Risk of Venous Thromboembolism by Cancer Type: A Network Meta-Analysis.

Patients with cancer have an increased risk of venous thromboembolism (VTE). Comparing tumor-specific VTE risk is complicated by factors such as surgery, disease stage, and chemotherapy. Network meta-analysis (NMA) using cancer types as network nodes enabled us to estimate VTE rates by leveraging comparisons across cancer types while adjusting for baseline VTE risk in individual studies. This study was conducted to estimate the risk of VTE by cancer type and factors influencing VTE risk. The Embase, MEDLINE, and Cochrane Library repositories were systematically searched to identify clinical trials and observational studies published from 2005 to 2022 that assessed the risk of primary cancer-related VTE among two or more distinct cancer types. Studies with similar cancer populations and study methods reporting VTE occurring within 1 year of diagnosis were included in the NMA. Relative VTE rates across cancer types were estimated with random-effects Bayesian NMAs. Absolute VTE rates were calculated from these estimates using the average VTE incidence in lung cancer (the most frequently reported type) as the "anchor." From 2,603 records reviewed, 30 studies were included in this NMA. The general network described 3,948,752 patients and 18 cancer types: 3.1% experienced VTE within 1 year of diagnosis, with cancer-specific rates ranging from 0.7 to 7.4%. Consistent with existing VTE risk prediction tools, pancreatic cancer was associated with higher-than-average VTE risk. Other cancer types with high VTE risk were brain and ovarian cancers. The relative rankings of VTE risk for certain cancers changed based on disease stage and/or receipt of chemotherapy or surgery.

Correction: Goodman et al. Human Papillomavirus Vaccine Impact and Effectiveness in Six High-Risk Populations: A Systematic Literature Review. Vaccines 2022, 10, 1543.

The authors wish to make the following corrections to this paper [...].

Human Papillomavirus Vaccine Impact and Effectiveness in Six High-Risk Populations: A Systematic Literature Review.

Specific adult populations known to be at high risk for human papillomavirus (HPV)-related disease, such as men who have sex with men, are inconsistently included in national immunization programs. No compilation of the evidence on the real-world impact and effectiveness of HPV vaccines across these populations exists. This systematic literature review identifies and synthesizes the evidence of the real-world impact and effectiveness of the quadrivalent and nonavalent HPV vaccines in high-risk populations: women with prior/current HPV-related anogenital disease, men who have sex with men, immunocompromised/immunosuppressed individuals, female sex workers, transgender and non-binary individuals, and patients with recurrent respiratory papillomatosis (RRP). The outcomes included anogenital precancers/cancers, head and neck cancers, genital warts, and RRP recurrence. From the 2216 records identified, 30 studies (25 effectiveness and 5 impact studies) were included in this systematic literature review. The results, quantity, and quality of these studies were highly variable. The evidence for effectiveness was of high quality only in women with prior/current cervical disease and in individuals with RRP, the most frequently studied populations. No studies of transgender/non-binary individuals or female sex workers were identified. The real-world evidence supports HPV vaccination among women with prior cervical disease and individuals with RRP. Significant real-world data gaps remain in these high-risk populations.

Systematic literature review of trials assessing recommended systemic treatments in hepatocellular carcinoma.

AIM: To identify and evaluate the similarity of all trials assessing recommended treatments for advanced hepatocellular carcinoma. MATERIALS & METHODS: Single arm and randomized trials from any phase and published any time up to February 2021 were systematically searched. RESULTS: From 5677 records reviewed, 50 trials were included in the review, and 24 for assessed for similarity. In the first-line (1L) setting, several trials assessing sorafenib were noted for enrolling patients with more severe disease and/or performance status than other 1L trials; trials within the second-line (2L) setting were generally similar. Median survival was <2 years in all trial arms. CONCLUSIONS: Trials assessing recommended treatments are largely similar and appropriate for quantitative comparisons of several efficacy and safety outcomes.

A systematic literature review of disease burden and clinical efficacy for patients with relapsed or refractory acute myeloid leukemia.

Acute myeloid leukemia (AML) is a rapidly progressive hematological malignancy that is difficult to cure. The prognosis is poor and treatment options are limited in case of relapse. A comprehensive assessment of current disease burden and the clinical efficacy of non-intensive therapies in this population are lacking. We conducted two systematic literature reviews (SLRs). The first SLR (disease burden) included observational studies reporting the incidence and economic and humanistic burden of relapsed/refractory (RR) AML. The second SLR (clinical efficacy) included clinical trials (phase II or later) reporting remission rates (complete remission [CR] or CR with incomplete hematologic recovery [CRi]) and median overall survival (mOS) in patients with RR AML or patients with de novo AML who are ineligible for intensive chemotherapy. For both SLRs, MEDLINE®/Embase® were searched from January 1, 2008 to January 31, 2020. Clinical trial registries were also searched for the clinical efficacy SLR. After screening, two independent reviewers determined the eligibility for inclusion in the SLRs based on full-text articles. The disease burden SLR identified 130 observational studies. The median cumulative incidence of relapse was 29.4% after stem cell transplant and 46.8% after induction chemotherapy. Total per-patient-per-month costs were $28,148-$29,322; costs and health care resource use were typically higher for RR versus non-RR patients. Patients with RR AML had worse health-related quality of life (HRQoL) scores than patients with de novo AML across multiple instruments, and lower health utility values versus other AML health states (i.e. newly diagnosed, remission, consolidation, and maintenance therapy). The clinical efficacy SLR identified 50 trials (66 total trial arms). CR/CRi rates and mOS have remained relatively stable and low over the last 2 decades. Across all arms, the median rate of CR/CRi was 18.3% and mOS was 6.2 months. In conclusion, a substantial proportion of patients with AML will develop RR AML, which is associated with significant humanistic and economic burden. Existing treatments offer limited efficacy, highlighting the need for more effective non-intensive treatment options.

Indirect treatment comparison of solriamfetol, modafinil, and armodafinil for excessive daytime sleepiness in obstructive sleep apnea.

STUDY OBJECTIVES: Excessive daytime sleepiness associated with obstructive sleep apnea affects 9%-22% of continuous positive airway pressure-treated patients. An indirect treatment comparison meta-analysis was performed to compare efficacy and safety of medications (solriamfetol, modafinil, and armodafinil) approved to treat excessive daytime sleepiness associated with obstructive sleep apnea. METHODS: Efficacy and safety measures assessed in this indirect treatment comparison included Epworth Sleepiness Scale (ESS), 20-minute Maintenance of Wakefulness Test (MWT20), Clinical Global Impression of Change (CGI-C), Functional Outcomes of Sleep Questionnaire (FOSQ), and incidence of treatment-emergent adverse events (any, serious, or leading to discontinuation). RESULTS: A systematic literature review identified 6 parallel-arm, placebo-controlled randomized controlled trials that randomized 1,714 total participants to placebo, solriamfetol, modafinil, or armodafinil. In this indirect treatment comparison, all comparators were associated with greater improvements than placebo on the ESS, MWT20, and CGI-C after 4, 8, and 12 weeks of treatment. Relative to comparators and placebo at 12 weeks, solriamfetol at 150 mg or 300 mg had the highest probabilities of improvement in the ESS, MWT20, and CGI-C. Modafinil (200 or 400 mg) and solriamfetol (150 or 300 mg) were associated with greater improvement on the FOSQ than placebo at 12 weeks. Less than 2% of patients using placebo or comparators experienced serious or discontinuation-related treatment-emergent adverse events. CONCLUSIONS: The results of this indirect treatment comparison show 12 weeks of treatment with solriamfetol, modafinil, and armodafinil resulted in varying levels of improvement on the ESS, MWT20, and CGI-C and similar safety risks in participants with excessive daytime sleepiness associated with obstructive sleep apnea. CITATION: Ronnebaum S, Bron M, Patel D, et al. Indirect treatment comparison of solriamfetol, modafinil, and armodafinil for excessive daytime sleepiness in obstructive sleep apnea. J Clin Sleep Med. 2021;17(12):2543-2555.

Comparability of European League Against Rheumatology-Recommended Pharmacological Treatments of Oral Ulcers Associated with Behçet's Disease: A Systematic Literature Review of Randomized Controlled Trials.

OBJECTIVE: Oral ulcers are the cardinal manifestation in Behçet's disease (BD). The 2018 European League Against Rheumatism (EULAR) recommendations describe treatments for BD-associated oral ulcers with mucocutaneous involvement; however, little comparative effectiveness information for these agents is available. In the absence of head-to-head trials, an indirect treatment comparison (ITC) could provide useful evidence regarding comparative effectiveness of BD treatments. The purpose of this study was to conduct a comparative systematic literature review (SLR) and similarity assessment of randomized controlled trials (RCTs) investigating the oral ulcer-related efficacy outcomes of EULAR-recommended treatments for BD-associated oral ulcers to determine the feasibility of an ITC. METHODS: An SLR was performed to identify relevant RCTs indexed in MEDLINE/Embase before May 29, 2019. RCT similarities for the ITC were assessed based on a step-wise process recommended by the International Society for Pharmacoeconomics and Outcomes Research. RESULTS: In total, 317 articles were identified, of which 14 RCTs, reflecting 11 EULAR-recommended treatments, were evaluated in a similarity assessment. Number of oral ulcers, resolution of oral ulcers, and healing time for oral ulcers were identified as the possible oral ulcer-related outcomes. After completing the similarity assessment of these outcomes, it was determined that a robust ITC was infeasible for the three oral ulcer-related outcomes due to heterogeneity in outcomes reporting, study design, and/or patient characteristics. More broadly, the results underscore the need for and consistent use of standardized measures for oral ulcer outcomes to facilitate comparative research. CONCLUSION: In the absence of head-to-head RCTs and infeasibility of quantitative ITC, comparative assessments for BD-associated oral ulcers are limited, including comparative effectiveness and cost-effectiveness evaluations. Healthcare decision-makers must continue to base treatment decisions on the extent and strength of available evidence (eg, robust RCTs), clinical guidelines, real-world experience, and patient considerations.

Epidemiologic, humanistic and economic burden of hepatocellular carcinoma in the USA: a systematic literature review.

AIM: To describe the epidemiologic, humanistic and economic burdens of hepatocellular carcinoma (HCC) in the USA. MATERIALS & METHODS: Studies describing the epidemiology and economic burden from national cohorts, any economic models, or any humanistic burden studies published 2008-2018 were systematically searched. RESULTS: HCC incidence was 9.5 per 100,000 person-years in most recent data, but was ∼100-times higher among patients with hepatitis/cirrhosis. Approximately a third of patients were diagnosed with advanced disease. Patients with HCC experienced poor quality of life. Direct costs were substantial and varied based on underlying demographics, disease stage and treatment received. Between 25-77% of patients did not receive surgical, locoregional or systemic treatment. CONCLUSION: Better treatments are needed to extend survival and improve quality of life for patients with HCC.

Endothelial inflammatory transcriptional responses to an altered plasma exposome following inhalation of diesel emissions.

BACKGROUND: Air pollution, especially emissions derived from traffic sources, is associated with adverse cardiovascular outcomes. However, it remains unclear how inhaled factors drive extrapulmonary pathology. OBJECTIVES: Previously, we found that canonical inflammatory response transcripts were elevated in cultured endothelial cells treated with plasma obtained after exposure compared with pre-exposure samples or filtered air (sham) exposures. While the findings confirmed the presence of bioactive factor(s) in the plasma after diesel inhalation, we wanted to better examine the complete genomic response to investigate (1) major responsive transcripts and (2) collected response pathways and ontogeny that may help to refine this method and inform the pathogenesis. METHODS: We assayed endothelial RNA with gene expression microarrays, examining the responses of cultured endothelial cells to plasma obtained from six healthy human subjects exposed to 100 µg/m(3) diesel exhaust or filtered air for 2 h on separate occasions. In addition to pre-exposure baseline samples, we investigated samples obtained immediately-post and 24 h-post exposure. RESULTS: Microarray analysis of the coronary artery endothelial cells challenged with plasma identified 855 probes that changed over time following diesel exhaust exposure. Over-representation analysis identified inflammatory cytokine pathways were upregulated both at the 2 and 24 h conditions. Novel pathways related to FOXO transcription factors and secreted extracellular factors were also identified in the microarray analysis. CONCLUSIONS: These outcomes are consistent with our recent findings that plasma contains bioactive and inflammatory factors following pollutant inhalation and provide a novel pathway to explain the well-reported extrapulmonary toxicity of ambient air pollutants.

Minireview: hey U(PS): metabolic and proteolytic homeostasis linked via AMPK and the ubiquitin proteasome system.

One of the master regulators of both glucose and lipid cellular metabolism is 5'-AMP-activated protein kinase (AMPK). As a metabolic pivot that dynamically responds to shifts in nutrient availability and stress, AMPK dysregulation is implicated in the underlying molecular pathology of a variety of diseases, including cardiovascular diseases, diabetes, cancer, neurological diseases, and aging. Although the regulation of AMPK enzymatic activity by upstream kinases is an active area of research, less is known about regulation of AMPK protein stability and activity by components of the ubiquitin-proteasome system (UPS), the cellular machinery responsible for both the recognition and degradation of proteins. Furthermore, there is growing evidence that AMPK regulates overall proteasome activity and individual components of the UPS. This review serves to identify the current understanding of the interplay between AMPK and the UPS and to promote further exploration of the relationship between these regulators of energy use and amino acid availability within the cell.

Emerging evidence of coding mutations in the ubiquitin-proteasome system associated with cerebellar ataxias.

Cerebellar ataxia (CA) is a disorder associated with impairments in balance, coordination, and gait caused by degeneration of the cerebellum. The mutations associated with CA affect functionally diverse genes; furthermore, the underlying genetic basis of a given CA is unknown in many patients. Exome sequencing has emerged as a cost-effective technology to discover novel genetic mutations, including autosomal recessive CA (ARCA). Five recent studies that describe how exome sequencing performed on a diverse pool of ARCA patients revealed 14 unique mutations in STUB1, a gene that encodes carboxy terminus of Hsp70-interacting protein (CHIP). CHIP mediates protein quality control through chaperone and ubiquitin ligase activities and is implicated in alleviating proteotoxicity in several neurodegenerative diseases. However, these recent studies linking STUB1 mutations to various forms of ataxia are the first indications that CHIP is directly involved in the progression of a human disease. Similar exome-sequencing studies have revealed novel mutations in ubiquitin-related proteins associated with CA and other neurological disorders. This review provides an overview of CA, describes the benefits and limitations of exome sequencing, outlines newly discovered STUB1 mutations, and theorizes on how CHIP and other ubiquitin-related proteins function to prevent neurological deterioration.

The ubiquitin ligase CHIP prevents SirT6 degradation through noncanonical ubiquitination.

The ubiquitin ligase CHIP (carboxyl terminus of Hsp70-interacting protein) regulates protein quality control, and CHIP deletion accelerates aging and reduces the life span in mice. Here, we reveal a mechanism for CHIP's influence on longevity by demonstrating that CHIP stabilizes the sirtuin family member SirT6, a lysine deacetylase/ADP ribosylase involved in DNA repair, metabolism, and longevity. In CHIP-deficient cells, SirT6 protein half-life is substantially reduced due to increased proteasome-mediated degradation, but CHIP overexpression in these cells increases SirT6 protein expression without affecting SirT6 transcription. CHIP noncanonically ubiquitinates SirT6 at K170, which stabilizes SirT6 and prevents SirT6 canonical ubiquitination by other ubiquitin ligases. In CHIP-depleted cells, SirT6 K170 mutation increases SirT6 half-life and prevents proteasome-mediated degradation. The global decrease in SirT6 expression in the absence of CHIP is associated with decreased SirT6 promoter occupancy, which increases histone acetylation and promotes downstream gene transcription in CHIP-depleted cells. Cells lacking CHIP are hypersensitive to DNA-damaging agents, but DNA repair and cell viability are rescued by enforced expression of SirT6. The discovery of this CHIP-SirT6 interaction represents a novel protein-stabilizing mechanism and defines an intersection between protein quality control and epigenetic regulation to influence pathways that regulate the biology of aging.

Back to your heart: ubiquitin proteasome system-regulated signal transduction.

Awareness of the regulation of cell signaling by post-translational ubiquitination has emerged over the past 2 decades. Like phosphorylation, post-translational modification of proteins with ubiquitin can result in the regulation of numerous cellular functions, for example, the DNA damage response, apoptosis, cell growth, and the innate immune response. In this review, we discuss recently published mechanisms by which the ubiquitin proteasome system regulates key signal transduction pathways in the heart, including MAPK JNK, calcineurin, FOXO, p53, and estrogen receptors α and ß. We then explore how ubiquitin proteasome system-specific regulation of these signal transduction pathways plays a role in the pathophysiology of common cardiac diseases, such as cardiac hypertrophy, heart failure, ischemia reperfusion injury, and diabetes. This article is part of a Special Section entitled "Post-translational Modification."

The mitochondrial 2-oxoglutarate carrier is part of a metabolic pathway that mediates glucose- and glutamine-stimulated insulin secretion.

Glucose-stimulated insulin secretion from pancreatic islet beta-cells is dependent in part on pyruvate cycling through the pyruvate/isocitrate pathway, which generates cytosolic alpha-ketoglutarate, also known as 2-oxoglutarate (2OG). Here, we have investigated if mitochondrial transport of 2OG through the 2-oxoglutarate carrier (OGC) participates in control of nutrient-stimulated insulin secretion. Suppression of OGC in clonal pancreatic beta-cells (832/13 cells) and isolated rat islets by adenovirus-mediated delivery of small interfering RNA significantly decreased glucose-stimulated insulin secretion. OGC suppression also reduced insulin secretion in response to glutamine plus the glutamate dehydrogenase activator 2-amino-2-norbornane carboxylic acid. Nutrient-stimulated increases in glucose usage, glucose oxidation, glutamine oxidation, or ATP:ADP ratio were not affected by OGC knockdown, whereas suppression of OGC resulted in a significant decrease in the NADPH:NADP(+) ratio during stimulation with glucose but not glutamine + 2-amino-2-norbornane carboxylic acid. Finally, OGC suppression reduced insulin secretion in response to a membrane-permeant 2OG analog, dimethyl-2OG. These data reveal that the OGC is part of a mechanism of fuel-stimulated insulin secretion that is common to glucose, amino acid, and organic acid secretagogues, involving flux through the pyruvate/isocitrate cycling pathway. Although the components of this pathway must remain intact for appropriate stimulus-secretion coupling, production of NADPH does not appear to be the universal second messenger signal generated by these reactions.

The FoxO family in cardiac function and dysfunction.

The Forkhead family of transcription factors mediates many aspects of physiology, including stress response, metabolism, commitment to apoptosis, and development. The Forkhead box subfamily O (FoxO) proteins have garnered particular interest due to their involvement in the modulation of cardiovascular biology. In this review, we discuss the mechanisms of FoxO regulation and outcomes of FoxO signaling under normal and pathological cardiovascular contexts.

Breast cancer quality control.

Tumorigenesis is regulated by several mechanisms including signalling, transcription and DNA replication. Now a cytoplasmic protein quality-control pathway is implicated in the suppression of breast cancer cell growth, suggesting a new role for quality-control mechanisms in suppressing cells with malignant potential.

Silencing of cytosolic or mitochondrial isoforms of malic enzyme has no effect on glucose-stimulated insulin secretion from rodent islets.

We have previously demonstrated a role for pyruvate cycling in glucose-stimulated insulin secretion (GSIS). Some of the possible pyruvate cycling pathways are completed by conversion of malate to pyruvate by malic enzyme. Using INS-1-derived 832/13 cells, it has recently been shown by other laboratories that NADP-dependent cytosolic malic enzyme (MEc), but not NAD-dependent mitochondrial malic enzyme (MEm), regulates GSIS. In the current study, we show that small interfering RNA-mediated suppression of either MEm or MEc results in decreased GSIS in both 832/13 cells and a new and more glucose- and incretin-responsive INS-1-derived cell line, 832/3. The effect of MEm to suppress GSIS in these cell lines was linked to a substantial decrease in cell growth, whereas MEc suppression resulted in decreased NADPH, shown previously to be correlated with GSIS. However, adenovirus-mediated delivery of small interfering RNAs specific to MEc and MEm to isolated rat islets, while leading to effective suppression of the targets transcripts, had no effect on GSIS. Furthermore, islets isolated from MEc-null MOD1(-/-) mice exhibit normal glucose- and potassium-stimulated insulin secretion. These results indicate that pyruvate-malate cycling does not control GSIS in primary rodent islets.

Metabolic cycling in control of glucose-stimulated insulin secretion.

Glucose-stimulated insulin secretion (GSIS) is central to normal control of metabolic fuel homeostasis, and its impairment is a key element of beta-cell failure in type 2 diabetes. Glucose exerts its effects on insulin secretion via its metabolism in beta-cells to generate stimulus/secretion coupling factors, including a rise in the ATP/ADP ratio, which serves to suppress ATP-sensitive K(+) (K(ATP)) channels and activate voltage-gated Ca(2+) channels, leading to stimulation of insulin granule exocytosis. Whereas this K(ATP) channel-dependent mechanism of GSIS has been broadly accepted for more than 30 years, it has become increasingly apparent that it does not fully describe the effects of glucose on insulin secretion. More recent studies have demonstrated an important role for cyclic pathways of pyruvate metabolism in control of insulin secretion. Three cycles occur in islet beta-cells: the pyruvate/malate, pyruvate/citrate, and pyruvate/isocitrate cycles. This review discusses recent work on the role of each of these pathways in control of insulin secretion and builds a case for the particular relevance of byproducts of the pyruvate/isocitrate cycle, NADPH and alpha-ketoglutarate, in control of GSIS.

The interplay of prolactin and the glucocorticoids in the regulation of beta-cell gene expression, fatty acid oxidation, and glucose-stimulated insulin secretion: implications for carbohydrate metabolism in pregnancy.

Carbohydrate metabolism in pregnancy reflects the balance between counterregulatory hormones, which induce insulin resistance, and lactogenic hormones, which stimulate beta-cell proliferation and insulin production. Here we explored the interactions of prolactin (PRL) and glucocorticoids in the regulation of beta-cell gene expression, fatty acid oxidation, and glucose-stimulated insulin secretion (GSIS). In rat insulinoma cells, rat PRL caused 30-50% (P < 0.001) reductions in Forkhead box O (FoxO)-1, peroxisome proliferator activator receptor (PPAR)-gamma coactivator-1alpha (PGC-1alpha), PPARalpha, and carnitine palmitoyltransferase 1 (CPT-1) mRNAs and increased Glut-2 mRNA and GSIS; conversely, dexamethasone (DEX) up-regulated FoxO1, PGC1alpha, PPARalpha, CPT-1, and uncoupling protein 2 (UCP-2) mRNAs in insulinoma cells and inhibited GSIS. Hydrocortisone had similar effects. The effects of DEX were attenuated by coincubation of cells with PRL. In primary rat islets, PRL reduced FoxO1, PPARalpha, and CPT-1 mRNAs, whereas DEX increased FoxO1, PGC1alpha, and UCP-2 mRNAs. The effects of PRL on gene expression were mimicked by constitutive overexpression of signal transducer and activator of transcription-5b. PRL induced signal transducer and activator of transcription-5 binding to a consensus sequence in the rat FoxO1 promoter, reduced nuclear FoxO1 protein levels, and induced its phosphorylation and cytoplasmic redistribution. DEX increased beta-cell fatty acid oxidation and reduced fatty acid esterification; these effects were attenuated by PRL. Thus, lactogens and glucocorticoids have opposing effects on a number of beta-cell genes including FoxO1, PGC1alpha, PPARalpha, CPT-1, and UCP-2 and differentially regulate beta-cell Glut-2 expression, fatty acid oxidation, and GSIS. These observations suggest new mechanisms by which lactogens may preserve beta-cell mass and function and maternal glucose tolerance despite the doubling of maternal cortisol concentrations in late gestation.

Chronic suppression of acetyl-CoA carboxylase 1 in beta-cells impairs insulin secretion via inhibition of glucose rather than lipid metabolism.

Acetyl-CoA carboxylase 1 (ACC1) currently is being investigated as a target for treatment of obesity-associated dyslipidemia and insulin resistance. To investigate the effects of ACC1 inhibition on insulin secretion, three small interfering RNA (siRNA) duplexes targeting ACC1 (siACC1) were transfected into the INS-1-derived cell line, 832/13; the most efficacious duplex was also cloned into an adenovirus and used to transduce isolated rat islets. Delivery of the siACC1 duplexes decreased ACC1 mRNA by 60-80% in 832/13 cells and islets and enzyme activity by 46% compared with cells treated with a non-targeted siRNA. Delivery of siACC1 decreased glucose-stimulated insulin secretion (GSIS) by 70% in 832/13 cells and by 33% in islets. Surprisingly, siACC1 treatment decreased glucose oxidation by 49%, and the ATP:ADP ratio by 52%, accompanied by clear decreases in pyruvate cycling activity and tricarboxylic acid cycle intermediates. Exposure of siACC1-treated cells to the pyruvate cycling substrate dimethylmalate restored GSIS to normal without recovery of the depressed ATP:ADP ratio. In siACC1-treated cells, glucokinase protein levels were decreased by 25%, which correlated with a 36% decrease in glycogen synthesis and a 33% decrease in glycolytic flux. Furthermore, acute addition of the ACC1 inhibitor 5-(tetradecyloxy)-2-furoic acid (TOFA) to beta-cells suppressed [(14)C]glucose incorporation into lipids but had no effect on GSIS, whereas chronic TOFA administration suppressed GSIS and glucose metabolism. In sum, chronic, but not acute, suppression of ACC1 activity impairs GSIS via inhibition of glucose rather than lipid metabolism. These findings raise concerns about the use of ACC inhibitors for diabetes therapy.