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Expression1
Departamento de Fisiologia e Biofísica, Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brasil;
*
Departamento de Nutrição e Dietética, Faculdade de Enfermagem e Nutrição, Universidade Federal de Mato Grosso, Cuiabá, MT, Brasil; and
Departamento de Bioquímica, Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brasil
2To whom correspondence should be addressed. E-mail: emc{at}unicamp.br.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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and phospholipase (PL)Cß1 contents of islets of rats fed LP were 30% lower than those of islets of rats fed NP (P < 0.05). In addition, PKC mRNA expression was reduced by 50% in islets from rats fed LP. In conclusion, a reduced expression of PKC and PLCß1 may be involved in the decreased insulin secretion by islets from LP rats after stimulation with CCh and PMA.
KEY WORDS: • low protein diet • carbamylcholine • insulin secretion • protein kinase C • phospholipase Cß1.
A relationship between a high prevalence of malnutrition and diabetes has been observed in developing countries. Malnutrition in general and dietary protein deprivation in particular are associated with low plasma glucose levels in rodents and humans (1 –5 ). Rats fed a diet containing a protein level comparable to that of undernourished humans have reduced insulin secretion as well as increased insulin sensitivity in peripheral tissues (2 ,4 –8 ). In rats with protein-energy deficiency, the severely blunted insulin secretory response to glucose is related to a reduction in pancreatic B-cell mass and a lower responsiveness to glucose by the remaining B cells (5 -10 ). Thus, the impairment of insulin secretion can be attributed in part to an intrinsic abnormality of the remaining B cells. However, protein-energy restriction may also affect extrapancreatic modulators of B-cell function such as the autonomic nervous system (11 ).
Cholinergic agents and glucose act synergistically on B cells to increase phosphoinositide (PI)3 hydrolysis and insulin secretion (12 ). PI hydrolysis is stimulated by phospholipase (PL)Cß1 through a mechanism coupled to G-protein. This coupling is initiated with the binding of the cholinergic agonist to muscarinic (M3) receptors located in the B-cell plasma membrane (13 ). PI hydrolysis results in the formation of 1,4,5 inositol triphosphate (IP3), which releases Ca2+ from intracellular stores, thereby increasing insulin secretion (14 ). Cholinergic agonists also activate PLC, which increases diacylglycerol (DAG) formation and stimulates protein kinase (PK)C. Thus, carbamylcholine (CCh)-induced insulin secretion can be reduced by inhibiting PKC (15 ).
Dietary protein deficiency decreases PKC activity in various rat tissues (16
). In this study, we examined the effects of CCh on insulin secretion and the expression of PKC and PLCß1 in islets isolated from rats fed a low protein diet.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The experiments described here were approved by the institutional (UNICAMP) Committee for Ethics in Animal Experimentation. Groups of 5 male Wistar rats (21 d old) from the breeding colony at UNICAMP were kept at 24°C with a 12-h light:dark cycle. The rats were randomly assigned to groups and fed an isocaloric diet containing 6% (low protein diet, LP) or 17% (normal protein diet, NP) protein for 8 wk. The composition and difference between the two isocaloric diets are described elsewhere (17 ) and in Table 1. During the experimental period, the rats consumed their respective diets and water ad libitum. At the end of the experimental period, the nutritional status of the rats was evaluated by measuring body weight, serum protein (Bio-Rad Laboratories GmbH, Munchen, Germany), albumin (18 ), glucose (DiaSys Diagnostic Systems, Holzheim, Germany), free fatty acid (FFA) levels (Nonesterified Fatty Acid C kit, Wako Chemicals, Neuss, Germany), and liver glycogen and fat content (19 ,20 ).
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Islets were isolated by collagenase digestion of the pancreas as described (21 ). For static incubation, groups of five islets were first incubated for 45 min at 37°C in Krebs-bicarbonate buffer with the following composition (in mmol/L): NaCl, 115; KCl, 5; CaCl2, 2.56; MgCl2, 1; NaHCO3, 24; and glucose, 5.6; the buffer was supplemented with 3 g of bovine serum albumin/L and equilibrated with a mixture of 95% O2:5% CO2, pH 7.4. This medium was then replaced with fresh buffer and the islets were incubated for 1 h with 8.3 mmol glucose/L and different concentrations of agonists. The insulin content of the medium at the end of the incubation period was measured by RIA (22 ). The CCh concentration producing a response that was 50% of the maximum (EC50) was expressed as the mean negative logarithm (pD2).
Western blotting.
Groups of islets were pelleted by centrifugation (15,000 x g) and then resuspended in 50–100 µL of homogenization buffer containing protease inhibitors, as described (12
,14
). After isolation by collagenase digestion of pancreata and subsequent separation on discontinuous lyophilized Ficoll DL-400 gradients, a pool of least 500 clean islets from each experimental group was homogenized by sonication (15 s) in an anti-protease cocktail (10 mmol/L imidazole, pH 8.0, 4 mmol/L EDTA, 1 mmol/L EGTA, 0,5 g/L pepstatin A, 2 g/L aprotinin, 2.5 mg/L leupeptin, 30 mg/L trypsin inhibitor, 200 µmol/L DL-dithiothreitol and 200 µmol/L phenylmethylsulfonyl fluoride. After sonication, an aliquot of extract was collected and the total protein content was determined by the dye-binding protein assay kit (Bio-Rad Laboratories, Hercules, CA). Samples containing 70 µg of protein from each experimental group were incubated for 5 min at 80°C with 4X concentrated Laemmli sample buffer (1 mmol sodium phosphate/L, pH 7.8, 0.1% bromophenol blue, 50% glycerol, 10% SDS, 2% mercaptoethanol) (4:1, v/v) and then run on 8% polyacrylamide gels at 120 V for 30 min. Electrotransfer of proteins to nitrocellulose membranes (Bio-Rad) was done for 1 h at 120 V (constant) in buffer containing methanol and SDS. After checking the efficiency of transfer by staining with Ponceau S, the membranes were blocked with 5% skimmed milk in TTBS (10 mmol Tris/L, 150 mmol NaCl/L, 0.5% Tween 20) overnight at 4°C. PKC and PLCß1 were detected in the membranes after a 2-h incubation at room temperature with mouse monoclonal antibodies against PKC and PLCß1 (Santa Cruz Biotechnology, Santa Cruz, CA) (diluted 1:500 in TTBS containing 3% dry skimmed milk). The membranes were then incubated with a rabbit anti-mouse immunoglobulin G (diluted 1:1000 in TTBS containing 3% dry skimmed milk) followed by a further 2 h incubation at room temperature with 125I -labeled protein A (diluted 1:1000 in TTBS containing 1% dry skimmed milk). Radiolabeled protein bound to the antibody was detected by autoradiography. Band intensities were quantified by optical densitometry (Scion Image, Frederick, MD).
mRNA expression.
Total RNA from 500 islets was extracted using Trizol reagent (Life Technologies, Paisley, UK). For the polymerase chain reaction (PCR), RNA was reverse-transcribed (RT) using random primers. The resulting cDNA were amplified by PCR using oligonucleotides complementary to sequences in the PKC gene (5'-CCTGCTCTACGGACTTATC-3' and 5'-TGTAGTATTCACCCTCCTC-3') and PVX (potato virus X) gene (5'- CGATCTCAAGCCACTCTCTCCG-3' and 5'-GTAGTTGAGGTAGTTGACCC-3'), with the latter used as an external control. Actin was not used as an internal control because its expression was altered under our conditions (LP islets). The PCR was done in a 25 µL reaction volume containing 1 µL of cDNA equivalent to 2 µg of RNA, 10 mmol cold dNTP/L (dATP, dCTP, dGTP, dTTP), 50 mmol MgCl2/L, 10X PCR buffer, 10 µmol of appropriate oligonucleotides primers/L, and 2 U of Taq polymerase (Life Technologies). The number of cycles was selected to allow linear amplification of the cDNA under study. The PCR conditions for amplification of PKC (Gene Bank (X07289), size of fragment obtained by PCR (500 pb), primers position (579–1078) and PVX (Gene Bank (D00344), size of fragment obtained by PCR (106 pb), primers position (5597–5702)) were as follows: 2 min at 94°C followed by 32 cycles (30 s each) at 94°C, 57°C and 72°C (PKC), and 2 min at 94°C followed by 23 cycles (30 s each) at 94°C, 57°C and 72°C (PVX). PVX RNA was obtained by in vitro transcription with RiboMAX Large Scale RNA Production System-T7 (Promega), following the instructions of the manufacturer. PVX sequence has no homology to any rat sequence as confirmed by BLAST search and RT-PCR (data not shown). Then, an aliquot of the external control was thawed on ice and 0.06 µg was mixed with fresh islets before extraction (23
).
The PCR products were separated on 1.5% agarose gels in Tris borate EDTA buffer 1X (TBE 1X) and stained with ethidium bromide. All PCR reactions included a negative control. The absence of genome contamination in the RNA samples was confirmed by the RT-negative RNA samples. Subsequent digitalization and relative band intensities were performed employing an Eagle Eye II documentation system (Stratagene, La Jolla, CA). The results were expressed as a ratio of target to standard signals.
Statistical analysis.
The results are expressed as means ± SEM. Student’s unpaired t test was generally used to compare the groups. Insulin secretion data were log-transformed to correct for heterogeneity in variance and then analyzed by two-way ANOVA, followed by the Tukey-Kramer test to determine significant differences between groups and among glucose and secretagogue concentrations, and to assess the interactions between these factors. The data were analyzed using the Statistica software package (Statsoft, Tulsa, OK). The level of significance was set at P < 0.05.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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After 8 wk, body weight, serum total protein, albumin and insulin levels of LP rats were lower, whereas serum FFA, liver glycogen and fat concentrations were greater than in NP rats (P < 0.05) (Table 2). The amount of protein in islets of rats fed NP and LP was similar. However, there were differences in the profile of soluble protein in islets of rats fed NP compared with those fed LP (not shown).
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Increasing concentrations of CCh (0.1–1000 µmol/L) dose dependently increased insulin secretion by islets from rats fed LP and NP, although absolute insulin secretion for each CCh concentration was higher in islets from rats fed NP than in those fed LP (Fig. 1 ). The EC50 were 2.15 ± 0.7 µmol/L and 4.64 ± 1.0 µmol/L for islets from rats fed NP and LP, respectively (P < 0.05).
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mRNA and protein expression.
Western blotting indicated a 30% reduction in the expression of PKC protein in islets from rats fed LP compared with those fed NP (P < 0.05) (Fig. 3
). Similarly, RT-PCR revealed a 50% reduction in the expression of PKC mRNA (P < 0.05) (Fig. 4
). The expression of PLCß1 protein was also reduced by 25% in islets from rats fed LP compared with those fed NP (P < 0.05) (Fig. 5
).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The neural modulation of ß-cells plays an important role in the control of insulin secretion. A relationship between loss of the first phase of secretion with the onset of type 2 diabetes has been established (25 –27 ). The first phase of insulin secretion is important for glucose tolerance and is partially dependent on the ACh-activation of M3 receptors present in the B-cell plasma membrane. Acetylcholine increases insulin secretion by activating M3 receptors (21 ,28 –30 ). In B cells, the coupling of ACh with this type of receptor stimulates PLC via G proteins (28 ,31 –33 ) to generate DAG and IP3, culminating with insulin secretion (29 ,34 ).
Because a low protein diet is associated with stress, with possible derangement of the sympathetic/parasympathetic equilibrium, we investigated the modulation of CCh-induced insulin secretion in rats fed a low protein diet. Insulin secretion induced by increasing concentrations of CCh was dose dependently increased in islets from both groups of rats. However, the dose-response curves for insulin secretion, as well as the EC50, indicated that the potency of CCh was significantly reduced in islets from rats fed LP compared with those fed NP (Fig. 1) .
Various intracellular messengers regulate insulin secretion in pancreatic islets. DAG and IP3 are second messengers involved in CCh-induced insulin secretion via PKC. The precise mechanism of action of PKC on insulin stimulation is not yet fully understood, although alterations in K+ and Ca2+ fluxes in ß cells are involved (35
–38
). PKC also stimulates secretion by facilitating the extrusion of insulin-containing granules (39
), and exogenous activators such as phorbol esters (TPA or PMA) or DAG analogs stimulate PKC translocation in rat islet cells (40
,41
), indicating a relationship between PKC and insulin secretion (35
). An attenuated PMA-induced insulin secretion was observed in islets from rats fed LP, suggesting a possible alteration in PKC levels. Several types of PKC are present in ß cells, with PKC as the major component (42
–44
). Because the content of PKC was reduced in islets from rats fed LP, this factor could account for a decrease in glucose- and CCh-induced insulin secretion in islets from rats fed LP.
PKC also provokes an apparent paradoxical decrease in the intracellular Ca2+ concentration in B cells, probably by reducing Ca2+ entry via L-type channels (45
). The Ca2+ efflux in LP was higher than in NP islets (not shown) confirming, although indirectly, the participation of PKC in this process.
In conclusion, alterations mainly in PKC levels and possibly other enzymes involved in this pathway, such as PLCß1, may contribute to the poor secretory response induced by glucose, CCh and PMA in islets from rats fed LP. A low protein diet apparently decreases the transcription of genes that encode proteins involved in insulin secretion. When present over a long period of time, these alterations may affect the glucose homeostasis in LP rats.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abreviations used: Ach, acetylcholine; CCh, carbamylcholine; DAG, diacylglycerol; FFA, free fatty acid; IP3, 1,4,5 inositol triphosphate; LP, low protein group; M3, muscarinic; NP, normal protein group; PCR, polymerase chain reaction; PI, phosphoinositide; PKC, protein kinase C; PLCß1, phospholipase Cß1; PMA, phorbol 12-myristate 13-acetate; PVX, potato virus X; RT, reverse transcribed; TTBS, Tris-Tween 20 buffered saline.
Manuscript received 28 August 2002. Initial review completed 14 October 2002. Revision accepted 26 November 2002.
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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