Search

Late Carboniferous–Early Permian granitoids are widespread in the Tianshan area and their tectonic setting is controversially discussed. Our research presents fresh whole-rock geochemical and Pb isotopic data, along with zircon U-Pb ages and Hf isotopic data for representative monzonitic and granitic intrusions in the Kumishi area. The aim is to decipher their magma sources and illuminate their geodynamic evolution. Zircon U-Pb dating results reveal that biotite monzonites in the Central Tianshan Belt were emplaced at 312.7 ± 2.9 Ma, while the quartz-monzonites and syenogranites in the South Tianshan Belt were formed at 284.5 ± 2.4 Ma and 283.4 ± 3.9 Ma, respectively. The biotite monzonites generally exhibit metaluminous and high-K calc-alkaline characteristics. They have a positive εHf(t) value (+4.9–+14.1), and are enriched in LREEs and LILEs but depleted in HREEs and HFSEs. These characteristics indicate that they were derived from a mixed magma source of the lower crust and the input of components derived from the mantle wedge above the subduction zone. The quartz-monzonites and syenogranites are high-K calc-alkaline to shoshonitic I-type granites, with εHf(t) values of +14.9–+15.5 and +6.6–+14.9, respectively. They are enriched in LREEs but depleted in HFSEs (e.g., Nb, Ta, and Ti), displaying relatively flat HREE patterns and negative Eu anomalies. The genesis of these rocks is attributed to a partial melting of the lower crust in which mantle-derived magmas participated, which was triggered by an upwelling asthenosphere in a post-collisional extensional geodynamic setting. These granitoids, together with regional analysis of other magmatism in the study area, suggest that the Kumishi area has experienced an evolution from subduction to post-collision from the Late Carboniferous to the Early Permian, which constrains the local closure of the Paleo-Asian Ocean.

The Chinese Altai is characterized by abundant granitoids, which not only are indicators of the interaction between crust and mantle but also provide critical constraints on the tectonic evolution of the orogen. This study presents zircon U‒Pb‒O isotopes, whole-rock major and trace element and Nd‒Hf‒Pb isotopes data for granite porphyries from the Keziergayin region in the Kelan Basin. The granite porphyries intrude in the Kangbutiebao Formation with zircon U‒Pb dating of 394 ± 3 Ma. They have the characteristics of subalkaline and metaluminous to weakly peraluminous and show geochemical affinity with I-type granite. The granite porphyry samples display negative εNd(t) (−1.9 to −1.4), positive εHf(t) (+4.3 to +11.4) values, with Nd–Hf decoupling; low Pb isotope compositions; δ18OV-SMOW (6.38‰–8.45‰) is less than 10‰, within the range of O isotopes of medium-basic igneous rocks. These geochemical signatures indicate that the granite porphyries originated from lower crust medium−basic igneous rocks extracted from the lithospheric mantle metasomatized by subducted melt. They are characterized by high SiO2 contents and Rb/Sr ratios; low CaO contents and K/Rb ratios, hinting that they were formed by highly evolved magmas, with fractionation crystallization of feldspar, apatite, garnet, allanite and/or monazite. The granite porphyries possess positive Rb, Th, U, Nd, Zr, Pb and light rare Earth elements (LREEs) anomalies with strong negative Ba, Nb, Ta, Sr, P, Ti and Eu anomalies, implying that their formation were related to an island arc. Combined with previous studies, it is suggested that the existence of the Early Devonian arc-basin system associated with subducting slab rollback in the Chinese Altai, which belongs to the Siberian active continental margin system.

The elemental accumulation and recycling in the metamorphosed Keketale VMS-type Pb-Zn deposit of the Altai Mountains are presented in this study. Based on detailed fieldwork and microscopic observation, the formation of the deposit involved syngenetic massive sulfide mineralization and epigenetic superimposed mineralization. Different generations of iron sulfides (i.e., pyrite and pyrrhotite) with contrasting textural, elemental, and sulfur isotopic features were generated in primary mineralization (including hydrothermal iron sulfides, colloform pyrite) and secondary modification (including annealed iron sulfides, oriented iron sulfides, and vein-pyrite). It is revealed that the spatial variation in textures and elements of hydrothermal iron sulfides depends on the inhomogeneous fluid compositions and varied environment in VMS hydrothermal system. Both leached sulfur from the footwall volcanic rocks and reduced sulfur by the TSR process are regarded as important sulfur sources. Furthermore, large sulfur isotopic fractionation and negative δ34S values were mainly caused by varied oxygen fugacity, and to a lesser extent, temperature fluctuation. The epigenetic polymetallic veins that contain sulfides and sulfosalts (e.g., jordanite-geocronite, bournonite-seligmannite, boulangerite) were considered as the products of metamorphic fluid scavenged the metal-rich strata. All things considered, it is indicated that two episodes of fluid with distinct origins were essential for the formation of the deposit. The predominant evolved seawater along with subordinate magmatic fluid mobilized metals from volcanic rocks and precipitated massive sulfides near the seafloor are vital for primary mineralization. The metamorphic fluid remobilized metals (i.e., FMEs: fluid mobile elements, e.g., Pb, As, Sb) from neighboring volcanic and pyroclastic rocks and destabilized them within the fractured zone are responsible for secondary mineralization, which enhances the economic value of the deposit. Accordingly, metal-rich Devonian strata had been successively swept by different origins of fluid, leading to progressively elemental enrichment and the formation of a large deposit. Furthermore, the current study enlightens that FME-bearing veins with economic benefits can be discovered near the metamorphosed VMS deposits.

This paper theoretically studies the interaction between an informed borrower and an uninformed lender facing possible default of a loan application. The lender is motivated to invest cognitive resources before making a lending decision. If the regulatory fine is weak, it is impossible for a bad-debt borrower to fully disclose his situation in the application. In this case, when the likelihood of a bad debt is low, the borrower always claims that nothing in the application is wrong. Otherwise, the borrower randomizes between full disclosure and information suppression. The transaction cost of the lender’s pre-lending cognition increases with the default probability, as the default probability is small and decreases thereafter. Evidence from a peer-to-peer lending platform with 816,274 observations between 2012 and 2015 in the United States is largely consistent with our model implications.

Summary: Mechanisms coordinating pancreatic β cell metabolism with insulin secretion are essential for glucose homeostasis. One key mechanism of β cell nutrient sensing uses the mitochondrial GTP (mtGTP) cycle. In this cycle, mtGTP synthesized by succinyl-CoA synthetase (SCS) is hydrolyzed via mitochondrial PEPCK (PEPCK-M) to make phosphoenolpyruvate, a high-energy metabolite that integrates TCA cycling and anaplerosis with glucose-stimulated insulin secretion (GSIS). Several strategies, including xenotopic overexpression of yeast mitochondrial GTP/GDP exchanger (GGC1) and human ATP and GTP-specific SCS isoforms, demonstrated the importance of the mtGTP cycle. These studies confirmed that mtGTP triggers and amplifies normal GSIS and rescues defects in GSIS both in vitro and in vivo. Increased mtGTP synthesis enhanced calcium oscillations during GSIS. mtGTP also augmented mitochondrial mass, increased insulin granule number, and membrane proximity without triggering de-differentiation or metabolic fragility. These data highlight the importance of the mtGTP signal in nutrient sensing, insulin secretion, mitochondrial maintenance, and β cell health. : Jesinkey et al. report that mitochondrial GTP (mtGTP) is an integrative nutrient sentinel regulating β cell function. Signaling from mtGTP raises calcium independent of oxidative phosphorylation to promote insulin secretion. Without overworking the β cell, mtGTP cycling potentiates insulin secretion, nutrient sensing, and mitochondrial expansion alongside promoting health and increasing insulin reserves. Keywords: mitochondrial GTP, PEPCK-M, insulin secretion, oxidative phosphorylation, phosphoenolpyruvate, anaplerosis, succinyl-CoA synthetase, stable isotope, metabolic flux, MIMOSA

Non–small cell lung cancer accounts for 85% of all types of lung cancer and is the leading cause of worldwide cancer-associated mortalities. MiR-124 is epigenetically silenced in various types of cancer and plays important roles in tumor development and progression. MiR-124 was also significantly downregulated in non–small cell lung cancer patients. Glycolysis has been considered as a feature of cancer cells; hypoxia-inducible factor 1-alpha/beta and Akt are key enzymes in the regulation of glycolysis and energy metabolism in cancer cells. However, the role of miR-124 in non–small cell lung cancer cell proliferation, glycolysis, and energy metabolism remains unknown. In this research, cell proliferation was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; furthermore, glucose consumption and lactic acid production were assessed; adenosine triphosphate content and NAD + /NADH were also detected. These tests were conducted using the normal non–small cell lung cancer cell line A549, which was transfected variedly with miR-mimics, miR-124 mimics, miR-124 inhibitor, pc-DNA3.1(+)-AKT1, and pc-DNA3.1(+)-AKT2 plasmid. Here, we show that miR-124 overexpression directly decreased cell growth, glucose consumption, lactate production, and energy metabolism. MiR-124 also negatively regulates glycolysis rate–limiting enzymes, glucose transporter 1 and hexokinase II. Our results also showed that miR-124 negatively regulates AKT1 and AKT2 but no regulatory effect on hypoxia-inducible factor 1-alpha/beta. Overexpression of AKT reverses the inhibitory effect of miR-124 on cell proliferation and glycolytic metabolism in non–small cell lung cancer. AKT inhibition blocks miR-124 silencing–induced AKT1/2, glucose transporter 1, hexokinase II activation, cell proliferation, and glycolytic or energy metabolism changes. In summary, this study demonstrated that miR-124 is able to inhibit proliferation, glycolysis, and energy metabolism, potentially by targeting AKT1/2–glucose transporter 1/hexokinase II in non–small cell lung cancer cells.

The effect of hydrogen peroxide (H2O2) oxidation on the physicochemical, gelation and antimicrobial properties of gellan gum was studied. The oxidized gellan gum (OGG) was characterized by measuring the carboxyl/carbonyl group contents, Fourier transform infrared spectroscopy (FTIR) and proton nuclear magnetic resonance (1H-NMR) spectroscopy. The H2O2 oxidation resulted in a large increase in the carboxyl groups in gellan gum. The OGG lost gelation ability by oxidation even in the presence of metal ions. The antimicrobial activities of the OGG against Gram-positive bacteria (Staphylococcus aureus), Gram-negative bacteria (Escherichia coli), and fungal (Aspergillus niger) were tested. The OGG could inhibit the growth of both bacteria and fungal, and the activity was improved with an increase in the oxidation level. Finally, the application of the OGG as an active coatings material to extend the storage of apples was tested.

In numerous economic scenarios, contracting parties may not have a clear picture of all the relevant aspects. A contracting party may be unaware of what she and/or others are entitled to determine. Therefore, she may reject a contract that is too good to be true. Further, a contracting party may actively exert cognitive effort before signing a contract, so as to avoid being trapped into the contractual agreement ex post. In this paper, we propose a general framework to investigate these strategic interactions with unawareness, reasoning and cognition and intend to unify the solution concepts in the contracting context with unawareness. We build our conceptual framework upon the classical principal-agent relationship and compare the behaviors under various degrees of the unaware agent’s sophistication.

Single nucleotide polymorphism (SNP) genotyping is playing an increasing role in genome mapping, pharmacogenetic studies, and drug discovery. To date, genome-wide scans and studies involving thousands of SNPs and samples have been hampered by the lack of a system that can perform genotyping with cost-effective throughput, accuracy, and reliability. To address this need, Orchid has developed an automated, ultra-high throughput system, SNPstream® UHT, which uses multiplexed PCR in conjunction with our next generation SNP-IT™ tag array single base extension genotyping technology. The system employs oligonucleotide microarrays manufactured in a 384-well format on a novel glass-bottomed plate. Multiplexed PCR and genotyping are performed in homogeneous reactions, and assay results are read by direct two-color fluorescence on the SNPstream UHT Array Imager. The system’s flexibility enables large projects involving thousands of SNPs and thousands of samples as well as small projects that have hundreds of SNPs and hundreds of samples to be done cost effectively. We have successfully demonstrated this system in greater than 1 000 000 genotyping assays with >96% of samples giving genotypes with >99% accuracy.

This paper provides an economic rationale for overachieving behavior in nonprofessional activities in the labor market. The intrinsically motivated worker uses his achievement in nonprofessional activity to signal his work ethic. When the worker's career concern is weak, he exerts no extra effort on nonprofessional activity.When the worker's career concern is strong, however, his effort level for the nonprofessional activity can go beyond the bliss point. With a very strong career concern, an obsessive behavior can arise in equilibrium, as the intrinsically motivated worker may choose to sacrifice the professional activity for the nonprofessional one in an earlier stage of his career. [ABSTRACT FROM AUTHOR]

Wall pressure fluctuations beneath a boundary layer are the main cause of structural vibration for hypersonic aircraft. To accurately predict the load environment of pressure fluctuations, a measurement in a hypersonic wind tunnel was carried out to investigate the characteristics of wall pressure fluctuations generated by different flow types. In the measurement, a linear sensor array was used to record the signal, and the beamforming algorithm was adopted to identify the spatial correlation of wall pressure fluctuations. The investigation discussed the main characteristics of the convective modes and acoustic modes for wall pressure fluctuations under different flow conditions, consisting of laminar flow, a transition, and fully developed turbulence. Two typical disturbances were found, both of which depend on the flow type and always reach their peak values during the transition period. Finally, a method was proposed to identify the acoustic modes and convective modes, and then an error analysis was performed. [ABSTRACT FROM AUTHOR]

The wall pressure fluctuations produced by a turbulent boundary layer (TBL) are the main excitation of structural vibrations and cabin noise in aircraft. To precisely estimate the structural vibration excited by a TBL, an improved technique is proposed and developed for the prediction of wall pressure fluctuations induced by a high-speed flow. First, an integrated expression is given to describe wall pressure fluctuations in different situations, and a conventional phase array technique is employed to identify the wave numbers of the wall pressure fluctuations and noise. Then, the pressure fluctuations are separated from the noise by a modified subsection approaching method. To improve the resolution of the low-frequency noise, an accelerated focusing method is developed and used in this paper. A variable spacing array design is proposed to improve the calculation accuracy of the broadband pressure fluctuation separation. In addition, a sensitivity analysis is carried out to fix the error range of the noise wave numbers in which the pressure fluctuation and noise calculation converges to the actual value. Finally, a wind-tunnel test is performed to validate the proposed method in this work. [ABSTRACT FROM AUTHOR]

A new attempt to measure the structure response generated by a turbulent boundary layer in a wind tunnel is proposed in this paper. To develop a scaling procedure that accommodates both the structural vibration and turbulent boundary-layer excitation for predicting the vibration response of a structure using a scaled model in a wind tunnel, a receptance method is used to extend the scaling procedure to a curved plate. Because the scaling equations are developed for a simply supported boundary and a clamped boundary, a modal analysis is used to confirm that the scaling equations are also applicable to a plate with unsupported boundary conditions. The characteristic parameters of the structural vibrations and the flow parameters for a full-scale object are both scaled. In addition, the scaling procedures consider the effects of the material used in the scaled model in predicting the vibrations of the full-scale structure. The scaling procedures are developed from theoretical methods, and numerical techniques and wind-tunnel measurements are used to validate the scaling procedures. The structural vibrations of a full-scale body are compared with the results obtained using the scaling procedure and the response of a scaled model to verify that the scaling procedures developed in this study are effective for predicting the structural response of full-scale bodies from wind-tunnel test data. [ABSTRACT FROM AUTHOR]

Lung cancer is one of the most malignant cancers with a high metastatic potential. The purpose of this study was to study the role and the underlying mechanism of miR-214 in lung cancer progression. The expression of miR-214 in normal lung and lung cancer tissue was analyzed by quantitative real-time PCR analysis. Furthermore, H1299 cells were infected with miR-214 lentivirus, and the effect of infection on cell viability and migration was analyzed. Carboxypeptidase-D (CPD), as a potential target of miR-214, was characterized in either normal lung or lung cancer tissues. The interaction of CPD expression with the tumor suppressing effect of miR-214 was characterized. We demonstrated that low miR-214 expression is a hallmark of lung cancer, especially high-grade and metastatic cancer. In vitro studies in H1299 cells confirmed that low miR-214 expression is associated with enhanced proliferation and migratory abilities. Similarly, CPD overexpression coincides with high-grade lung cancer and the CPD overexpression could reverse the inhibitory effects of miR- 214. miR-214 is a tumor suppressor in lung cancer. miR-214 inhibits lung cancer progression by targeting CPD. The miR-214-CPD axis may be a therapeutic axis for lung cancer patients. [ABSTRACT FROM AUTHOR]

A key sensor of cellular energy status, AMP-activated protein kinase (AMPK), interacts allosterically with AMP to maintain an active state. When active, AMPK triggers a metabolic switch, decreasing the activity of anabolic pathways and enhancing catabolic processes such as lipid oxidation to restore the energy balance. Unlike oxidative tissues, in which AMP is generated from adenylate kinase during states of high energy demand, the ornithine cycle enzyme argininosuccinate synthetase (ASS) is a principle site ofAMP generation in the liver. Here we show that ASS regulates hepatic AMPK, revealing a central role for ureagenesis flux in the regulation of metabolism via AMPK. Treatment of primary rat hepatocytes with amino acids increased gluconeogenesis and ureagenesis and, despite nutrient excess, induced both AMPK and acetyl-CoA carboxylase (ACC) phosphorylation. Antisense oligonucleotide knockdown of hepatic ASS1 expression in vivo decreased liver AMPK activation, phosphorylation of ACC, and plasma β-hydroxybutyrate concentrations. Taken together these studies demonstrate that increased amino acid flux can activate AMPK through increased AMP generated by ASS, thus providing a novel link between protein catabolism, ureagenesis, and hepatic lipid metabolism. [ABSTRACT FROM AUTHOR]

Mitochondrial GTP (mtGTP)-insensitive mutations in glutamate dehydrogenase (GDHH454Y) result in fasting and amino acid-induced hypoglycemia in hyperinsulinemia hyperammonemia (HI/HA). Surprisingly, hypoglycemia may occur in this disorder despite appropriately suppressed insulin. To better understand the islet-specific contribution, transgenic mice expressing the human activating mutation in β-cells (H454Y mice) were characterized in vivo. As in the humans with HI/HA, H454Y mice had fasting hypoglycemia, but plasma insulin concentrations were similar to the controls. Paradoxically, both glucose- and glutamine-stimulated insulin secretion were severely impaired in H454Y mice. Instead, lack of a glucagon response during hypoglycemic clamps identified impaired counterregulation. Moreover, both insulin and glucagon secretion were impaired in perifused islets. Acute pharmacologic inhibition of GDH restored both insulin and glucagon secretion and normalized glucose tolerance in vivo. These studies support the presence of an mtGTP-dependent signal generated via β-cell GDH that inhibits α-cells. As such, in children with activating GDH mutations of HI/HA, this insulin-independent glucagon suppression may contribute importantly to symptomatic hypoglycemia. The identification of a human mutation causing congenital hypoglucagonemic hypoglycemia highlights a central role of the mtGTP-GDH-glucagon axis in glucose homeostasis. [ABSTRACT FROM AUTHOR]

Ten secondary metabolites, including one new monoterpene rhamnoside (1), five terpenoids (2-6), two nucleosides (7-8), and two phenylethanoid glycosides (9-10) were isolated from the roots of Rehmannia glutinosa. Their structures were determined by spectroscopic analysis such as NMR and HR-ESI-MS. In the tyrosinase inhibitory assay, compounds 2, 6 and 8 showed inhibition against tyrosinase. Compounds 1, 4, 5, 6, 9 and 10 are being reported in the genus Rehmannia for the first time. [ABSTRACT FROM AUTHOR]

The chapter surveys recent developments in economics of contract interpretation. First, we point out the relevance of issue of contract interpretation to contracting problems. We then introduce a general economic model of contract interpretation. It explains why parties write gaps and fairly general terms in contracts, how the court should interpret them, and whether courts should always enforce what contracting parties write. Moreover, we explain why there are contradictions in contracts. [ABSTRACT FROM AUTHOR]

The article introduces unawareness of actions into the standard moral hazard model in contract theory. We allow the contracting party (the principal or the agent) to be unaware of his or the other party's actions. The principal may also have an incorrect belief about the awareness of the agent. We provide a solution concept where the principal contemplates the incentive scheme according to his conjecture of the agent's mind and also contemplates informing the agent through the contract. In the post-contractual stage, either party may be surprised by the other party's action. Finally, we analyze the value of awareness for each party, and present the negative result that awareness is not always valuable. [ABSTRACT FROM AUTHOR]

Background • To investigate the value of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the diagnosis of lung nodules related enlarged mediastinal lymph nodes (MLNs). Methods • Clinical data of 108 patients with lung nodules related enlarged MLNs who underwent EBUS-TBNA in our single center were retrospectively analyzed from January 2020 to December 2021. The sensitivity and specificity of EBUS-TBNA in malignancy diagnosis were evaluated. Associations between ultrasonic image measurement indexes and malignancy diagnosis were explored. The receiver operating characteristic (ROC) curve of these indexes, the area under curve (AUC), and the corresponding cut-off values were calculated to predict malignant MLNs. Results • Sensitivity, specificity, and accuracy of EBUS)TBNA in the diagnosis of lung nodules related malignant MLNs were 89.47%, 100%, and 92.59%, respectively. There were significantly higher proportions of malignant MLNs with clear boundary, short diameter ≥1 cm, lower long to short diameter ratio, abundant flow of blood, and destructed medulla than that of benign ones (P < .05). According to ROC curve analysis, the cut-off value of short diameters for predicting malignant MLNs was 1.085 cm, and the AUC was 0.796 (95% confidence interval: 0.724-0.868, P < .001). Corresponding sensitivity and specificity were 61.36% and 80.00%, respectively. The cut)off value of the long to short diameter ratio for predicting malignancy was 1.405, and the AUC was 0.697 (95% confidence interval: 0.609-0.790, P<.001). Corresponding sensitivity and specificity were 70.00% and 71.97%, respectively. Conclusion • EBUS-TBNA has a satisfactory accuracy of lung nodules related MLNs diagnosis. Short diameters and long to short diameter ratio of lung nodules related MLNs in ultrasonic image may contribute to the prediction of malignant lymph nodes. [ABSTRACT FROM AUTHOR]

We study information disclosure in a vertically differentiated duopoly with unaware consumers. Sellers have private information about the adverse effect of their products, while consumers are unaware of existence of such adverse effect unless they are informed by the sellers. We show that information remains hidden only if information disclosure reduces the size of the market. In such a case, whether information is disclosed depends on the intensity of competition, the difference of the adverse effect between the two sellers, and the timing at which pricing and information disclosure decisions are made. [ABSTRACT FROM AUTHOR]

Synthesis of phosphoenolpyruvate (PEP) from oxaloacetate is an absolute requirement for gluconeogenesis from mitochondrial substrates. Generally, this reaction has solely been attributed to the cytosolic isoform of PEPCK (PEPCK-C), although loss of the mitochondrial isoform (PEPCK-M) has never been assessed. Despite catalyzing the same reaction, to date the only significant role reported in mammals for the mitochondrial isoform is as a glucose sensor necessary for insulin secretion. We hypothesized that this nutrient-sensing mitochondrial GTP-dependent pathway contributes importantly to gluconeogenesis. PEPCK-M was acutely silenced in gluconeogenic tissues of rats using antisense oligonucleotides both in vivo and in isolated hepatocytes. Silencing PEPCK-M lowers plasma glucose, insulin, and triglycerides, reduces white adipose, and depletes hepatic glycogen, but raises lactate. There is a switch of gluconeogenic substrate preference to glycerol that quantitatively accounts for a third of glucose production. In contrast to the severe mitochondrial deficiency characteristic of PEPCK-C knock-out livers, hepatocytes from PEPCK-M-deficient livers maintained normal oxidative function. Consistent with its predicted role, gluconeogenesis rates from hepatocytes lacking PEPCK-M are severely reduced for lactate, alanine, and glutamine, but not for pyruvate and glycerol. Thus, PEPCK-M has a direct role in fasted and fed glucose homeostasis, and this mitochondrial GTP-dependent pathway should be reconsidered for its involvement in both normal and diabetic metabolism. [ABSTRACT FROM AUTHOR]

Maturity Onset Diabetes of the Young-type 3 (MODY-3) has been linked to mutations in the transcription factor hepatic nuclear factor (HNF)-1α, resulting in deficiency in glucose-stimulated insulin secretion. In INS-i cells overexpressing doxycycline-inducible HNF-1α dominant-negative (DN-) gene mutations, and islets from Hnf-1α knock-out mice, insulin secretion was impaired in response to glucose (15 mM) and other nutrient secretagogues. Decreased rates of insulin secretion in response to glutamine plus leucine and to methyl pyruvate, but not potassium depolarization, indicate defects specific to mitochondrial metabolism. To identify the biochemical mechanisms responsible for impaired insulin secretion, we used [sup31]P NMR measured mitochondrial ATP synthesis (distinct from glycolytic ATP synthesis) together with oxygen consumption measurements to determine the efficiency of mitochondrial oxidative phosphorylation. Mitochondrial uncoupling was significantly higher in DN-HNF-1α cells, such that rates of ATP synthesis were decreased by approximately one-half in response to the secretagogues glucose, glutamine plus leucine, or pyruvate. In addition to closure of the ATP-sensitive K[sup+] channels with mitochondrial ATP synthesis, mitochondrial production of second messengers through increased anaplerotic flux has been shown to be critical for coupling metabolism to insulin secretion. [sup13]C-Isotopomer analysis and tandem mass spectrometry measurement of Krebs cycle intermediates revealed a negative impact of DN-HNF-1α and Hnf-1α knock-out on mitochondrial second messenger production with glucose but not amino acids. Taken together, these results indicate that, in addition to reduced glycolytic flux, uncoupling of mitochondrial oxidative phosphorylation contributes to impaired nutrient-stimulated insulin secretion with either mutations or loss of HNF-1α. [ABSTRACT FROM AUTHOR]