Sex-Specific Skeletal Muscle Gene Expression Responses to Exercise Reveal Novel Direct Mediators of Insulin Sensitivity Change.

BACKGROUND: Understanding the causal pathways, systems, and mechanisms through which exercise impacts human health is complex. This study explores molecular signaling related to whole-body insulin sensitivity (Si) by examining changes in skeletal muscle gene expression. The analysis considers differences by biological sex, exercise amount, and exercise intensity to identify potential molecular targets for developing pharmacologic agents that replicate the health benefits of exercise. METHODS: The study involved 53 participants from the STRRIDE I and II trials who completed eight months of aerobic training. Skeletal muscle gene expression was measured using Affymetrix and Illumina technologies, while pre- and post-training Si was assessed via an intravenous glucose tolerance test. A novel gene discovery protocol, integrating three literature-derived and data-driven modeling strategies, was employed to identify causal pathways and direct causal factors based on differentially expressed transcripts associated with exercise intensity and amount. RESULTS: In women, the transcription factor targets identified were primarily influenced by exercise amount and were generally inhibitory. In contrast, in men, these targets were driven by exercise intensity and were generally activating. Transcription factors such as ATF1, CEBPA, BACH2, and STAT1 were commonly activating in both sexes. Specific transcriptional targets related to exercise-induced Si improvements included TACR3 and TMC7 for intensity-driven effects, and GRIN3B and EIF3B for amount-driven effects. Two key signaling pathways mediating aerobic exercise-induced Si improvements were identified: one centered on estrogen signaling and the other on phorbol ester (PKC) signaling, both converging on the epidermal growth factor receptor (EGFR) and other relevant targets. CONCLUSIONS: The signaling pathways mediating Si improvements from aerobic exercise differed by sex and were further distinguished by exercise intensity and amount. Transcriptional adaptations in skeletal muscle related to Si improvements appear to be causally linked to estrogen and PKC signaling, with EGFR and other identified targets emerging as potential skeletal muscle-specific drug targets to mimic the beneficial effects of exercise on Si.

Mitochondrial lipid oxidation is impaired in cultured myotubes from obese humans.

OBJECTIVE: The skeletal muscle of obese humans is characterized by an inability to appropriately respond to alterations in substrate availability. The purpose of this study was to determine if this metabolic inflexibility with obesity is retained in mitochondria of human skeletal muscle cells raised in culture (HSkMC) and to identify potential mechanisms involved. DESIGN: Mitochondrial respiration was measured in permeabilized myotubes cultured from lean and obese individuals before and after a 24-h lipid incubation. RESULTS: Mitochondrial respiration (state 3) in the presence of lipid substrate (palmitoyl carnitine) increased by almost twofold after lipid incubation in HSkMC from lean, but not obese subjects, indicative of metabolic inflexibility with obesity. The 24-h lipid incubation increased mitochondrial DNA (mtDNA) copy number in HSkMC from lean subjects by +16% (P<0.05); conversely, mtDNA copy number decreased in myotubes cultured from obese individuals (-13%, P=0.06). When respiration data were normalized to mtDNA copy number and other indices of mitochondrial content (COX-IV protein content and CS activity), the significant treatment effects of lipid incubation persisted in the lean subjects, suggesting concomitant alterations in mitochondrial function; no similar adjustment was evident in HSkMC from obese individuals. CONCLUSION: These data indicate that the skeletal muscle of obese individuals inherently lacks metabolic flexibility in response to lipid exposure, which consists of an inability to increase mitochondrial respiration in the presence of lipid substrate and perhaps by an inability to induce mitochondrial proliferation.

Exercise dose response in muscle.

Exercise increases peak VO2 partially through muscle adaptations. However, understanding muscle adaptations related to exercise dose is incomplete. This study investigated exercise training dose on capillaries per fiber and capillaries per area; and citrate synthase from vastus lateralis and related both to changes in peak VO2. This randomized trial compared 3 exercise doses: low amount-moderate intensity (n=40), low amount-high intensity (n=47), high amount-high intensity (n=41), and a control group (n=35). Both measures of capillary supply increased in all exercise groups (p<0.05). Low amount-high intensity and high amount-high intensity improved citrate synthase (p<0.05) and the low amount-moderate intensity citrate synthase approached significance (p=0.059). Muscle improvements were only related to improvements in peak VO2 in high amount-high intensity (citrate synthase, r=0.304; capillaries:fiber, r= - 0.318; p<0.05 and capillaries/mm2 r= - 0.310, p<0.05). These data suggest muscle adaptations occur following both low and high exercise doses, but are only related to improved peak VO2 following high amount-high intensity training.

Electron Transport Regulates Cellular Differentiation in the Filamentous Cyanobacterium Calothrix.

Differentiation of the filamentous cyanobacteria Calothrix sp strains PCC 7601 and PCC 7504 is regulated by light spectral quality. Vegetative filaments differentiate motile, gas-vacuolated hormogonia after transfer to fresh medium and incubation under red light. Hormogonia are transient and give rise to vegetative filaments, or to heterocystous filaments if fixed nitrogen is lacking. If incubated under green light after transfer to fresh medium, vegetative filaments do not differentiate hormogonia but may produce heterocysts directly, even in the presence of combined nitrogen. We used inhibitors of thylakoid electron transport (3-[3,4-dichlorophenyl]-1,1-dimethylurea and 2,5-dibromo-3-methyl-6-isopropyl-p-benzoquinone) to show that the opposing effects of red and green light on cell differentiation arise through differential excitations of photosystems I and II. Red light excitation of photosystem I oxidizes the plastoquinone pool, stimulating differentiation of hormogonia and inhibiting heterocyst differentiation. Conversely, net reduction of plastoquinone by green light excitation of photosystem II inhibits differentiation of hormogonia and stimulates heterocyst differentiation. This photoperception mechanism is distinct from the light regulation of complementary chromatic adaptation of phycobilisome constituents. Although complementary chromatic adaptation operates independently of the photocontrol of cellular differentiation, these two regulatory processes are linked, because the general expression of phycobiliprotein genes is transiently repressed during hormogonium differentiation. In addition, absorbance by phycobilisomes largely determines the light wavelengths that excite photosystem II, and thus the wavelengths that can imbalance electron transport.

Hormogonium Differentiation in the Cyanobacterium Calothrix: A Photoregulated Developmental Process.

Hormogonium differentiation is part of the developmental cycle in many heterocystous cyanobacteria. Hormogonia are involved in the dispersal and survival of the species in its natural habitat. The formation of these differentiated filaments has been shown to depend on several environmental conditions, including spectral light quality. We report here morphological and ultrastructural changes associated with the formation of hormogonia, as well as optimal light conditions required for their differentiation in the cyanobacterium Calothrix sp PCC 7601. The action spectrum for hormogonium differentiation is similar to that which triggers complementary chromatic adaptation because red and green radiation display antagonistic effects in both cases. However, these two photoregulated processes also show major differences. Transcription analyses of genes that are specifically expressed during hormogonium differentiation, as well as of genes encoding phycobiliproteins, suggest that two different photoregulatory pathways may exist in this cyanobacterium.

Skeletal muscle GLUT4 protein concentration and aging in humans.

The insulin resistance of aging has been attributed to a postreceptor defect in skeletal muscle. The present study examined whether a reduction in the concentration of the insulin-stimulated glucose transporter (GLUT4) in skeletal muscle was associated with advancing age in men (n = 55) and women (n = 29). Insulin sensitivity (minimal model) was negatively associated (P < 0.001) with age (range, 18-80 years) in men (r = -0.44) and women (r = -0.58). GLUT4 protein concentration in the vastus lateralis was also negatively associated (P < 0.05) with age (men, r = -0.28; women, r = -0.51). There was no relation (P > 0.15) between GLUT4 content in the gastrocnemius and age. GLUT4 concentration in the vastus lateralis was positively associated (P < 0.01) with insulin sensitivity in both sexes (r = 0.42); this relationship persisted in the men after adjusting for overall adiposity, regional adiposity, and cardiorespiratory fitness. These findings suggest that a decrement in GLUT4 protein concentration in skeletal muscle may at least partially contribute to the insulin resistance of aging in humans.

Isolation and molecular characterization of the gene encoding allophycocyanin B, a terminal energy acceptor in cyanobacterial phycobillsomes.

Phycobilisomes are the major constituents of the light-harvesting apparatus in both cyanobacteria and red algae and consist of a central core with radiating rods. From a genomic library of the cyanobacterium Calothrix 7601, a DNA fragment encoding allophycocyanin B, one of the two terminal energy acceptors of the core, was isolated and its nucleotide sequence was determined. Unlike all the other known genes encoding phycobiliproteins, the allophycocyanin B gene, apcD, is transcribed as a monocistronic unit. Mapping of the transcripts was performed and, in contrast to some of the Calothrix genes that encode rod components, transcription was shown to occur regardless of chromatic tight received during cell growth.

Transcriptional analysis of the cyanobacterial gvpABC operon in differentiated cells: occurrence of an antisense RNA complementary to three overlapping transcripts.

Cyanobacteria are photosynthetic prokaryotes able to colonize almost all kinds of ecosystems. Some of them exhibit differentiation processes and/or may establish tight symbiotic associations. Upon changes in the environmental conditions, the cyanobacterium Calothrix 7601 differentiates hormogonia which are short filaments of small cells resulting from cellular division and fragmentation of the long filaments of vegetative cells. In Calothrix, hormogonia are characterized by their gliding motility and by a massive production of gas vesicles which confer buoyancy. At least four genes are involved in the formation of gas vesicles, three of which are organized in one operon (gvpABC). Four different RNA species, only present after induction of hormogonia differentiation, result from transcription of this operon. Mapping of the 5' and 3' ends of these transcripts demonstrates the presence of gvpA, gvpAB and gvpABC transcripts, all three having the same 5' end. Each of the three transcripts terminates a few bases downstream from stem-and-loop structures. Most interestingly, the fourth transcript is an antisense RNA starting from the 3' end of the gvpB gene and ending within the gvpA gene. This antisense RNA can thus form an homologous duplex with the three other transcripts, thereby being able to impair translation and/or modify mRNA stability.

A developmentally regulated gvpABC operon is involved in the formation of gas vesicles in the cyanobacterium Calothrix 7601.

In the filamentous cyanobacterium Calothrix PCC7601, gas-vesicle (GV) formation is restricted to specialized filaments, called hormogonia. The differentiation of these cells is controlled by environmental factors, such as light intensity and/or wavelength. The structural gene (gvpA) encoding a GV protein in this cyanobacterium has been previously cloned and sequenced. Two other genes, gvpB and gvpC have been found in the sequence downstream from gvpA. The gvpB gene corresponds to a second copy of gvpA, encoding an identical protein. Unlike the GV protein, the product of the gvpC gene is predominantly hydrophilic, as deduced from nucleotide sequence. Interestingly, the internal part of the gvpC gene is composed of four contiguous repeats, each containing 99 bp, forming highly homologous repeats in the deduced amino acid sequence. Another kind of periodicity has been detected inside the 99-bp repeats, suggesting that the gvpC gene might have evolved by amplification of a 33-bp-long primordial building block. The function of this gene remains to be elucidated. Finally, we have shown that the three genes, gvpA, gvpB, and gvpC, are organized in an operon that is exclusively expressed during GV formation in hormogonia.

A role for the signal transduction protein PII in the control of nitrate/nitrite uptake in a cyanobacterium.

In the cyanobacterium Synechococcus sp. strain PCC 7942, ammonium exerts a rapid and reversible inhibition of the nitrate and nitrite uptake, and the PII protein (GlnB) is differentially phosphorylated depending on the intracellular N/C balance. RNA/DNA hybridizations, as well as nitrate and nitrite uptake experiments, were carried out with the wild-type strain and a PII-null mutant. The transcriptional control by ammonium of the expression of the nir-nrt ABCD-narB operon remained operative in the mutant but, in contrast to the wild-type strain, the mutant took up nitrate and nitrite even in the presence of ammonium. Moreover, the wild-type phenotype was restored by insertion of a copy of the wild-type glnB gene in the genome of the PII-null mutant. These results indicate that the unphosphorylated form of PII is involved in the short-term inhibition by ammonium of the nitrate and nitrite uptake in Synechococcus sp. strain PCC 7942.

Muscle hypertrophy with large-scale weight loss and resistance training.

The combined effects of exercise and energy restriction on changes in body fat and fat-free mass (FFM) are controversial. This study was conducted to determine whether muscle hypertrophy is possible during weight loss. Fourteen obese females received a 3360-kJ/d liquid diet for 90 d. Seven subjects received a weight training (WT) regimen and seven subjects remained sedentary (C). Biopsy samples were obtained from the vastus lateralis muscle at baseline and after 90 d of treatment. The average weight loss over the 90-d period was 16 kg with approximately 24% of the weight loss from FFM and 76% from fat. The amount and composition of the weight loss did not differ between WT and C groups. The cross-sectional area of slow twitch and fast twitch fibers was unchanged by treatment in C subjects but significantly increased in WT subjects. It appears that weight training can produce hypertrophy in skeletal muscle during severe energy restriction and large-scale weight loss.

Characterization and kinetics of the biosynthesis of some nitrogen fixation (nif) gene products in Klebsiella pneumoniae.

Analysis of 14C pulse-labelled proteins, synthesized by a Nif Klebsiella pneumoniae strain and by a number of genetically mapped nif::Mu and nif deletion mutants, was performed by two-dimensional gel electrophoresis. By comparison of the autoradiograms, six nif-specific polypeptides were identified. In addition to the previously characterized nifK, nifD, nifH and nifl products, the product of nifF was identified as a polypeptide of 10,000 daltons and pI about 4.5 and the product of nifU as a polypeptide of 22,000 daltons and pI 5. Moreover, the biosynthesis of nifF and nifU polypeptides was shown to be prevented in mutants affecting the regulatory gene nifA, which is known to control the biosynthesis of the other nit genes products so far identified. In all cases, the biochemical phenotypes of the different polar mutants were in good agreement with those expected from the transcriptional organization of the nif cluster previously established by genetic analysis. Kinetic studies of both nitrogenase activity and of the biosynthesis of the six nif-specific polypeptides were performed with the Nif' strain, incubated either under conditions of derepression or under conditions of repression by NH4+ ions. Upon derepression, the biosynthesis of the six nif polypeptides, which belong to four different transcriptional units, seems to be coordinated since they appear simultaneously after a lag of 45 minutes. Under those conditions, both in vivo and in vitro nitrogenase activities were detectable only 30 minutes later. Upon addition of NH4+ ions, the biosynthesis of the six nif polypeptides was rapidly abolished. However, the kinetics of residual biosynthesis, probably due to the transcription of preexisting mRNAs, was not similar for the six nif products. The nifU product was no longer detectable after 5 minutes, the nifF, K, D and J products were not detectable after 30 minutes, whereas some nifH product was still slightly detectable after 60 minutes.

Prochlorothrix hollandica PCC 9006: genomic properties of an axenic representative of the chlorophyll a/b-containing oxyphotobacteria.

Prochlorothrix hollandica is an oxygenic photosynthetic prokaryote that differs from the cyanobacteria in having chlorophyll a/b-protein complexes instead of phycobilisomes as major light-harvesting antennae. We report the isolation and culturing of an axenic strain of P. hollandica, available from the Pasteur Culture Collection of Cyanobacteria as strain PCC 9006. The strain has a mean DNA base composition of 51.6 +/- 0.1 mol% G+C and a genomic complexity of 3.37 +/- 0.17 x 10(9) daltons (5,505 kb). A reiterated DNA sequence represents approximately 4.4% of the genome. Restriction enzyme isoschizomers with different sensitivities to base methylation were used to demonstrate that most A residues in the sequence GATC are methylated in P. hollandica DNA and that this methylation increases with culture age. Furthermore, some C residues are methylated, although the specificity of the C methylation system does not match that of well-characterized C methylases. Nucleotide analysis showed that up to approximately 3.5% of both dA and dC residues are methylated in P. hollandica DNA.

Association between muscle fiber composition and blood pressure levels during exercise in men.

Normotensive individuals with a magnified blood pressure (BP) level during exercise have an increased risk for developing hypertension. The purpose of this study was to determine if skeletal muscle fiber type is related to the BP level during exercise. Peak BP was determined in 35 normotensive, middle-aged (mean +/- SE, 46.0 +/- 1.8 years) men during maximal treadmill exercise. Fiber distribution (I, IIa, IIb) was measured in muscle samples (percutaneous needle biopsy) from the vastus lateralis and lateral gastrocnemius. The systolic BP during exercise was significantly (P < .05) related to the percentage of type IIb fibers in both the vastus lateralis (r = 0.37) and gastrocnemius (r = 0.38). Mean arterial pressure BP was also related to the percentage of type IIb fibers in the gastrocnemius (r = 0.39, P < .05), with a similar trend evident in the vastus lateralis (r = 0.31, P = 0.08). The percentage of type IIb muscle fibers in both muscle groups was associated with (P < .05) body fat (vastus lateralis, r = 0.44; gastrocnemius, r = 0.43). There were no relationships between the relative percentage of type I or IIa fibers with any BP parameters. Maximal oxygen consumption was negatively related to BP, but only when expressed relative to body weight (mL x kg(-1) x min(-1)). These data suggest that muscle morphology is related to the blood pressure level during exercise and provides insight into factors that may predispose individuals toward the development of hypertension and cardiovascular disease.

The influence of aging on muscle strength and muscle fiber characteristics with special reference to eccentric strength.

It is well established that aging seriously reduces isometric and concentric muscle strength due to atrophy, deterioration of mechanical properties, and motor unit loss. However, there is limited information on the impact of aging on eccentric strength despite the fact that such forces play an equally important role during daily activities. The purpose of this study was to examine the influence of aging on three expressions of muscle strength (isometric, concentric, and eccentric) in relation to muscle fiber characteristics, with special emphasis on eccentric force. Sedentary but healthy men (age range 18-80 years, n = 60) and women (20-74 years, n = 30) were tested for maximal effort isometric, concentric, and eccentric (1.05, 2.09, 3.14 rads.s-1) quadriceps strength, body composition, and muscle fiber characteristics of the vastus lateralis (men only). There was a significant (p < .05) approximately 30 N per decade decline in isometric and concentric forces, but only 9 N per decade reduction in eccentric strength. There was a significant reduction in Type II muscle fiber area with aging (p < .05). Isometric, eccentric, and concentric force correlated r = .33, r = .32 (p < .05), and r = .12 (p > .05) with Type II muscle fiber area, respectively. The correlation between age and fat-free mass/force ratio ranged from r = .39 to .43 in men and r = .27 to .50 in women. The data suggest a relative preservation of eccentric strength with aging in men and women that seems to be independent of muscle mass or muscle fiber type or size.

Effect of short-term exercise training on leptin and insulin action.

The purpose of the study was to determine the effect of short-term exercise training (7 consecutive days for 60 min/d at 75% maximal oxygen consumption [VO2 max]), which did not change body mass on fasting plasma leptin concentration and insulin action. Young, lean subjects (n = 16; age, 21.9 +/- 0.6 years; body fat, 17.5% +/- 1.5%) and older subjects with relatively more adipose tissue (n = 14; age, 58.6 +/- 1.4 years; body fat, 28.3% +/- 1.3%) were studied (mean +/- SE). Fasting plasma leptin was significantly (P < .05) related to adiposity (fat mass, r = .58; % body fat, r = .76) in this population. Body mass did not change (P < .05) in any of the groups with training (71.8 +/- 2.5 v 71.9 +/- 2.5 kg). The insulin sensitivity index (SI determined from an intravenous glucose tolerance test (IVGTT) improved significantly (P < .05) in both the young group (4.8 +/- 0.6 v6.9 +/- 0.8 x 10(-4)/ min (microU/mL) and the older group (3.2 +/- 0.6 v 5.9 +/- 1.0 x 10(-4)/min (microU/mL)). Fasting leptin did not change with training in either group (10.4 +/- 1.6 v 9.2 +/- 1.0 ng/mL). These findings suggest that exercise does not independently affect the fasting plasma leptin concentration and the improvement in insulin action with exercise is not associated with an alteration in fasting leptin in healthy sedentary lean and relatively lean subjects.

Plasma cholesteryl ester transfer protein activity is not linked to insulin sensitivity.

Plasma cholesteryl ester transfer protein (CETP) activity has been reported to decline during a hyperinsulinemic-euglycemic clamp. It has been suggested that this suppressive effect of acute hyperinsulinemia is linked to whole body insulin sensitivity, and that the insulin resistance that accompanies obesity leads to high plasma CETP activity found in obese subjects. In the present study, we used 2 experimental approaches to examine the putative link between CETP and insulin action. First, we examined if the clamp-induced suppression of plasma CETP activity is linked to whole body insulin sensitivity. Plasma CETP activity was measured at the beginning and end of a 2-hour hyperinsulinemic-euglycemic clamp in 18 nondiabetic individuals before and after an exercise training regimen that improved insulin sensitivity without weight loss. CETP activity decreased in response to the clamp procedure in 16 of 18 subjects, and on average, by 9% (P <.001). While training decreased plasma CETP activity (10%, P <.05), the improvement in insulin sensitivity had no statistical effect on the clamp-induced suppression of plasma CETP activity (training*clamp, P =.26). Second, we examined if insulin resistance is associated with an elevation in fasting plasma CETP activity when the influence of adiposity and diabetes were negated. Plasma CETP activity was measured in 41 women (12 insulin-sensitive lean; 8 insulin-resistant lean; 10 insulin-sensitive obese; 11 insulin-resistant obese). The level of insulin sensitivity had no significant effect on fasting plasma CETP activity, but CETP levels were 25% higher in obese subjects (P <.01). Thus, neither experimental approach provided evidence that plasma CETP levels are linked to insulin and insulin sensitivity. These data suggest that the elevated CETP activity found in obese patients is less associated with hyperinsulinemia and the accompanying insulin resistance, but rather is more related to some other metabolic complication of obesity.

Effects of fitness level and the regional distribution of fat on carbohydrate metabolism and plasma lipids in middle- to older-aged men.

Many cross-sectional studies have demonstrated the influences of fitness level or the regional distribution of fat on lipid and carbohydrate metabolism; however, the relative contribution of these two variables in the same subjects has not been extensively examined. The purpose of this study was to determine the impact of regional adiposity on plasma lipids and carbohydrate metabolism in middle- to older-aged men with a wide range of fitness levels. Forty-six sedentary and exercise-trained men (age [mean +/- SE], 52.8 +/- 0.88 years) were included in this study. Fitness level was assessed by (a) time to exhaustion, and (2) maximal oxygen uptake achieved during an incremental treadmill test. Plasma lipid levels were determined in the basal, fasting state. Carbohydrate metabolism was evaluated by the glucose and insulin responses (total glucose and insulin areas under the curve, insulin sensitivity index [ISI]) to a 75-g, 2-hour oral glucose tolerance test (OGTT). Abdomen to hip ratio (AHR) was used as the index of regional adiposity. Multiple regression analysis indicated that fitness level and the percentage of body fat were significant predictors (approximately 56% of total variance) for total insulin area under the curve and the ISI. A comparison between the sedentary and trained subjects showed that training resulted in an improved ISI at an equal AHR. Fitness level was also the only significant multiple regression predictor for high-density lipoprotein (HDL)-cholesterol (25% of total variance) and accounted for the greatest amount of variance in triglyceride levels (34%), although AHR was also a significant predictor (6%).(ABSTRACT TRUNCATED AT 250 WORDS)

Impact of insulin resistance on lipoprotein subpopulation distribution in lean and morbidly obese nondiabetic women.

The purpose of this study was to examine the effects of insulin resistance on the lipoprotein subpopulation distribution of very-low-density, low-density, and high-density lipoproteins (VLDL, LDL, and HDL) in lean and morbidly obese nondiabetic women. Lean women (body mass index [BMI], 20 to 27 kg/m2) stratified by BMI were divided into insulin-sensitive (SL, n = 12) and insulin-resistant (RL, n = 8) groups according to Bergman's minimal model, SI. A group of obese women (BMI, 30 to 53 kg/m2), also stratified by BMI, were divided into insulin-sensitive (SO, n = 10) and insulin-resistant (RO, n = 11) groups in a similar fashion. Resistant groups were similar to sensitive groups (SL v RL and SO vRO) in age, weight, percent body fat, and waist circumference, ie, total and regional adiposity. VLDL, LDL, and HDL subpopulation distributions were determined in fasting plasma samples by nuclear magnetic resonance (NMR) spectroscopy. The average particle sizes of all 3 classes of lipoproteins were similar for the SL and RL groups. In contrast, RO subjects had larger VLDL, smaller LDL, and smaller HDL, than SO subjects (P < .05). Lower concentrations of large LDL and large HDL were found in RO compared with SO subjects (P < .05). In obese women, but not in lean women, VLDL size was associated with plasma insulin (r = .60, P < .005), while LDL size and HDL size were negatively correlated with plasma insulin (r = -.39, P < .05 and r = -.38, P < .05) and positively correlated with SI (r = .54, P < .01 and r = .42, P < .05). These results suggest that in obese women, insulin resistance may be involved in the formation of lipoprotein subpopulation distributions that are associated with vascular disease.