Insulin Resistance In Healthy Subjects Research Articles

Interferon Upregulation Associates with Insulin Resistance in Humans.

In humans, insulin resistance is a physiological response to infections developed to supply sufficient energy to the activated immune system. This metabolic adaptation facilitates the immune response but usually persists after the recovery period of the infection and predisposes the hosts to type 2 diabetes and vascular injury. In patients with diabetes, superimposed insulin resistance worsens metabolic control and promotes diabetic ketoacidosis. Pathogenic mechanisms underlying insulin resistance during microbial invasions remain to be fully defined. However, interferons cause insulin resistance in healthy subjects and other population groups, and their production is increased during infections, suggesting that this group of molecules may contribute to reduced insulin sensitivity. In agreement with this notion, gene expression profiles [transcriptomes] from patients with insulin resistance show a robust overexpression of interferon-stimulated genes [interferon signature]. In addition, serum levels of interferon and surrogates for interferon activity are elevated in patients with insulin resistance. Circulating levels of interferon-γ-inducible protein-10, neopterin, and apolipoprotein L1 correlate with insulin resistance manifestations, such as hypertriglyceridemia, reduced HDL-c, visceral fat, and homeostasis model assessment-insulin resistance. Furthermore, interferon downregulation improves insulin resistance. Antimalarials such as hydroxychloroquine reduce interferon production and improve insulin resistance, reducing the risk for type 2 diabetes and cardiovascular disease. In addition, diverse clinical conditions that feature interferon upregulation are associated with insulin resistance, suggesting that interferon may be a common factor promoting this adaptive response. Among these conditions are systemic lupus erythematosus, sarcoidosis, and infections with severe acute respiratory syndrome-coronavirus-2, human immunodeficiency virus, hepatitis C virus, and Mycobacterium tuberculosis.

Abstract #1184266: ASSOCIATION OF TRIGLYCERIDE AND GLUCOSE (TyG) INDEX WITH CAROTID INTIMAL MEDIAL THICKNESS (IMT) IN APPERANTLY HEALTHY SUBJECTS : THE CHENNAI URBAN RURAL EPIDEMIOLOGY STUDY (CURES)

Insulin resistance has been associated with metabolic syndrome , diabetes and cardiovascular disorders. The triglyceride and glucose (TyG) index can be obtained easily by measuring blood glucose and serum triglyceride levels. It has also shown to be a useful surrogate to identify insulin resistance in healthy subjects. Carotid intimal medial thickness (IMT) is a marker, which is strongly associated with cardiovascular disease. This paper deals with the relationship between TyG index and carotid IMT in apparently healthy subjects.

Diagnostic accuracy of serum alanine aminotransferase as biomarker for nonalcoholic fatty liver disease and insulin resistance in healthy subjects, using 3T MR spectroscopy.

Recognition of the close relationship of nonalcoholic fatty liver disease (NAFLD) with diabetes mellitus 2, obesity, metabolic syndrome, and cardiovascular disease has stimulated growing interest in NAFLD as a public health problem. Serum alanine aminotransferase (ALT) has been proposed as a marker of NAFLD, but levels are within the range currently considered “normal” in a large proportion of NAFLD subjects.The aim of the study was to determine the diagnostic accuracy of serum ALT for identifying individuals with NAFLD, using 3-Tesla (T) magnetic resonance spectroscopy (1H-MRS).A cross-sectional study was conducted in 129 healthy subjects. Liver triglyceride content was quantified by 1H-MRS. NAFLD was defined as liver triglyceride content greater than 5.56%.Liver triglyceride content was >5.56% in 79 participants (NAFLD) and lower in the remaining 50 (normal). Serum ALT levels correlated positively with liver triglyceride content (r = 0.58, P < .001), Homeostatic Model Assessment for Insulin Resistance (r = 0.32, P < .01), and fasting insulin (r = 0.31, P < .01), and inversely correlated with adiponectin (r = 0.35, P < .01) and high-density lipoprotein cholesterol (r = 0.32, P < .01). Regression analysis showed that serum ALT was the best predictor of NAFLD (P < .01). Optimal serum ALT cut-off to predict NAFLD was 23 IU/L (area under receiver-operating characteristic curve: 0.93; sensitivity: 0.94; specificity: 0.72).This study shows that serum ALT is a sensitive and accurate biomarker of NAFLD if the “normal” ALT value is revised and established at a lower level. An ALT threshold of 23 IU/L identified 94% of individuals with NAFLD in the present series, using 3-T 1H-MRS for liver triglyceride quantification.

Sex-dependent association between circulating irisin levels and insulin resistance in healthy adults

BackgroundIrisin, a myokine, expressed by muscle and adipose tissue, has been reported to stimulate conversion of white into brown adipose tissue. The beneficial health effects of exercise are thought to be mediated in part, via increased production of irisin. ObjectiveThe primary aim of this study was to assess the association between plasma irisin levels glycaemic indices in healthy adults. Associations between irisin and lipid levels, CRP and body composition were explored as secondary outcomes. MethodsA cross-sectional sample of forty nine (n = 49) free living healthy males (n = 28) and females (n = 21), between the ages of 18 and 65, with body mass index (BMI) within the healthy range, were recruited. Body weight, height, and body composition measurements were taken. Fasting blood samples were collected for the analysis of glucose, insulin and irisin levels. Insulin resistance score, HOMA-IR, was calculated using fasting blood glucose and insulin values. The relationship between plasma irisin levels and anthropometric measurements, glucose, insulin and HOMA-IR was determined using Spearman's bivariate correlation test. ResultsA significant inverse relationship was found between plasma irisin levels and insulin(r = −0.380; P = 0.007) and HOMA-IR(r = −0.362; P = 0.011). This relation was further strengthened in males when the data was stratified by gender. Circulating irisin levels were positively correlated with HDL-C (r = 0.39; P = 0.05) in male participants. Additionally, there was a significant negative correlation between percent body fat (r = −0.43, P < 0.05) and body fat mass (r = −0.47, P < 0.05) and circulating irisin levels in male participants. ConclusionsThis study reports a sex-dependent inverse relationship between plasma irisin levels and insulin resistance in healthy subjects.

Postprandial lipemia induces endothelial dysfunction and higher insulin resistance in healthy subjects

ObjectiveTo assess the effect of postprandial lipemia on endothelial function, insulin resistance, and lipid profile in healthy subjects. Patients and methodsA prospective, interventional study in 14 healthy young men aged 18–25 years who were given a high-fat meal. Endothelial function was measured using flow-mediated dilation (FMD) in the brachial artery, flow velocity, mean arterial pressure and serum nitrite/nitrate levels (NO2/NO3). Glucose, insulin, total cholesterol, and triglyceride levels were also tested. Insulin resistance was determined by calculating the HOMA-IR index (Homeostatic Model Assessment-Insulin Resistance). ResultsBaseline FMD was 5.9±1.1%. Postprandial lipemia reduced endothelial function by approximately 50% in the first (3.3±0.5%, p=0.03) and second (3.3±0.4%, p=0.04) moment, respectively. This finding was associated to an increased flow rate in the brachial artery and lower NO2/NO3 levels (p<0.05). Higher cholesterol and triglyceride levels were found 1h and 2h postprandial (p<0.05). HOMA-IR was significantly increased 1h and 2h postprandial (p<0.05). ConclusionsPostprandial lipemia causes changes in circulating lipid profile and induces endothelial dysfunction and higher insulin resistance.

Low-salt diet increases insulin resistance in healthy subjects

Low-salt (LS) diet activates the renin-angiotensin-aldosterone and sympathetic nervous systems, both of which can increase insulin resistance (IR). We investigated the hypothesis that LS diet is associated with an increase in IR in healthy subjects. Healthy individuals were studied after 7 days of LS diet (urine sodium <20 mmol/d) and 7 days of high-salt (HS) diet (urine sodium >150 mmol/d) in a random order. Insulin resistance was measured after each diet and compared statistically, unadjusted and adjusted for important covariates. One hundred fifty-two healthy men and women, aged 39.1 ± 12.5 years (range, 18-65) and with body mass index of 25.3 ± 4.0 kg/m 2, were included in this study. Mean (SD) homeostasis model assessment index was significantly higher on LS compared with HS diet (2.8 ± 1.6 vs 2.4 ± 1.7, P < .01). Serum aldosterone (21.0 ± 14.3 vs 3.4 ± 1.5 ng/dL, P < .001), 24-hour urine aldosterone (63.0 ± 34.0 vs 9.5 ± 6.5 μg/d, P < .001), and 24-hour urine norepinephrine excretion (78.0 ± 36.7 vs 67.9 ± 39.8 μg/d, P < .05) were higher on LS diet compared with HS diet. Low-salt diet was significantly associated with higher homeostasis model assessment index independent of age, sex, blood pressure, body mass index, serum sodium and potassium, serum angiotensin II, plasma renin activity, serum and urine aldosterone, and urine epinephrine and norepinephrine. Low-salt diet is associated with an increase in IR. The impact of our findings on the pathogenesis of diabetes and cardiovascular disease needs further investigation.

Short-term administration of the atypical antipsychotic olanzapine induces insulin resistance in healthy subjects, independent of weight gain or psychiatric disease

Short-term administration of the atypical antipsychotic olanzapine induces insulin resistance in healthy subjects, independent of weight gain or psychiatric disease

Mechanisms of Insulin Resistance After Insulin-Induced Hypoglycemia in Humans: The Role of Lipolysis

OBJECTIVEChanges in glucose metabolism occurring during counterregulation are, in part, mediated by increased plasma free fatty acids (FFAs), as a result of hypoglycemia-activated lipolysis. However, it is not known whether FFA plays a role in the development of posthypoglycemic insulin resistance as well.RESEARCH DESIGN AND METHODSWe conducted a series of studies in eight healthy volunteers using acipimox, an inhibitor of lipolysis. Insulin action was measured during a 2-h hyperinsulinemic-euglycemic clamp (plasma glucose [PG] 5.1 mmo/l) from 5:00 p.m. to 7:00 p.m. or after a 3-h morning hyperinsulinemic-glucose clamp (from 10 a.m. to 1:00 p.m.), either euglycemic (study 1) or hypoglycemic (PG 3.2 mmol/l, studies 2–4), during which FFA levels were allowed to increase (study 2), were suppressed by acipimox (study 3), or were replaced by infusing lipids (study 4). [6,6-2H2]-Glucose was infused to measure glucose fluxes.RESULTSPlasma adrenaline, norepinephrine, growth hormone, and cortisol levels were unchanged (P > 0.2). Glucose infusion rates (GIRs) during the euglycemic clamp were reduced by morning hypoglycemia in study 2 versus study 1 (16.8 ± 2.3 vs. 34.1 ± 2.2 μmol/kg/min, respectively, P < 0.001). The effect was largely removed by blockade of lipolysis during hypoglycemia in study 3 (28.9 ± 2.6 μmol/kg/min, P > 0.2 vs. study 1) and largely reproduced by replacement of FFA in study 4 (22.3 ± 2.8 μmol/kg/min, P < 0.03 vs. study 1). Compared with study 2, blockade of lipolysis in study 3 decreased endogenous glucose production (2 ± 0.3 vs. 0.85 ± 0.1 μmol/kg/min, P < 0.05) and increased glucose utilization (16.9 ± 1.85 vs. 28.5 ± 2.7 μmol/kg/min, P < 0.05). In study 4, GIR fell by ∼23% (22.3 ± 2.8 μmol/kg/min, vs. study 3, P = 0.058), indicating a role of acipimox per se on insulin action.CONCLUSIONLipolysis induced by hypoglycemia counterregulation largely mediates posthypoglycemic insulin resistance in healthy subjects, with an estimated overall contribution of ∼39%.

Helicobacter pylori Infection as a Risk Factor for Insulin Resistance

This study aimed to determine the relation between Helicobacter pylori infection and insulin resistance in healthy subjects. In a cross-sectional case control study between January and April 2007, a total of 71 healthy subjects without the exclusion criteria completed the study. Forty-three (60.6%) patients were H. pylori positive and 28 (39.4%) patients were H. pylori negative. Age and body mass index of the patients were not significantly different between the two groups (32.2 +/- 14.2 vs. 33 +/- 8.05 years and 23.15 +/- 4.5 vs. 24.04 +/- 3.2 kg/m(2), respectively). H-pylori-positive patients had significantly higher HOMA-IR level compared to H-pylori-negative patients (3.54 +/- 2.2 vs. 2.46 +/- 1.9, respectively) (P < 0.05). Fasting serum insulin level was significantly higher in the H-pylori-positive group compared with the H-pylori-negative group (19.41 +/- 3.08 vs. 16.57 +/- 2.02 microU/ml, respectively) (P < 0.05). Our findings suggest recognition of H. pylori infection as a risk factor for insulin resistance.

Abdominal fat distribution and insulin resistance in Indian women with polycystic ovarian syndrome

The relationship between insulin resistance and abdominal fat distribution was studied in Indian patients with PCOS. Subcutaneous fat, together with a family history of type 2 diabetes mellitus, was the best marker of insulin resistance.

Severe impairment of endothelial function with the HIV-1 protease inhibitor indinavir is not mediated by insulin resistance in healthy subjects.

Endothelial dysfunction may contribute to increased cardiovascular events among HIV-1-infected patients receiving antiretroviral therapy. The HIV-1 protease inhibitor indinavir causes both vascular dysfunction and insulin resistance, but the relationship between the two disturbances is not established. Endothelium-dependent vasodilation (EDV), insulin-mediated vasodilation (IMV), and whole body and leg glucose uptake during a euglycemic hyperinsulinemic clamp (40 mU/m(2)/min) were measured before and after four weeks of indinavir in nine healthy men. EDV fell from 270 +/- 67% above basal to 124 +/- 30% (P = 0.04) and IMV from 56 +/- 14% above basal to 8 +/- 8% (P = 0.001) with indinavir. During the clamp, arteriovenous glucose difference and leg glucose uptake were not significantly different after indinavir and whole-body glucose uptake was only modestly reduced (8.0 +/- 0.8 vs. 7.2 +/- 0.8 mg/kg/min, P = 0.04). The change in EDV did not correlate with the change in whole-body glucose uptake after indinavir (r = 0.21, P = 0.6). Despite marked impairment of endothelial function and IMV with indinavir, only modest, inconsistent reductions in measures of insulin-stimulated glucose uptake occurred. This suggests that indinavir's effects on glucose metabolism are not directly related to indinavir-associated endothelial dysfunction. Studies of the vascular effects of newer protease inhibitors are needed.

The Dual Substrate Specificity of Aldehyde Oxidase 1 for Retinal and Acetaldehyde and its Role in ABCA1 Mediated Efflux

The high triglyceride, low high-density-lipoprotein (HDL) syndrome, visceral obesity, hypertension, and insulin resistance with or without hyperglycemia are the hallmarks of type 2 diabetes mellitus (T2DM) and the metabolic syndrome (MS). Patients with T2DM or MS are at high risk for vascular disease, myocardial infarction and stroke [1]. Insulin resistance, as a major determinant of disease progression, is associated with TNF-α[2] and MCP-1 expression in visceral fat. MCP-1 expression results in macrophage accumulation in visceral fat and adipokine secretion [3]. Furthermore, insulin resistance is associated with impaired lipoprotein lipase (LPL) expression [4], enhanced secretion of apoB containing lipoproteins associated with hypertriglyceridemia [5] and activation of the renin/angiotensin/aldosterone system leading also to elevated blood pressure [6]. While the adipokine adiponectin seems not to be causally related to insulin resistance in healthy subjects [7] haplotypes in the adiponectin promoter are associated with increased risk of T2DM [8]. Obesity suppresses adiponectin secretion [9] and serum adiponectin correlates positively with HDL cholesterol [7] [10] and negatively with plasma triglycerides [7]. A key function of HDL in the process of reverse cholesterol transport is to transport cholesterol from peripheral tissues to the liver for biliary excretion [11]. Insulin resistance, metabolic overload and the dysregulation of adipokine and cytokine secretion promote nonalcoholic fatty liver disease (NAFLD) [12].

Cocoa Reduces Blood Pressure and Insulin Resistance and Improves Endothelium-Dependent Vasodilation in Hypertensives

Consumption of flavanol-rich dark chocolate (DC) has been shown to decrease blood pressure (BP) and insulin resistance in healthy subjects, suggesting similar benefits in patients with essential hypertension (EH). Therefore, we tested the effect of DC on 24-hour ambulatory BP, flow-mediated dilation (FMD), and oral glucose tolerance tests (OGTTs) in patients with EH. After a 7-day chocolate-free run-in phase, 20 never-treated, grade I patients with EH (10 males; 43.7+/-7.8 years) were randomized to receive either 100 g per day DC (containing 88 mg flavanols) or 90 g per day flavanol-free white chocolate (WC) in an isocaloric manner for 15 days. After a second 7-day chocolate-free period, patients were crossed over to the other treatment. Noninvasive 24-hour ambulatory BP, FMD, OGTT, serum cholesterol, and markers of vascular inflammation were evaluated at the end of each treatment. The homeostasis model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), and insulin sensitivity index (ISI) were calculated from OGTT values. Ambulatory BP decreased after DC (24-hour systolic BP -11.9+/-7.7 mm Hg, P<0.0001; 24-hour diastolic BP -8.5+/-5.0 mm Hg, P<0.0001) but not WC. DC but not WC decreased HOMA-IR (P<0.0001), but it improved QUICKI, ISI, and FMD. DC also decreased serum LDL cholesterol (from 3.4+/-0.5 to 3.0+/-0.6 mmol/L; P<0.05). In summary, DC decreased BP and serum LDL cholesterol, improved FMD, and ameliorated insulin sensitivity in hypertensives. These results suggest that, while balancing total calorie intake, flavanols from cocoa products may provide some cardiovascular benefit if included as part of a healthy diet for patients with EH.

Insulin resistance and C-reactive protein as independent risk factors for non-alcoholic fatty liver disease in non-obese Asian men.

Although insulin resistance is often considered the link between obesity and non-alcoholic fatty liver disease (NAFLD), the role of insulin resistance, independent of obesity, as a NAFLD risk factor in non-obese men has been less well established. Systemic inflammation may be accompanied by insulin resistance in healthy subjects. The goal of the present study was to examine if insulin resistance and systemic inflammatory markers are independent predictors of NAFLD in non-obese men. The authors conducted a cross-sectional survey of 120 patients with NAFLD and 240 controls matched by age and body mass index. Controls had no evidence of alcohol abuse, hepatitis B or C, obesity, or previous history of diabetes, fasting hyperglycemia or hypertension. Diagnosis of NAFLD was based on an elevated alanine aminotransferase level and sonographic evidence of a fatty liver. Insulin resistance was determined using a homeostasis model assessment (HOMA-IR). The age-adjusted risk of developing NAFLD was strongly associated with the elevated levels in measurements of uric acid, fasting blood sugar, triglycerides, apolipoprotein B, C-reactive protein (CRP) and HOMA-IR, and decreased levels of high density lipoprotein cholesterol and apolipoprotein A-I. Multivariate analysis based on univariate analysis indicated that an increase in CRP (odds ratio [OR] = 1.37; 95% confidence interval [CI]: 1.06-1.77) per 1 SD (1.48 mg/L) and HOMA-IR (OR = 2.28; 95% CI: 1.67-3.11) per 1 SD (0.63) were independent risk factors for NAFLD. Insulin resistance and systemic inflammatory response are of key importance for inducing NAFLD, particularly in apparently healthy non-obese men.

W09.242 Measurement of abdominal fat by sonography for assessment of insulin resistance in healthy subjects

W09.242 Measurement of abdominal fat by sonography for assessment of insulin resistance in healthy subjects

W09.242 Measurement of abdominal fat by sonography for assessment of insulin resistance in healthy subjects

W09.242 Measurement of abdominal fat by sonography for assessment of insulin resistance in healthy subjects

Glucose flux is normalized by compensatory hyperinsulinaemia in growth hormone-induced insulin resistance in healthy subjects, while skeletal muscle protein synthesis remains unchanged

Glucose flux is normalized by compensatory hyperinsulinaemia in growth hormone-induced insulin resistance in healthy subjects, while skeletal muscle protein synthesis remains unchanged

Glucose flux is normalized by compensatory hyperinsulinaemia in growth hormone-induced insulin resistance in healthy subjects, while skeletal muscle protein synthesis remains unchanged.

The aim of this present investigation was to study the relationship between the reduction in insulin sensitivity accompanying 5 days of treatment with growth hormone (GH; 0.05 mg.24 h(-1).kg(-1)) and intracellular substrate oxidation rates in six healthy subjects, while maintaining glucose flux by a constant glucose infusion and adjusting insulin infusion rates to achieve normoglycaemia (feedback clamp). Protein synthesis rates in skeletal muscle (flooding dose of L-[(2)H(5)]phenylalanine) were determined under these conditions. We also compared changes in insulin sensitivity after GH treatment with simultaneous changes in energy requirements, protein synthesis rates, nitrogen balance, 3-methylhistidine excretion in urine, body composition and the hormonal milieu. After GH treatment, 70% more insulin was required to maintain normoglycaemia (P<0.01). The ratio between glucose infusion rate and serum insulin levels decreased by 34% at the two levels of glucose infusion tested (P<0.05). Basal levels of C-peptide, insulin-like growth factor (IGF)-I and IGF-binding protein-3 increased almost 2-fold, while levels of glucose, insulin, glucagon, GH and IGF-binding protein-1 remained unchanged. Non-esterified fatty acid levels decreased (P<0.05). In addition, 24 h urinary nitrogen excretion decreased by 26% (P<0.01) after GH treatment, while skeletal muscle protein synthesis and 3-methylhistidine excretion in urine remained unchanged. Energy expenditure increased by 5% (P<0.05) after treatment, whereas fat and carbohydrate oxidation were unaltered. In conclusion, when glucose flux was normalized by compensatory hyperinsulinaemia under conditions of GH-induced insulin resistance, intracellular rates of oxidation of glucose and fat remained unchanged. The nitrogen retention accompanying GH treatment seems to be due largely to improved nitrogen balance in non-muscle tissue.

LL-paraoxonase genotype is associated with a more severe degree of homeostasis model assessment IR in healthy subjects.

The LL genotype among subjects with paraoxonase (PON) polymorphism Met-Leu 54 has been shown to be associated with elevated risk of coronary heart disease. Indeed, insulin resistance (IR) is a well known cardiovascular risk factor that is likely attributable to a genetic background, lifestyle, and environmental factors such oxidative stress. Because subjects sharing the LL genotype have a more elevated degree of oxidative stress, one cannot rule out that in those subjects a more severe degree of IR can occur. Thus, the possible relationship between PON gene polymorphism and degree of IR was investigated. In 213 healthy subjects, the degree of IR was assessed by the homeostasis model assessment, and the Met-Leu 54 PON polymorphism was detected. The frequency was 0.366 for the LL genotype, 0.469 for the LM genotype, and 0.164 for the MM genotype. Comparing the three genotype groups, LL genotype had the more severe degree of IR, compared with LM (P < 0.01) and MM (P < 0.01) genotypes. No difference between LM and MM genotypes was found (P = 0.49). Subjects carrying the LL genotype were associated with the IR syndrome picture more than individuals carrying the M allele because they were more overweight and had the highest levels of triglycerides and blood pressure and the lowest values of plasma high-density lipoprotein cholesterol. In a multivariate stepwise regression analysis, LL genotype was a significant predictor of IR, independent of age, sex, body mass index, fasting plasma triglycerides, and high-density lipoprotein cholesterol (P < 0.001). In conclusion, the presence of LL PON genotype is associated with a more severe degree of IR. Thus, IR might be the possible missing link between Met-Leu 54 PON polymorphism and the increased cardiovascular risk.

Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects.

The reason for the 3- to 4-h delay between a rise in plasma free fatty acid (FFA) levels and the development of insulin resistance remains unknown. In the current study, we have tested the hypothesis that the delay may be caused by the need for plasma FFAs to first enter muscle cells and to be re-esterified there before causing insulin resistance. To this end, we have determined intramyocellular triglyceride (IMCL-TG) content with proton nuclear magnetic resonance ((1)H-NMR) spectroscopy in healthy volunteers before and 4 h after lowering of plasma FFAs (with euglycemic-hyperinsulinemic clamping) or after increasing plasma FFAs (with lipid plus heparin infusions). Increasing plasma FFAs (from 516 to 1,207 micromol/l or from 464 to 1,857 micromol/l, respectively) was associated with acute increases in IMCL-TG from 100 to 109 +/- 5% (P < 0.05) or to 133 +/- 11% (P < 0.01), respectively, and with a significant increase in insulin resistance (P < 0.05 after 3.5 h). Lowering of plasma FFAs from 560 to 41 micromol/l was associated with a tendency for IMCL-TG to decrease (from 100 to 95 +/- 3%). Changes in plasma FFAs correlated linearly with IMCL-TG (r = 0.74, P < 0.003). The demonstration that acute changes in plasma FFAs were accompanied by corresponding changes in IMCL-TG and with the development of insulin resistance, taken together with previous reports of a close correlation between IMCL-TG and insulin resistance, supported the notion that accumulation of IMCL-TG is a step in the development of FFA-induced insulin resistance.