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We have recently shown that overnight exposure of INS-1E insulinoma cells to palmitate in the presence of high glucose causes defects in both mitochondrial energy metabolism and glucose-stimulated insulin secretion (GSIS). Here we report experiments designed to test the involvement of mitochondrial uncoupling protein-2 (UCP2) in these glucolipotoxic effects. Measuring real-time oxygen consumption in siRNA-transfected INS-1E cells, we show that deleterious effects of palmitate on the glucose sensitivity of mitochondrial respiration and on the coupling efficiency of oxidative phosphorylation are independent of UCP2. Consistently, palmitate impairs GSIS to the same extent in cells with and without UCP2. Furthermore, we knocked down UCP2 in spheroid INS-1E cell clusters (pseudoislets) to test whether or not UCP2 regulates insulin secretion during prolonged glucose exposure. We demonstrate that there are no differences in temporal GSIS kinetics between perifused pseudoislets with and without UCP2. We conclude that UCP2 is not involved in palmitate-induced impairment of GSIS in INS-1E insulinoma cells and is not needed for the amplification of insulin release. These conclusions inform ongoing debate on the disputed biochemical and physiological functions of the beta cell UCP2. 相似文献
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Akos A. Gerencser 《BBA》2018,1859(9):817-828
Mitochondrial metabolism plays a central role in insulin secretion in pancreatic beta-cells. Generation of protonmotive force and ATP synthesis from glucose-originated pyruvate are critical steps in the canonical pathway of glucose-stimulated insulin secretion. Mitochondrial metabolism is intertwined with pathways that are thought to amplify insulin secretion with mechanisms distinct from the canonical pathway, and the relative importance of these two pathways is controversial. Here I show that glucose-induced mitochondrial membrane potential (MMP) hyperpolarization is necessary for, and predicts, the rate of insulin secretion in primary cultured human beta-cells. When glucose concentration is elevated, increased metabolism results in a substantial MMP hyperpolarization, as well as in increased rates of ATP synthesis and turnover marked by faster cell respiration. Using modular kinetic analysis I explored what properties of cellular energy metabolism enable a large glucose-induced change in MMP in human beta-cells. I found that an ATP-dependent pathway activates glucose or substrate oxidation, acting as a positive feedback in energy metabolism. This activation mechanism is essential for concomitant fast respiration and high MMP, and for a high magnitude glucose-induced MMP hyperpolarization and therefore for insulin secretion. 相似文献
4.
《Cell metabolism》2022,34(2):240-255.e10
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5.
Patel R. Singh J. Yago M.D. Vilchez J.R. Martínez-Victoria E. Mañas M. 《Molecular and cellular biochemistry》2004,261(1):105-110
This investigation characterised the effects of exogenous insulin on exocrine pancreatic secretion in anaesthetised healthy and diabetic rats. Animals were rendered diabetic by a single injection of streptozotocin (STZ, 60 mg kg–1 I.P.). Age-matched controls were injected citrate buffer. Rats were tested for hyperglycaemia 4 days after STZ injection and 7–8 weeks later when they were used for the experiments. Following anaesthesia (1 g kg–1 urethane I.P.), laparotomy was performed and the pancreatic duct cannulated for collection of pure pancreatic juice. Basal pancreatic juice flow rate in diabetic rats was significantly (p < 0.001) increased whereas protein and amylase outputs were significantly (p < 0.001) decreased compared to control rats. Insulin (1 IU, I.P.) produced in healthy rats significant increases in pancreatic flow rate, amylase secretion and protein output compared to basal (p < 0.05). Insulin action also included a reduction in blood glucose (152.7 ± 16.9 mg dl–1, n= 6, prior to insulin and 42.0 ± 8.4 mg dl–1, n= 4, 100 min later). In fact, flow rate and glycaemia showed a strong negative correlation (p < 0.01, Pearson). Pretreatment with atropine (0.2 mg kg–1, I.V.) abolished the effects of insulin on secretory parameters despite a similar reduction in glycaemia; in this series of experiments the correlation between flow rate and blood glucose was lost. In diabetic rats, insulin (4 IU, I.P.) did not modify exocrine pancreatic secretion. There was a fall in blood glucose (467.6 ± 14.0 mg dl–1, n= 10, prior to insulin and 386.6 ± 43.6 mg dl–1, n= 7, 120 min later). Rats, however, did not become hypoglycaemic. Similar results were observed in diabetic atropinized rats. The results of this study indicate that the effects of insulin on exocrine pancreatic secretion in anaesthetised healthy rats are mediated by hypoglycaemia-evoked vagal cholinergic activation. (Mol Cell Biochem 261: 105–110, 2004) 相似文献
6.
《Bioorganic & medicinal chemistry letters》2020,30(5):126857
The discovery and optimization of a novel series of GPR142 agonists are described. These led to the identification of compound 21 (LY3325656), which demonstrated anti-diabetic benefits in pre-clinical studies and ADME/PK properties suitable for human dosing. Compound 21 is the first GPR142 agonist molecule advancing to phase 1 clinic trials for the treatment of Type 2 diabetes. 相似文献
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Iwao Takahashi Naoya Noguchi Koji Nata Tomoyuki Kaneiwa Takayuki Ikeda Masahide Asano Akiyo Yamauchi Akira Uruno Michiaki Unno Shin Takasawa Akira Sugawara 《Biochemical and biophysical research communications》2009,383(1):113-141
Heparan sulfate (HS) binds with several signaling molecules and regulates ligand-receptor interactions, playing an essential role in embryonic development. Here we showed that HS was intensively expressed in pancreatic islet β-cells after 1 week of age in mice. The enzymatic removal of HS in isolated islets resulted in attenuated glucose-induced insulin secretion with a concomitant reduction in gene expression of several key components in the insulin secretion machinery. We further depleted islet HS by inactivating the exostosin tumor-like 3 gene specifically in β-cells. These mice exhibited abnormal islet morphology with reduced β-cell proliferation after 1 week of age and glucose intolerance due to defective insulin secretion. These results demonstrate that islet HS is involved in the regulation of postnatal islet maturation and required to ensure normal insulin secretion. 相似文献
8.
The hexosamine biosynthesis pathway regulates insulin secretion via protein glycosylation in mouse islets 总被引:6,自引:0,他引:6
Zraika S Dunlop M Proietto J Andrikopoulos S 《Archives of biochemistry and biophysics》2002,405(2):275-279
The hexosamine biosynthesis pathway plays a role in the modification of cellular proteins via the provision of substrate for addition of O-linked N-acetylglucosamine (GlcNAc). The relative importance of the GlcNAc modification of proteins to insulin secretion from pancreatic beta-cells has not been investigated and so remains unclear. In the present study, we show that inhibition of the hexosamine biosynthesis pathway decreases insulin secretion from mouse islets in response to a number of secretagogues, including glucose. This impairment in beta-cell function could not be attributed to reduced islet insulin content, altered ATP levels, or cell death and was restored with the addition of N-acetylglucosamine, a substrate that enters the pathway below the point of inhibition. Western blot analysis revealed that decreased islet protein glycosylation paralleled the decrease in insulin secretion following inhibition of the pathway. In conclusion, the data suggest a role for the hexosamine biosynthesis pathway in regulating the secretion of insulin by altering protein glycosylation. This finding may have implications for the development of type 2 diabetes, as chronic increase in flux through the hexosamine biosynthesis pathway may lead to the deterioration of beta-cell function via abnormal protein glycosylation. 相似文献
9.
The aim of this study was to test if a beta-cell defect is associated to deterioration of glucose tolerance early during the natural history of the type 2 diabetes mellitus . In 41 overweight women, with macrosomic infants in their antecedent deliveries, measures of insulin response and insulin sensitivity were derived from a short (45 min) iv glucose test. The early (EIR) and the late (LIR) phase insulin responses and the insulin sensitivity index (Si) were calculated. According the response to 75 g oral glucose test the subjects were divided into two groups: Imparired glucose tolerance (IGT;n = 12), and normal glucose tolerance (NGT; n = 29). EIR was reduced in IGT group (14.9 ± 3.6 vs 37.0 ± 4.0; p< 0.002). Glucose tolerance during oral glucose tolerance test (OGTT), correlated inversly to EIR (r=-0.45; n=41; p< 0.01). A strong correlation of EIR to LIR (r=0.88; n = 41; p< 0.001) but no correlation between glucose tolerance and Si was found. 相似文献
10.
Spacek T Santorová J Zacharovová K Berková Z Hlavatá L Saudek F Jezek P 《The international journal of biochemistry & cell biology》2008,40(8):1522-1535
Increased ATP/ADP ratio resulting from enhanced glycolysis and oxidative phosphorylation represents a plausible mechanism controlling the glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells. Although specific bioenergetics might be involved, parallel studies of cell respiration and mitochondrial membrane potential (ΔΨm) during GSIS are lacking. Using high resolution respirometry and parallel ΔΨm monitoring by two distinct fluorescence probes we have quantified bioenergetics in rat insulinoma INS-1E cells representing a suitable model to study in vitro insulin secretion. Upon glucose addition to glucose-depleted cells we demonstrated a simultaneous increase in respiration and ΔΨm during GSIS and showed that the endogenous state 3/state 4 respiratory ratio hyperbolically increased with glucose, approaching the maximum oxidative phosphorylation rate at maximum GSIS. Attempting to assess the basis of the “toxic” effect of fatty acids on insulin secretion, GSIS was studied after linoleic acid addition, which diminished respiration increase, ΔΨm jump, and magnitude of insulin release, and reduced state 3/state 4 dependencies on glucose. Its effects were due to protonophoric function, i.e. uncoupling, since without glucose, linoleic acid accelerated both state 3 and state 4 respiration by similar extent. In turn, state 3 respiration increased marginally with linoleic acid at 10–20 mM glucose. We conclude that upon glucose addition in physiological range, the INS-1E cells are able to regulate the oxidative phosphorylation rate from nearly zero to maximum and that the impairment of GSIS by linoleic acid is caused by mitochondrial uncoupling. These findings may be relevant to the pathogenesis of type 2 diabetes. 相似文献
11.
Silver RJ Mehta S Soeldner JS Martin BC Warram JH Goldfine AB 《Obesity (Silver Spring, Md.)》2006,14(1):67-72
Objective: We sought to determine the role of the acute insulin secretory response to glucose (AIRg) in predicting weight gain in normoglycemic persons with no family history of diabetes, who are at low risk for development of disease. Research Methods and Procedures: One hundred five individuals (64 men and 41 women) who underwent measures of weight and AIRg and insulin sensitivity index (SI) by intravenous glucose tolerance test between 1963 and 1983 were surveyed again for weight between 1994 and 1999, with a mean follow‐up of 26 ± 4 years. Results: Mean change in weight was 8 ± 10 kg. Annualized weight change was calculated as change in kilograms divided by change in year and averaged 0.27 ± 0.04 kg/yr. Dividing the cohort by either median AIRg or median SI demonstrated no association of either AIRg or SI with total or annualized weight gain. Subgroup analysis by ideal body weight or gender did not alter the association. Furthermore, no association between AIRg and weight gain rate was seen within insulin‐sensitive or ‐resistant subgroups, although younger age at entry was associated with greater rates of weight gain. Discussion: Our data suggest that neither AIRg nor SI plays a role in predicting weight gain in normoglycemic individuals with no family history of diabetes. 相似文献
12.
Role of peroxisome proliferator-activated receptor gamma in glucose-induced insulin secretion 总被引:4,自引:0,他引:4
Peroxisome proliferator-activated receptor (PPAR) isoforms (α and γ) are known to beexpressed in pancreatic islets as well as in insulin-producing cell lines.Ligands of PPAR have been shoWn toenhance glucose-induced insulin secretion in rat pancreatic islets.However,their effect on insulin secretionis still unclear.To understand the molecular mechanism by which PPAR7 exerts its effect on glucose-induced insulin secretion,we examined the endogenous activity of PPAR isoforms,and studied the PPARyfunction and its target gene expression in INS-1 cells.We found that:(1)endogenous PPARγ was activatedin a ligand-dependent manner in INS-1 cells;(2)overexpression of PPARy in the absence of PPARγ ligandsenhanced glucose-induced insulin secretion,which indicates that the increased glucose-induced insulin secretionis a PPARγ-mediated event;(3)the addition of both PPARγ and retinoid X receptor (RXR) ligands showed asynergistic effect on the augmentation of reporter activity,suggesting that the hetero-dimerization of PPAR7and RXR is required for the regulation of the target genes;(4)PPARs upregulated both the glucose transporter2 (GLUT2) and Cbl-associated protein (CAP) genes in INS-1 cells.Our findings suggest an importantmechanistic pathway in which PPARγ enhances glucose-induced insulin secretion by activating the expressionof GLUT2 and CAP genes in a ligand-dependent manner. 相似文献
13.
Propionate inhibits glucose-induced insulin secretion in isolated rat pancreatic islets 总被引:1,自引:0,他引:1
Ximenes HM Hirata AE Rocha MS Curi R Carpinelli AR 《Cell biochemistry and function》2007,25(2):173-178
Dietary fibers, probably by generating short chain fatty acids (SCFA) through enterobacterial fermentation, have a beneficial effect on the control of glycemia in patients with peripheral insulin resistance. We studied the effect of propionate on glucose-induced insulin secretion in isolated rat pancreatic islets. Evidence is presented that propionate, one of the major SCFA produced in the gut, inhibits insulin secretion induced by high glucose concentrations (11.1 and 16.7 mM) in incubated and perfused pancreatic islets. This short chain fatty acid reduces [U-(14)C]-glucose decarboxylation and raises the conversion of glucose to lactate. Propionate causes a significant decrease of both [1-(14)C]- (84%) and [2-(14)C]-pyruvate (49%) decarboxylation. These findings indicate pyruvate dehydrogenase as the major site for the propionate effect. These observations led us to postulate that the reduction in glucose oxidation and the consequent decrease in the ATP/ADP ratio may be the major mechanism for the lower insulin secretion to glucose stimulus induced by propionate. 相似文献
14.
Ratnakar R. Bynigeri Sasikala Mitnala Rupjyoti Talukdar Surya S. Singh Nageshwar R. Duvvuru 《Journal of cellular biochemistry》2020,121(1):840-855
Pancreatic stellate cells (PSCs) secrete various factors, which can influence the β-cell function. The identification of stellate cell infiltration into the islets in pancreatic diseases suggests possible existence of cross-talk between these cells. To elucidate the influence of PSCs on β-cell function, mouse PSCs were cocultured with Min6 cells using the Transwell inserts. Glucose-stimulated insulin secretion from Min6 cells in response to PSCs was quantified by enzyme-linked immunosorbent assay and insulin gene expression was measured by quantitative polymerase chain reaction. Upon cytometric identification of IL6 in PSC culture supernatants, Min6 cells were cultured with IL6 to assess its influence on the insulin secretion and gene expression. PLC-IP3 pathway inhibitors were added in the cocultures, to determine the influence of PSC-secreted IL6 on Glucose-stimulated insulin secretion from Min6 cells. Increased insulin secretion with a concomitant decrease in total insulin content was noticed in PSC-cocultured Min6 cells. Although increased GSIS was noted from IL6-treated Min6 cells, no change in the total insulin content was noted. Coculture of Min6 cells with PSCs or their exposure to IL6 did not alter either the expression of β-cell-specific genes or that of miRNA-375. PSC-cocultured Min6 cells, in the presence of PLC-IP3 pathway inhibitors (U73122, Neomycin, and Xestospongin C), did not revoke the observed increase in GSIS. In conclusion, the obtained results indicate that augmented insulin secretion from Min6 cells in response to PSC secretions is independent of IL6-mediated PLC-IP3 pathway. 相似文献
15.
R P Robertson 《Journal of cellular biochemistry》1992,48(3):227-233
Non-insulin dependent diabetes mellitus (NIDDM) is characterized by a specific defect in glucose recognition by the pancreatic islet beta cell. This is in clear distinction to patients with insulin dependent diabetes mellitus (IDDM) who undergo pancreatic islet beta cell death and no longer have the ability to synthesize, store, and release insulin. Defective glucose-induced first phase insulin responses in patients with NIDDM can be partially restored by exogenous insulin treatment and by other pharmacologic therapy. These observations provide strength for the theory of glucose desensitization of the pancreatic beta cell as an important secondary defect in the pathogenesis of abnormal insulin secretion in NIDDM. However, even though defective insulin secretion is an essential part of the pathogenesis of NIDDM, in itself it is not sufficient. A multiplicative effect is required involving interaction between tissue resistance to insulin action and defective insulin secretion whose product is the syndrome of NIDDM. 相似文献
16.
Post-translational modifications (PTMs) such as phosphorylation and ubiquitination are well-studied events with a recognized importance in all aspects of cellular function. By contrast, protein S-acylation, although a widespread PTM with important functions in most physiological systems, has received far less attention. Perturbations in S-acylation are linked to various disorders, including intellectual disability, cancer and diabetes, suggesting that this less-studied modification is likely to be of considerable biological importance. As an exemplar, in this review, we focus on the newly emerging links between S-acylation and the hormone insulin. Specifically, we examine how S-acylation regulates key components of the insulin secretion and insulin response pathways. The proteins discussed highlight the diverse array of proteins that are modified by S-acylation, including channels, transporters, receptors and trafficking proteins and also illustrate the diverse effects that S-acylation has on these proteins, from membrane binding and micro-localization to regulation of protein sorting and protein interactions. 相似文献
17.
Shuai Han Heling Pan Jianhua Zhang Li Tan Dawei Ma Junying Yuan Jia-Rui Wu 《Cell research》2011,21(4):588-599
Using an image-based screen for small molecules that can affect Golgi morphology, we identify a small molecule, Sioc145, which can enlarge the Golgi compartments and promote protein secretion. More importantly, Sioc145 potentiates insulin secretion in a glucose-dependent manner. We show that Sioc145 selectively activates novel protein kinase Cs (nPKCs; δ and ɛ) but not conventional PKCs (cPKCs; α, βI and βII) in INS-1E insulinoma cells. In contrast, PMA, a non-selective activator of cPKCs and nPKCs, promotes insulin secretion independent of glucose concentrations. Furthermore, we demonstrate that Sioc145 and PMA show differential abilities in depolarizing the cell membrane, and suggest that Sioc145 promotes insulin secretion in the amplifying pathway downstream of KATP channels. In pancreatic islets, the treatment with Sioc145 enhances the second phase of insulin secretion. Increased insulin granules close to the plasma membrane are observed after Sioc145 treatment. Finally, the administration of Sioc145 to diabetic GK rats increases their serum insulin levels and improves glucose tolerance. Collectively, our studies identify Sioc145 as a novel glucose-dependent insulinotropic compound via selectively activating nPKCs. 相似文献
18.
Wen Kong Lu-lu Chen Juan Zheng Hao-hao Zhang Xiang Hu Tian-shu Zeng Di Hu 《Experimental biology and medicine (Maywood, N.J.)》2015,240(2):220-229
Resveratrol (RSV), a natural compound, is known for its effects on energy homeostasis. Here we investigated the effects of RSV and possible mechanism in insulin secretion of high-fat diet rats. Rats were randomly divided into three groups as follows: NC group (animals were fed ad libitum with normal chow for 8 weeks), HF group (animals were fed ad libitum with high-fat diet for 8 weeks), and HFR group (animals were treated with high-fat diet and administered with RSV for 8 weeks). Insulin secretion ability of rats was assessed by hyperglycemic clamp. Mitochondrial biogenesis genes, mitochondrial respiratory chain activities, reactive oxidative species (ROS), and several mitochondrial antioxidant enzyme activities were evaluated in islet. We found that HF group rats clearly showed low insulin secretion and mitochondrial complex dysfunction. Expression of silent mating type information regulation 2 homolog- 1 (SIRT1) and related mitochondrial biogenesis were significantly decreased. However, RSV administration group (HFR) showed a marked potentiation of glucose-stimulated insulin secretion. This effect was associated with elevated SIRT1 protein expression and antioxidant enzyme activities, resulting in increased mitochondrial respiratory chain activities and decreased ROS level. This study suggests that RSV may increase islet mitochondrial complex activities and antioxidant function to restore insulin secretion dysfunction induced by high-fat diet. 相似文献
19.
Ming Hu Inês Cebola Gaelle Carrat Shuying Jiang Sameena Nawaz Amna Khamis Mickaël Canouil Philippe Froguel Anke Schulte Michele Solimena Mark Ibberson Piero Marchetti Fabian L. Cardenas-Diaz Paul J. Gadue Benoit Hastoy Leonardo Almeida-Souza Harvey McMahon Guy A. Rutter 《Cell reports》2021,34(5):108703
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20.
Free fatty acids are known to play a key role in promoting loss of insulin sensitivity, thereby causing insulin resistance
and type 2 diabetes. However, the underlying mechanism involved is still unclear. In searching for the cause of the mechanism,
it has been found that palmitate inhibits insulin receptor (IR) gene expression, leading to a reduced amount of IR protein
in insulin target cells. PDK1-independent phosphorylation of PKCε causes this reduction in insulin receptor gene expression. One of the pathways through which fatty acid can induce insulin
resistance in insulin target cells is suggested by these studies. We provide an overview of this important area, emphasizing
the current status. 相似文献