RESUMO
Inadequate intake of essential minerals such as iron and zinc is a public health concern in the UK, particularly for girls and young women. Approximately 30% and 50% of the zinc and iron, respectively, in the UK diet is provided by cereals. In wheat, most of the iron and zinc is contained within the aleurone cell layer; however, aleurone is removed during processing of wheat into white flour. While elemental iron powder is added back into white flour at the milling stage, there is no restoration of zinc. Elemental iron powder has very low bioavailability, and therefore, in our current Biotechnology and Biological Sciences Research Council Diet and Health Research Industry Club-funded project, we are investigating the potential use of aleurone as a bioavailable source of minerals that could be added to wheat-based foods. This work has relevance for the food industry and may establish the use of aleurone as a functional food ingredient for fortification of a range of cereal-based food products.
RESUMO
Interesterified (IE) fats are used in a wide range of food products and were introduced as a replacement for trans fats, which are known to be detrimental to cardiovascular health. However, the effects of interesterification on metabolism and subsequent effects on cardiovascular health are not understood and previous studies have seldom investigated industrially-relevant IE fats. No legislation currently exists regarding the labelling of IE fats in food products and therefore estimates of average consumption rates in the UK population are currently unavailable. In order to meet the urgent need for a systematic investigation of the health effects of consumer-relevant IE fats, it is essential to estimate current IE fat intakes and to investigate biological mechanisms that might mediate acute and chronic cardiometabolic effects of commercially relevant IE fats.
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Mismatch repair (MMR) deficiency, which underlies hereditary nonpolyposis colorectal cancer, has recently been linked to a number of sporadic human cancers as well. Deficiency in this repair process renders cells resistant to many clinically active chemotherapy agents. As a result, it is of relevance to find an agent that selectively targets MMR-deficient cells. We have recently shown that the halogenated thymidine (dThd) analogues iododeoxyuridine (IdUrd) and bromodeoxyuridine (BrdUrd) selectively target MutL homologue-1 (MLH1)-deficient human cancer cells for radiosensitization. The levels of IdUrd and BrdUrd in cellular DNA directly correlate with the ability of these analogues to increase the sensitivity of cells and tissues to ionizing radiation, and data from our laboratory have demonstrated that MLH1-mediated MMR status impacts dThd analogue DNA levels, and consequently, analogue-induced radiosensitization. Here, we have extended these studies and show that, both in human and murine cells, MutS homologue-2 (MSH2) is also involved in processing dThd analogues in DNA. Using both E1A-transformed Msh2+/+ and Msh2-/- murine embryonic stem (ES)-derived cells (throughout this report we use Msh2+/+ and Msh2-/- to refer to murine ES-derived cell lines that are wild type or mutant, respectively, for the murine Msh2 gene) and human endometrial cancer cells differing in MSH2 status, we see the classic cytotoxic response to 6-thioguanine (6-TG) in Msh2+/+ and human HEC59/2-4 (MSH2+) MMR-proficient cells, whereas Msh2-/- cells and human HEC59 (MSH2-/-) cells are tolerant (2-log difference) to this agent. In contrast, there is very little cytotoxicity in Msh2+/+ ES-derived and HEC59/2-4 cells to IdUrd, whereas Msh2-/- and HEC59 cells are more sensitive to IdUrd. High-performance liquid chromatography analysis of IdUrd and BrdUrd levels in DNA suggests that this differential cytotoxicity may be due to lower analogue levels in MSH2+ murine and human tumor cells. The DNA levels of IdUrd and BrdUrd continue to decrease over time in Msh2+/+ cells following incubation in drug-free medium, whereas they remain high in Msh2-/- cells. This trend was also found in MSH2-deficient human endometrial cancer cells (HEC59) when compared with HEC59/2-4 (hMsh2-corrected) cells. As a result of higher analogue levels in DNA, Msh2-/- cells are selectively targeted for radiosensitization by IdUrd. Fluorescence-activated cell-sorting analysis of Msh2+/+ and Msh2-/- cells shows that selective toxicity of the halogenated nucleotide analogues is not correlated with a G2-M cell cycle arrest and apoptosis, as is found for selective killing of Msh2+/+ cells by 6-TG. Together, these data demonstrate MSH2 involvement in the processing of IdUrd and BrdUrd in DNA, as well as the differential cytotoxicity and cell cycle effects of the halogenated dThd analogues compared with 6-TG. Therefore, IdUrd and BrdUrd may be used clinically to selectively target both MLH1- and MSH2-deficient, drug-resistant cells for radiosensitization.
Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Bromodesoxiuridina/farmacologia , Proteínas de Ligação a DNA , DNA/metabolismo , Idoxuridina/farmacologia , Proteínas Proto-Oncogênicas/fisiologia , Radiossensibilizantes/farmacologia , Tioguanina/farmacologia , Proteínas E1A de Adenovirus/genética , Animais , Pareamento Incorreto de Bases , Bromodesoxiuridina/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Transformada , DNA/genética , Reparo do DNA , Nucleotídeos de Desoxicitosina/metabolismo , Relação Dose-Resposta a Droga , Humanos , Idoxuridina/metabolismo , Cinética , Camundongos , Camundongos Knockout , Proteína 2 Homóloga a MutS , Proteínas Proto-Oncogênicas/genética , Nucleotídeos de Timina/metabolismoRESUMO
Deficiency in DNA mismatch repair (MMR) is found in some hereditary (hereditary nonpolyposis colorectal cancer) and sporadic colon cancers as well as other common solid cancers. MMR deficiency has recently been shown to impart cellular resistance to multiple chemical agents, many of which are commonly used in cancer chemotherapy. It is therefore of interest to find an approach that selectively targets cells that have lost the ability to perform MMR. In this study, we examine the response of MMR-proficient (hMLH1+) and MMR-deficient (hMLH1-) colon carcinoma cell lines to the halogenated thymidine (dThd) analogues iododeoxyuridine (IdUrd) and bromodeoxyuridine (BrdUrd) before and after irradiation. These dThd analogues are used clinically as experimental sensitizing agents in radioresistant human cancers, and there is a direct correlation between the levels of dThd analogue DNA incorporation and tumor radiosensitization. In contrast to the well-characterized, marked increase in cytotoxicity (> 1 log cell kill) found with 6-thioguanine exposures in HCT116/3-6 (hMLH1+) cells compared to HCT116 (hMLH1-) cells, we found only modest cytotoxicity (10-20% cell kill) in both cell lines when treated with IdUrd or BrdUrd for 1 population doubling. Upon further analysis, the levels of halogenated dThd analogues in DNA were significantly lower (two to three times lower) in HCT116/3-6 cells than in HCT116 cells, and similar results were found in Mlh1+/+ spontaneously immortalized murine embryonic fibroblasts and fibroblasts from Mlh1 knockout mice. As a result of the higher levels of the dThd analogue in DNA, there was an increase in radiation sensitivity in HCT116 cells but not in HCT116/3-6 cells after pretreatment with IdUrd or BrdUrd when compared to treatment with radiation alone. Additionally, we found no differences in the cellular metabolic pathways for dThd analogue DNA incorporation because the enzyme activities of dThd kinase and thymidylate synthase, as well as the levels of triphosphate pools, were similar in HCT116 and HCT116/3-6 cells. These data suggest that the hMLH1 protein may participate in the recognition and subsequent removal of halogenated dThd analogues from DNA. Consequently, whereas MMR-deficient cells and tumor xenografts have shown intrinsic resistance to a large number of chemotherapeutic agents, the 5-halogenated dThd analogues appear to selectively target such cells for potential enhanced radiation sensitivity.
Assuntos
Neoplasias do Colo/genética , Proteínas de Neoplasias/metabolismo , Timidina/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Bromouracila/análogos & derivados , Proteínas de Transporte , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Reparo do DNA , DNA de Neoplasias/biossíntese , DNA de Neoplasias/efeitos dos fármacos , Desoxirribonucleotídeos/metabolismo , Humanos , Proteína 1 Homóloga a MutL , Proteínas Nucleares , Radiação Ionizante , Tioguanina/metabolismo , Tioguanina/farmacologia , Timidina/análogos & derivados , Timidina Quinase/metabolismo , Timidilato Sintase/metabolismo , Células Tumorais Cultivadas , Uridina/análogos & derivados , Uridina/metabolismo , Uridina/farmacologiaRESUMO
Our previous data demonstrated that cells deficient in MutL homologue-1 (MLH1) expression had a reduced and shorter G(2) arrest after high-dose-rate ionizing radiation (IR), suggesting that the mismatch re pair (MMR) system mediates this cell cycle checkpoint. We confirmed this observation using two additional isogenetically matched human MLH1 (hMLH1)-deficient and -proficient human tumor cell systems: human ovarian cancer cells, A2780/CP70, with or without ectopically expressed hMLH1, and human colorectal carcinoma cells, RKO, with or without azacytidine treatment to reexpress hMLH1. We also examined matched MutS homologue-2 (hMSH2)-deficient and -proficient human endometrial carcinoma HEC59 cell lines to determine whether hMSH2, and MMR in general, is involved in IR-related G(2) arrest responses. As in MLH1-deficient cells, cells lacking hMSH2 demonstrated a similarly altered G(2) arrest in response to IR (6 Gy). These differences in IR-induced G(2) arrest between MMR-proficient and -deficient cells were found regardless of whether synchronized cells were irradiated in G(0)/G(1) or S phase, indicating that MMR indeed dramatically affects the G(2)-M checkpoint arrest. However, unlike the MMR-dependent damage tolerance response to 6-thioguanine exposures, no significant difference in the clonogenic survival of MMR-deficient cells compared with MMR-proficient cells was noted after high-dose-rate IR. In an attempt to define the signal transduction mechanisms responsible for MMR-mediated G(2) arrest, we examined the levels of tyrosine 15 phosphorylation of cdc2 (phospho-Tyr15-cdc2), a key regulator of the G(2)-M transition. Increased phospho-Tyr15-cdc2 levels were observed in both MMR-proficient and -deficient cell lines after IR. However, the levels of the phospho-Tyr15-cdc2 rapidly decreased in MMR (hMLH1 or hMSH2)-deficient cell lines at times coincident with progress from the IR-induced G(2) arrest through M phase. Thus, differences in the levels of phospho-Tyr15-cdc2 after high-dose-rate IR correspond temporally with the observed differences in the IR-induced G(2) arrest, suggesting that MMR proteins may exert their effect on IR-induced G(2) arrest by signaling the cdc2 pathway. Although MMR status does not significantly affect the survival of cells after high-dose-rate IR, it seems to regulate the G(2)-M checkpoint and might affect overall mutation rates.
Assuntos
Pareamento Incorreto de Bases , Proteína Quinase CDC2/fisiologia , Reparo do DNA/fisiologia , Fase G2/fisiologia , Proteínas Adaptadoras de Transdução de Sinal , Proteína Quinase CDC2/metabolismo , Proteínas de Transporte , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Sobrevivência Celular/efeitos da radiação , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Fase G2/efeitos dos fármacos , Fase G2/efeitos da radiação , Humanos , Proteína 1 Homóloga a MutL , Proteínas de Neoplasias/deficiência , Proteínas Nucleares , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Fosforilação , Fase S/efeitos dos fármacos , Fase S/fisiologia , Fase S/efeitos da radiação , Transdução de Sinais/fisiologia , Transdução de Sinais/efeitos da radiação , Tioguanina/farmacologia , Células Tumorais CultivadasRESUMO
We have demonstrated previously an improved therapeutic index for oral 5-iodo-2-deoxypyrimidinone-2'-deoxyribose (IPdR) compared with oral and continuous infusion of 5-iodo-2'-deoxyuridine (IUdR) as a radiosensitizing agent using three different human tumor xenografts in athymic mice. IPdR is a prodrug that is efficiently converted to IUdR by a hepatic aldehyde oxidase, resulting in high IPdR and IUdR plasma levels in mice for > or =1 h after p.o. IPdR. Athymic mice tolerated oral IPdR at up to 1500 mg/kg/day given four times per day for 6-14 days without significant systemic toxicities. In anticipation of an investigational new drug application for the first clinical Phase I and pharmacology study of oral IPdR in humans, we studied the drug pharmacokinetics and host toxicities in two non-rodent, animal species. For the IPdR systemic toxicity and toxicology study, twenty-four male or female ferrets were randomly assigned to four IPdR dosage groups receiving 0, 15, 150, and 1500 mg/kg/day by oral gavage x 14 days prior to sacrifice on study day 15. All ferrets survived the 14-day treatment. Ferrets receiving 1500 mg/kg/day showed observable systemic toxicities with diarrhea, emesis, weight loss, and decreased motor activity beginning at days 5-8 of the 14-day schedule. Overall, both male and female ferrets receiving IPdR at 1500 mg/kg/day experienced significant weight loss (9 and 19%, respectively) compared with controls after the 14-day treatment. No weight loss or other systemic toxicities were observed in other IPdR dosage groups. Grossly, no anatomical lesions were noted at complete necropsy, although liver weights were increased in both male and female ferrets in the two higher IPdR dosage groups. Histologically, IPdR-treated animals showed dose-dependent microscopic changes in liver consisting of minimal to moderate cytoplasmic vacuolation of hepatocytes, which either occurred in the periportal area (high dosage group) or diffusely throughout the liver (lower dosage groups). Female ferrets in the highest IPdR dose group also showed decreased kidney and uterus weights at autopsy without any associated histological changes. No histological changes were found in central nervous system tissues. No significant abnormalities in blood cell counts, liver function tests, kidney function tests, or urinalysis were noted. Hepatic aldehyde oxidase activity was decreased to approximately 50 and 30% of control ferrets in the two higher IPdR dosage groups, respectively, after the 14-day treatment period. The % IUdR-DNA incorporation in ferret bone marrow at the completion of IPdR treatment was < or =0.05% in the two lower dosage groups and approximately 2% in the 1500 mg/kg/day dosage group. The % IUdR-DNA in normal liver was < or =0.05% in all IPdR dosage groups. In a pharmacokinetic study in four Rhesus monkeys, we determined the plasma concentrations of IPdR after a single i.v. bolus of 50 mg/kg over 20 min. Using a two-compartment model to fit the plasma pharmacokinetic data, we found that IPdR was cleared in these non-human primates in a biexponential manner with an initial rapid distributive phase (mean T1/2alpha = 6.5 min), followed by an elimination phase with a mean T1/2 of 63 min. The mean maximum plasma concentration of IPdR was 124+/-43 microM with a mean total body clearance of 1.75+/-0.95 l/h/kg. IPdR was below detection (<0.5 microM) in the cerebrospinal fluid. We conclude that there are dose-limiting systemic toxicities to a 14-day schedule of p.o. IPdR at 1500 mg/kg/day in ferrets that were not found previously in athymic mice. However, no significant hematological, biochemical, or histopathological changes were found. Hepatic aldehyde oxidase activity was reduced in a dose-dependent in ferret liver, suggesting partial enzyme saturation by this IPdR schedule. The plasma pharmacokinetic profile in Rhesus monkeys showing biexponential clearance is similar to our published data in athymic mice. These data are being applied
Assuntos
Nucleosídeos de Pirimidina/farmacocinética , Nucleosídeos de Pirimidina/toxicidade , Radiossensibilizantes/farmacocinética , Radiossensibilizantes/toxicidade , Aldeído Oxirredutases/metabolismo , Animais , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , DNA/metabolismo , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Furões , Testes Hematológicos , Idoxuridina/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Macaca mulatta , Masculino , Pró-Fármacos/farmacocinética , Pró-Fármacos/toxicidade , Estômago/efeitos dos fármacos , Estômago/patologia , Urina/químicaRESUMO
Postreplicational mismatch repair (MMR) proteins are capable of recognizing and processing not only single base-pair mismatches and insertion-deletion loops (IDLs) that occur during DNA replication, but also adducts in DNA resulting from treatment with cancer chemotherapy agents. These include widely varying types of DNA adducts resulting from methylating agents such as MNNG, MNU, temozolomide, and procarbazine; CpG crosslinks resulting from cisplatin and carboplatin; and S(6)-thioguanine and S(6)-methylthioguanine residues in DNA. Although MMR proteins can recognize both replicational errors and chemotherapy-induced adducts in DNA, the end results of this recognition are very different. Base-base mismatches and IDLs can be repaired by MMR, restoring genomic integrity, whereas MMR-mediated recognition and processing of chemotherapy-induced adducts in DNA results in apoptosis. After the loss of MMR, the inability of cells to recognize and correct single base-pair mismatches and insertion-deletion loops can lead to secondary mutations in proto-oncogenes and tumor-suppressor genes, thereby contributing to the development of cancer. In addition, the inability of MMR-deficient cells to recognize chemotherapy-induced adducts in DNA can result in a damage-tolerant phenotype that translates to clinically significant resistance by allowing for selection of MMR-deficient cancer cells. We have shown recently that these MMR-deficient, drug-resistant cells can be targeted for radiosensitization by the halogenated thymidine analogs iododeoxyuridine (IdUrd) and bromodeoxyuridine (BrdUrd). These thymidine (dThd) analogs become incorporated into DNA and form reactive uracil radicals after ionizing radiation (IR), increasing strand breaks. IdUrd and BrdUrd appear to be removed from DNA in MMR-proficient cells with limited toxicity or disruption of the cell cycle, while accumulating at much higher levels in MMR-deficient cells. As a result, it is possible to effectively increase the radiosensitization of MMR-deficient cells at levels of halogenated dThd analog that demonstrate limited toxicity to MMR-proficient cells. This indicates that a combined approach of IdUrd or BrdUrd with IR may be effective in killing MMR-deficient tumors in patients, which are resistant to many cancer chemotherapy agents commonly used in the clinic.
Assuntos
Antineoplásicos/farmacologia , Pareamento Incorreto de Bases/genética , Reparo do DNA/fisiologia , DNA de Neoplasias/genética , Neoplasias/genética , Inibidores da Síntese de Ácido Nucleico/farmacologia , Radiossensibilizantes/farmacologia , Apoptose , Bromodesoxiuridina/farmacologia , Ciclo Celular/efeitos dos fármacos , Terapia Combinada , Adutos de DNA , Resistencia a Medicamentos Antineoplásicos , Humanos , Idoxuridina/farmacologia , Mutagênese/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/radioterapiaRESUMO
BACKGROUND: Influenza causes increased morbidity and mortality among patients in longterm care facilities, but little information is available on the impact of influenza in acute care settings. We wished to have such information when revising our hospital influenza control policy. METHODS: We reviewed recent reports of influenza among patients in acute care hospitals and surveyed large (approximately 500-bed) acute care teaching hospitals by telephone to determine the nature of their influenza control policies. RESULTS: Seventeen reports of influenza outbreaks in acute care hospitals were published from 1959 to 1994. Influenza A caused 13 of these outbreaks. Five involved children and 12 involved adults. The mean number of patients in each outbreak was 14 (range 1 to 49), with a mortality rate of 0% to 50% (median 0%, mean 6.5%). Health care workers were implicated in transmission in five reports. Vaccine was used infrequently during the outbreaks, and use of chemoprophylaxis was not reported. Our survey of current practices in 15 university-affiliated hospitals from 12 states revealed that all offered vaccine in the fall but none required either immunoprophylaxis or chemoprophylaxis at any time. Only three had formal policies detailing management of influenza in the hospital. CONCLUSIONS: Nosocomial influenza in acute care hospitals is infrequently reported and associated with a low mortality rate. Health care workers rarely comply with preventive measures, and few institutions have formal influenza control policies.
Assuntos
Infecção Hospitalar/prevenção & controle , Surtos de Doenças/prevenção & controle , Hospitais de Ensino , Controle de Infecções/métodos , Influenza Humana/prevenção & controle , Doença Aguda , Adulto , Criança , Infecção Hospitalar/epidemiologia , Mortalidade Hospitalar , Humanos , Lactente , Influenza Humana/epidemiologia , Inquéritos e Questionários , Estados Unidos/epidemiologiaRESUMO
BACKGROUND/OBJECTIVES: Dietary triacylglycerols (TAGs) containing palmitic acid in the sn-2 position might impair insulin release and increase plasma glucose. We tested this hypothesis by comparing postprandial responses to fats with varying proportions of palmitic acid in the sn-2 position. SUBJECTS/METHODS: Using a crossover-designed randomized controlled trial in healthy men (n=25) and women (n=25), we compared four meals on postprandial changes in glucose (primary outcome), insulin, C-peptide, glucose, glucose-dependent insulinotropic polypeptide (GIP) and polypeptide YY (PYY) concentrations. The meals provided 14 g protein, 85 g carbohydrate and 50 g test fat, supplied as high oleic sunflower (HOS) oil (control), palm olein (PO), interesterified palm olein (IPO) and lard containing 0.6, 9.2, 39.1 and 70.5 mol% palmitic acid at sn-2, respectively. RESULTS: No differences in plasma glucose, insulin and C-peptide response between meals were found. GIP release was lower (P<0.001) for IPO and lard compared with HOS and PO meals; the maximal increments (geometric mean and 95% confidence interval) for HOS, PO, IPO and lard were 515 (468, 569), 492 (448, 540), 398 (350, 452) and 395 (364, 429) ng/l, respectively. There was a trend for the postprandial increase in PYY to be lower in women on the IPO and lard meals than those on the HOS and PO meals. CONCLUSIONS: Dietary TAGs with an increased proportion of palmitic acid in the sn-2 position do not have acute adverse effects on the insulin and glucose response to meals in healthy men and women, but they decrease GIP release.
Assuntos
Glicemia/metabolismo , Polipeptídeo Inibidor Gástrico/metabolismo , Insulina/sangue , Ácido Palmítico/efeitos adversos , Adolescente , Adulto , Peptídeo C/sangue , Estudos Cross-Over , Gorduras na Dieta/administração & dosagem , Método Duplo-Cego , Feminino , Polipeptídeo Inibidor Gástrico/sangue , Voluntários Saudáveis , Humanos , Masculino , Refeições , Pessoa de Meia-Idade , Ácido Oleico/administração & dosagem , Ácido Palmítico/administração & dosagem , Ácido Palmítico/química , Peptídeo YY/sangue , Óleos de Plantas/administração & dosagem , Período Pós-Prandial/fisiologia , Óleo de Girassol , Triglicerídeos/administração & dosagem , Adulto JovemRESUMO
BACKGROUND/OBJECTIVES: Dietary triacylglycerols containing palmitic acid in the sn-2 position might impair insulin release and increase plasma glucose. SUBJECTS/METHODS: We used a cross-over designed feeding trial in 53 healthy Asian men and women (20-50 years) to test this hypothesis by exchanging 20% energy of palm olein (PO; control) with randomly interesterified PO (IPO) or high oleic acid sunflower oil (HOS). After a 2-week run-in period on PO, participants were fed PO, IPO and HOS for 6 week consecutively in randomly allocated sequences. Fasting (midpoint and endpoint) and postprandial blood at the endpoint following a test meal (3.54 MJ, 14 g protein, 85 g carbohydrate and 50 g fat as PO) were collected for the measurement of C-peptide, insulin, glucose, plasma glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, lipids and apolipoproteins; pre-specified primary and secondary outcomes were postprandial changes in C-peptide and plasma glucose. RESULTS: Low density lipoprotein cholesterol was 0.3 mmol/l (95% confidence interval (95% CI)) 0.1, 0.5; P<0.001) lower on HOS than on PO or IPO as predicted, indicating good compliance to the dietary intervention. There were no significant differences (P=0.58) between diets among the 10 male and 31 female completers in the incremental area under the curve (0-2 h) for C-peptide in nmol.120 min/l: GM (95% CI) were PO 220 (196, 245), IPO 212 (190, 235) and HOS 224 (204, 244). Plasma glucose was 8% lower at 2 h on IPO vs PO and HOS (both P<0.05). CONCLUSION: Palmitic acid in the sn-2 position does not adversely impair insulin secretion and glucose homeostasis.