Background Insulin resistance and hyperinsulinemia are featuresof obesity, non-insulin-dependent diabetes mellitus, and otherdisorders. Skeletal muscle is a major site of insulin action,and insulin sensitivity may be related to the fatty-acid compositionof the phospholipids within the muscle membranes involved inthe action of insulin.
Methods We determined the relation between the fatty-acid compositionof skeletal-muscle phospholipids and insulin sensitivity intwo groups of subjects. In one study, we obtained samples ofthe rectus abdominis muscle from 27 patients undergoing coronaryartery surgery; fasting serum insulin levels provided an indexof insulin sensitivity. In the second study, a biopsy of thevastus lateralis muscle was performed in 13 normal men, andinsulin sensitivity was assessed by euglycemic-clamp studies.
Results In the patients undergoing surgery, the fasting seruminsulin concentration (a measure of insulin resistance) wasnegatively correlated with the percentage of individual long-chainpolyunsaturated fatty acids in the phospholipid fraction ofmuscle, particularly arachidonic acid (r = -0.63, P<0.001);the total percentage of C20-22 polyunsaturated fatty acids (r= -0.68, P<0.001); the average degree of fatty-acid unsaturation(r = -0.61, P<0.001); and the ratio of the percentage ofC20:4 n-6 fatty acids to the percentage of C20:3 n-6 fatty acids(r = -0.55, P<0.01), an index of fatty-acid desaturase activity.In the normal men, insulin sensitivity was positively correlatedwith the percentage of arachidonic acid in muscle (r = 0.76,P<0.01), the total percentage of C20-22 polyunsaturated fattyacids (r = 0.76, P<0.01), the average degree of fatty-acidunsaturation (r = 0.62, P<0.05), and the ratio of C20:4 n-6to C20:3 n-6 (rho = 0.78, P = 0.007).
Conclusions Decreased insulin sensitivity is associated withdecreased concentrations of polyunsaturated fatty acids in skeletal-musclephospholipids, raising the possibility that changes in the fatty-acidcomposition of muscles modulate the action of insulin.
Hyperinsulinemia, which reflects the impaired sensitivity oftissue to the action of insulin (insulin resistance), is a riskfactor for several common disorders1,2. Insulin resistance isa characteristic finding in patients with non-insulin-dependentdiabetes mellitus, is common in persons at increased risk forthis type of diabetes,3 and also occurs in persons with normalglucose tolerance,4 frequently in association with obesity,2hypertension,5 hyperlipidemia,6 and coronary artery disease1,2.It has been postulated that insulin resistance, through compensatoryhyperinsulinemia, has a pathogenic role in the development ofthese disorders1,7.
Skeletal muscle is the principal site of insulin-mediated glucosedisposal8. The binding of insulin to its receptors on muscleplasma membranes initiates a cascade of events that culminatesin the transport of glucose into the cell, where it is eithermetabolized or stored as glycogen9. Variations in the rate ofinsulin-stimulated glycogen synthesis in muscle account formost of the variance in insulin sensitivity among normal subjects,10and impairment of this pathway is also the main contributorto the insulin resistance in patients with non-insulin-dependentdiabetes11. Although much is known about the pathways of glucosemetabolism, the molecular factors that mediate the action ofinsulin and cause the variation in the insulin responsivenessof these pathways remain to be elucidated.
The fatty-acid composition of membranes is one cellular factorthat may influence the action of insulin within skeletal muscle.The physicochemical properties of membranes are largely determinedby the nature of the fatty acids within the phospholipid bilayer,which in turn may influence diverse cellular functions, includinghormonal responsiveness12. Increasing the content of polyunsaturatedfatty acids within cell membranes in cultured cells increasesmembrane fluidity, the number of insulin receptors, and theaction of insulin13,14,15,16; converse effects occur when theconcentration of saturated fatty acids in the membranes is increased15,17.In rats made insulin resistant with a high-fat diet, the resistancecan be prevented by the inclusion of n-3 polyunsaturated fattyacids in the diet, but only under circumstances in which thehighly unsaturated long-chain (22-carbon) derivatives of thesefatty acids become incorporated in the phospholipid componentof muscle cells18. In humans, insulin sensitivity has been correlatedwith the ratio of n-6 polyunsaturated fatty acids to saturatedfatty acids in serum phospholipids19.
These studies led to the hypothesis that the fatty-acid compositionof skeletal-muscle phospholipids may influence the action ofinsulin and thus contribute to the variations in insulin sensitivityin humans. To test this hypothesis, we performed two studiesin which the fatty-acid composition of skeletal-muscle phospholipidswas examined in relation to estimates of insulin sensitivity.
Methods
We studied two groups of subjects, one composed of patientswith coronary artery disease (group 1) and one composed of normalsubjects (group 2). The study protocols were approved by theinstitutional ethics committee, and all subjects gave writteninformed consent.
Group 1
Group 1 was composed of 27 patients (20 men and 7 women) whowere undergoing elective coronary artery bypass surgery. Tobe eligible, patients had to be 65 years of age or younger,to be in reasonably good health apart from the presence of coronaryartery disease, and to have a fasting plasma glucose concentrationof less than 120 mg per deciliter (<6.7 mmol per liter).This plasma glucose concentration was chosen because fastingserum insulin concentrations provide an inverse index of insulinsensitivity in subjects with lower values, on the basis of theinverse correlations (r = -0.6 to -0.7) between the fastingserum insulin concentration and indexes of insulin sensitivityderived from glucose-clamp studies4,20.
In this group the mean (±SD) age was 58 ±8 years,with a body-mass index (the weight in kilograms divided by thesquare of the height in meters) of 26.7 ±2.4, fastingplasma glucose level of 99 ±9 mg per deciliter (5.5 ±0.5mmol per liter), serum insulin level of 11.8 ±4.9 microU per milliliter (84 ±35 pmol per liter), plasma triglyceridelevel of 202 ±92 mg per deciliter (2.3 ±1.0 mmolper liter), cholesterol level of 241 ±50 mg per deciliter(6.2 ±1.3 mmol per liter), and high-density lipoprotein(HDL) cholesterol level of 35 ±9 mg per deciliter (0.91±0.23 mmol per liter). These patients were being treatedwith a variety of cardiovascular medications, including oraland transdermal nitrates, thiazide diuretics, -adrenergic-antagonists,calcium-channel-blocking drugs, and angiotensin-converting-enzymeinhibitors, none of which were discontinued before the studybegan.
On the morning of the operation, a venous blood sample was collectedbetween 7:30 a.m. and 8:30 a.m. after an overnight fast. Plasmaand serum were stored at -20 °C for subsequent measurementof lipid and insulin concentrations. A biopsy of the rectusabdominis muscle (weighing 100 to 1000 mg), which was exposedat the lower end of the sternal incision, was performed intraoperativelybefore cardiopulmonary bypass was initiated. Any adherent fatand ligamentous tissue was removed immediately, after whichthe muscle sample was clamped with metal tongs precooled inliquid nitrogen and stored at -70 °C until analyzed.
Group 2
Group 2 was composed of 13 normal men. No man had any historyof hypertension, abnormal glucose tolerance, or coronary arterydisease, and none were taking medication regularly. The mean(±SD) age in this group was 30 ±11 years, witha body-mass index of 23.0 ±3.0, fasting plasma glucoselevel of 87 ±8 mg per deciliter (4.8 ±0.4 mmolper liter), serum insulin level of 5.8 ±2.8 micro U permilliliter (42 ±20 pmol per liter), plasma triglyceridelevel of 67 ±51 mg per deciliter (0.8 ±0.6 mmolper liter), cholesterol level of 152 ±36 mg per deciliter(3.9 ±0.9 mmol per liter), and HDL cholesterol levelof 37 ±9 mg per deciliter (0.96 ±0.22 mmol perliter).
Two basal blood samples were taken 20 minutes apart between8 a.m. and 9 a.m. after an overnight fast, for the measurementof plasma glucose and lipid and serum insulin concentrations.Insulin sensitivity was then determined with use of a euglycemic-hyperinsulinemicclamp21. A primed continuous infusion of insulin (Actrapid HM,Novo Industries, Copenhagen, Denmark) was administered for 120minutes at a rate of 40 mU per square meter of body-surfacearea per minute to achieve hyperinsulinemia (an insulin levelof approximately 100 micro U per milliliter [approximately 700pmol per liter]). Euglycemia was maintained by a variable-rateinfusion of glucose, which was adjusted on the basis of frequentblood glucose measurements. The quantity of glucose infusedduring the final 60 minutes, corrected for body-surface area,provided an index of the insulin sensitivity of the whole body(expressed in terms of the number of milligrams of glucose infusedper square meter per minute). In six subjects glucose-clampstudies were performed on more than one occasion; the reportedinsulin sensitivity represents the mean value. On completionof the glucose-clamp study, a percutaneous biopsy of skeletalmuscle (vastus lateralis) was performed with the patient underlocal anesthesia. The tissue was processed as in the study involvinggroup 1.
Analytical Methods
Plasma glucose concentrations were measured by the glucose oxidasemethod (Yellow Springs Instruments, Yellow Springs, Ohio). Seruminsulin concentrations were determined by a double-antibodyradioimmunoassay22. Plasma cholesterol23 and triglyceride24concentrations were estimated with automated enzymatic methods.Plasma HDL cholesterol was measured after other classes of lipoproteinshad been precipitated with phosphotungstic acid and magnesiumchloride25.
For the extraction and derivatization of the fatty-acid componentsof muscle phospholipids, all solvents contained 0.01 percentbutylated hydroxytoluene as an antioxidant. Muscle tissue washomogenized in a mixture of chloroform and methanol (2:1 vol/vol),and the total lipid extracts were prepared according to themethod of Folch et al.26. Phospholipids were separated fromless polar lipids by solid-phase extraction on Sep-Pak silicacartridges (Waters, Milford, Mass.). Approximately 95 percentof the [14C]phosphatidylcholine added to the total lipid extractin chloroform-methanol was recovered with the use of this procedure.Phospholipids were transmethylated with 14 percent boron trifluorideat 85 °C for 60 minutes. The methyl fatty acids were thenseparated and quantitated on a gas chromatograph 5890 seriesII (Hewlett-Packard, Waltham, Mass.) fitted with a capillarycolumn (DB-23, J & W Scientific, Folsom, Calif.). The fattyacids were identified by comparing their retention times withthose of authentic standard mixtures.
Data Analysis
For both studies the content of individual fatty acids in skeletal-musclephospholipids was expressed as a percentage of the total fattyacids identified (minor fatty-acid peaks [<0.4 percent oftotal] were excluded from the calculations). The principal polyunsaturatedfatty acids and their metabolic interconversions are shown inFigure 1. Several fatty-acid indexes were derived from the primarydata: the total percentage of C20-22 polyunsaturated fatty acids,which was calculated as the sum of the percentages of the individualhighly polyunsaturated long-chain fatty acids C20:4 n-6, C20:5n-3, C22:4 n-6, C22:5 n-6, C22:5 n-3, and C22:6 n-3; the averagedegree of fatty-acid unsaturation (the unsaturation index),which was calculated as the average number of double bonds perfatty-acid residue multiplied by 100; the ratio of the percentageof C20:4 n-6 (C20:4) fatty acids to the percentage of C20:3n-6 (C20:3) fatty acids; and the ratio of the percentage ofC20:3 n-6 (C20:3) fatty acids to the percentage of C18:2 n-6(C18:2) fatty acids. The ratios of C20:4 to C20:3 and C20:3to C18:2 are product-precursor ratios for the reactions controlledby 5-desaturase and 6-desaturase, respectively (Figure 1).
Figure 1. The Principal Polyunsaturated Fatty Acids of the n-6 and n-3 Series and Their Metabolic Interconversions.
The chemical formula for each fatty acid is shown; for example, C18:2 n-6 indicates a chain length of 18 carbon atoms with two double bonds, the first of which is in the 6th position from the methyl end of the chain. Humans are unable to synthesize n-6 and n-3 polyunsaturated fatty acids and consequently depend on dietary sources. The parent C18 fatty acids are largely derived from seed oils. After ingestion, each can be converted to long-chain derivatives by the sequential action of tissue desaturase and elongase as indicated. The synthesis of long-chain n-3 polyunsaturated fatty acids from C18:3 n-3 is slow in humans; however, the ingestion of marine foods provides a ready source, principally of C20:5 and C22:6 n-3.
Statistical Analysis
Statistical analyses were performed with the Statview 512+ statisticalpackage (Abacus Concepts/Brainpower, Calabassas, Calif.). Allresults are expressed as the mean ±SD. The relationsbetween variables were analyzed by simple correlation and multipleregression (partial correlation). Because the data from a singlesubject resulted in a skewed distribution of the ratio of C20:4to C20:3 in group 2, the relation with insulin sensitivity wasalso analyzed nonparametrically (with the Spearman rank-correlationcoefficient).
Results
Group 1
The fatty-acid profile of muscle phospholipids and correlationswith the fasting serum insulin concentration in the 27 patientswith coronary artery disease are shown in Table 1. Accordingto univariate analysis, the serum insulin concentration wasinversely correlated with the percentages of the individuallong-chain polyunsaturated fatty acids C20:4 n-6 (arachidonicacid), C22:4 n-6, C22:5 n-6, and C22:5 n-3; the percentage ofC20-22 polyunsaturated fatty acids (Figure 2A); the unsaturationindex; and the ratio of C20:4 to C20:3 (Figure 2B). The fastingserum insulin concentration was also positively correlated withthe percentage of C18:2 n-6 (linoleic acid).
Table 1. The Profile of Fatty Acids in the Phospholipid Fraction of Skeletal Muscle and Correlations with Fasting Serum Insulin Concentrations in 27 Patients with Coronary Artery Disease.
Figure 2. Fasting Serum Insulin Concentrations in Relation to the Percentage of C20-22 Polyunsaturated Fatty Acids (Panel A) and the Ratio of C20:4 to C20:3 (Panel B) in Skeletal-Muscle Phospholipids in Patients with Coronary Artery Disease.
To convert values for serum insulin to picomoles per liter, multiply by 7.18.
Age, sex, and treatment with thiazide diuretics or -adrenergicantagonists (agents reported to impair insulin sensitivity27)were not correlated with the fasting serum insulin concentration(data not shown). However, body-mass index was significantlycorrelated with the fasting serum insulin concentration (r =0.55, P = 0.003), and weak negative correlations (-0.38 r -0.47, P<0.05) were found between body-mass index and thepercentages of C20:4 n-6, C22:5 n-3, and C20-22 polyunsaturatedfatty acids and the unsaturation index.
Because of interactions between the serum insulin concentration,the body-mass index, and fatty-acid composition, multiple regressionanalysis was used to determine the independent predictors ofthe fasting serum insulin concentration. Although the fastingserum insulin concentration was not significantly related toage, sex, or the use of medication, these variables were alsoentered in the regression model because of their reported influenceon insulin sensitivity27,28,29. Table 1 shows the partial correlationcoefficients relating the percentages of fatty acids presentto the fasting serum insulin concentration. Significant (P<0.05)inverse relations were found between the adjusted serum insulinconcentrations and the percentages of C20:4 n-6, C22:4 n-6,C22:5 n-6, C22:5 n-3, and C20-22 polyunsaturated fatty acids;the unsaturation index; and the ratio of C20:4 to C20:3. Therelations between the percentages of fatty acids and body-massindex disappeared after the latter was adjusted for the effectsof serum insulin. A stepwise regression model incorporatingage, sex, body-mass index, the use of medication, and the musclecontent of C20:4 n-6, C22:4 n-6, and C22:5 n-3 accounted for81 percent of the variation in the fasting serum insulin concentration(with body-mass index and the fatty acids contributing 30 percentand 50 percent, respectively).
Group 2
The index of insulin sensitivity derived from glucose-clampstudies varied widely among the 13 normal men (mean, 279 mgof glucose per square meter per minute; range, 117 to 519 [1.55mmol of glucose per square meter per minute; range, 0.65 to2.89]) and had a strong inverse correlation with the fastingserum insulin concentration (r = -0.69, P = 0.01). Body-massindex was not significantly correlated with either the fastingserum insulin concentration (r = 0.52, P = 0.07) or insulinsensitivity (r = -0.20, P = 0.5).
The fatty-acid composition of muscle phospholipids and simplecorrelations with the fasting serum insulin concentration andinsulin sensitivity are shown in Table 2. Despite the fact thata different muscle was analyzed, the fatty-acid compositionof the muscle from these men was very similar to that of thepatients in group 1. As in group 1, the fasting serum insulinconcentration was inversely correlated with the percentagesof C20:4 n-6 and C20-22 polyunsaturated fatty acids and withthe ratio of C20:4 to C20:3.
Table 2. The Profile of Fatty Acids in the Phospholipid Fraction of Skeletal Muscle and Simple Correlations with Fasting Serum Insulin Concentrations and Insulin Sensitivity in 13 Normal Men.
Insulin sensitivity was correlated positively with the percentagesof C20:4 n-6 and C20-22 polyunsaturated fatty acids (Figure 3A)and with the unsaturation index (Table 2). The relationof insulin sensitivity to the ratio of C20:4 to C20:3 is shownin Figure 3B. In this figure there is a single outlying result,the inclusion of which renders the relation nonsignificant bysimple correlation (r = 0.48, P = 0.10), but significant bynonparametric analysis (rho = 0.78, P = 0.007). With the exclusionof this subject's data from the analysis, there was a strongpositive correlation between the ratio of C20:4 to C20:3 andinsulin sensitivity (r = 0.84, P<0.001). This subject, whohad the highest ratio of C20:4 to C20:3, also had the lowestfasting serum insulin concentration (consistently below theassay detection limit of 2.1 micro U per milliliter).
Figure 3. Index of Insulin Sensitivity in Relation to the Percentage of C20-22 Polyunsaturated Fatty Acids (Panel A) and the Ratio of C20:4 to C20:3 (Panel B) in Skeletal-Muscle Phospholipids in Normal Men.
The index of insulin sensitivity was derived from glucose-clamp studies and is expressed in terms of the number of milligrams of glucose infused per square meter per minute. The dashed regression line and reported correlation coefficient in Panel B are for the values for 12 men; the outlying result in 1 man was excluded (see the Results section for details). To convert values for the insulin-sensitivity index to millimoles per square meter per minute, multiply by 0.0056.
Significant relations were found between other fatty-acid valuesand the estimates of insulin sensitivity in these normal men(Table 2), but not in the patients with coronary artery disease.
Discussion
In these two independent cross-sectional studies we found strongrelations between the phospholipid fatty-acid composition ofskeletal muscle, which is the main insulin-sensitive tissue,and estimates of insulin sensitivity. In the study of patientswith coronary artery disease, the level of long-chain polyunsaturatedfatty acids (arachidonic acid in particular) was inversely correlatedwith the fasting serum insulin concentration independently ofthe effects of age, sex, adiposity, and therapy. The key findingswere replicated in the normal men, in whom the level of long-chainpolyunsaturated fatty acids was positively correlated with theindex of insulin sensitivity derived from glucose-clamp studies.
These results are consistent with the notion that the fatty-acidcomposition of skeletal-muscle phospholipids influences insulinsensitivity, as is the demonstration in isolated cells thatdirect alterations in the fatty-acid composition of membranesinduce changes in insulin responsiveness14,17. Alternatively,insulin resistance could cause changes in the composition offatty acids. Studies of insulin deficiency indicate that insulinhas a permissive effect on fatty-acid desaturase activity30,31,32.Thus, reduced levels of unsaturated fatty acids in the membranemay be due to a net reduction in the action of insulin, as aconsequence of either insulin resistance or insulin deficiency.Another consideration is that insulin resistance may be dueto hyperinsulinemia, as has been observed in experimental hyperinsulinemia33and in patients with insulinomas34. Finally, insulin sensitivitymay not be directly related to the fatty-acid composition ofmuscles at all; the composition may simply be a marker for theeffect of some unidentified third factor that modulates insulinsensitivity.
Assuming that long-chain polyunsaturated fatty acids withinmuscle-membrane phospholipids influence the action of insulin,how might they do so? They may modulate the function of membraneproteins mediating the action of insulin, such as insulin receptorsand glucose transporters, through effects on the physical propertiesof the surrounding lipid environment35. In this regard, thereis evidence from studies of patients with adrenoleukodystrophythat the accumulation of long-chain saturated fatty acids withinadrenocortical cells may, through increased microviscosity ofthe membrane, result in reduced responsiveness to corticotropinstimulation and hence adrenocortical insufficiency36. Alternatively,polyunsaturated fatty acids might influence the action of insulinby acting as precursors for the generation of second messengers,37such as eicosanoids or diacylglycerols38. Eicosanoids, whichinclude the prostaglandins, thromboxanes, and leukotrienes,are derived from C20 polyunsaturated fatty acids39. The diversebiologic actions of these chemical mediators are partly dependenton the nature of the fatty acids within the precursor phospholipidpool. Thus, the strong positive correlation between arachidonicacid (C20:4 n-6) and the indexes of insulin sensitivity in bothstudies may represent an effect on insulin action of eicosanoidsspecifically derived from this parent fatty acid.
All n-6 and n-3 polyunsaturated fatty acids within membranesare derived from dietary sources. Subsequent metabolic conversionby microsomal elongase and desaturases (Figure 1) modifies therelative availability of individual polyunsaturated fatty acidsfor membrane incorporation. The ratio of C20:4 to C20:3, theproduct-precursor ratio for the reaction catalyzed by 5-desaturase,was directly related to estimates of insulin sensitivity inthis study, raising the possibility that reduced 5-desaturaseactivity contributes to impaired insulin action by reducingthe amounts of long-chain polyunsaturated fatty acids in themembranes. Studies in animals indicate that the fatty-acid compositionof muscles may be influenced by the fatty-acid composition ofthe diet,18 but this issue has not been studied in humans.
The fatty-acid composition of total cell phospholipids was determinedin this study. Since phospholipids are confined to membranes,the results are indicative of the fatty-acid profile of totalcell membranes. However, only a portion of these may be involvedin insulin-mediated glucose disposal. These include the plasmamembrane, where the action of insulin is initiated, and microsomes,which exchange glucose transporters with the plasma membrane40.Nevertheless, there is continuous and rapid transfer of phospholipidsbetween membranes,41 and there is evidence (at least in cardiacmuscle) that the relative ranking of the major polyunsaturatedfatty acids is preserved among the various cell membranes andreflected in the analysis of total cell phospholipids42. Therefore,if the action of insulin is dependent on the fatty-acid compositionof muscle membranes, it may be due to interactions within themembranes specifically involved in the action of insulin, althoughwe cannot exclude a more general effect of membranes.
In summary, our results, in conjunction with those of studiesin cell systems and animals, suggest that variations in insulinsensitivity are related to differences in the membrane contentof long-chain polyunsaturated fatty acids within skeletal-musclephospholipids. It is therefore possible that abnormalities inthe fatty-acid composition of membranes may be involved in thepathogenesis of a cluster of disorders linked to insulin resistanceand hyperinsulinemia, including obesity, hypertension, non-insulin-dependentdiabetes, and coronary artery disease.
Supported by the National Health and Medical Research Councilof Australia, the Oilseeds Research Council of Australia, andthe research and development program established by Beecham(Australia) Pty. Ltd. under the Pharmaceutical Industry DevelopmentProgramme.
We are indebted to the cardiothoracic surgeons of St. Vincent'sHospital for their help with tissue sampling and to Ms. JudithSowden for technical assistance.
Source Information
From the Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, New South Wales, Australia.
Address reprint requests to Dr. Storlien at the Department of Medicine (Endocrinology), University of Sydney, NSW 2006, Australia.
References
Reaven GM. Banting lecture 1988: role of insulin resistance in human disease. Diabetes 1988;37:1595-1607. [Abstract]
DeFronzo RA, Ferrannini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991;14:173-194. [Abstract]
Eriksson J, Franssila-Kallunki A, Ekstrand A, et al. Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus. N Engl J Med 1986;321:337-343. [Abstract]
Hollenbeck C, Reaven GM. Variations in insulin-stimulated glucose uptake in healthy individuals with normal glucose tolerance. J Clin Endocrinol Metab 1987;64:1169-1173. [Free Full Text]
Ferrannini E, Buzzigoli G, Bonadonna R, et al. Insulin resistance in essential hypertension. N Engl J Med 1987;317:350-357. [Abstract]
Zavaroni I, Dall'Aglio E, Alpi O, et al. Evidence for an independent relationship between plasma insulin and concentration of high density lipoprotein cholesterol and triglyceride. Atherosclerosis 1985;55:259-266. [CrossRef][Medline]
Zavaroni I, Bonora E, Pagliara M, et al. Risk factors for coronary artery disease in healthy persons with hyperinsulinemia and normal glucose tolerance. N Engl J Med 1989;320:702-706. [Abstract]
DeFronzo RA, Jacot E, Jequier E, Maeder E, Wahren J, Felber JP. The effect of insulin on the disposal of intravenous glucose: results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes 1981;30:1000-1007. [Medline]
Moller DE, Flier JS. Insulin resistance -- mechanisms, syndromes, and implications. N Engl J Med 1991;325:938-948. [Medline]
Lillioja S, Mott DM, Zawadzki JK, Young AA, Abbott WG, Bogardus C. Glucose storage is a major determinant of in vivo "insulin resistance" in subjects with normal glucose tolerance. J Clin Endocrinol Metab 1986;62:922-927. [Free Full Text]
Shulman GI, Rothman DL, Jue T, Stein P, DeFronzo RA, Shulman RG. Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. N Engl J Med 1990;322:223-228. [Abstract]
Hagve T-A. Effects of unsaturated fatty acids on cell membrane functions. Scand J Clin Lab Invest 1988;48:381-388. [Medline]
Yorek M, Leeney E, Dunlap J, Ginsberg B. Effect of fatty acid composition on insulin and IGF-I binding in retinoblastoma cells. Invest Ophthalmol Vis Sci 1989;30:2087-2092. [Free Full Text]
Ginsberg BH, Chaterjee P, Yorek M. Increased membrane fluidity is associated with greater sensitivity to insulin. Diabetes 1987;36:Suppl 1:51A-51A.abstract
Ginsberg BH, Jabour J, Spector AA. Effect of alterations in membrane lipid unsaturation on the properties of the insulin receptor of Ehrlich ascites cells. Biochim Biophys Acta 1982;690:157-164. [Medline]
Field CJ, Ryan EA, Thomson ABR, Clandinin MT. Dietary fat and the diabetic state alter insulin binding and the fatty acyl composition of the adipocyte plasma membrane. Biochem J 1988;253:417-424. [Medline]
Grunfeld C, Baird KL, Kahn CR. Maintenance of 3T3-L1 cells in culture media containing saturated fatty acids decreases insulin binding and insulin action. Biochem Biophys Res Commun 1981;103:219-226. [CrossRef][Medline]
Storlien LH, Jenkins AB, Chisholm DJ, Pascoe WS, Khouri S, Kraegen EW. Influence of dietary fat composition on development of insulin resistance in rats: relationship to muscle triglyceride and omega-3 fatty acids in muscle phospholipid. Diabetes 1991;40:280-289. [Abstract]
Pelikanova T, Kohout M, Valek J, Base J, Kazdova L. Insulin secretion and insulin action related to the serum phospholipid fatty acid pattern in healthy men. Metabolism 1989;38:188-192. [CrossRef][Medline]
Saad MF, Lillioja S, Nyomba BL, et al. Racial differences in the relation between blood pressure and insulin resistance. N Engl J Med 1991;324:733-739. [Abstract]
DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979;237:E214-E223. [Free Full Text]
Morgan CR, Lazarow A. Immunoassay of insulin: two antibody system: plasma insulin levels of normal, subdiabetic and diabetic rats. Diabetes 1963;12:115-126.
Allain CC, Poon LS, Chan CSG, Richmond W, Fu PC. Enzymatic determination of total serum cholesterol. Clin Chem 1974;20:470-475. [Abstract]
Bucolo G, David H. Quantitative determination of serum triglycerides by the use of enzymes. Clin Chem 1973;19:476-482. [Abstract]
Burstein M, Scholnick HR, Morfin R. Rapid method for the isolation of lipoproteins from human serum by precipitation with polyanions. J Lipid Res 1970;11:583-595. [Abstract]
Folch J, Lees M, Sloane Stanley GH. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 1957;226:497-509. [Free Full Text]
Lithell HOL. Effect of antihypertensive drugs on insulin, glucose, and lipid metabolism. Diabetes Care 1991;14:203-209. [Abstract]
Rowe JW, Minaker KL, Pallotta JA, Flier JS. Characterization of the insulin resistance of aging. J Clin Invest 1983;71:1581-1587.
Yki-Jarvinen H. Sex and insulin sensitivity. Metabolism 1984;33:1011-1015. [CrossRef][Medline]
Faas FH, Carter WJ. Altered fatty acid desaturation and microsomal fatty acid composition in the streptozotocin diabetic rat. Lipids 1980;15:953-961. [CrossRef]
El Boustani S, Causse JE, Descomps B, Monnier L, Mendy F, Crastes de Paulet A. Direct in vivo characterization of 5 desaturase activity in humans by deuterium labeling: effect of insulin. Metabolism 1989;38:315-321. [CrossRef][Medline]
Tilvis RS, Miettinen TA. Fatty acid compositions of serum lipids, erythrocytes, and platelets in insulin-dependent diabetic women. J Clin Endocrinol Metab 1985;61:741-745. [Free Full Text]
Rizza RA, Mandarino LJ, Genest J, Baker BA, Gerich JE. Production of insulin resistance by hyperinsulinaemia in man. Diabetologia 1985;28:70-75. [Medline]
Nankervis A, Proietto J, Aitken P, Alford F. Hyperinsulinaemia and insulin insensitivity: studies in subjects with insulinoma. Diabetologia 1985;28:427-431. [CrossRef][Medline]
Stubbs CD, Smith AD. The modification of mammalian membrane polyunsaturated fatty acid composition in relation to membrane fluidity and function. Biochim Biophys Acta 1984;779:89-137. [Medline]
Whitcomb RW, Linehan WM, Knazek RA. Effects of long-chain, saturated fatty acids on membrane microviscosity and adrenocorticotropin responsiveness of human adrenocortical cells in vitro. J Clin Invest 1988;81:185-188.
Saltiel AR. Second messengers of insulin action. Diabetes Care 1990;13:244-256. [Abstract]
Stralfors P. Insulin stimulation of glucose uptake can be mediated by diacylglycerol in adipocytes. Nature 1988;335:554-556. [CrossRef][Medline]
Willis AL. Essential fatty acids, prostaglandins and related eicosanoids. In: Nutrition Reviews' present knowledge in nutrition. 5th ed. Washington, D.C.: Nutrition Foundation, 1984:90-115.
Klip A, Paquet MR. Glucose transport and glucose transporters in muscle and their metabolic regulation. Diabetes Care 1990;13:228-243. [Abstract]
Voelker DR. Organelle biogenesis and intracellular lipid transport in eukaryotes. Microbiol Rev 1991;55:543-560. [Free Full Text]
Wahle KW, Milne L, McIntosh G. Regulation of polyunsaturated fatty acid metabolism in tissue phospholipids of obese (fa/fa) and lean (Fa/-) Zucker rats. 1. Effect of dietary lipids on cardiac tissue. Lipids 1991;26:16-22. [Medline]
Woods, M. N, Wanke, C. A, Ling, P.-R., Hendricks, K. M, Tang, A. M, Knox, T. A, Andersson, C. E, Dong, K. R, Skinner, S. C, Bistrian, B. R
(2009). Effect of a dietary intervention and n-3 fatty acid supplementation on measures of serum lipid and insulin sensitivity in persons with HIV. Am. J. Clin. Nutr.
90: 1566-1578
[Abstract][Full Text]
van Woudenbergh, G. J., van Ballegooijen, A. J., Kuijsten, A., Sijbrands, E. J.G., van Rooij, F. J.A., Geleijnse, J. M., Hofman, A., Witteman, J. C.M., Feskens, E. J.M.
(2009). Eating Fish and Risk of Type 2 Diabetes: A population-based, prospective follow-up study. Diabetes Care
32: 2021-2026
[Abstract][Full Text]
Price, E. R., Guglielmo, C. G.
(2009). The effect of muscle phospholipid fatty acid composition on exercise performance: a direct test in the migratory white-throated sparrow (Zonotrichia albicollis). Am. J. Physiol. Regul. Integr. Comp. Physiol.
297: R775-R782
[Abstract][Full Text]
Palmquist, D. L.
(2009). Omega-3 Fatty Acids in Metabolism, Health, and Nutrition and for Modified Animal Product Foods. Professional Animal Scientist
25: 207-249
[Abstract]
Robbez Masson, V., Lucas, A., Gueugneau, A.-M., Macaire, J.-P., Paul, J.-L., Grynberg, A., Rousseau, D.
(2008). Long-Chain (n-3) Polyunsaturated Fatty Acids Prevent Metabolic and Vascular Disorders in Fructose-Fed Rats. J. Nutr.
138: 1915-1922
[Abstract][Full Text]
Tardy, A.-L., Giraudet, C., Rousset, P., Rigaudiere, J.-P., Laillet, B., Chalancon, S., Salles, J., Loreau, O., Chardigny, J.-M., Morio, B.
(2008). Effects of trans MUFA from dairy and industrial sources on muscle mitochondrial function and insulin sensitivity. J. Lipid Res.
49: 1445-1455
[Abstract][Full Text]
de Wilde, J., Mohren, R., van den Berg, S., Boekschoten, M., Dijk, K. W.-V., de Groot, P., Muller, M., Mariman, E., Smit, E.
(2008). Short-term high fat-feeding results in morphological and metabolic adaptations in the skeletal muscle of C57BL/6J mice. Physiol. Genomics
32: 360-369
[Abstract][Full Text]
Bergeron, K., Julien, P., Davis, T. A., Myre, A., Thivierge, M. C.
(2007). Long-chain n-3 fatty acids enhance neonatal insulin-regulated protein metabolism in piglets by differentially altering muscle lipid composition. J. Lipid Res.
48: 2396-2410
[Abstract][Full Text]
Schirmer, M. A., Phinney, S. D.
(2007). {gamma}-Linolenate Reduces Weight Regain in Formerly Obese Humans. J. Nutr.
137: 1430-1435
[Abstract][Full Text]
Corcoran, M. P, Lamon-Fava, S., Fielding, R. A
(2007). Skeletal muscle lipid deposition and insulin resistance: effect of dietary fatty acids and exercise. Am. J. Clin. Nutr.
85: 662-677
[Abstract][Full Text]
Gingras, A.-A., White, P. J., Chouinard, P. Y., Julien, P., Davis, T. A., Dombrowski, L., Couture, Y., Dubreuil, P., Myre, A., Bergeron, K., Marette, A., Thivierge, M. C.
(2007). Long-chain omega-3 fatty acids regulate bovine whole-body protein metabolism by promoting muscle insulin signalling to the Akt-mTOR-S6K1 pathway and insulin sensitivity. J. Physiol.
579: 269-284
[Abstract][Full Text]
Lindgarde, F., Vessby, B., Ahren, B.
(2006). Serum cholesteryl fatty acid composition and plasma glucose concentrations in Amerindian women.. Am. J. Clin. Nutr.
84: 1009-1013
[Abstract][Full Text]
Warensjo, E., Sundstrom, J., Lind, L., Vessby, B.
(2006). Factor analysis of fatty acids in serum lipids as a measure of dietary fat quality in relation to the metabolic syndrome in men.. Am. J. Clin. Nutr.
84: 442-448
[Abstract][Full Text]
Mainieri, D., Summermatter, S., Seydoux, J., Montani, J.-P., Rusconi, S., Russell, A. P., Boss, O., Buchala, A. J., Dulloo, A. G.
(2006). A role for skeletal muscle stearoyl-CoA desaturase 1 in control of thermogenesis. FASEB J.
20: 1751-1753
[Abstract][Full Text]
Aas, V., Rokling-Andersen, M. H., Kase, E. T., Thoresen, G. H., Rustan, A. C.
(2006). Eicosapentaenoic acid (20:5 n-3) increases fatty acid and glucose uptake in cultured human skeletal muscle cells. J. Lipid Res.
47: 366-374
[Abstract][Full Text]
Phinney, S. D
(2005). Fatty acids, inflammation, and the metabolic syndrome. Am. J. Clin. Nutr.
82: 1151-1152
[Full Text]
Min, Y., Lowy, C., Ghebremeskel, K., Thomas, B., Offley-Shore, B., Crawford, M.
(2005). Unfavorable effect of type 1 and type 2 diabetes on maternal and fetal essential fatty acid status: a potential marker of fetal insulin resistance. Am. J. Clin. Nutr.
82: 1162-1168
[Abstract][Full Text]
Okada, T., Furuhashi, N., Kuromori, Y., Miyashita, M., Iwata, F., Harada, K.
(2005). Plasma palmitoleic acid content and obesity in children. Am. J. Clin. Nutr.
82: 747-750
[Abstract][Full Text]
Hjelte, L. E., Nilsson, A.
(2005). Arachidonic Acid and Ischemic Heart Disease. J. Nutr.
135: 2271-2273
[Full Text]
Riserus, U., Tan, G. D., Fielding, B. A., Neville, M. J., Currie, J., Savage, D. B., Chatterjee, V. K., Frayn, K. N., O'Rahilly, S., Karpe, F.
(2005). Rosiglitazone Increases Indexes of Stearoyl-CoA Desaturase Activity in Humans: Link to Insulin Sensitization and the Role of Dominant-Negative Mutation in Peroxisome Proliferator-Activated Receptor-{gamma}. Diabetes
54: 1379-1384
[Abstract][Full Text]
Faerch, K., Lau, C., Tetens, I., Pedersen, O. B., Jorgensen, T., Borch-Johnsen, K., Glumer, C.
(2005). A Statistical Approach Based on Substitution of Macronutrients Provides Additional Information to Models Analyzing Single Dietary Factors in Relation to Type 2 Diabetes in Danish Adults: the Inter99 Study. J. Nutr.
135: 1177-1182
[Abstract][Full Text]
Mitchell, T. W., Turner, N., Hulbert, A. J., Else, P. L., Hawley, J. A., Lee, J. S., Bruce, C. R., Blanksby, S. J.
(2004). Exercise alters the profile of phospholipid molecular species in rat skeletal muscle. J. Appl. Physiol.
97: 1823-1829
[Abstract][Full Text]
Baylin, A., Campos, H.
(2004). Arachidonic Acid in Adipose Tissue Is Associated with Nonfatal Acute Myocardial Infarction in the Central Valley of Costa Rica. J. Nutr.
134: 3095-3099
[Abstract][Full Text]
O'Connor, C. I., Lawrence, L. M., St. Lawrence, A. C., Janicki, K. M., Warren, L. K., Hayes, S.
(2004). The effect of dietary fish oil supplementation on exercising horses. J ANIM SCI
82: 2978-2984
[Abstract][Full Text]
Lara-Castro, C., Garvey, W. T.
(2004). Diet, Insulin Resistance, and Obesity: Zoning in on Data for Atkins Dieters Living in South Beach. J. Clin. Endocrinol. Metab.
89: 4197-4205
[Abstract][Full Text]
Benatti, P., Peluso, G., Nicolai, R., Calvani, M.
(2004). Polyunsaturated Fatty Acids: Biochemical, Nutritional and Epigenetic Properties. J. Am. Coll. Nutr.
23: 281-302
[Abstract][Full Text]
Clore, J. N., Stillman, J. S., Li, J., O'Keefe, S. J. D., Levy, J. R.
(2004). Differential effect of saturated and polyunsaturated fatty acids on hepatic glucose metabolism in humans. Am. J. Physiol. Endocrinol. Metab.
287: E358-E365
[Abstract][Full Text]
Fukuchi, S., Hamaguchi, K., Seike, M., Himeno, K., Sakata, T., Yoshimatsu, H.
(2004). Role of Fatty Acid Composition in the Development of Metabolic Disorders in Sucrose-Induced Obese Rats. Exp. Biol. Med.
229: 486-493
[Abstract][Full Text]
Straczkowski, M., Kowalska, I., Nikolajuk, A., Dzienis-Straczkowska, S., Kinalska, I., Baranowski, M., Zendzian-Piotrowska, M., Brzezinska, Z., Gorski, J.
(2004). Relationship Between Insulin Sensitivity and Sphingomyelin Signaling Pathway in Human Skeletal Muscle. Diabetes
53: 1215-1221
[Abstract][Full Text]
Terpstra, A. H.
(2004). Effect of conjugated linoleic acid on body composition and plasma lipids in humans: an overview of the literature. Am. J. Clin. Nutr.
79: 352-361
[Abstract][Full Text]
Turner, N., Lee, J. S., Bruce, C. R., Mitchell, T. W., Else, P. L., Hulbert, A. J., Hawley, J. A.
(2004). Greater effect of diet than exercise training on the fatty acid profile of rat skeletal muscle. J. Appl. Physiol.
96: 974-980
[Abstract][Full Text]
Gaster, M., Rustan, A. C., Aas, V., Beck-Nielsen, H.
(2004). Reduced Lipid Oxidation in Skeletal Muscle From Type 2 Diabetic Subjects May Be of Genetic Origin: Evidence From Cultured Myotubes. Diabetes
53: 542-548
[Abstract][Full Text]
Tiikkainen, M., Bergholm, R., Rissanen, A., Aro, A., Salminen, I., Tamminen, M., Teramo, K., Yki-Jarvinen, H.
(2004). Effects of equal weight loss with orlistat and placebo on body fat and serum fatty acid composition and insulin resistance in obese women. Am. J. Clin. Nutr.
79: 22-30
[Abstract][Full Text]
Jen, K-L. C., Buison, A., Pellizzon, M., Ordiz, F. Jr., Santa Ana, L., Brown, J.
(2003). Differential Effects of Fatty Acids and Exercise on Body Weight Regulation and Metabolism in Female Wistar Rats. Exp. Biol. Med.
228: 843-849
[Abstract][Full Text]
Mougios, V., Ring, S., Petridou, A., Nikolaidis, M. G.
(2003). Duration of coffee- and exercise-induced changes in the fatty acid profile of human serum. J. Appl. Physiol.
94: 476-484
[Abstract][Full Text]
Bavenholm, P. N., Kuhl, J., Pigon, J., Saha, A. K., Ruderman, N. B., Efendic, S.
(2003). Insulin Resistance in Type 2 Diabetes: Association with Truncal Obesity, Impaired Fitness, and Atypical Malonyl Coenzyme A Regulation. J. Clin. Endocrinol. Metab.
88: 82-87
[Abstract][Full Text]
Andersson, A., Nalsen, C., Tengblad, S., Vessby, B.
(2002). Fatty acid composition of skeletal muscle reflects dietary fat composition in humans. Am. J. Clin. Nutr.
76: 1222-1229
[Abstract][Full Text]
Das, U. N.
(2002). Is Metabolic Syndrome X an Inflammatory Condition?. Exp. Biol. Med.
227: 989-997
[Abstract][Full Text]
Jiang, R., Manson, J. E., Stampfer, M. J., Liu, S., Willett, W. C., Hu, F. B.
(2002). Nut and Peanut Butter Consumption and Risk of Type 2 Diabetes in Women. JAMA
288: 2554-2560
[Abstract][Full Text]
Louheranta, A. M, Sarkkinen, E. S, Vidgren, H. M, Schwab, U. S, Uusitupa, M. I.
(2002). Association of the fatty acid profile of serum lipids with glucose and insulin metabolism during 2 fat-modified diets in subjects with impaired glucose tolerance. Am. J. Clin. Nutr.
76: 331-337
[Abstract][Full Text]
Das, U. N
(2002). Long-chain polyunsaturated fatty acids and diabetes mellitus. Am. J. Clin. Nutr.
75: 780-781
[Full Text]
Wahl, H. G., Kausch, C., Machicao, F., Rett, K., Stumvoll, M., Haring, H.-U.
(2002). Troglitazone Downregulates {Delta}-6 Desaturase Gene Expression in Human Skeletal Muscle Cell Cultures. Diabetes
51: 1060-1065
[Abstract][Full Text]
Wu, B. J., Else, P. L., Storlien, L. H., Hulbert, A. J.
(2002). Molecular activity of Na+/K+-ATPase from different sources is related to the packing of membrane lipids. J. Exp. Biol.
204: 4271-4280
[Abstract][Full Text]
Jula, A., Marniemi, J., Huupponen, R., Virtanen, A., Rastas, M., Ronnemaa, T.
(2002). Effects of Diet and Simvastatin on Serum Lipids, Insulin, and Antioxidants in Hypercholesterolemic Men: A Randomized Controlled Trial. JAMA
287: 598-605
[Abstract][Full Text]
Greco, A. V., Mingrone, G., Giancaterini, A., Manco, M., Morroni, M., Cinti, S., Granzotto, M., Vettor, R., Camastra, S., Ferrannini, E.
(2002). Insulin Resistance in Morbid Obesity: Reversal With Intramyocellular Fat Depletion. Diabetes
51: 144-151
[Abstract][Full Text]
Harding, A.-H., Sargeant, L. A., Welch, A., Oakes, S., Luben, R. N., Bingham, S., Day, N. E., Khaw, K.-T., Wareham, N. J.
(2001). Fat Consumption and HbA1c Levels: The EPIC-Norfolk Study. Diabetes Care
24: 1911-1916
[Abstract][Full Text]
Abadie, J. M., Malcom, G. T., Porter, J. R., Svec, F.
(2001). Dehydroepiandrosterone Alters Zucker Rat Soleus and Cardiac Muscle Lipid Profiles. Exp. Biol. Med.
226: 782-789
[Abstract][Full Text]
Meyer, K. A., Kushi, L. H., Jacobs, D. R. Jr., Folsom, A. R.
(2001). Dietary Fat and Incidence of Type 2 Diabetes in Older Iowa Women. Diabetes Care
24: 1528-1535
[Abstract][Full Text]
Boden, G., Lebed, B., Schatz, M., Homko, C., Lemieux, S.
(2001). Effects of Acute Changes of Plasma Free Fatty Acids on Intramyocellular Fat Content and Insulin Resistance in Healthy Subjects. Diabetes
50: 1612-1617
[Abstract][Full Text]
Hickner, R. C., Privette, J., McIver, K., Barakat, H.
(2001). Fatty acid oxidation in African-American and Caucasian women during physical activity. J. Appl. Physiol.
90: 2319-2324
[Abstract][Full Text]
Salmeron, J., Hu, F. B, Manson, J. E, Stampfer, M. J, Colditz, G. A, Rimm, E. B, Willett, W. C
(2001). Dietary fat intake and risk of type 2 diabetes in women. Am. J. Clin. Nutr.
73: 1019-1026
[Abstract][Full Text]
Berry, E.M.
(2001). Are diets high in omega-6 polyunsaturated fatty acids unhealthy?. Eur Heart J Suppl
3: D37-D41
[Abstract]
Krebs, M., Krssak, M., Nowotny, P., Weghuber, D., Gruber, S., Mlynarik, V., Bischof, M., Stingl, H., Fürnsinn, C., Waldhäusl, W., Roden, M.
(2001). Free Fatty Acids Inhibit the Glucose-Stimulated Increase of Intramuscular Glucose-6-Phosphate Concentration in Humans. J. Clin. Endocrinol. Metab.
86: 2153-2160
[Abstract][Full Text]
Cunnane, S. C, Ross, R., Bannister, J. L, Jenkins, D. J.
(2001). {beta}-Oxidation of linoleate in obese men undergoing weight loss. Am. J. Clin. Nutr.
73: 709-714
[Abstract][Full Text]
Helge, J. W., Wu, B. J., Willer, M., Daugaard, J. R., Storlien, L. H., Kiens, B.
(2001). Training affects muscle phospholipid fatty acid composition in humans. J. Appl. Physiol.
90: 670-677
[Abstract][Full Text]
Montell, E., Turini, M., Marotta, M., Roberts, M., Noe, V., Ciudad, C. J., Mace, K., Gomez-Foix, A. M.
(2001). DAG accumulation from saturated fatty acids desensitizes insulin stimulation of glucose uptake in muscle cells. Am. J. Physiol. Endocrinol. Metab.
280: E229-E237
[Abstract][Full Text]
Berrino, F., Bellati, C., Secreto, G., Camerini, E., Pala, V., Panico, S., Allegro, G., Kaaks, R.
(2001). Reducing Bioavailable Sex Hormones through a Comprehensive Change in Diet: the Diet and Androgens (DIANA) Randomized Trial. Cancer Epidemiol. Biomarkers Prev.
10: 25-33
[Abstract][Full Text]
Pratley, R. E., Baier, L., Pan, D. A., Salbe, A. D., Storlien, L., Ravussin, E., Bogardus, C.
(2000). Effects of an Ala54Thr polymorphism in the intestinal fatty acid-binding protein on responses to dietary fat in humans. J. Lipid Res.
41: 2002-2008
[Abstract][Full Text]
Kim, J.-Y., Nolte, L. A., Hansen, P. A., Han, D.-H., Ferguson, K., Thompson, P. A., Holloszy, J. O.
(2000). High-fat diet-induced muscle insulin resistance: relationship to visceral fat mass. Am. J. Physiol. Regul. Integr. Comp. Physiol.
279: R2057-R2065
[Abstract][Full Text]
Andersson, A., Sjodin, A., Hedman, A., Olsson, R., Vessby, B.
(2000). Fatty acid profile of skeletal muscle phospholipids in trained and untrained young men. Am. J. Physiol. Endocrinol. Metab.
279: E744-E751
[Abstract][Full Text]
Evans, W. J
(2000). Vitamin E, vitamin C, and exercise. Am. J. Clin. Nutr.
72: 647S-652
[Abstract][Full Text]
Kim, Y.-B., Uotani, S., Pierroz, D. D., Flier, J. S., Kahn, B. B.
(2000). In Vivo Administration of Leptin Activates Signal Transduction Directly in Insulin-Sensitive Tissues: Overlapping but Distinct Pathways from Insulin. Endocrinology
141: 2328-2339
[Abstract][Full Text]
Ferrara, L. A., Raimondi, A. S., d'Episcopo, L., Guida, L., Dello Russo, A., Marotta, T.
(2000). Olive Oil and Reduced Need for Antihypertensive Medications. Arch Intern Med
160: 837-842
[Abstract][Full Text]
Simopoulos, A. P
(1999). Essential fatty acids in health and chronic disease. Am. J. Clin. Nutr.
70: 560S-569
[Abstract][Full Text]
Helge, J. W., Ayre, K. J., Hulbert, A. J., Kiens, B., Storlien, L. H.
(1999). Regular Exercise Modulates Muscle Membrane Phospholipid Profile in Rats. J. Nutr.
129: 1636-1642
[Abstract][Full Text]
Schmitz-Peiffer, C., Craig, D. L., Biden, T. J.
(1999). Ceramide Generation Is Sufficient to Account for the Inhibition of the Insulin-stimulated PKB Pathway in C2C12 Skeletal Muscle Cells Pretreated with Palmitate. J. Biol. Chem.
274: 24202-24210
[Abstract][Full Text]
Wijendran, V., Bendel, R. B, Couch, S. C, Philipson, E. H, Thomsen, K., Zhang, X., Lammi-Keefe, C. J
(1999). Maternal plasma phospholipid polyunsaturated fatty acids in pregnancy with and without gestational diabetes mellitus: relations with maternal factors. Am. J. Clin. Nutr.
70: 53-61
[Abstract][Full Text]
Bruton, J. D., Katz, A., Westerblad, H.
(1999). Insulin increases near-membrane but not global Ca2+ in isolated skeletal muscle. Proc. Natl. Acad. Sci. USA
96: 3281-3286
[Abstract][Full Text]
Ernsberger, P., Ishizuka, T., Liu, S., Farrell, C. J., Bedol, D., Koletsky, R. J., Friedman, J. E.
(1999). Mechanisms of Antihyperglycemic Effects of Moxonidine in the Obese Spontaneously Hypertensive Koletsky Rat (SHROB). J. Pharmacol. Exp. Ther.
288: 139-147
[Abstract][Full Text]
Ayre, K. J., Phinney, S. D., Tang, A. B., Stern, J. S.
(1998). Exercise training reduces skeletal muscle membrane arachidonate in the obese (fa/fa) Zucker rat. J. Appl. Physiol.
85: 1898-1902
[Abstract][Full Text]
Hansen, P. A., Han, D. H., Marshall, B. A., Nolte, L. A., Chen, M. M., Mueckler, M., Holloszy, J. O.
(1998). A High Fat Diet Impairs Stimulation of Glucose Transport in Muscle. FUNCTIONAL EVALUATION OF POTENTIAL MECHANISMS. J. Biol. Chem.
273: 26157-26163
[Abstract][Full Text]
Clore, J. N., Li, J., Gill, R., Gupta, S., Spencer, R., Azzam, A., Zuelzer, W., Rizzo, W. B., Blackard, W. G.
(1998). Skeletal muscle phosphatidylcholine fatty acids and insulin sensitivity in normal humans. Am. J. Physiol. Endocrinol. Metab.
275: E665-E670
[Abstract][Full Text]
Ling, P.-R., Boyce, P., Bistrian, B. R.
(1998). Role of Arachidonic Acid in the Regulation of the Inflammatory Response in TNF-{alpha}-treated Rats. JPEN J Parenter Enteral Nutr
22: 268-275
[Abstract]
Ferrannini, E.
(1998). Insulin Resistance versus Insulin Deficiency in Non-Insulin-Dependent Diabetes Mellitus: Problems and Prospects. Endocr. Rev.
19: 477-490
[Abstract][Full Text]
Andersson, A., Sjodin, A., Olsson, R., Vessby, B.
(1998). Effects of physical exercise on phospholipid fatty acid composition in skeletal muscle. Am. J. Physiol. Endocrinol. Metab.
274: E432-E438
[Abstract][Full Text]
Petersen, K. F., Jacob, R., West, A. B., Sherwin, R. S., Shulman, G. I.
(1997). Effects of insulin-like growth factor I on glucose metabolism in rats with liver cirrhosis. Am. J. Physiol. Endocrinol. Metab.
273: E1189-E1193
[Abstract][Full Text]
Schmitz-Peiffer, C., Oakes, N. D., Browne, C. L., Kraegen, E. W., Biden, T. J.
(1997). Reversal of chronic alterations of skeletal muscle protein kinase C from fat-fed rats by BRL-49653. Am. J. Physiol. Endocrinol. Metab.
273: E915-E921
[Abstract][Full Text]
Huang, C.-h., Lin, H.-n., Li, S., Wang, G.
(1997). Influence of the Positions of cis Double Bonds in the sn-2-Acyl Chain of Phosphatidylethanolamine on the Bilayer's Melting Behavior. J. Biol. Chem.
272: 21917-21926
[Abstract][Full Text]
Nestel, P. J., Pomeroy, S. E., Sasahara, T., Yamashita, T., Liang, Y. L., Dart, A. M., Jennings, G. L., Abbey, M., Cameron, J. D.
(1997). Arterial Compliance in Obese Subjects Is Improved With Dietary Plant n-3 Fatty Acid From Flaxseed Oil Despite Increased LDL Oxidizability. Arterioscler. Thromb. Vasc. Bio.
17: 1163-1170
[Abstract][Full Text]
Kliewer, S. A., Sundseth, S. S., Jones, S. A., Brown, P. J., Wisely, G. B., Koble, C. S., Devchand, P., Wahli, W., Willson, T. M., Lenhard, J. M., Lehmann, J. M.
(1997). Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc. Natl. Acad. Sci. USA
94: 4318-4323
[Abstract][Full Text]
Widen, E., Lehto, M., Kanninen, T., Walston, J., Shuldiner, A. R., Groop, L. C.
(1995). Association of a Polymorphism in the {beta}3-Adrenergic-Receptor Gene with Features of the Insulin Resistance Syndrome in Finns. NEJM
333: 348-352
[Abstract][Full Text]
Phinney, S. D.
(1995). Physical Activity and Risk of Gastrointestinal Hemorrhage in the Elderly. JAMA
273: 521-522
[Abstract]
Wang, Z.-q., Lin, H.-n., Li, S., Huang, C.-h.
(1995). Phase Transition Behavior and Molecular Structures of Monounsaturated Phosphatidylcholines. J. Biol. Chem.
270: 2014-2023
[Abstract][Full Text]
Nugent, C., Prins, J. B., Whitehead, J. P., Wentworth, J. M., Chatterjee, V. K. K., O'Rahilly, S.
(2001). Arachidonic Acid Stimulates Glucose Uptake in 3T3-L1 Adipocytes by Increasing GLUT1 and GLUT4 Levels at the Plasma Membrane. EVIDENCE FOR INVOLVEMENT OF LIPOXYGENASE METABOLITES AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR gamma. J. Biol. Chem.
276: 9149-9157
[Abstract][Full Text]
-adrenergic-antagonists, calcium-channel-blocking drugs, and angiotensin-converting-enzyme inhibitors, none of which were discontinued before the study began. 
5-desaturase and 
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