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1.
José L Ortiz Marcelo W Guarini Gisella R Borzone Pablo R Olmos 《Biomedical engineering online》2010,9(1):35
Background
It is known that tight control of glucose in the Intensive Care Unit reduces morbidity and mortality not only in diabetic patients but also in those non-diabetics who become transiently hyperglycemic. Taking advantage of a recently marketed subcutaneous glucose sensor we designed an Automatic Insulin Infusion System (AIIS) for inpatient treatment, and tested its stability under simulated clinical conditions. 相似文献2.
Sarita Dhuper Hillel W Cohen Josephine Daniel Padmasree Gumidyala Vipin Agarwalla Rosemarie St Victor Sunil Dhuper 《Cardiovascular diabetology》2007,6(1):1-9
Background
Inhibition of vascular smooth muscle cell (vSMC) proliferation by oral anti-hyperglycemic agents may have a role to play in the amelioration of vascular disease in diabetes. Thiazolidinediones (TZDs) inhibit vSMC proliferation but it has been reported that they anomalously stimulate [3H]-thymidine incorporation. We investigated three TZDs, two biguanides and two sulfonylureas for their ability of inhibit vSMC proliferation. People with diabetes obviously have fluctuating blood glucose levels thus we determined the effect of media glucose concentration on the inhibitory activity of TZDs in a vSMC preparation that grew considerably more rapidly under high glucose conditions. We further explored the mechanisms by which TZDs increase [3H]-thymidine incorporation.Methods
VSMC proliferation was investigated by [3H]-thymidine incorporation into DNA and cell counting. Activation and inhibition of thymidine kinase utilized short term [3H]-thymidine uptake. Cell cycle events were analyzed by FACS.Results
VSMC cells grown for 3 days in DMEM with 5% fetal calf serum under low (5 mM glucose) and high (25 mM glucose) increased in number by 2.5 and 4.7 fold, respectively. Rosiglitazone and pioglitazone showed modest but statistically significantly greater inhibitory activity under high versus low glucose conditions (P < 0.05 and P < 0.001, respectively). We confirmed an earlier report that troglitazone (at low concentrations) causes enhanced incorporation of [3H]-thymidine into DNA but did not increase cell numbers. Troglitazone inhibited serum mediated thymidine kinase induction in a concentration dependent manner. FACS analysis showed that troglitazone and rosiglitazone but not pioglitazone placed a slightly higher percentage of cells in the S phase of a growing culture. Of the biguanides, metformin had no effect on proliferation assessed as [3H]-thymidine incorporation or cell numbers whereas phenformin was inhibitory in both assays albeit at high concentrations. The sulfonylureas chlorpropamide and gliclazide had no inhibitory effect on vSMC proliferation assessed by either [3H]-thymidine incorporation or cell numbers.Conclusion
TZDs but not sulfonylureas nor biguanides (except phenformin at high concentrations) show favorable vascular actions assessed as inhibition of vSMC proliferation. The activity of rosiglitazone and pioglitazone is enhanced under high glucose conditions. These data provide further in vitro evidence for the potential efficacy of TZDs in preventing multiple cardiovascular diseases. However, the plethora of potentially beneficial actions of TZDs in cell and animal models have not been reflected in the results of major clinical trials and a greater understanding of these complex drugs is required to delineate their ultimate clinical utility in preventing macrovascular disease in diabetes. 相似文献3.
Background
Diabetes Mellitus is a chronic disease and many patients of which require frequent subcutaneous insulin injection to maintain proper blood glucose levels. Due to the inconvenience of insulin administration, an orally active insulin replacement has long been a prime target for many pharmaceutical companies. Demethylasterriquinone (DMAQ) B1, extracted from tropical fungus, Pseudomassaria sp., has been reported to be an orally effective agent at lowering circulating glucose levels in diabetic (db/db) mice; however, the cytotoxicity associated with the quinone moiety has not been addressed thus far. 相似文献4.
5.
Background
The Bacillus subtilis glucokinase operon was predicted to be comprised of the genes, yqgP (now named gluP), yqgQ, and glcK. We have previously established a role for glcK in glucose metabolism. In the absence of enzymes that phosphorylate glucose, such as GlcK and/or enzyme IIGlc, accumulated cytoplasmic glucose can be transported out of the cell. Genes within the glucokinase operon were not previously known to play a role in glucose transport. Here we describe the expression of gluP and its function in glucose transport. 相似文献6.
Background
The benefits of self-monitoring blood glucose levels are unclear in patients with type 2 diabetes mellitus who do not use insulin, but there are considerable costs. We sought to determine the cost effectiveness of self-monitoring for patients with type 2 diabetes not using insulin.Methods
We performed an incremental cost-effectiveness analysis of the self-monitoring of blood glucose in adults with type 2 diabetes not taking insulin. We used the United Kingdom Prospective Diabetes Study (UKPDS) model to forecast diabetes-related complications, corresponding quality-adjusted life years and costs. Clinical data were obtained from a systematic review comparing self-monitoring with no self-monitoring. Costs and utility decrements were derived from published sources. We performed sensitivity analyses to examine the robustness of the results.Results
Based on a clinically modest reduction in hemoglobin A1C of 0.25% (95% confidence interval 0.15–0.36) estimated from the systematic review, the UKPDS model predicted that self-monitoring performed 7 or more times per week reduced the lifetime incidence of diabetes-related complications compared with no self-monitoring, albeit at a higher cost (incremental cost per quality-adjusted life year $113 643). The results were largely unchanged in the sensitivity analysis, although the incremental cost per quality-adjusted life year fell within widely cited cost-effectiveness thresholds when testing frequency or the price per test strip was substantially reduced from the current levels.Interpretation
For most patients with type 2 diabetes not using insulin, use of blood glucose test strips for frequent self-monitoring (≥ 7 times per week) is unlikely to represent efficient use of finite health care resources, although periodic testing (e.g., 1 or 2 times per week) may be cost-effective. Reduced test strip price would likely also improve cost-effectiveness.Self-monitoring of blood glucose in patients with diabetes who use insulin may contribute to improved glycemic control and reduced hypoglycemia by allowing for self-adjustments in insulin dose to be made based on meter readings.1 Self-monitoring may also allow for appropriate changes in diet and physical activity to be made. However, the benefits of self-monitoring of blood glucose for patients not using insulin are less clear. Hypoglycemia is less frequent in this population2 and is confined mainly to those taking secretagogues. The degree to which patients can adjust the dose of oral antidiabetes drugs in response to readings is limited.Nevertheless, self-monitoring of blood glucose is routinely recommended for patients who are not using insulin.1 This results in major investments in this technology by patients and payers.3 In 2006, $250 million was spent on blood glucose test strips in 8 publicly funded drugs plans in Newfoundland and Labrador, Nova Scotia, Quebec, Ontario, Manitoba, Saskatchewan and British Columbia, while over $120 million was spent in privately funded drug plans in Canada.4 In some publicly funded drug plans in Canada, blood glucose test strips are among the top 5 classes in terms of total expenditure,5 with costs exceeding those for all oral antidiabetes drugs combined.4,6 It is estimated that more than 50% of the total expenditure on blood glucose test strips is for patients with type 2 diabetes who are not using insulin.3 Costs related to test strips are expected to rise steadily5,7 because of the increasing prevalence of type 2 diabetes.8Decisions about the prescribing and reimbursement of blood glucose test strips require consideration of information about the costs and clinical benefits.9,10 As part of a larger initiative to determine the optimal use of this technology, we sought to determine the cost-effectiveness of self-monitoring of blood glucose for patients with type 2 diabetes who do not use insulin, based on data from our systematic review11 of the available clinical evidence. 相似文献7.
Tomás?Gutiérrez Valentina?Parra Rodrigo?Troncoso Christian?Pennanen Ariel?Contreras-Ferrat César?Vasquez-Trincado Pablo?E?Morales Camila?Lopez-Crisosto Cristian?Sotomayor-Flores Mario?Chiong Beverly?A?Rothermel Sergio?Lavandero
Background
Cardiac hypertrophy is characterized by alterations in both cardiac bioenergetics and insulin sensitivity. Insulin promotes glucose uptake by cardiomyocytes and its use as a substrate for glycolysis and mitochondrial oxidation in order to maintain the high cardiac energy demands. Insulin stimulates Ca2+ release from the endoplasmic reticulum, however, how this translates to changes in mitochondrial metabolism in either healthy or hypertrophic cardiomyocytes is not fully understood.Results
In the present study we investigated insulin-dependent mitochondrial Ca2+ signaling in normal and norepinephrine or insulin like growth factor-1-induced hypertrophic cardiomyocytes. Using mitochondrion-selective Ca2+-fluorescent probes we showed that insulin increases mitochondrial Ca2+ levels. This signal was inhibited by the pharmacological blockade of either the inositol 1,4,5-triphosphate receptor or the mitochondrial Ca2+ uniporter, as well as by siRNA-dependent mitochondrial Ca2+ uniporter knockdown. Norepinephrine-stimulated cardiomyocytes showed a significant decrease in endoplasmic reticulum-mitochondrial contacts compared to either control or insulin like growth factor-1-stimulated cells. This resulted in a reduction in mitochondrial Ca2+ uptake, Akt activation, glucose uptake and oxygen consumption in response to insulin. Blocking mitochondrial Ca2+ uptake was sufficient to mimic the effect of norepinephrine-induced cardiomyocyte hypertrophy on insulin signaling.Conclusions
Mitochondrial Ca2+ uptake is a key event in insulin signaling and metabolism in cardiomyocytes.8.
Ruyuan Deng Aifang Nie Fangfang Jian Yun Liu Hongju Tang Juan Zhang Yuqing Zhang Li Shao Fengying Li Libin Zhou Xiao Wang Guang Ning 《Biochimica et Biophysica Acta (BBA)/General Subjects》2014
Background
It has been recognized that insulin hypersecretion can lead to the development of insulin resistance and type 2 diabetes mellitus. There is substantial evidence demonstrating that thiazolidinediones are able to delay and prevent the progression of pancreatic β-cell dysfunction. However, the mechanism underlying the protective effect of thiazolidinediones on β-cell function remains elusive.Methods
We synchronously detected the effects of troglitazone on insulin secretion and AMP-activated protein kinase (AMPK) activity under various conditions in isolated rat islets and MIN6 cells.Results
Long-term exposure to high glucose stimulated insulin hypersecretion and inhibited AMPK activity in rat islets. Troglitazone-suppressed insulin hypersecretion was closely related to the activation of AMPK. This action was most prominent at the moderate concentration of glucose. Glucose-stimulated insulin secretion was decreased by long-term troglitazone treatment, but significantly increased after the drug withdrawal. Compound C, an AMPK inhibitor, reversed troglitazone-suppressed insulin secretion in MIN6 cells and rat islets. Knockdown of AMPKα2 showed a similar result. In MIN6 cells, troglitazone blocked high glucose-closed ATP-sensitive K+ (KATP) channel and decreased membrane potential, along with increased voltage-dependent potassium channel currents. Troglitazone suppressed intracellular Ca2 + response to high glucose, which was abolished by treatment with compound C.Conclusion
Our results suggest that troglitazone provides β-cell “a rest” through activating AMPK and inhibiting insulin hypersecretion, and thus restores its response to glucose.General significance
These data support that AMPK activation may be an important mechanism for thiazolidinediones preserving β-cell function. 相似文献9.
Juliana Falcato Vecina Alexandre Gabarra Oliveira Tiago Gomes Araujo Sueli Regina Baggio Cristiane Okuda Torello Mario Jose Abdalla Saad Mary Luci de Souza Queiroz 《Life sciences》2014
Aims
The search for natural agents that minimize obesity-associated disorders is receiving special attention. In this regard, the present study aimed to evaluate the prophylactic effect of Chlorella vulgaris (CV) on body weight, lipid profile, blood glucose and insulin signaling in liver, skeletal muscle and adipose tissue of diet-induced obese mice.Main methods
Balb/C mice were fed either with standard rodent chow diet or high-fat diet (HFD) and received concomitant treatment with CV for 12 consecutive weeks. Triglyceride, free fatty acid, total cholesterol and fractions of cholesterol were measured using commercial assay. Insulin and leptin levels were determined by enzyme-linked immunosorbent assay (ELISA). Insulin and glucose tolerance tests were performed. The expression and phosphorylation of IRβ, IRS-1 and Akt were determined by Western blot analyses.Key findings
Herein we demonstrate for the first time in the literature that prevention by CV of high-fat diet-induced insulin resistance in obese mice, as shown by increased glucose and insulin tolerance, is in part due to the improvement in the insulin signaling pathway at its main target tissues, by increasing the phosphorylation levels of proteins such as IR, IRS-1 and Akt. In parallel, the lower phosphorylation levels of IRS-1ser307 were observed in obese mice. We also found that CV administration prevents high-fat diet-induced dyslipidemia by reducing triglyceride, cholesterol and free fatty acid levels.Significance
We propose that the modulatory effect of CV treatment preventing the deleterious effects induced by high-fat diet is a good indicator for its use as a prophylactic–therapeutic agent against obesity-related complications. 相似文献10.
Koyanagi M Asahara S Matsuda T Hashimoto N Shigeyama Y Shibutani Y Kanno A Fuchita M Mikami T Hosooka T Inoue H Matsumoto M Koike M Uchiyama Y Noda T Seino S Kasuga M Kido Y 《PloS one》2011,6(8):e23238
Aim
We previously found that chronic tuberous sclerosis protein 2 (TSC2) deletion induces activation of mammalian target of rapamycin Complex 1 (mTORC1) and leads to hypertrophy of pancreatic beta cells from pancreatic beta cell-specific TSC2 knockout (βTSC2−/−) mice. The present study examines the effects of TSC2 ablation on insulin secretion from pancreatic beta cells.Methods
Isolated islets from βTSC2−/− mice and TSC2 knockdown insulin 1 (INS-1) insulinoma cells treated with small interfering ribonucleic acid were used to investigate insulin secretion, ATP content and the expression of mitochondrial genes.Results
Activation of mTORC1 increased mitochondrial DNA expression, mitochondrial density and ATP production in pancreatic beta cells of βTSC2−/− mice. In TSC2 knockdown INS-1 cells, mitochondrial DNA expression, mitochondrial density and ATP production were increased compared with those in control INS-1 cells, consistent with the phenotype of βTSC2−/− mice. TSC2 knockdown INS-1 cells also exhibited augmented insulin secretory response to glucose. Rapamycin inhibited mitochondrial DNA expression and ATP production as well as insulin secretion in response to glucose. Thus, βTSC2−/− mice exhibit hyperinsulinemia due to an increase in the number of mitochondria as well as enlargement of individual beta cells via activation of mTORC1.Conclusion
Activation of mTORC1 by TSC2 ablation increases mitochondrial biogenesis and enhances insulin secretion from pancreatic beta cells. 相似文献11.
Background
The role of glucokinase (GCK) in the pathogenesis of maturity-onset diabetes of the young is well established. However, its role in the common form of type 2 diabetes is far from convincing. We investigated the role of the G-to-A polymorphism in the hepatic GCK promoter on insulin sensitivity and beta cell function in 63 normotensive Asian Indians with normal glucose tolerance. As proposed by Matsuda and DeFronzo, hepatic insulin sensitivity (ISIH) and total body insulin sensitivity (ISIM) were estimated from the oral glucose tolerance test. Beta cell function was estimated using %B from the Homeostasis Model Assessment and insulingenic index (dI/dG). 相似文献12.
William J L’Amoreaux Allison Santora Jonathan F Blaize Janto Tachjadi Abdeslem El Idrissi 《Journal of biomedical science》2010,17(Z1):S11
Background
Pancreatic β-cells release insulin via an electrogenic response triggered by an increase in plasma glucose concentrations. The critical plasma glucose concentration has been determined to be ~3 mM, at which time both insulin and GABA are released from pancreatic β-cells. Taurine, a β-sulfonic acid, may be transported into cells to balance osmotic pressure. The taurine transporter (TauT) has been described in pancreatic tissue, but the function of taurine in insulin release has not been established. Uptake of taurine by pancreatic β-cells may alter membrane potential and have an effect on ion currents. If taurine uptake does alter β-cell current, it might have an effect on exocytosis of cytoplasmic vesicle. We wished to test the effect of taurine on regulating release of insulin from the pancreatic β-cell.Methods
Pancreatic β-cell lines Hit-TI5 (Syrian hamster) and Rin-m (rat insulinoma) were used in these studies. Cells were grown to an 80% confluence on uncoated cover glass in RPMI media containing 10% fetal horse serum. The cells were then adapted to a serum-free, glucose free environment for 24 hours. At that time, the cells were treated with either 1 mM glucose, 1 mM taurine, 1 mM glucose + 1 mM taurine, 3 mM glucose, or 3 mM glucose + 1 mM taurine. The cells were examined by confocal microscopy for cytoplasmic levels of insulin.Results
In both cell lines, 1 mM glucose had no effect on insulin levels and served as a control. Cells starved of glucose had a significant reduction (p<0.001) in the level of insulin, but this level was significantly higher than all other treatments. As expected, the 3 mM glucose treatment resulted in a statistically lower (p<0.001) insulin level than control cells. Interestingly, 1 mM taurine also resulted in a statistically lower level of insulin (p<0.001) compared to controls when either no glucose or 1 mM glucose was present. Cells treated with 1 mM taurine plus 3 mM glucose showed a level of insulin similar to that of 3 mM glucose alone.Conclusions
Taurine administration can alter the electrogenic response in β-cell lines, leading to a change in calcium homeostasis and a subsequent decrease in intracellular insulin levels. The consequence of these actions could represent a method of increasing plasma insulin levels leading to a decrease in plasma glucose levels.13.
14.
Zhong‐Cheng Luo Anne‐Monique Nuyt Edgard Delvin William D. Fraser Pierre Julien Francois Audibert Isabelle Girard Bryna Shatenstein Cheri Deal Emilie Grenier Carole Garofalo Emile Levy 《Obesity (Silver Spring, Md.)》2013,21(1):210-216
Objective:
It remains uncertain whether leptin and adiponectin levels are correlated in maternal vs. fetal circulations. Little is known about whether leptin and adiponectin affect insulin sensitivity during fetal life.Design and Methods:
In a prospective singleton pregnancy cohort (n = 248), we investigated leptin and adiponectin concentrations in maternal (at 24‐28 and 32‐35 weeks of gestation) and fetal circulations, and their associations with fetal insulin sensitivity (glucose/insulin ratio, proinsulin level).Results:
Comparing concentrations in cord vs. maternal blood, leptin levels were 50% lower, but adiponectin levels more than doubled. Adjusting for gestational age at blood sampling, consistent and similar positive correlations (correlation coefficients: 0.31‐0.34, all P < 0.0001) were observed in leptin or adiponectin levels in maternal (at 24‐28 or 32‐25 weeks of gestation) vs. fetal circulations. For each SD increase in maternal plasma concentration at 24‐28 weeks, cord plasma concentration increased by 12.7 (95% confidence interval 6.8‐18.5) ng/ml for leptin, and 2.9 (1.8‐4.0) µg/ml for adiponectin, respectively (adjusted P < 0.0001). Fetal insulin sensitivity was negatively associated with cord blood leptin (each SD increase was associated with a 5.4 (2.1‐8.7) mg/dl/µU/ml reduction in cord plasma glucose/insulin ratio, and a 5.6 (3.9, 7.4) pmol/l increase in proinsulin level, all adjusted P < 0.01) but not adiponectin (P > 0.4) levels). Similar associations were observed in nondiabetic full‐term pregnancies (n = 211).Conclusions:
The results consistently suggest a maternal impact on fetal leptin and adiponectin levels, which may be an early life pathway in maternal‐fetal transmission of the propensity to obesity and insulin resistance. 相似文献15.
Background
Focal Adhesion Kinase (FAK) is recently reported to regulate insulin resistance by regulating glucose uptake in C2C12 skeletal muscle cells. However, the underlying mechanism for FAK-mediated glucose transporter-4 translocation (Glut-4), responsible for glucose uptake, remains unknown. Recently actin remodeling was reported to be essential for Glut-4 translocation. Therefore, we investigated whether FAK contributes to insulin-induced actin remodeling and harbor Glut-4 for glucose transport and whether downregulation of FAK affects the remodeling and causes insulin resistance. 相似文献16.
Ohara-Imaizumi M Yoshida M Aoyagi K Saito T Okamura T Takenaka H Akimoto Y Nakamichi Y Takanashi-Yanobu R Nishiwaki C Kawakami H Kato N Hisanaga S Kakei M Nagamatsu S 《PloS one》2010,5(12):e15553
Background
A variant of the CDKAL1 gene was reported to be associated with type 2 diabetes and reduced insulin release in humans; however, the role of CDKAL1 in β cells is largely unknown. Therefore, to determine the role of CDKAL1 in insulin release from β cells, we studied insulin release profiles in CDKAL1 gene knockout (CDKAL1 KO) mice.Principal Findings
Total internal reflection fluorescence imaging of CDKAL1 KO β cells showed that the number of fusion events during first-phase insulin release was reduced. However, there was no significant difference in the number of fusion events during second-phase release or high K+-induced release between WT and KO cells. CDKAL1 deletion resulted in a delayed and slow increase in cytosolic free Ca2+ concentration during high glucose stimulation. Patch-clamp experiments revealed that the responsiveness of ATP-sensitive K+ (KATP) channels to glucose was blunted in KO cells. In addition, glucose-induced ATP generation was impaired. Although CDKAL1 is homologous to cyclin-dependent kinase 5 (CDK5) regulatory subunit-associated protein 1, there was no difference in the kinase activity of CDK5 between WT and CDKAL1 KO islets.Conclusions/Significance
We provide the first report describing the function of CDKAL1 in β cells. Our results indicate that CDKAL1 controls first-phase insulin exocytosis in β cells by facilitating ATP generation, KATP channel responsiveness and the subsequent activity of Ca2+ channels through pathways other than CDK5-mediated regulation. 相似文献17.
Karla Martínez Ramón de Anda Georgina Hernández Adelfo Escalante Guillermo Gosset Octavio T Ramírez Francisco G Bolívar 《Microbial cell factories》2008,7(1):1
Background
Escherichia coli strains lacking the phosphoenolpyruvate: carbohydrate phosphotransferase system (PTS) are capable of coutilizing glucose and other carbon sources due to the absence of catabolite repression by glucose. In these strains, the lack of this important regulatory and transport system allows the coexistence of glycolytic and gluconeogenic pathways. Strains lacking PTS have been constructed with the goal of canalizing part of the phosphoenolpyruvate (PEP) not consumed in glucose transport to the aromatic pathway. The deletion of the ptsHIcrr operon inactivates PTS causing poor growth on this sugar; nonetheless, fast growing mutants on glucose have been isolated (PB12 strain). However, there are no reported studies concerning the growth potential of a PTS- strain in mixtures of different carbon sources to enhance the production of aromatics compounds. 相似文献18.
Background
The critically ill can have persistent dysglycemia during the “subacute” recovery phase of their illness because of altered gene expression; it is also not uncommon for these patients to receive continuous enteral nutrition during this time. The optimal short-acting subcutaneous insulin therapy that should be used in this clinical scenario, however, is unknown. Our aim was to conduct a qualitative numerical study of the glucose-insulin dynamics within this patient population to answer the above question. This analysis may help clinicians design a relevant clinical trial.Methods
Eight virtual patients with stress hyperglycemia were simulated by means of a mathematical model. Each virtual patient had a different combination of insulin resistance and insulin deficiency that defined their unique stress hyperglycemia state; the rate of gluconeogenesis was also doubled. The patients received 25 injections of subcutaneous regular or Lispro insulin (0-6 U) with 3 rates of continuous nutrition. The main outcome measurements were the change in mean glucose concentration, the change in glucose variability, and hypoglycemic episodes. These end points were interpreted by how the ultradian oscillations of glucose concentration were affected by each insulin preparation.Results
Subcutaneous regular insulin lowered both mean glucose concentrations and glucose variability in a linear fashion. No hypoglycemic episodes were noted. Although subcutaneous Lispro insulin lowered mean glucose concentrations, glucose variability increased in a nonlinear fashion. In patients with high insulin resistance and nutrition at goal, “rebound hyperglycemia” was noted after the insulin analog was rapidly metabolized. When the nutritional source was removed, hypoglycemia tended to occur at higher Lispro insulin doses. Finally, patients with severe insulin resistance seemed the most sensitive to insulin concentration changes.Conclusions
Subcutaneous regular insulin consistently lowered mean glucose concentrations and glucose variability; its linear dose-response curve rendered the preparation better suited for a sliding-scale protocol. The longer duration of action of subcutaneous regular insulin resulted in better glycemic-control metrics for patients who were continuously postprandial. Clinical trials are needed to examine whether these numerical results represent the glucose-insulin dynamics that occur in intensive care units; if present, their clinical effects should be evaluated.19.
《Cell calcium》2015,58(5-6):366-375
In healthy pancreatic islets, glucose-stimulated changes in intracellular calcium ([Ca2+]i) provide a reasonable reflection of the patterns and relative amounts of insulin secretion. We report that [Ca2+]i in islets under stress, however, dissociates with insulin release in different ways for different stressors. Islets were exposed for 48 h to a variety of stressors: cytokines (low-grade inflammation), 28 mM glucose (28G, glucotoxicity), free fatty acids (FFAs, lipotoxicity), thapsigargin (ER stress), or rotenone (mitochondrial stress). We then measured [Ca2+]i and insulin release in parallel studies. Islets exposed to all stressors except rotenone displayed significantly elevated [Ca2+]i in low glucose, however, increased insulin secretion was only observed for 28G due to increased nifedipine-sensitive calcium-channel flux. Following 3–11 mM glucose stimulation, all stressors substantially reduced the peak glucose-stimulated [Ca2+]i response (first phase). Thapsigargin and cytokines also substantially impacted aspects of calcium influx and ER calcium handling. Stressors did not significantly impact insulin secretion in 11 mM glucose for any stressor, although FFAs showed a borderline reduction, which contributed to a significant decrease in the stimulation index (11:3 mM glucose) observed for FFAs and also for 28G. We also clamped [Ca2+]i using 30 mM KCl + 250 μM diazoxide to test the amplifying pathway. Only rotenone-treated islets showed a robust increase in 3–11 mM glucose-stimulated insulin secretion under clamped conditions, suggesting that low-level mitochondrial stress might activate the metabolic amplifying pathway. We conclude that different stressors dissociate [Ca2+]i from insulin secretion differently: ER stressors (thapsigargin, cytokines) primarily affect [Ca2+]i but not conventional insulin secretion and ‘metabolic’ stressors (FFAs, 28G, rotenone) impacted insulin secretion. 相似文献
20.
Windholz J Kovacs P Tönjes A Dittrich K Blüher S Kiess W Stumvoll M Körner A 《PloS one》2011,6(7):e22101