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Department of Medical Cell Biology, Uppsala University, Box 571, SE-751 23 Uppsala, Sweden
(Correspondence should be addressed to H K Nyblom; Email: hanna.nyblom{at}mcb.uu.se)
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Abstract |
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 Top Abstract IntroductionMaterials and methodsResultsDiscussionDeclaration of InterestFundingReferences |
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionDeclaration of InterestFundingReferences |
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Materials and methods |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionDeclaration of InterestFundingReferences |
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Reagents of analytical grade and Milli-Q water were used. Culture plates were from Falcon (BD Biosciences Labware, Franklin Lakes, NJ, USA). RPMI 1640 culture medium, Dulbecco's PBS, HEPES, fetal bovine serum (FBS), glutamine, sodium pyruvate, penicillin and streptomycin were purchased from Invitrogen. BSA was obtained from Roche Diagnostics. The antibody against BiP was from Abcam (Cambridge, UK). The antibodies against phosphorylated AMPK (p-AMPK), AMPK, phosphorylated acyl-CoA carboxylase (p-ACC), acyl-CoA carboxylase (ACC) and phosphorylated eIF2
(p-eIF2) were purchased from Cell Signaling (Beverly, MA, USA). The anti-rabbit immunoglobulin G antibody conjugated to horseradish peroxidase was purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA). The antibody against C/EBP homologous protein (CHOP), glucose, HEPES, insulin peroxidase, 2-mercaptoethanol, protease inhibitor cocktail (PIC), sodium deoxycholate, sodium orthovanadate, Thesit and triolein were obtained from Sigma. The rat insulin standard was from Novo Nordisk (Bagsvaerd, Denmark). Guinea pig anti-mouse insulin antibodies were produced in our laboratory. IgG-certified 96-well microtitre plates were purchased from Nunc (Roskilde, Denmark).
Cell culture
INS-1E cells were kindly supplied by Claes Wollheim and Pierre Maechler, Geneva, Switzerland, and cultured (passages 79–83) for 24 h in 6-, 12- or 24-well plates at 37 °C in a humidified atmosphere containing 5% CO2 in RPMI 1640 medium containing 11 mM glucose and supplemented with 10 mM HEPES, 10% heat-inactivated FBS, 2 mM glutamine, 1 mM sodium pyruvate, 50 µM 2-mercaptoethanol, 100 units/ml penicillin and 100 µg/ml streptomycin. After the initial culture period, the culture medium was replaced by an identical medium with the exception of the glucose concentration, which was 5.5, 11 or 27 mM with or without 0.3 or 1 mM AICAR. Culture was continued for 5 days, a time period required to obtain alterations in GSIS in INS-1E cells in response to culture in the presence of elevated glucose concentrations (Nyblom et al. 2006). Culture medium was changed every 48 h.
Insulin secretion and content
After 5-day culture in 24-well plates, when the INS-1E cells were confluent, insulin release and content were measured, as described previously (Nyblom et al. 2006). In short, after pre-incubation of the cells in glucose-free buffer supplemented with 0.1% (w/v) BSA, the glucose-free buffer was replaced by the same buffer supplemented with either 3 or 15 mM glucose and the cells were incubated for 30 min at 37 °C. Samples of insulin release were stored at –20 °C until analysis, which was performed by a competitive ELISA (Bergsten & Hellman 1993). After insulin release measurements, the cells were washed twice with PBS and lysed with a buffer containing 10 mM Tris, 150 mM NaCl, 0.1% (w/v) SDS, 1% (v/v) Triton X-100, 1% (w/v) sodium deoxycholate, 5 mM EDTA and adjusted to pH 7.2. PIC was added to the lysis buffer prior to the sample preparation. Total protein content was determined by the DC Protein Assay (Bio-Rad).
Apoptosis assay
Apoptosis was measured with the Cell Death Detection ELISAPLUS kit (Roche), which determines the amount of apoptotic mono- and oligonucleosomes in a sample. After the culture period, INS-1E cells from a 24-well plate were washed with PBS and lysed with 200 µl of the supplied lysis buffer. After a 30-min incubation at room temperature, the lysate was spun at 177 g for 10 min. The assay was performed using 20 µl supernatant in the ELISA, according to the manufacturer's instructions. Apoptosis, determined by optical density, was correlated with total protein determined by the DC Protein Assay.
TG content
INS-1E cells from two wells in a 6-well plate were scraped and suspended in 100 µl buffer containing 20 mM Tris, 150 mM NaCl, 2 mM EDTA and 1% (v/v) Triton X-100 (pH 7.5). TGs were extracted in 3 ml chloroform:methanol (2:1, v/v). Samples were resuspended in 50 µl chloroform from which 20 µl, in duplicate, were transferred to microtubes and air dried. Thesit (5 µl, 10% w/v) was added to the dry pellet. After the Thesit had dried, 10 µl H2O was added (Briaud et al. 2001). TGs were measured using a commercial kit (Infinity TGs Liquid Stable Reagent; Thermo Electron, Melbourne, Australia) and the TG content was correlated with total protein determined by the DC Protein Assay. The triolein standard curve, used to determine the TG content, was treated in parallel with the samples.
Western blot
INS-1E cells were lysed in a buffer containing 10 mM Tris (pH 7.2), 150 mM NaCl, 0.1% (w/v) SDS, 1% (v/v) Triton X-100, 1% (w/v) sodium deoxycholate, 5 mM EDTA, 1 mM sodium orthovanadate and PIC. Total protein content was determined by the DC Protein Assay. The samples were separated by SDS-PAGE (10%), electrophoretically transferred to polyvinylidene fluoride (PVDF) membranes and probed with antibodies against p-AMPK (1:1500 dilution), AMPK (1:3000 dilution), p-ACC (1:1000 dilution), ACC (1:1000 dilution), p-eIF2 (1:1000 dilution), BiP (1:10 000 dilution) or CHOP (1:2000 dilution). Signal detection was performed using enhanced chemiluminescence (ECL) (Advanced or Plus) detection kit (Amersham Biosciences) and the Fluor-S MAX Multi-Imager (Bio-Rad). Signals were quantified using the Quantity One software (Bio-Rad). Subsequently, the PVDF membranes were stained with Coomassie, imaged, scanned and quantified with Quantity One software. The expression level of each protein was normalized to the corresponding Coomassie-stained lane.
Statistical analysis
Differences in insulin secretion, TG content, apoptosis and differences in protein expression levels were evaluated using ANOVA with Tukey's post hoc test. P<0.05 was considered significant. Values were expressed as means±S.E.M.
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Results |
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Insulin secretion in response to 3 or 15 mM glucose was measured from INS-1E cells cultured for 5 days at 5.5, 11 or 27 mM glucose (Fig. 1). As reported previously (Nyblom et al. 2006), insulin release in response to 15 mM glucose was drastically reduced for the cells cultured at 27 mM glucose compared with the cells cultured at 11 mM glucose. When AMPK agonist AICAR (0.3 mM) was included during culture of INS-1E cells at 27 mM glucose, insulin secretion in response to 15 mM glucose was similar to the levels observed in control cells cultured in the presence of 11 mM glucose (Fig. 1). Insulin release in the presence of 3 mM glucose was raised, however. When the AICAR concentration was increased to 1 mM, basal insulin release increased further and stimulatory release was curtailed. Similar results were obtained for the cells cultured in the presence of 11 mM glucose with enhanced insulin secretion at 15 mM glucose in the presence of 0.3 mM AICAR, which was reversed when 1 mM of the agonist was added to the culture medium. Basal insulin secretion at 3 mM glucose was dose dependently increased by AICAR also for the cells cultured at 11 mM glucose (Fig. 1).
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Extended culture of INS-1E cells at elevated glucose levels leads to glucose-derived de novo lipid synthesis and accumulation (Nyblom et al. 2008). After 5 days of culture at elevated glucose levels, a fivefold increase in fatty acyls was observed (Nyblom et al. 2008). In the present study, it was tested whether the observed beneficial effect of 0.3 mM AICAR on GSIS was connected with decreased levels of TGs. To this aim, TG levels were determined in INS-1E cells cultured for 5 days at 5.5, 11 or 27 mM glucose with or without AICAR (Fig. 4). The TG content increased twofold for the cells cultured at 27 mM glucose when compared with the cells cultured at 11 mM glucose and more than threefold when compared with the cells cultured at 5.5 mM glucose, which is comparable with our previous NMR-based measurements (Nyblom et al. 2008). When 0.3 or 1 mM AICAR was included during culture of INS-1E cell, the TG content was not affected in the cells cultured in the presence of 11 or 27 mM glucose, however.
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Deterioration of GSIS in β-cells exposed to elevated levels of glucose is connected with the loss of β-cell mass (Eizirik et al. 1992, Butler et al. 2003, Leonardi et al. 2003). Based on the improved secretory response observed in the presence of 0.3 mM AICAR (Fig. 1), we hypothesized that AICAR reversed such loss of β-cells. Apoptosis was measured in INS-1E cells cultured for 5 days at 5.5, 11 or 27 mM glucose in the presence or absence of AICAR. Apoptosis was not affected in the cells cultured at 11 mM glucose but increased sevenfold in the cells cultured in the presence of 27 mM glucose compared with the cells cultured in the presence of 5.5 mM glucose (Fig. 5). When 1 mM AICAR was included in the culture medium, the number of apoptotic cells observed after culture at 27 mM glucose was significantly reduced. No decrease in apoptosis was observed when 0.3 mM AICAR was included.
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Apoptosis has been connected with endoplasmic reticulum (ER) stress in INS-1E cells exposed to elevated glucose concentrations for extended time periods (Wang et al. 2005a). When the levels of ER stress-related protein CHOP (Harding & Ron 2002) were measured, there was a glucose-regulated increase in the pro-apoptotic protein (Fig. 6). After 1 mM AICAR was included during culture of INS-1E cells, CHOP levels were diminished both in the cells cultured at 11 and 27 mM glucose. No reduction in the CHOP levels was observed when 0.3 mM AICAR was included during culture. When the levels of p-eIF2 and BiP were measured in INS-1E cells cultured at elevated glucose concentrations in the presence or absence of 0.3 or 1 mM AICAR, neither glucose nor AICAR altered the levels of the proteins.
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Discussion |
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Activated AMPK was determined by measuring phosphorylated levels of AMPK and ACC as in other studies (da Silva Xavier et al. 2003, Yamashita et al. 2004). Using this approach, increased phosphorylation of the kinase and its downstream target was observed in the presence of 1 mM but not 0.3 mM AICAR. It could be concluded that improved GSIS observed in the presence of the lower AICAR concentration was not caused by an increase in the ratio of p-AMPK and AMPK or p-ACC and ACC. The present study demonstrated that AICAR had pleiotropic effects on insulin secretion. First, AICAR enhanced GSIS but this insulinotrophic effect of the AMPK agonist was abolished in a concentration-dependent manner. KATP channel conductivity has been proposed to be the target of the stimulating effect of AICAR for insulin release (Wang et al. 2005b), whereas diminished glucose metabolism with the reduction in ATP generation and Ca2+ influx may be a mechanism of the inhibiting effect of the agonist (da Silva Xavier et al. 2003). Secondly, AICAR elevated basal insulin release in a concentration-dependent manner irrespective of the culture glucose concentration. The rise in basal insulin release induced by AICAR has been observed previously (Akkan & Malaisse 1994, Salt et al. 1998, da Silva Xavier et al. 2003, Wang et al. 2005b) and has been attributed to enhanced glucose metabolism and has also been observed when β-cells are exposed to elevated levels of fatty acids (Zhou & Grill 1994, Milburn et al. 1995). By contrast, INS-1E cells exposed to chronic hyperglycaemia have shown impaired GSIS without increase in basal insulin secretion, although elevated levels of total fatty acyls were recorded (Nyblom et al. 2008). Enhanced glucose metabolism is probably not responsible for elevated basal release in the presence of AICAR since glucose metabolism has been reported to be unaffected or even decreased by the agonist (da Silva Xavier et al. 2003). Instead, activation of AMPK is associated with enhanced glucose utilization and fatty acid oxidation (Zhang & Kim 1995, Winder & Hardie 1999, Winder 2001, Zhou et al. 2001, Yamauchi et al. 2002) and decreased lipogenesis (Zhang & Kim 1995, Zhou et al. 2001).
Lowered apoptosis in the presence of AICAR has been demonstrated in β-cells exposed to elevated levels of glucose and fatty acids (El-Assaad et al. 2003) and attributed to redirection of fatty acids from esterification to oxidation (Corton et al. 1995, Merrill et al. 1997, Velasco et al. 1997, Muoio et al. 1999, El-Assaad et al. 2003). In β-cells exposed to elevated glucose concentrations, lipid de novo synthesis occurs (Berne 1975, Dunlop & Larkins 1985, Roche et al. 1998, Nyblom et al. 2008). Given the results that AICAR did not affect the TG content of the β-cells in the present and a previous similarly designed study (Yamashita et al. 2004), the explanation of redirection from esterification to oxidation seems less plausible under conditions of elevated glucose levels alone. In addition, metformin has been reported to affect insulin secretion in β-cells positively without lowering the TG content of the cell (Lupi et al. 2002b). Deposition of excess fatty acids as the TGs has been both positively and negatively correlated with fatty acid-induced β-cell death (Shimabukuro et al. 1998, Higa et al. 1999, Cnop et al. 2001, Lupi et al. 2002b). It appears that the constituent fatty acids incorporated into the TGs are the determinants to what extent the lipid accumulation is detrimental or not, where both chain length and degree of saturation could play roles (Cnop et al. 2001, Busch et al. 2005). In this context, it was observed that β-cell lipid accumulation in the presence of externally applied saturated fatty acid palmitate was clearly harmful, affecting the morphology of the ER (Moffitt et al. 2005). Under such conditions, redirection from esterification to oxidation of fatty acids becomes critical and may be operative (El-Assaad et al. 2003). An explanation between the difference in lipid accumulation in the presence of glucose and fatty acids was offered when it was demonstrated that lipogenesis in response to hyperglycaemia resulted in the generation of both saturated and unsaturated fatty acid species in proportions similar to those found in control cells (Nyblom et al. 2008), which is less harmful for β-cell function than when exposed to saturated fatty acids (Moffitt et al. 2005). It remains to be determined to what extent these proportions are altered when sterol regulatory element binding protein (SREBP)-1c is overexpressed, making the cell more prone to lipogenesis. When overexpressing the lipogenic transcription factor (Wang et al. 2003, Diraison et al. 2004), increased TG levels were observed in islets and INS-1E cells, which were normalized by AICAR (Diraison et al. 2004, Yamashita et al. 2004). The observed decrease in apoptosis without changes in the TG content in the present study renders further support for the view that lipid accumulation per se is not detrimental for the β-cell (Cnop et al. 2001). In two recent studies, it was reported that AICAR increased apoptosis (Cai et al. 2007, Kim et al. 2007). The fact that p-AMPK levels were not reduced but rather increased after prolonged exposure to elevated glucose levels in the insulinoma cell line used may contribute to explain the divergent effect of the agonist in these cells.
Prolonged elevated glucose concentrations have also been associated with ER stress (Wang et al. 2005a). ER stress is induced under conditions of enhanced protein synthesis. If the protein load surpasses the capacity of the ER to handle cargo proteins, accumulation of unfolded or misfolded proteins in the ER occurs, which elicits the unfolded protein response (UPR). The UPR is a cellular programme by which the cell attempts to alleviate ER stress (Rutkowski & Kaufman 2004). If not alleviated, signalling pathways are initiated leading to apoptosis, where CHOP is a component protein (Harding & Ron 2002). From the observation that AICAR reduced the levels of the pro-apoptotic protein CHOP, it can be proposed that ER stress alleviation is a contributing mechanism by which AICAR reduces apoptosis under glucotoxic conditions. However, no change in the phosphorylation of eIF2 was observed. Although the lack of effects on p-eIF2 may be due to time kinetics in the phosphorylation of the protein (Laybutt et al. 2007), a more plausible explanation is that the enhanced CHOP expression is the result of mechanisms not related to ER stress.
In conclusion, although AICAR-induced activation of AMPK reduced apoptosis and improved insulin release in β-cells exposed to high glucose concentrations, these positive effects occurred at different concentrations of the agonist. Indeed, when AICAR at a given concentration positively affected one β-cell parameter, other β-cell parameters deteriorated. These effects of AICAR on β-cell function and mass make the administration of the agonist questionable as a strategy to treat individuals with type 2 diabetes mellitus.
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Declaration of Interest |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionDeclaration of InterestFundingReferences |
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Funding |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionDeclaration of InterestFundingReferences |
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Acknowledgements |
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References |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionDeclaration of InterestFundingReferences |
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Bergsten P & Hellman B 1993 Glucose-induced amplitude regulation of pulsatile insulin secretion from individual pancreatic islets. Diabetes 42 670–674.[Abstract]
Berne C 1975 The metabolism of lipids in mouse pancreatic islets. The biosynthesis of triacylglycerols and phospholipids. Biochemical Journal 152 667–673.[Web of Science][Medline]
Briaud I, Harmon JS, Kelpe CL, Segu VB & Poitout V 2001 Lipotoxicity of the pancreatic β-cell is associated with glucose-dependent esterification of fatty acids into neutral lipids. Diabetes 50 315–321.
Busch AK, Gurisik E, Cordery DV, Sudlow M, Denyer GS, Laybutt DR, Hughes WE & Biden TJ 2005 Increased fatty acid desaturation and enhanced expression of stearoyl coenzyme A desaturase protects pancreatic β-cells from lipoapoptosis. Diabetes 54 2917–2924.
Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA & Butler PC 2003 β-cell deficit and increased β-cell apoptosis in humans with type 2 diabetes. Diabetes 52 102–110.
Cai Y, Martens GA, Hinke SA, Heimberg H, Pipeleers D & Van de Casteele M 2007 Increased oxygen radical formation and mitochondrial dysfunction mediate β cell apoptosis under conditions of AMP-activated protein kinase stimulation. Free Radical Biology and Medicine 42 64–78.[CrossRef][Web of Science][Medline]
Cnop M, Hannaert JC, Hoorens A, Eizirik DL & Pipeleers DG 2001 Inverse relationship between cytotoxicity of free fatty acids in pancreatic islet cells and cellular triglyceride accumulation. Diabetes 50 1771–1777.
Corton JM, Gillespie JG, Hawley SA & Hardie DG 1995 5-Aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells? European Journal of Biochemistry 229 558–565.[Web of Science][Medline]
Diraison F, Motakis E, Parton LE, Nason GP, Leclerc I & Rutter GA 2004 Impact of adenoviral transduction with SREBP1c or AMPK on pancreatic islet gene expression profile: analysis with oligonucleotide microarrays. Diabetes 53 S84–S91.
Dunlop ME & Larkins RG 1985 Pancreatic islets synthesize phospholipids de novo from glucose via acyl-dihydroxyacetone phosphate. Biochemical and Biophysical Research Communications 132 467–473.[CrossRef][Web of Science][Medline]
Eizirik DL, Korbutt GS & Hellerstrom C 1992 Prolonged exposure of human pancreatic islets to high glucose concentrations in vitro impairs the β-cell function. Journal of Clinical Investigation 90 1263–1268.[Web of Science][Medline]
El-Assaad W, Buteau J, Peyot ML, Nolan C, Roduit R, Hardy S, Joly E, Dbaibo G, Rosenberg L & Prentki M 2003 Saturated fatty acids synergize with elevated glucose to cause pancreatic β-cell death. Endocrinology 144 4154–4163.[CrossRef][Web of Science][Medline]
El-Mir MY, Nogueira V, Fontaine E, Averet N, Rigoulet M & Leverve X 2000 Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. Journal of Biological Chemistry 275 223–228.
Harding HP & Ron D 2002 Endoplasmic reticulum stress and the development of diabetes: a review. Diabetes 51 S455–S461.
Higa M, Zhou YT, Ravazzola M, Baetens D, Orci L & Unger RH 1999 Troglitazone prevents mitochondrial alterations, β cell destruction, and diabetes in obese prediabetic rats. PNAS 96 11513–11518.
Kahn BB, Alquier T, Carling D & Hardie DG 2005 AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metabolism 1 15–25.[CrossRef][Web of Science][Medline]
Kim WH, Lee JW, Suh YH, Lee HJ, Lee SH, Oh YK, Gao B & Jung MH 2007 AICAR potentiates ROS production induced by chronic high glucose: roles of AMPK in pancreatic β-cell apoptosis. Cellular Signalling 19 791–805.[CrossRef][Web of Science][Medline]
Laybutt DR, Preston AM, Akerfeldt MC, Kench JG, Busch AK, Biankin AV & Biden TJ 2007 Endoplasmic reticulum stress contributes to β cell apoptosis in type 2 diabetes. Diabetologia 50 752–763.[CrossRef][Web of Science][Medline]
Leclerc I, Woltersdorf WW, da Silva Xavier G, Rowe RL, Cross SE, Korbutt GS, Rajotte RV, Smith R & Rutter GA 2004 Metformin, but not leptin, regulates AMP-activated protein kinase in pancreatic islets: impact on glucose-stimulated insulin secretion. American Journal of Physiology. Endocrinology and Metabolism 286 E1023–E1031.
Leonardi O, Mints G & Hussain MA 2003 β-cell apoptosis in the pathogenesis of human type 2 diabetes mellitus. European Journal of Endocrinology 149 99–102.[CrossRef][Web of Science][Medline]
Lupi R, Del Guerra S, Fierabracci V, Marselli L, Novelli M, Patane G, Boggi U, Mosca F, Piro S, Del Prato S et al. 2002a Lipotoxicity in human pancreatic islets and the protective effect of metformin. Diabetes 51 S134–S137.
Lupi R, Dotta F, Marselli L, Del Guerra S, Masini M, Santangelo C, Patane G, Boggi U, Piro S, Anello M et al. 2002b Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: evidence that β-cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated. Diabetes 51 1437–1442.
Malaisse WJ, Conget I, Sener A & Rorsman P 1994 Insulinotropic action of AICA riboside. II. Secretory, metabolic and cationic aspects. Diabetes Research 25 25–37.[Medline]
Marchetti P, Del Guerra S, Marselli L, Lupi R, Masini M, Pollera M, Bugliani M, Boggi U, Vistoli F, Mosca F et al. 2004 Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin. Journal of Clinical Endocrinology and Metabolism 89 5535–5541.
Merrill GF, Kurth EJ, Hardie DG & Winder WW 1997 AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. American Journal of Physiology 273 E1107–E1112.[Web of Science][Medline]
Milburn JL Jr, Hirose H, Lee YH, Nagasawa Y, Ogawa A, Ohneda M, BeltrandelRio H, Newgard CB, Johnson JH & Unger RH 1995 Pancreatic β-cells in obesity. Evidence for induction of functional, morphologic, and metabolic abnormalities by increased long chain fatty acids. Journal of Biological Chemistry 270 1295–1299.
Moffitt JH, Fielding BA, Evershed R, Berstan R, Currie JM & Clark A 2005 Adverse physicochemical properties of tripalmitin in β cells lead to morphological changes and lipotoxicity in vitro. Diabetologia 48 1819–1829.[CrossRef][Web of Science][Medline]
Muoio DM, Seefeld K, Witters LA & Coleman RA 1999 AMP-activated kinase reciprocally regulates triacylglycerol synthesis and fatty acid oxidation in liver and muscle: evidence that sn-glycerol-3-phosphate acyltransferase is a novel target. Biochemical Journal 338 783–791.[CrossRef][Web of Science][Medline]
Nyblom HK, Thorn K, Ahmed M & Bergsten P 2006 Mitochondrial protein patterns correlating with impaired insulin secretion from INS-1E cells exposed to elevated glucose concentrations. Proteomics 6 5193–5198.[CrossRef][Web of Science][Medline]
Nyblom HK, Nord LI, Andersson R, Kenne L & Bergsten P 2008 Glucose-induced de novo synthesis of fatty acyls causes proportional increases in INS-1E cellular lipids. NMR in Biomedicine 21 357–365.[CrossRef][Web of Science][Medline]
Roche E, Farfari S, Witters LA, Assimacopoulos-Jeannet F, Thumelin S, Brun T, Corkey BE, Saha AK & Prentki M 1998 Long-term exposure of β-INS cells to high glucose concentrations increases anaplerosis, lipogenesis, and lipogenic gene expression. Diabetes 47 1086–1094.[Abstract]
Rutkowski DT & Kaufman RJ 2004 A trip to the ER: coping with stress. Trends in Cell Biology 14 20–28.[CrossRef][Web of Science][Medline]
Rutter GA, Da Silva Xavier G & Leclerc I 2003 Roles of 5'-AMP-activated protein kinase (AMPK) in mammalian glucose homoeostasis. Biochemical Journal 375 1–16.[CrossRef][Web of Science][Medline]
Salt IP, Johnson G, Ashcroft SJ & Hardie DG 1998 AMP-activated protein kinase is activated by low glucose in cell lines derived from pancreatic β cells, and may regulate insulin release. Biochemical Journal 335 533–539.[Web of Science][Medline]
Shimabukuro M, Zhou YT, Levi M & Unger RH 1998 Fatty acid-induced β cell apoptosis: a link between obesity and diabetes. PNAS 95 2498–2502.
da Silva Xavier G, Leclerc I, Varadi A, Tsuboi T, Moule SK & Rutter GA 2003 Role for AMP-activated protein kinase in glucose-stimulated insulin secretion and preproinsulin gene expression. Biochemical Journal 371 761–774.[CrossRef][Web of Science][Medline]
Unger RH, Zhou YT & Orci L 1999 Regulation of fatty acid homeostasis in cells: novel role of leptin. PNAS 96 2327–2332.
Velasco G, Geelen MJ & Guzman M 1997 Control of hepatic fatty acid oxidation by 5'-AMP-activated protein kinase involves a malonyl-CoA-dependent and a malonyl-CoA-independent mechanism. Archives of Biochemistry and Biophysics 337 169–175.[CrossRef][Web of Science][Medline]
Wang H, Maechler P, Antinozzi PA, Herrero L, Hagenfeldt-Johansson KA, Bjorklund A & Wollheim CB 2003 The transcription factor SREBP-1c is instrumental in the development of β-cell dysfunction. Journal of Biological Chemistry 278 16622–16629.
Wang H, Kouri G & Wollheim CB 2005a ER stress and SREBP-1 activation are implicated in β-cell glucolipotoxicity. Journal of Cell Science 118 3905–3915.
Wang CZ, Wang Y, Di A, Magnuson MA, Ye H, Roe MW, Nelson DJ, Bell GI & Philipson LH 2005b 5-Amino-imidazole carboxamide riboside acutely potentiates glucose-stimulated insulin secretion from mouse pancreatic islets by KATP channel-dependent and -independent pathways. Biochemical and Biophysical Research Communications 330 1073–1079.[CrossRef][Web of Science][Medline]
Winder WW 2001 Energy-sensing and signaling by AMP-activated protein kinase in skeletal muscle. Journal of Applied Physiology 91 1017–1028.
Winder WW & Hardie DG 1999 AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes. American Journal of Physiology 277 E1–E10.[Web of Science][Medline]
Yamashita T, Eto K, Okazaki Y, Yamashita S, Yamauchi T, Sekine N, Nagai R, Noda M & Kadowaki T 2004 Role of uncoupling protein-2 up-regulation and triglyceride accumulation in impaired glucose-stimulated insulin secretion in a β-cell lipotoxicity model overexpressing sterol regulatory element-binding protein-1c. Endocrinology 145 3566–3577.
Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K et al. 2002 Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nature Medicine 8 1288–1295.[CrossRef][Web of Science][Medline]
Zhang S & Kim KH 1995 Glucose activation of acetyl-CoA carboxylase in association with insulin secretion in a pancreatic β-cell line. Journal of Endocrinology 147 33–41.
Zhou YP & Grill VE 1994 Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle. Journal of Clinical Investigation 93 870–876.[Web of Science][Medline]
Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N et al. 2001 Role of AMP-activated protein kinase in mechanism of metformin action. Journal of Clinical Investigation 108 1167–1174.[CrossRef][Web of Science][Medline]
Received in final form 24 June 2008
Accepted 25 June 2008
Made available online as an Accepted Preprint 25 June 2008
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