasympathetic drive to the pancreas contribute to hyperinsulinemia, obesity, and diabetes in humans (2001) Metabolism, 50, pp. 223-230Quilliot, D., Zannad, F., Ziegler, O., Impaired response of cardiac autonomic nervous system to glucose load in severe obesity (2005) Metabolism, 54, pp. 966-974Inoue, S., Bray, G.A., The effects of subdiaphragmatic vagotomy in rats with ventromedial hypothalamic obesity (1977) Endocrinology, 100, pp. 108-114Edvell, A., Lindstrom, P., Vagotomy in young obese hyperglycemic mice: Effects on syndrome development and islet proliferation (1998) Am J Physiol, 274, pp. E1034-E1039Balbo, S.L., Mathias, P.C., Bonfleur, M.L., Alves, H.F., Siroti, F.J., Monteiro, O.G., Ribeiro, F.B., Souza, A.C., Vagotomy reduces obesity in MSG-treated rats (2000) Res Commun Mol Pathol Pharmacol, 108, pp. 291-296Balbo, S.L., Grassiolli, S., Ribeiro, R.A., Bonfleur, M.L., Gravena, C., Brito Mdo, N., Andreazzi, A.E., Torrezan, R., Fat storage is partially dependent on vagal activity and insulin secretion of hypothalamic obese rat (2007) Endocrine, 31, pp. 142-148Scheurink, A.J., Steffens, A.B., Roossien, B., Balkan, B., Sympathoadrenal function in genetically obese Zucker rats (1992) Physiol Behav, 52, pp. 679-685Barnard, R.J., Wen, S.J., Exercise and diet in the prevention and control of the metabolic syndrome (1994) Sports Med, 18, pp. 218-228Olney, J.W., Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate (1969) Science, 164, pp. 719-721Olney, J.W., Glutamate-induced neuronal necrosis in the infant mouse hypothalamus. An electron microscopic study (1971) J Neuropathol Exp Neurol, 30, pp. 75-90Martins, A.C., Souza, K.L., Shio, M.T., Mathias, P.C., Lelkes, P.I., Garcia, R.M., Adrenal medullary function and expression of catecholamine-synthesizing enzymes in mice with hypothalamic obesity (2004) Life Sci, 74, pp. 3211-3222Nardelli, T.R., Ribeiro, R.A., Balbo, S.L., Vanzela, E.C., Carneiro, E.M., Boschero, A.C., Bonfleur, M.L., Taurine prevents fat deposition and ameliorates plasma lipid profile in monosodium glutamate-obese rats (2011) Amino Acids, 41, pp. 901-908Ribeiro, R.A., Balbo, S.L., Roma, L.P., Camargo, R.L., Barella, L.F., Vanzela, E.C., Carneiro, E.M., Bonfleur, M.L., Impaired muscarinic type 3 (M3) receptor/PKC and PKA pathways in islets form MSG-obese rats (2013) Mol Biol Rep, 40, pp. 4521-4528Scomparin, D.X., Grassiolli, S., Marcal, A.C., Gravena, C., Andreazzi, A.E., Mathias, P.C., Swim training applied at early age is critical to adrenal medulla catecholamine content and to attenuate monosodium L-glutamate-obesity onset in mice (2006) Life Sci, 79, pp. 2151-2156Andreazzi, A.E., Scomparin, D.X., Mesquita, F.P., Balbo, S.L., Gravena, C., De Oliveira, J.C., Rinaldi, W., Mathias, P.C., Swimming exercise at weaning improves glycemic control and inhibits the onset of monosodium L-glutamate-obesity in mice (2009) J Endocrinol, 201, pp. 351-359Scomparin, D.X., Grassiolli, S., Gomes, R.M., Torrezan, R., De Oliveira, J.C., Gravena, C., Pera, C.C., Mathias, P.C., Low-Intensity swimming training after weaning improves glucose and lipid homeostasis in MSG hypothalamic obese mice (2011) Endocr Res, 36, pp. 83-90Delghingaro-Augusto, V., Decary, S., Peyot, M.L., Latour, M.G., Lamontagne, J., Paradis-Isler, N., Lacharite-Lemieux, M., Bergeron, R., Voluntary running exercise prevents beta-cell failure in susceptible islets of the Zucker diabetic fatty rat (2012) Am J Physiol Endocrinol Metab, 302, pp. E254-E264Balbo, S.L., Bonfleur, M.L., Carneiro, E.M., Amaral, M.E., Filiputti, E., Mathias, P.C., Parasympathetic activity changes insulin response to glucose and neurotransmitters (2002) Diabetes Metab, 28, pp. 3S13-3S17. , discussion 13S108-13S112Harms, P.G., Ojeda, S.R., A rapid and simple procedure for chronic cannulation of the rat jugular vein (1974) J Appl Physiol, 36, pp. 391-392Ribeiro, R.A., Vanzela, E.C., Oliveira, C.A., Bonfleur, M.L., Boschero, A.C., Carneiro, E.M., Taurine supplementation: Involvement of cholinergic/phospholipase C and protein kinase A pathways in potentiation of insulin secretion and Ca2+ handling in mouse pancreatic islets (2010) Br J Nutr, 104, pp. 1148-1155Bernardis, L.L., Patterson, B.D., Correlation between 'Lee index' and carcass fat content in weanling and adult female rats with hypothalamic lesions (1968) J Endocrinol, 40, pp. 527-528Pollard, H.B., Ornberg, R., Levine, M., Brocklehurst, K., Forsberg, E., Lelkes, P.I., Morita, K., Regulation of secretion from adrenal chromaffin cells (1985) Physiologist, 28, pp. 247-254Gautam, D., Han, S.J., Hamdan, F.F., Jeon, J., Li, B., Li, J.H., Cui, Y., Wess, J., A critical role for beta cell M3 muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo (2006) Cell Metab, 3, pp. 449-461Theintz, G.E., The endocrine impact of sports (1986) Schweiz Med Wochenschr, 116, pp. 413-418Nonogaki, K., New insights into sympathetic regulation of glucose and fat metabolism (2000) Diabetologia, 43, pp. 533-549Holloszy, J.O., Exercise-induced increase in muscle insulin sensitivity (2005) J Appl Physiol, 99, pp. 338-343. , (1985)Frosig, C., Richter, E.A., Improved insulin sensitivity after exercise: Focus on insulin signaling (2009) Obesity (Silver Spring), 17, pp. S15-S20. , 03Corcoran, M.P., Lamon-Fava, S., Fielding, R.A., Skeletal muscle lipid deposition and insulin resistance: Effect of dietary fatty acids and exercise (2007) Am J Clin Nutr, 85, pp. 662-677Miranda, R.A., Branco, R.C., Gravena, C., Barella, L.F., Da Silva Franco, C.C., Andreazzi, A.E., De Oliveira, J.C., De Freitas Mathias, P.C., Swim training of monosodium L-glutamate-obese mice improves the impaired insulin receptor tyrosine phosphorylation in pancreatic islets (2013) Endocrine, 43, pp. 571-578Zoppi, C.C., Calegari, V.C., Silveira, L.R., Carneiro, E.M., Boschero, A.C., Exercise training enhances rat pancreatic islets anaplerotic enzymes content despite reduced insulin secretion (2011) Eur J Appl Physiol, 111, pp. 2369-2374Calegari, V.C., Zoppi, C.C., Rezende, L.F., Silveira, L.R., Carneiro, E.M., Boschero, A.C., Endurance training activates AMP-activated protein kinase, increases expression of uncoupling protein 2 and reduces insulin secretion from rat pancreatic islets (2011) J Endocrinol, 208, pp. 257-264Tsuchiya, M., Manabe, Y., Yamada, K., Furuichi, Y., Hosaka, M., Fujii, N.L., Chronic exercise enhances insulin secretion ability of pancreatic islets without change in insulin content in non-diabetic rats (2013) Biochem Biophys Res Commun, 430, 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Taurine Prevents Fat Deposition And Ameliorates Plasma Lipid Profile In Monosodium Glutamate-obese Rats

The aim of the present study was to evaluate the preventive effects of taurine (TAU) supplementation upon monosodium glutamate (MSG)-induced obesity. Rats treated during the first 5 days of life with MSG or saline were distributed into the following groups: control (CTL), CTL-treated with TAU (CTAU), MSG and MSG-supplemented with TAU (MTAU). CTAU and MTAU received 2.5% of TAU in their drinking water from 21 to 90 days of life. At the end of treatment, MSG and MTAU rats were hyperinsulinemic, glucose intolerant and insulin resistant, as judged by the HOMA index. MSG and MTAU rat islets secreted more insulin at 16.7 mM glucose compared to CTL. MSG rats also showed higher triglycerides (TG) and non-esterified fatty acids (NEFA) plasma levels, Lee Index, retroperitoneal and periepidydimal fat pads, compared with CTL, whereas plasma lipid concentrations and fat depots were lower in MTAU, compared with MSG rats. In addition, MSG rats had a higher liver TG content compared with CTL. TAU decreased liver TG content in both supplemented groups, but fat content only in MTAU rats. TAU supplementation did not change glucose homeostasis, insulin secretion and action, but reduced plasma and liver lipid levels in MSG rats. © Springer-Verlag 2010.414901908Anuradha, C.V., Balakrishnan, S.D., Taurine attenuates hypertension and improves insulin sensitivity in the fructose-fed rat: An animal model of insulin resistance (1999) Can J Physiol Pharmacol, 77, pp. 749-754Balbo, S.L., Mathias, P.C., Bonfleur, M.L., Alves, H.F., Siroti, F.J., Monteiro, O.G., Ribeiro, F.B., Souza, A.C., Vagotomy reduces obesity in MSG-treated rats (2000) Res Commun Mol Pathol Pharmacol, 108, pp. 291-296Balbo, S.L., Grassiolli, S., Ribeiro, R.A., Bonfleur, M.L., Gravena, C., Brito Mdo, N., Andreazzi, A.E., Torrezan, R., Fat storage is partially dependent on vagal activity and insulin secretion of hypothalamic obese rat (2007) Endocrine, 31, pp. 142-148Bernardis, L.L., Patterson, B.D., Correlation between 'Lee index' and carcass fat content in weanling and adult female rats with hypothalamic lesions (1968) J Endocrinol, 40, pp. 527-528Bonora, E., Targher, G., Alberiche, M., Bonadonna, R.C., Saggiani, F., Zenere, M.B., Monauni, T., Muggeo, M., Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: Studies in subjects with various degrees of glucose tolerance and insulin sensitivity (2000) Diabetes Care, 23, pp. 57-63Boujendar, S., Reusens, B., Merezak, S., Ahn, M.T., Arany, E., Hill, D., Remacle, C., Taurine supplementation to a low protein diet during foetal and early postnatal life restores a normal proliferation and apoptosis of rat pancreatic islets (2002) Diabetologia, 45, pp. 856-866Carneiro, E.M., Latorraca, M.Q., Araujo, E., Beltra, M., Oliveras, M.J., Navarro, M., Berna, G., Martin, F., Taurine supplementation modulates glucose homeostasis and islet function (2009) J Nutr Biochem, 20, pp. 503-511Chen, W., Matuda, K., Nishimura, N., Yokogoshi, H., The effect of taurine on cholesterol degradation in mice fed a high-cholesterol diet (2004) Life Sci, 74, pp. 1889-1898Cherif, H., Reusens, B., Dahri, S., Remacle, C., Hoet, J.J., Stimulatory effects of taurine on insulin secretion by fetal rat islets cultured in vitro (1996) J Endocrinol, 151, pp. 501-506Cherif, H., Reusens, B., Ahn, M.T., Hoet, J.J., Remacle, C., Effects of taurine on the insulin secretion of rat fetal islets from dams fed a low-protein diet (1998) J Endocrinol, 159, pp. 341-348Choi, M.J., Kim, J.H., Chang, K.J., The effect of dietary taurine supplementation on plasma and liver lipid concentrations and free amino acid concentrations in rats fed a high-cholesterol diet (2006) Adv Exp Med Biol, 583, pp. 235-242Dashti, N., The effect of low density lipoproteins, cholesterol, and 25-hydroxycholesterol on apolipoprotein B gene expression in HepG2 cells (1992) J Biol Chem, 267, pp. 7160-7169Dawson Jr., R., Acute and long lasting neurochemical effects of monosodium glutamate administration to mice (1983) Neuropharmacology, 22, pp. 1417-1419Duivenvoorden, I., Teusink, B., Rensen, P.C., Romijn, J.A., Havekes, L.M., Voshol, P.J., Apolipoprotein C3 deficiency results in dietinduced obesity and aggravated insulin resistance in mice (2005) Diabetes, 54, pp. 664-671Folch, J., Lees, M., Sloane Stanley, G.H., A simple method for the isolation and purification of total lipides from animal tissues (1957) J Biol Chem, 226, pp. 497-509Huxtable, R.J., Physiological actions of taurine (1992) Physiol Rev, 72, pp. 101-163Kahn, S.E., Prigeon, R.L., Schwartz, R.S., Fujimoto, W.Y., Knopp, R.H., Brunzell, J.D., Porte Jr., D., Obesity, body fat distribution, insulin sensitivity and islet beta-cell function as explanations for metabolic diversity (2001) J Nutr, 131, pp. 354S-360SKaniuk, N.A., Kiraly, M., Bates, H., Vranic, M., Volchuk, A., Brumell, J.H., Ubiquitinated-protein aggregates form in pancreatic betacells during diabetes-induced oxidative stress and are regulated by autophagy (2007) Diabetes, 56, pp. 930-939Kaplan, B., Karabay, G., Zagyapan, R.D., Ozer, C., Sayan, H., Duyar, I., Effects of taurine in glucose and taurine administration (2004) Amino Acids, 27, pp. 327-333Kulakowski, E.C., Maturo, J., Hypoglycemic properties of taurine: Not mediated by enhanced insulin release (1984) Biochem Pharmacol, 33, pp. 2835-2838Macho, L., Fickova, M., Jezova Zorad, S., Late effects of postnatal administration of monosodium glutamate on insulin action in adult rats (2000) Physiol Res, 49 (1 SUPPL.), pp. S79-S85Martins, A.C., Souza, K.L., Shio, M.T., Mathias, P.C., Lelkes, P.I., Garcia, R.M., Adrenal medullary function and expression of catecholamine- synthesizing enzymes in mice with hypothalamic obesity (2004) Life Sci, 74, pp. 3211-3222Matthews, D.R., Hosker, J.P., Rudenski, A.S., Naylor, B.A., Treacher, D.F., Turner, R.C., Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man (1985) Diabetologia, 28, pp. 412-419Maturo, J., Kulakowski, E.C., Taurine binding to the purified insulin receptor (1988) Biochem Pharmacol, 37, pp. 3755-3760Mizushima, S., Nara, Y., Sawamura, M., Yamori, Y., Effects of oral taurine supplementation on lipids and sympathetic nerve tone (1996) Adv Exp Med Biol, 403, pp. 615-622Murakami, S., Kondo, Y., Nagate, T., Effects of long-term treatment with taurine in mice fed a high-fat diet: Improvement in cholesterol metabolism and vascular lipid accumulation by taurine (2000) Adv Exp Med Biol, 483, pp. 177-186Murakami, S., Kondo, Y., Toda, Y., Kitajima, H., Kameo, K., Sakono, M., Fukuda, N., Effect of taurine on cholesterol metabolism in hamsters: Up-regulation of low density lipoprotein (LDL) receptor by taurine (2002) Life Sci, 70, pp. 2355-2366Nakaya, Y., Minami, A., Harada, N., Sakamoto, S., Niwa, Y., Ohnaka, M., Taurine improves insulin sensitivity in the Otsuka Long-Evans Tokushima Fatty rat, a model of spontaneous type 2 diabetes (2000) Am J Clin Nutr, 71, pp. 54-58Nandhini, A.T., 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Lower Expression Of Pkaα Impairs Insulin Secretion In Islets Isolated From Low-density Lipoprotein Receptor (ldlr -/-) Knockout Mice

Hypercholesterolemic low-density lipoprotein receptor knockout mice (LDLR -/-) show normal whole-body insulin sensitivity, but impaired glucose tolerance due to a reduced insulin secretion in response to glucose. Here, we investigate the possible mechanisms involved in such a defect in isolated LDLR -/- mice islets. Low-fat chow-fed female and male mice aged 20 weeks, LDLR -/- mice, and wild-type (WT) mice were used in this study. Static insulin secretion, cytoplasmatic Ca 2+ analysis, and protein expression were measured in islets isolated from LDLR -/- and WT mice. At basal (2.8 mmol/L) and stimulatory (11.1 mmol/L) glucose concentrations, the insulin secretion rates induced by depolarizing agents such as KCl, l-arginine, and tolbutamide were significantly reduced in LDLR -/- when compared with control (WT) islets. In addition, KCl-induced Ca 2+ influx at 2.8 mmol/L glucose was lower in LDLR -/- islets, suggesting a defect downstream of the substrate metabolism step of the insulin secretion pathway. Insulin secretion induced by the protein kinase A (PKA) activators forskolin and 3-isobutyl-1-methyl-xanthine, in the presence of 11.1 mmol/L glucose, was lower in LDLR -/- islets and was normalized in the presence of the protein kinase C pathway activators carbachol and phorbol 12-myristate 13-acetate. Western blotting analysis showed that phospholipase Cβ 2 expression was increased and PKAα was decreased in LDLR -/- compared with WT islets. Results indicate that the lower insulin secretion observed in islets from LDLR -/- mice at postprandial levels of glucose can be explained, at least in part, by the reduced expression of PKAα in these islets. © 2011 Elsevier Inc.60811581164Fujimoto, W.Y., Background and recruitment data for the U.S. Diabetes Prevention Program (2000) Diabetes Care, 23, pp. 11-B13Wilson, P.W., Diabetes mellitus and coronary heart disease (1998) Am J Kidney Dis, 32, pp. 89-100Haffner, S.M., Management of dyslipidemia in adults with diabetes (1998) Diabetes Care, 21 (1), pp. 160-178Ginsberg, H.N., Zhang, Y.-L., Hernandez-Ono, A., Regulation of plasma triglycerides in insulin resistance and diabetes (2005) Archives of Medical Research, 36 (3), pp. 232-240. , DOI 10.1016/j.arcmed.2005.01.005, PII S0188440905000068, Current Trends in DiabetesGinsberg, H.N., Lipoprotein physiology in nondiabetic and diabetic states. Relationship to atherogenesis (1991) Diabetes Care, 14, pp. 839-855Caparevic, Z., Kostic, N., Ilic, S., Oxidized LDL and C-reactive protein as markers for detection of accelerated atherosclerosis in type 2 diabetes (2006) Med Pregl, 59, pp. 160-164Cohen, M.P., Jin, Y., Lautenslager, G.T., Increased plasma glycated low-density lipoprotein concentrations in diabetes: A marker of atherogenic risk (2004) Diabetes Technology and Therapeutics, 6 (3), pp. 348-356. , DOI 10.1089/152091504774198043Breslow, J.L., Mouse models of atherosclerosis (1996) Science, 272 (5262), pp. 685-688Ishibashi, S., Brown, M.S., Goldstein, J.L., Gerard, R.D., Hammer, R.E., Herz, J., Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery (1993) Journal of Clinical Investigation, 92 (2), pp. 883-893Merat, S., Casanada, F., Sutphin, M., Palinski, W., Reaven, P.D., Western-type diets induce insulin resistance and hyperinsulinemia in LDL receptor-deficient mice but do not increase aortic atherosclerosis compared with normoinsulinemic mice in which similar plasma cholesterol levels are achieved by a fructose-rich diet (1999) Arteriosclerosis, Thrombosis, and Vascular Biology, 19 (5), pp. 1223-1230Schreyer, S.A., Vick, C., Lystig, T.C., LDL receptor but not apolipoprotein e deficiency increases diet-induced obesity and diabetes in mice (2002) Am J Physiol Endocrinol Metab, 282, pp. 207-E214Bonfleur, M.L., Vanzela, E.C., Ribeiro, R.A., Primary hypercholesterolaemia impairs glucose homeostasis and insulin secretion in low-density lipoprotein receptor knockout mice independently of high-fat diet and obesity (2010) Biochim Biophys Acta, 1801, pp. 183-190Scott, 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 (5), pp. 470-475Bradford, 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. 248-254Newton, A.C., Protein kinase C: Structural and spatial regulation by phosphorylation, cofactors, and macromolecular interactions (2001) Chemical Reviews, 101 (8), pp. 2353-2364. , DOI 10.1021/cr0002801Xia, F., Gao, X., Kwan, E., Lam, P.P.L., Chan, L., Sy, K., Sheu, L., Tsushima, R.G., Disruption of pancreatic β-cell lipid rafts modifies K v2.1 channel gating and insulin exocytosis (2004) Journal of Biological Chemistry, 279 (23), pp. 24685-24691. , DOI 10.1074/jbc.M314314200Schulla, V., Renstrom, E., Feil, R., Feil, S., Franklin, I., Gjinovci, A., Jing, X.-J., Hofmann, F., Impaired insulin secretion and glucose tolerance in β cell-selective Ca v1.2 Ca 2+ channel null mice (2003) EMBO Journal, 22 (15), pp. 3844-3854. , DOI 10.1093/emboj/cdg389Iwashima, Y., Abiko, A., Ushikubi, F., Hata, A., Kaku, K., Sano, H., Eto, M., Downregulation of the voltage-dependent calcium channel (VDCC) β-subunit mRNAs in pancreatic islets of type 2 diabetic rats (2001) Biochemical and Biophysical Research Communications, 280 (3), pp. 923-932. , DOI 10.1006/bbrc.2000.4122Straub, S.G., Sharp, G.W.G., Glucose-stimulated signaling pathways in biphasic insulin secretion (2002) Diabetes/Metabolism Research and Reviews, 18 (6), pp. 451-463. , DOI 10.1002/dmrr.329Gembal, M., Detimary, P., Gilon, P., Gao, Z.-Y., Henquin, J.-C., Mechanisms by which glucose can control insulin release independently from its action on adenosine triphosphate-sensitive K + channels in mouse B cells (1993) Journal of Clinical Investigation, 91 (3), pp. 871-880Gembal, M., Gilon, P., Henquin, J.C., Evidence that glucose can control insulin release independently from its action on ATP-sensitive K+ channels in mouse B cells (1992) J Clin Invest, 89, pp. 1288-1295Sato, Y., Aizawa, T., Komatsu, M., Dual functional role of membrane depolarization/Ca2+ influx in rat pancreatic B-cell (1992) Diabetes, 41, pp. 438-443Jones, P.M., Persaud, S.J., Protein kinases, protein phosphorylation, and the regulation of insulin secretion from pancreatic β-cells (1998) Endocrine Reviews, 19 (4), pp. 429-461Boschero, A.C., Szpak-Glasman, M., Carneiro, E.M., Oxotremorine-m potentiation of glucose-induced insulin release from rat islets involves M3 muscarinic receptors (1995) Am J Physiol, 268, pp. 336-E342Malaisse, W.J., Pipeleers, D.G., Levy, J., The stimulus-secretion coupling of glucose-induced insulin release. XVI. 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Early Onset Of Obesity Induces Reproductive Deficits In Female Rats

The incidence of obesity is increasing rapidly all over the world and results in numerous health detriments, including disruptions in reproduction. However, the mechanisms by which excess body fat interferes with reproductive functions are still not fully understood. After weaning, female rats were treated with a cafeteria diet or a chow diet (control group). Biometric and metabolic parameters were evaluated in adulthood. Reproductive parameters, including estradiol, progesterone, LH and prolactin during the proestrus afternoon, sexual behavior, ovulation rates and histological analysis of ovaries were also evaluated. Cafeteria diet was able to induce obesity in female rats by increasing body and fat pad weight, which resulted in increased levels of triglycerides, total cholesterol, LDL and induced insulin resistance. The cafeteria diet also negatively affected female reproduction by reducing the number of oocytes and preantral follicles, as well as the thickness of the follicular layer. Obese females did not show preovulatory progesterone and LH surges, though plasma estradiol and prolactin showed preovulatory surges similar to control rats. Nevertheless, sexual receptiveness was not altered by cafeteria diet. 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Short-term Calorie Restriction Improves Glucose Homeostasis In Old Rats: Involvement Of Ampk

The occurrence of metabolic disorders, such as diabetes, obesity, atherosclerosis, and hypertension, increases with age. Inappropriate food intake, when combined with genetic and hormonal factors, can trigger the occurrence of these diseases in aged organisms. This study investigated whether short-term calorie restriction (CR; 40% of the intake of control animals (CTL) for 21 days) benefits 1-year-old (CR1yr) and 2-year-old (CR2yr) Wistar rats, with regard to insulin secretion and action. Plasma insulin and the insulin secreted by isolated islets were measured with radioimmunoassay, and the insulin sensitivity of peripheral tissues was assessed with the intraperitoneal glucose tolerance test (IPGTT), intraperitoneal insulin tolerance test, and hepatic and muscle adenosine monophosphate-activated protein kinase (AMPK) phosphorylation measurements. Body weight, epididymal fat pad, epididymal fat pad/body weight index, plasma glucose, and insulin were lower in the CR1yr than in the control (CTL1yr) rats. Serum cholesterol, triglycerides, and protein, as well as hepatic and muscle glycogen content, were similar between the CR and CTL groups. The IPGTT was higher in CR2yr and CTL2yr rats than in CR1yr and CTL1yr rats, and insulin sensitivity was higher in CR1yr and CR2yr rats than in their respective CTLs. This was associated with an increase in hepatic and muscle AMPK phosphorylation. No differences in glucose-induced insulin secretion in the isolated islets were observed between CRs and their respective CTL rats. In conclusion, short-term calorie restriction provoked more severe alterations in CR1yr than CR2yr rats. The normoglycemia observed in both CR groups seems to be due to an increase in insulin sensitivity, with the involvement of liver and muscle AMPK.398895901Amaral, M.E., Ueno, M., Oliveira, C.A., Borsonello, N.C., Vanzela, E.C., Ribeiro, R.A., Reduced expression of SIRT1 is associated with diminished glucose-induced insulin secretion in islets from calorie-restricted rats (2011) J. Nutr. Biochem, 22 (6), pp. 554-559. , doi:10.1016/j.jnutbio.2010.04.010. PMID: 20801633Anderson, R.M., Weindruch, R., Metabolic reprogramming, caloric restriction and aging (2010) Trends Endocrinol. Metab, 21 (3), pp. 134-141. , doi:10.1016/j. tem.2009.11.005. PMID:20004110Assmann, A., Hinault, C., Kulkarni, R.N., Growth factor control of pancreatic islet regeneration and function (2009) Pediatr. Diabetes, 10 (1), pp. 14-32. , doi:10.1111/j.1399-5448.2008.00468.x. PMID:18828795Barzilai, N., Gabriely, I., The role of fat depletion in the biological benefits of caloric restriction (2001) J. 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PMID:12569120Kraegen, E.W., Saha, A.K., Preston, E., Wilks, D., Hoy, A.J., Cooney, G.J., Increased malonyl-CoA and diacylglycerol content and reduced AMPK activity accompany insulin resistance induced by glucose infusion in muscle and liver of rats (2006) Am. J. Physiol. Endocrinol. Metab, 290 (3), pp. E471-E479. , doi:10. 1152/ajpendo.00316.2005. PMID:16234268Liu, Y., Wan, Q., Guan, Q., Gao, L., Zhao, J., High-fat diet feeding impairs both the expression and activity of AMPKa in rats' skeletal muscle (2006) Biochem. Biophys. Res. Commun, 339 (2), pp. 701-707. , doi:10.1016/j.bbrc.2005.11.068. PMID: 16316631Lo, S., Russell, J.C., Taylor, A.W., Determination of glycogen in small tissue samples (1970) J. Appl. Physiol, 28 (2), pp. 234-236. , PMID:5413312Malandrucco, I., Pasqualetti, P., Giordani, I., Manfellotto, D., de Marco, F., Alegiani, F., Very-low-calorie diet: A quick therapeutic tool to improve _ cell function in morbidly obese patients with type 2 diabetes (2012) Am. J. Clin. 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Cholesterol Reduction Ameliorates Glucose-induced Calcium Handling And Insulin Secretion In Islets From Low-density Lipoprotein Receptor Knockout Mice

Aims/hypothesis Changes in cellular cholesterol level may contribute to beta cell dysfunction. Islets from low density lipoprotein receptor knockout (LDLR-/-) mice have higher cholesterol content and secrete less insulin than wild-type (WT) mice. Here, we investigated the association between cholesterol content, insulin secretion and Ca2 + handling in these islets. Methods Isolated islets from both LDLR-/- and WT mice were used for measurements of insulin secretion (radioimmunoassay), cholesterol content (fluorimetric assay), cytosolic Ca2 + level (fura-2AM) and SNARE protein expression (VAMP-2, SNAP-25 and syntaxin-1A). Cholesterol was depleted by incubating the islets with increasing concentrations (0-10 mmol/l) of methyl-beta-cyclodextrin (MβCD). Results The first and second phases of glucose-stimulated insulin secretion (GSIS) were lower in LDLR-/- than in WT islets, paralleled by an impairment of Ca2 + handling in the former. SNAP-25 and VAMP-2, but not syntaxin-1A, were reduced in LDLR -/- compared with WT islets. Removal of excess cholesterol from LDLR-/- islets normalized glucose- and tolbutamide-induced insulin release. Glucose-stimulated Ca2 + handling was also normalized in cholesterol-depleted LDLR-/- islets. Cholesterol removal from WT islets by 0.1 and 1.0 mmol/l MβCD impaired both GSIS and Ca2 + handling. In addition, at 10 mmol/l MβCD WT islet showed a loss of membrane integrity and higher DNA fragmentation. Conclusion Abnormally high (LDLR -/- islets) or low cholesterol content (WT islets treated with MβCD) alters both GSIS and Ca2 + handling. Normalization of cholesterol improves Ca2 + handling and insulin secretion in LDLR-/- islets. © 2013 Elsevier B.V.18314769775Perley, M.J., Kipnis, D.M., Plasma insulin responses to oral and intravenous glucose: Studies in normal and diabetic subjects (1967) J. Clin. Invest., 46, pp. 1954-1962Ginsberg, H.N., Diabetic dyslipidemia: Basic mechanisms underlying the common hypertriglyceridemia and low HDL cholesterol levels (1996) Diabetes, 45 (SUPPL. 3), pp. 27-S30Wilson, P.W., McGee, D.L., Kannel, W.B., Obesity, very low density lipoproteins, and glucose intolerance over fourteen years: The Framingham Study (1981) Am. J. Epidemiol., 114, pp. 697-704Lewis, G.F., Carpentier, A., Adeli, K., Giacca, A., Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes (2002) Endocr. Rev., 23, pp. 201-229Reaven, G.M., Chen, Y.D., Jeppesen, J., Maheux, P., Krauss, R.M., Insulin resistance and hyperinsulinemia in individuals with small, dense low density lipoprotein particles (1993) J. Clin. Invest., 92, pp. 141-146Cerf, M.E., High fat diet modulation of glucose sensing in the beta-cell (2007) Med. Sci. Monit., 13, pp. 12-RA17Eto, K., Yamashita, T., Matsui, J., Terauchi, Y., Noda, M., Kadowaki, T., Genetic manipulations of fatty acid metabolism in beta-cells are associated with dysregulated insulin secretion (2002) Diabetes, 51 (SUPPL. 3), pp. 414-S420Hao, M., Head, W.S., Gunawardana, S.C., Hasty, A.H., Piston, D.W., Direct effect of cholesterol on insulin secretion: A novel mechanism for pancreatic beta-cell dysfunction (2007) Diabetes, 56, pp. 2328-2338Brunham, L.R., Kruit, J.K., Pape, T.D., Timmins, J.M., Reuwer, A.Q., Vasanji, Z., Marsh, B.J., Hayden, M.R., Beta-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment (2007) Nat. Med., 13, pp. 340-347Ishikawa, M., Iwasaki, Y., Yatoh, S., Kato, T., Kumadaki, S., Inoue, N., Yamamoto, T., Shimano, H., Cholesterol accumulation and diabetes in pancreatic beta-cell-specific SREBP-2 transgenic mice: A new model for lipotoxicity (2008) J. Lipid Res., 49, pp. 2524-2534Bonfleur, M.L., Vanzela, E.C., Ribeiro, R.A., De Gabriel Dorighello, G., De França Carvalho, C.P., Collares-Buzato, C.B., Carneiro, E.M., De Oliveira, H.C., Primary hypercholesterolaemia impairs glucose homeostasis and insulin secretion in low-density lipoprotein receptor knockout mice independently of high-fat diet and obesity (2010) Biochim. Biophys. Acta, 1801, pp. 183-190De Souza, J.C., De Oliveira, C.A., Carneiro, E.M., Boschero, A.C., De Oliveira, H.C., Cholesterol toxicity in pancreatic islets from LDL receptor-deficient mice (2010) Diabetologia, 53, pp. 2461-2462. , (author reply 2463-2464)Ohvo-Rekilä, H., Ramstedt, B., Leppimäki, P., Slotte, J.P., Cholesterol interactions with phospholipids in membranes (2002) Prog. Lipid Res., 41, pp. 66-97Róg, T., Pasenkiewicz-Gierula, M., Effects of epicholesterol on the phosphatidylcholine bilayer: A molecular simulation study (2003) Biophys. J., 84, pp. 1818-1826Wiser, O., Trus, M., Hernández, A., Renström, E., Barg, S., Rorsman, P., Atlas, D., The voltage sensitive Lc-type Ca2 + channel is functionally coupled to the exocytotic machinery (1999) Proc. Natl. Acad. Sci. U. S. A., 96, pp. 248-253Xia, F., Gao, X., Kwan, E., Lam, P.P., Chan, L., Sy, K., Sheu, L., Tsushima, R.G., Disruption of pancreatic beta-cell lipid rafts modifies Kv2.1 channel gating and insulin exocytosis (2004) J. Biol. Chem., 279, pp. 24685-24691Vikman, J., Jimenez-Feltström, J., Nyman, P., Thelin, J., Eliasson, L., Insulin secretion is highly sensitive to desorption of plasma membrane cholesterol (2009) FASEB J., 23, pp. 58-67Xia, F., Xie, L., Mihic, A., Gao, X., Chen, Y., Gaisano, H.Y., Tsushima, R.G., Inhibition of cholesterol biosynthesis impairs insulin secretion and voltage-gated calcium channel function in pancreatic beta-cells (2008) Endocrinology, 149, pp. 5136-5145Rizzo, M.A., Magnuson, M.A., Drain, P.F., Piston, D.W., A functional link between glucokinase binding to insulin granules and conformational alterations in response to glucose and insulin (2002) J. Biol. Chem., 277, pp. 34168-34175Bonfleur, M.L., Ribeiro, R.A., Balbo, S.L., Vanzela, E.C., Carneiro, E.M., De Oliveira, H.C., Boschero, A.C., Lower expression of PKAα impairs insulin secretion in islets isolated from low-density lipoprotein receptor (LDLR(-/-)) knockout mice (2011) Metabolism, 60, pp. 1158-1164Boschero, A.C., Delattre, E., The mechanism of gentamicin-inhibited insulin release by isolated islets (1985) Arch. Int. Pharmacodyn. Ther., 273, pp. 167-176Scott, 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. 470-475Bradford, 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. 248-254Rezende, L.F., Vieira, A.S., Negro, A., Langone, F., Boschero, A.C., Ciliary neurotrophic factor (CNTF) signals through STAT3-SOCS3 pathway and protects rat pancreatic islets from cytokine-induced apoptosis (2009) Cytokine, 46, pp. 65-71Czubryt, M.P., Ramjiawan, B., Pierce, G.N., The nuclear membrane integrity assay (1997) Mol. Cell. Biochem., 172, pp. 97-102Colell, A., García-Ruiz, C., Lluis, J.M., Coll, O., Mari, M., Fernández-Checa, J.C., Cholesterol impairs the adenine nucleotide translocator-mediated mitochondrial permeability transition through altered membrane fluidity (2003) J. Biol. Chem., 278, pp. 33928-33935Lundbaek, J.A., Birn, P., Girshman, J., Hansen, A.J., Andersen, O.S., Membrane stiffness and channel function (1996) Biochemistry, 35, pp. 3825-3830Churchward, M.A., Rogasevskaia, T., Höfgen, J., Bau, J., Coorssen, J.R., Cholesterol facilitates the native mechanism of Ca2 +-triggered membrane fusion (2005) J. Cell Sci., 118, pp. 4833-4848Takahashi, N., Hatakeyama, H., Okado, H., Miwa, A., Kishimoto, T., Kojima, T., Abe, T., Kasai, H., Sequential exocytosis of insulin granules is associated with redistribution of SNAP25 (2004) J. Cell Biol., 165, pp. 255-262Kruit, J.K., Kremer, P.H., Dai, L., Tang, R., Ruddle, P., De Haan, W., Brunham, L.R., Hayden, M.R., Cholesterol efflux via ATP-binding cassette transporter A1 (ABCA1) and cholesterol uptake via the LDL receptor influences cholesterol-induced impairment of beta cell function in mice (2010) Diabetologia, 53, pp. 1110-1119Hao, M., Bogan, J.S., Cholesterol regulates glucose-stimulated insulin secretion through phosphatidylinositol 4,5-bisphosphate (2009) J. Biol. 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Reduced Expression Of Sirt1 Is Associated With Diminished Glucose-induced Insulin Secretion In Islets From Calorie-restricted Rats

Alterations in food intake such as caloric restriction modulate the expression of SIRT1 and SIRT4 proteins that are involved in pancreatic β-cell function. Here, we search for a possible relationship between insulin secretion and the expression of SIRT1, SIRT4, PKC and PKA in islets from adult rats submitted to CR for 21 days. Rats were fed with an isocaloric diet (CTL) or received 60% (CR) of the food ingested by CTL. The dose-response curve of insulin secretion to glucose was shifted to the right in the CR compared with CTL islets (EC 50 of 15.1±0.17 and 10.5±0.11 mmol/L glucose). Insulin release by the depolarizing agents arginine and KCl was reduced in CR compared with CTL islets. Total islet insulin content and glucose oxidation were also reduced in CR islets. Leucine-stimulated secretion was similar in both groups, slightly reduced in CR islets stimulated by leucine plus glutamine but higher in CR islets stimulated by ketoisocaproate (KIC). Insulin secretion was also higher in CR islets stimulated by carbachol, compared with CTL islets. No differences in the rise of cytosolic Ca 2+ concentrations stimulated by either glucose or KCl were observed between groups of islets. Finally, SIRT1, but not SIRT4, protein expression was lower in CR compared with CTL islets, whereas no differences in the expression of PKC and PKA proteins were observed. 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Impaired Muscarinic Type 3 (m3) Receptor/pkc And Pka Pathways In Islets From Msg-obese Rats

Monosodium glutamate-obese rats are glucose intolerant and insulin resistant. Their pancreatic islets secrete more insulin at increasing glucose concentrations, despite the possible imbalance in the autonomic nervous system of these rats. Here, we investigate the involvement of the cholinergic/protein kinase (PK)-C and PKA pathways in MSG β-cell function. Male newborn Wistar rats received a subcutaneous injection of MSG (4 g/kg body weight (BW)) or hyperosmotic saline solution during the first 5 days of life. At 90 days of life, plasma parameters, islet static insulin secretion and protein expression were analyzed. Monosodium glutamate rats presented lower body weight and decreased nasoanal length, but had higher body fat depots, glucose intolerance, hyperinsulinemia and hypertrigliceridemia. Their pancreatic islets secreted more insulin in the presence of increasing glucose concentrations with no modifications in the islet-protein content of the glucose-sensing proteins: the glucose transporter (GLUT)-2 and glycokinase. However, MSG islets presented a lower secretory capacity at 40 mM K+ (P < 0.05). The MSG group also released less insulin in response to 100 μM carbachol, 10 μM forskolin and 1 mM 3-isobutyl-1-methyl-xantine (P < 0.05, P < 0.0001 and P < 0.01). These effects may be associated with a the decrease of 46 % in the acetylcholine muscarinic type 3 (M3) receptor, and a reduction of 64 % in PKCα and 36 % in PKAα protein expressions in MSG islets. Our data suggest that MSG islets, whilst showing a compensatory increase in glucose-induced insulin release, demonstrate decreased islet M3/PKC and adenylate cyclase/PKA activation, possibly predisposing these prediabetic rodents to the early development of β-cell dysfunction. © 2013 Springer Science+Business Media Dordrecht.40745214528Tengholm, A., Gylfe, E., Oscillatory control of insulin secretion (2009) Mol Cell Endocrinol, 297 (1-2), pp. 58-72. , 18706473 10.1016/j.mce.2008.07.009 1:CAS:528:DC%2BD1cXhsFajt7rNCnop, M., Welsh, N., Jonas, J.C., Jorns, A., Lenzen, S., Eizirik, D.L., Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: Many differences, few similarities (2005) Diabetes, 54 (SUPPL. 2), pp. 97-S107. , 16306347 10.2337/diabetes.54.suppl-2.S97 1:CAS:528:DC%2BD2MXht12gs7nFRibeiro, R.A., Santos-Silva, J.C., Vettorazzi, J.F., Cotrim, B.B., Mobiolli, D.D., Boschero, A.C., Carneiro, E.M., Taurine supplementation prevents morpho-physiological alterations in 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