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Departments of Endocrinology and Metabolism and Diabetes (P.M., S.D.G., L.M., R.L., M.M., M.P., M.B., S.D.P.) and Oncology (U.B., F.V., F.M.), Transplant Unit, University of Pisa, 56124 Pisa, Italy
Address all correspondence and requests for reprints to: Piero Marchetti, M.D., Department of Endocrinology and Metabolism, Section of Diabetes, Ospedale Cisanello, Via Paradisa 2, 56124 Pisa, Italy. E-mail: marchant{at}immr.med.unipi.it.
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Abstract |
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Introduction |
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The insulin release defects of type 2 diabetes have been extensively studied in vivo and are mainly characterized by impairment of glucose-stimulated insulin release (5). However, due to the strict relationships among insulin secretion, prevalent plasma glucose concentration, and degree of insulin sensitivity (6), identification of defects of ß-cell function in vivo may be a difficult task. A more direct assessment of the properties of the diabetic ß-cell would therefore allow to better look for alterations associated with and/or responsible for impaired insulin secretion in type 2 diabetes.
So far, little information is available on the insulin release characteristics of pancreatic islets from type 2 diabetic donors. Fernandez-Alvarez et al. (7) found that pancreatic islets from two diabetic patients had reduced glucose-stimulated insulin secretion, whereas the defect after leucine and glutamine challenge was less marked. Other authors (8) observed that the islets from three type 2 diabetic donors released insulin in pulses, the amplitude of which was reduced. In a more recent work, it has been shown that the function of islets from a group of type 2 diabetic patients was characterized by abnormal glucose-stimulated insulin release during perifusion experiments (9).
In addition to functional defects, islets in type 2 diabetes may have decreased ß-cell mass, as recently supported by the findings by Butler et al. (10) on autoptic pancreatic tissue. The reduction of insulin-secreting cell mass was attributed to increased apoptosis without major impairment in neogenesis (10).
In the present study, we report data on the function and survival of pancreatic islets isolated from six type 2 diabetic organ donors, in which reduced insulin content, decreased amount of mature insulin granules, impaired glucose-induced insulin secretion, reduced insulin mRNA expression, and increased apoptosis with enhanced activity of caspase-3 and -8 were found. These alterations were associated with evidence of increased oxidative stress. In addition, we investigated on the effects of therapeutical concentration of metformin on these parameters. Metformin is widely used in the treatment of type 2 diabetic patients (11). In addition, this drug was shown to reduce the conversion to type 2 diabetes in high-risk persons (12). Although metformin is not supposed to have effect on insulin secretion, studies with the perfused rat pancreas (13) and in vitro experiments with isolated human islets (14) have shown improved insulin release in response to glucose in the presence of the drug. In addition, previous work has demonstrated that metformin can restore normal secretory pattern in isolated rat pancreatic islets incubated in the presence of elevated glucose or free fatty acid (FFA) concentrations (15). Finally, we have reported that in islets prepared from nondiabetic donors, metformin prevented the desensitization of pancreatic ß-cells induced by prolonged exposure to high glucose (16) or increased concentrations of FFAs (17, 18). The decision to test metformin was based on these considerations, and the results showed that the drug can reverse most of the alterations found in type 2 diabetes islets. The effect was due, at least in part, to a reduction of oxidative stress.
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Materials and Methods |
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The islets were isolated from six type 2 diabetic and 10 nondiabetic cadaveric organ donors (Table 1
). Diagnosis of diabetes was made by family physicians on the basis of currently accepted criteria (1). Cold ischemia time was 11.5 ± 2.1 and 11.9 ± 2.3 h for diabetic and nondiabetic pancreases, respectively. The glands were obtained and processed with the approval of the ethics committee of our institution.
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Electron microscopy evaluation
Electron microscopy studies were performed as previously described (20). Samples were fixed with 2.5% glutaraldehyde in 0.1 M cacodylate buffer (pH 7.4) for 1 h at 4 C. After rinsing in cacodylate buffer, islet pellets were postfixed in 1% cacodylate buffered osmium tetroxide for 2 h at room temperature and then dehydrated in a graded series of ethanol, transferred to propylene oxide, and embedded in Epon-Araldite. Ultrathin sections (60–80 nm thick) were cut with a diamond knife, placed on formvar-carbon-coated copper grids (200 mesh), and stained with uranyl acetate and lead citrate. Morphometric analyses were performed as detailed elsewhere (21). Micrographs were obtained at x10,000. Every microscopic field was analyzed to count ß-, 
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-, and apoptotic cells. To quantify ß-cell granules, a graticule (11 x 11 cm) composed of 169 points was placed on the micrographs and the number of points intersecting the ß-cell granules was counted. The volume density (milliliter percent) of the granules was calculated according to the formula: VD = 
/Pt, where is the number of points within the subcellular component and Pt is the total number of points.
Insulin secretion experiments
Insulin secretion studies were performed by the batch incubation method or by using a perifusion system (18, 19, 22). In the batch incubation experiments, after a 45-min preincubation period at 60 mg/dl (3.3 mmol/liter) glucose, groups of approximately 30 islets of comparable size were kept at 37 C for 45 min in Krebs-Ringer bicarbonate solution, 0.5% albumin (pH 7.4) containing 60 mg/dl (3.3 mmol/liter) glucose. At the end of this period, medium was completely removed and replaced with Krebs-Ringer bicarbonate solution containing 30, 100, or 300 mg/dl (1.7, 5.5, or 16.7 mmol/liter) glucose. After an additional 45-min incubation, samples (500 µl) from the different media were taken and stored at –20 C until insulin concentrations were measured by immunoradiometric assay (Pantec Forniture Biomediche, Turin, Italy). In these experiments, islet insulin content was measured after overnight acid-alcohol extraction. In the perifusion studies, batches of approximately 50 islets were perifused at 37 C (flow rate of 1 ml/min) for 30 min with 60 mg/dl (3.3 mmol/liter) glucose and then challenged with 300 mg/dl (16.7 mmol/liter) glucose.
Evaluation of islet cell death and caspase-3 and -8 activity
Islet cell death was assessed by the Cell Death Detection ELISAplus assay (Roche Diagnostics, Mannheim, Germany), which evaluates cytoplasmic histone-associated DNA fragments. The procedure was performed according to the recommendations by the manufacturer and as previously described for human islet experiments (20). Aliquots of approximately 15 islets of comparable size were incubated in duplicate for 30 min with a lysis buffer at room temperature and then centrifuged at 200 x g for 10 min at 4 C. Aliquots of the supernatant (20 µl) were placed into microtiter plate wells and coated with streptavidin. Eighty microliters of a mixture containing anti-histone-biotin antibody and anti-DNA-POD antibody was then added, and incubation was allowed for 120 min at room temperature. Then the preparations were washed, and 100 µl of a solution containing ABTS (the substrate for peroxidase) was added. At the end of 15 min incubation, absorbance of samples was read spectrophotometrically at 405 nm.
Caspase-3 and caspase-8 activity was determined using the caspase-3 colorimetric protease assay kit and the caspase-8 colorimetric protease assay kit (Chemicon, Temecula, CA), respectively. Batches of control and type 2 diabetic islets (in duplicates) were washed twice in cold PBS, resuspended in 50 µl cell lysis buffer, and incubated in ice for 10 min. Cell lysates were pelleted by centrifugation at 10,000 x g for 1 min, and the supernatants were transferred to fresh tubes. The protein content of the supernatants was measured by the Lowry method, and then 150 µg protein, diluted to a volume of 50 µl with cell lysis buffer, was placed into microtiter plate well. Fifty microliters of 2x reaction buffer with 10 mmol/liter dithiothreitol and 5 µl of the 4 mmol/liter DEVD-p-nitroanilide substrate or 4 mmol/liter LEHD-p-nitroanilide substrate were added to each well, followed by 2 h incubation at 37 C. OD for each specimen was determined spectrophotometrically at 405 nm.
Determination of nitrotyrosine
Nitrotyrosine concentration was determined in islet cell lysates by an ELISA method as previously described (23). White 96-well plates (Iwaki, Japan) were coated with 200 µl of standard curve samples (15–0.166 nmol/liter) or 1 µg/µl of islet cell lysates (65 µl/well) in 0.1 mol/liter carbonate-bicarbonate buffer (135 µl) (pH 9.6) and kept overnight at 4 C. Nonspecific binding was blocked by 1% BSA in PBS plus 0.05% Tween 20 for 1 h at 37 C, and the wells were incubated with purified monoclonal antinitrotyrosine mouse IgG (Upstate Biotechnology, Lake Placid, NY) for 1 h at 37 C. Then the plates were washed and incubated with a peroxidase-conjugated goat antimouse IgG secondary antibody for 45 min at 37 C. The peroxidase reaction product was generated using tetramethyl-benzidine microwell peroxidase substrate (Sigma-Aldrich, St. Louis, MO) (150 µl/well). Plates were incubated 5–10 min at room temperature and OD was read at 492 nm in a microplate reader.
Quantitative PCR (real-time RT-PCR) experiments
Total RNA was extracted from human pancreatic islets and handled as previously described (24) using the RNeasy protect mini kit (QIAGEN, Santa Clarita, CA) and then quantified by absorbance at A260/A280 (ratio > 1.65) nm in a spectrophotometer (Perkin-Elmer, Norwalk, CT). Its integrity was assessed after electrophoresis in 1.0% agarose gels by ethidium bromide staining. For quantitative RT-PCR, the cDNA synthesis was performed from 2 µg of total RNA, and the oligonucleotides of interest were obtained from Assay-on-Demand gene expression products (Applied Biosystems, Foster City, CA). To avoid amplification of genomic DNA, the primers were designed to span exon-exon borders. The probes were labeled with FAM at the 5' end and TAMRA at the 3' end. PCR amplification (40 cycles) was performed in a total volume of 25 µl containing 1 µl cDNA sample, 200 nmol/l of each primer, 100 nmol/liter of the corresponding probe, and 12.5 µl of TaqMan universal PCR master mix. Polymerase was activated by preincubation at 95 C for 10 min. mRNA level of target genes was quantified and normalized for ß-actin as previously described (20, 24).
Western immunoblotting analysis of protein kinase C (PKC) ß2-protein
The procedure was performed as published previously (25, 26) and slightly modified to be applied to human islets. Islet cells lysate aliquots, containing 250 µg protein, were immunoprecipitated by incubation with an anti-PKC ß2-antibody (Santa Cruz Biotechnology, Santa Cruz, CA) for 20 h at 4 C on a rotating device. After the addition of Protein A-Sepharose (Sigma-Aldrich), immunocomplexes were resolved in SDS-PAGE and transferred to nitrocellulose. Bound antibodies were detected by using procedures carried out according to the manufacturer’s instructions (ECL, Amersham Biosciences, Buckinghamshire, UK). Bands of interest were quantified by a densitometer (GS 690, Bio-Rad Laboratories, Hercules, CA) using a MultiAnalyst/PC-PC software for Image Analysis Systems (version 1.02, Bio-Rad Laboratories).
Statistical analysis
Results are expressed as mean ± SD. For any given experiment, results from each pancreas were averaged, and n indicated the number of pancreases used in that specific setting. Comparison between groups was done by the two-tailed, unpaired Student’s t test, and/or ANOVA comparison, as appropriate (18, 19, 20).
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Results |
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Insulin content was 115 ± 31 µU/islet (690 ± 186 pmol/islet) in islets isolated from control pancreases (n = 10) and 73 ± 30 µU/islet (438 ± 180 pmol/islet) in islets prepared from type 2 diabetes subjects (n = 6) (P < 0.05). After 24 h incubation with metformin, hormone content did not change significantly in control cells (129 ± 35 µU/islet or 774 ± 210 pmol/islet), but it increased in type 2 diabetes islets (108 ± 25 µU/islet or 648 ± 150 pmol/islet, P < 0.05 vs. untreated type 2 islets, NS vs. controls).
ß-Cell proportion was slightly, although significantly, different between control (n = 4) and type 2 diabetes (n = 4) islets (69 ± 4 vs. 61 ± 3%, P < 0.05). The respective percentages of -cells (22 ± 4 vs. 25 ± 7%) and -cells (9 ± 2 vs. 14 ± 5%) did not differ significantly between the two groups, and exposure to metformin did not change these percentages (not shown). Diabetic ß-cells contained a lower amount of insulin granules (Table 2), with a decreased proportion of the mature ones (Table 2). Treatment with metformin determined an increase of insulin granules and normalized the relative percentages of mature and immature granules (Fig. 1 and Table 2). These changes were accompanied by modification of insulin mRNA expression in type 2 diabetes islets (n = 6) insulin mRNA was markedly lower than that of control islets (n = 10) (P < 0.05) and increased significantly (P < 0.05 vs. untreated diabetic islets) after exposure to metformin (Fig. 2).
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), insulin release in response to 30 and 100 mg/dl (1.7 and 5.5 mmol/liter) glucose was comparable in control (n = 10) and diabetic (n = 6) islets. However, at 300 mg/dl (16.7 mmol/liter) glucose type 2 diabetic islets released less insulin (P < 0.05) than control cells. Preexposure to metformin was associated with a significant improvement of insulin release from diabetic islets (P < 0.05 vs. untreated type 2 diabetes islets) at high glucose stimulation (Fig. 3). In perifusion experiments (four pancreases), acute glucose challenge induced the expected early phase insulin release in control but not in diabetic islets (Fig. 4). Preincubation of type 2 diabetes islets with metformin partially restored early-phase insulin secretion (Fig. 4). During the 1- to 8-min interval, insulin secretion was 41.7 ± 17.4 and 23.0 ± 4.5 µU/min (250.2 ± 104.4 and 138.0 ± 27.0 pmol/min) in control and type 2 diabetes islets, respectively (P < 0.05). After 24 h treatment with metformin, the respective values were 46.5 ± 14.7 (NS vs. untreated control islets) and 30.8 ± 8.8 µU/min (279.0 ± 88.2 and 184.8 ± 52.8 pmol/min) (P < 0.05 vs. untreated type 2 diabetes islets).
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As shown in Fig. 5, assessment of islet cell death by an ELISA method revealed a greater amount of apoptosis in type 2 diabetes than in control islets. This was accompanied by a significant increase in the activity of caspase-3 and caspase-8. Metformin did not affect death rate of control islets. On the contrary, incubation of type 2 diabetes islets with metformin was associated with reduced cell death (NS vs. control islets). This was accompanied by normalization of caspase-3 and caspase-8 activities (Fig. 5).
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- and/or -cells. Nitrotyrosine measurement
Nitrotyrosine levels were, respectively, 7.4 ± 0.4 and 10.2 ± 0.5 nmol/liter in control islets (n = 10) and type 2 diabetes islets (n = 6) (P < 0.05). Preincubation with metformin did not change nitrotyrosine levels in control islet cells (7.2 ± 0.2 nmol/liter), but it decreased nitrotyrosine concentration in type 2 diabetes islets (7.9 ± 0.3 nmol/liter, P < 0.05 vs. untreated diabetic islets).
Quantitative RT-PCR studies and immunoblotting experiments
The expression of PKCß2, both at the transcription and the protein levels, was 30–40% higher in type 2 diabetes islets (n = 5) than in control islets (n = 5) (Fig. 5
). Preincubation with metformin caused the normalization of PKCß2 mRNA and protein expression (Fig. 6).
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). A different pattern of mRNA expression of manganese (Mn)-superoxide dismutase (SOD), Cu/Zn-SOD, catalase, and glutathione (GSH) peroxidase between control and diabetic islets was observed as well (Fig. 7). Incubation with metformin was associated with normalization of the expression of catalase and GSH peroxidase, whereas mRNA expression of Mn-SOD and Cu/Zn-SOD was not significantly affected by the drug (Fig. 7).
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Discussion |
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In agreement with previous observations (7, 8, 9), our data indicate that type 2 diabetes islets secrete less insulin than control islets in response to glucose. The defect is characterized by loss of first-phase insulin secretion, and metformin incubation determined a quantitative as well as a qualitative restoration of insulin release. This effect was associated with replenishment of islet insulin storage (as indicated by the increase of total insulin content and mature insulin granules), possibly due to a more efficient insulin synthesis (as indicated by increased insulin mRNA).
In type 2 diabetes, a defect of ß-cell survival exists. Recently, by examining autoptic pancreatic tissue, Butler et al. (10) reported a several-fold increase in the frequency of ß-cell apoptosis. Our data, by using isolated islets, confirm this finding, which was associated, in our study, with increased activity of caspase-3 and caspase-8, neutral proteases specifically activated during the apoptotic process (27). We found that metformin exerted an antiapoptotic effect, which was paralleled by a reduction of caspase-3 and -8 activity.
In our study, we observed an increased concentration of nitrotyrosine in type 2 diabetes islets. Nitrotyrosine derives from the reaction of superoxide and nitric oxide and is considered a reliable marker of oxidative stress (23). In addition, we found changes in the expression of several enzymes involved in cell redox balance. We are therefore inclined to believe that the functional and survival defects found in type 2 diabetes islets are due, at least in part, to increased oxidative stress. This concept is in agreement with previous findings by Sakuraba et al. (28), who found enhanced oxidative stress-related DNA damage and reduced expression of Mn-SOD and Cu/Zn SOD mRNA on histology of autoptic pancreata of Japanese type 2 diabetic patients.
The degree of oxidative stress results from the balance of formation of reactive oxygen species (ROS) and antioxidant defense. It is known that elevations in glucose and possibly FFA levels induce production of ROS (29, 30). A major source of ROS is the mitochondrion, in which increased availability of substrates causes enhanced oxidation activity and production of oxygen derivatives (29, 30). In addition, our data suggest that in type 2 diabetes islet cells the PKC-NADPH oxidase pathway may contribute to the overproduction of superoxide anions. In fact, we found that the expression of both enzymes was significantly increased. It is believed that PKC activation is due, at least in part, to the presence of free radicals and that, in turn, PKC activates NADPH oxidase to further production of superoxide (31).
On the other hand, it is well recognized that ß-cells have reduced antioxidant defenses and that potentiating such defenses reduces the toxic effects of several compounds (32, 33, 34, 35, 36). In our experiments, we observed changes in the expression of several enzymes committed to scavenge free radicals in type 2 diabetes islets. In particular, our findings confirm previous data showing reduced expression of Mn-SOD and Cu/Zn SOD mRNA in type 2 diabetes islets (28). On the contrary, the expression of catalase and GSH peroxidase was increased, suggesting an attempt to enhance the elimination of ROS through pathways different from dismutase activity. In this regard, it has been shown that inactivation of hydrogen peroxide is a critical step for the removal of reactive oxygen species in insulin-producing cells and that exposure to H2O2 increases mRNA expression of catalase in in vitro systems (32). Interestingly, in our study we found a well-measurable expression of catalase, whereas in rat islets this enzyme seems to be barely expressed (32), suggesting that important differences might exist between human and rodent islets in this regard.
Within this scenario, we found that when the islets from type 2 diabetic patients were exposed for 24 h to metformin, nitrotyrosine levels decreased and PKC and NADPH expression returned toward control values. In addition, in our experiments metformin did not affect the expression of SODs, but it significantly reduced catalase and GSH peroxidase expression. We interpret these findings as clues for a positive effect of metformin on the redox balance of islet cells. Previous work conducted in other experimental models indeed supports the antioxidant properties of metformin. Faure et al. (37) reported that in high fructose-fed rats metformin improved red cell antioxidant enzyme activities and circulating GSH levels. Moreover, metformin was shown to exert antioxidant activity in streptozotocin-induced diabetic rats (38) and to decrease erythrocyte susceptibility to oxidative stress in type 2 diabetic patients (39). The drug is known to inhibit oxidative phosphorylation (40). Although the mechanisms by which this effect is achieved are still unclear, recent evidence suggests that metformin can enter the mitochondria, accumulate within these organelles, and inhibit complex 1 of the respiratory chain (41). Therefore, when islet cells are exposed to the drug, a lower amount of ROS of mitochondrial origin is likely to be produced, which restores a sort of vicious circle, leading to reduced oxidative stress.
In conclusion, our study shows for the first time that islets isolated from type 2 diabetic patients have several functional and survival defects, which can be ameliorated by exposure to metformin. An increased oxidative stress may contribute to the functional and survival alterations of diabetic islets, and metformin at therapeutic concentration appears to improve islet cell redox state. Further studies are needed to evaluate whether a prolonged and persistent exposure of pancreatic islet cells to concentrations of metformin in the range used in the present in vitro study can prevent, at least in part, the decline of ß-cell function that seems to occur in type 2 diabetic patients irrespective of antidiabetic treatment (42).
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Footnotes |
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Abbreviations: FFA, Free fatty acid; GSH, glutathione; NADPH, nicotinamide adenine dinucleotide phosphate reduced; PKC, protein kinase C; ROS, reactive oxygen species; SOD, superoxide dismutase.
Received February 3, 2004.
Accepted August 5, 2004.
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Arg IRS-1 polymorphism. Diabetes 51:1419–1424
}2 in the modulation of insulin secretion. Am J Physiol Endocrinol Metab 286:E560–E567
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