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Departments of Medicine (D.E.K., K.V.W., T.M.M., B.H.G.) and Radiology (J.C.P., F.L.T.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261; and Medical Research Service, Pittsburgh Veterans Affairs Medical Center (D.E.K.), Pittsburgh, Pennsylvania 15240
Address all correspondence and requests for reprints to: David E. Kelley, M.D., Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, MUH N809, Pittsburgh, Pennsylvania 15213.
Abstract
Skeletal muscle insulin resistance (IR) is typically severe in type 2 diabetes mellitus (DM). However, the factors that account for interindividual differences in the severity of IR are not well understood. The current study was undertaken to examine the respective roles of plasma FFA, regional adiposity, and other metabolic factors as determinants of the severity of skeletal muscle IR in type 2 DM. Twenty-three subjects (12 women and 11 men) with type 2 DM underwent positron emission tomography imaging using [18F]2-fluoro-2-deoxyglucose during euglycemic insulin infusions (120 mU/min·m2) to measure skeletal muscle IR, using Patlak analysis of the tissue activity curves. Body composition analysis included body mass index, fat mass, and fat-free mass by dual energy x-ray tomography, and computed tomography determinations of visceral adiposity, thigh adipose tissue distribution, and muscle composition. Body mass index, fat mass, subfascial adiposity in the thigh, and visceral adipose tissue (VAT) were all significantly related to skeletal muscle IR (r = -0.48 to -0.63; P < 0.01). However, the strongest simple correlate of IR in skeletal muscle was insulin-suppressed plasma FFA (r = -0.81; P < 0.001). VAT was the sole component of adiposity that significantly correlated with insulin-suppressed plasma FFA concentration (r = 0.64; P < 0.001). These findings indicate that the severity of skeletal muscle IR in type 2 DM is closely related to the IR of suppressing lipolysis and that plasma fatty acids and VAT are key elements mediating the link between obesity and skeletal muscle IR in type 2 DM.
THERE HAS BEEN a long-standing interest in the role of plasma FFA in the pathogenesis of skeletal muscle insulin resistance (IR) in obesity and type 2 diabetes mellitus (DM) (1). Experimental manipulations that elevate plasma FFA have been shown to induce IR in vivo, although this effect takes several hours to become manifest (2, 3, 4, 5). Recent studies indicate that the mechanism by which FFA induce IR in skeletal muscle is through inhibition of insulin signaling at PI3K and a related inhibition of glucose transport (6). In skeletal muscle, inhibition of hexokinase, pyruvate dehydrogenase, and glycogen synthase by fatty acids or long chain acyl coenzyme A have also been reported (4, 7, 8). The metabolic phenotype of IR induced in skeletal muscle by FFA, namely, inhibition of insulin signaling, glucose transport, and phosphorylation and a substantial impairment of muscle glycogen formation (3, 6, 9), is very similar to the metabolic phenotype of skeletal muscle IR observed in type 2 DM (10). It has therefore been an attractive postulate that FFA contributes to the pathophysiology of IR in this disorder. In support of this concept, Santomauro (11) recently reported that reductions in plasma FFA, achieved by acipimox suppression of lipolysis, reduced IR in type 2 DM. As intriguing as these data seem for supporting the hypothesis that FFA mediate the severity of skeletal muscle IR in type 2 DM, there are important caveats to this line of reasoning. First, the large majority of studies that have investigated FFA-induced IR have examined healthy, nondiabetic volunteers (2, 3, 4, 5, 9), with only a few studies carried out in individuals with type 2 DM (11, 12). Second, the levels of plasma FFA that have been attained by experimental manipulations (e.g. lipid emulsion and heparin infusions) generally far exceed the usual physiological range of plasma FFA. Thus, additional data obtained in patients with type 2 DM and within a range of values of plasma FFA that occur physiologically would be useful to further evaluate the role of substrate competition in the pathogenesis of skeletal muscle IR in type 2 DM.
The current study was undertaken to examine the hypothesis that plasma FFA modulates the severity of skeletal muscle IR in type 2 DM. Plasma FFA were measured during fasting and insulin-stimulated conditions, and the variance in skeletal muscle IR was examined in relation to these values. Other metabolic characteristics, such as fasting hyperglycemia, hemoglobin A1c (HbA1c), and lipid profiles, were also examined. Positron emission tomography (PET) imaging was used to obtain a tissue-specific measure of insulin action in skeletal muscle (13) Because obesity causes IR and has been shown to influence the severity of IR in type 2 DM (14, 15, 16, 17, 18), volunteers with type 2 DM in the current study had measurements made of body mass index (BMI), fat mass (FM), and visceral adiposity. These measurements also included thigh adiposity, including measurement of muscle composition and the subfascial deposition of adipose tissue in the thigh. These body composition determinations provided a more complete context with which to assess whether FFA served as a surrogate measure of adiposity in relation to skeletal muscle IR.
Subjects and Methods
Subjects
Twenty-three subjects with type 2 DM, 11 men and 12 women,
participated in this study, and their clinical characteristics are
shown in Table 1
. Their mean age was
56 ± 2 yr, with a mean known duration of diabetes of
approximately 7 ± 1 yr. The baseline HbA1c
was 8.5 ± 0.5%, with a range from 5.3–11.7%, and a fasting
plasma glucose of 12.7 ± 0.8 mmol/liter. Characteristic of type 2
DM, this group of volunteers had a moderate elevation of plasma
triglyceride and low density lipoprotein cholesterol and a moderately
reduced mean value for high density lipoprotein cholesterol
(HDL-C).
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Body composition
Body composition was assessed by weight and height using calibrated scales, a dual energy x-ray absorptiometry scan, a cross-sectional computed tomography (CT) scan of the abdomen, and CT scans of the midthigh to determine adipose tissue distribution and, in the case of the thigh images, to determine muscle composition. CT scans of the abdomen were not obtained in four subjects (three women and one man) due to technical reasons. To determine overall FM and fat-free mass (FFM), dual energy x-ray absorptiometry (model DPX-L, Lunar Corp., Madison, WI) was performed using software version 1.3Z. CT (9800 CT scanner, General Electric, Milwaukee, WI) was used for a single cross-sectional scan of 10-mm thickness centered at the L4–L5 vertebral disc space using 170 mA with a scanning time of 2 sec and a 512 x 512 matrix, as previously described (19). The boundary between visceral and sc adipose tissue (SAT) was defined using the abdominal wall musculature in continuity with the deep fascia of the paraspinal muscles. The same image was also purposely displayed at a negative window to clearly visualize the superficial fascia (i.e. Scarpa’s fascia) within the SAT, and a cursor was used to demarcate this boundary, as previously described (20). The cross-sectional area of adipose tissue (AT) was calculated as the number of pixels (0.6 mm) occupied by tissue in the fat density range [-190 to -30 Hounsfield units (HU)], using commercially available software (GE Medical Systems). Subjects also had cross-sectional CT of the midthigh to determine AT distribution at this location and cross-sectional area and the attenuation values of skeletal muscle, as previously described (21). Briefly, areas of bone, AT, and skeletal muscle were measured by selecting the following regions of interest defined by attenuation values: more than 200 HU for bone, -30 to -190 HU for adipose tissue, and 0–100 HU for skeletal muscle.
PET imaging of skeletal muscle insulin sensitivity
At entry into the study, a volunteer began a 4-wk period during which prior diabetic treatment was discontinued and diet treatment alone was used. At the start of this baseline period, nutritional instruction was given for a weight-maintaining diet. On the evening before PET imaging, subjects were admitted to the University of Pittsburgh General Clinical Research Center and received a standardized dinner (7 kcal/kg BW; American Dietary Association diet plan) and then were fasted, except for water, until completion of the insulin infusion studies the following day. PET imaging studies were performed at the University of Pittsburgh PET Imaging Center. The next morning, an antecubital venous catheter was placed for insulin and glucose infusions and for injection of tracer for PET studies. A radial arterial catheter was placed to permit rapid blood sampling after the injection of [18F]2-fluoro-2-deoxyglucose ([18F]FDG), so that the arterial concentrations could be defined as an input function in the determination of muscle [18F]FDG uptake. Catheters for infusions and sampling were kept patent with saline; heparin was not used. After a baseline sample for insulin, C peptide, plasma FFA, lipoproteins, and plasma glucose determinations, an insulin infusion (120 mU/m2·min) was started, and subjects were brought to and maintained at euglycemia using the glucose clamp technique. Samples for FFA were collected in EDTA, placed on ice, and promptly centrifuged, then frozen at -80 C until assay by an enzymatic method (Wako NEFA, Wako Chemical GmbH, Neuss, Germany). After 2.5 h of insulin infusion, subjects were positioned in the PET scanner so that midthigh corresponded to the midpoint of the scanner’s field of view. A transmission scan was collected using enclosed rotating rods of 68Ge/68Ga to measure individual attenuation coefficients, which were applied during reconstruction of images for quantitative mapping of radioactivity. Dynamic PET imaging took place over 60 min, beginning with iv injection of 4 mCi [18F]FDG. Blood sampling for plasma [18F]FDG radioactivity began simultaneously with PET scanning. Blood was centrifuged, and radioactivity in 0.1 ml plasma was counted using a Packard Canbarra well counter (Downers Grove, IL). Insulin infusion and euglycemia were maintained during PET imaging. A 60-min dynamic PET scan was simultaneously initiated (16 frames: 4 x 30 sec, 4 x 2 min, 6 x 5 min, 2 x 10 min). Sampling of arterial blood for plasma [18F]FDG radioactivity was obtained at 6-sec intervals for 2 min, at 20-sec intervals for 1 min, at 30-sec intervals for 1 min, and at 5, 7, 10, 15, 20, and 30 min, then every 10 min until 60 min postinjection of [18F]FDG. Exact timing of each sample was recorded. The PET scans were acquired three-dimensional imaging modes using a Siemens ECAT Advanced Rotating Tomography scanner (Iselin, NJ). The Siemens ECAT ART scanner acquired 47 imaging planes [three-dimensional; in-plane resolution, 6.0 mm; FWHM (ramp filter); axial slice width, 3.4 mm]. The three-dimensional ART had a scatter fraction that was approximately 37% (22), and these emission data were corrected for scattered photons using a model-based correction method (23, 24).
Three cross-sectional CT scans of 1-cm thickness were obtained of the upper, mid, and lower boundaries of the midthigh and were coregistered with the corresponding PET transmission images as previously described (25). Regions of interest (ROIs) were drawn in medial and lateral thigh muscle using Imagetool (CTI PET Systems, Knoxville, TN) software and saved as template files for application to the PET images. The ROIs were applied across multiple planes of the dynamic PET scans after correction of the PET data for radioactive decay. The tissue-time activity data within the ROIs were converted to units of radioactivity concentration (microcuries per ml) using an empiric phantom-based calibration factor (microcuries per ml/PET counts/pixel).
Modeling of PET data
Data from the time-activity curves of skeletal muscle
[18F]FDG imaging and arterial input functions
were analyzed using the standard Patlak graphical analysis, which gives
the overall uptake of [18F]FDG
(26). The Patlak plot is a graphical method that applies
well to heterogeneous and homogeneous tissues (27). It is
mainly used under the assumption that the substances are irreversibly
trapped in a system. After equilibration between
[18F]FDG in tissue and in plasma and assuming
dephosphorylation not present, Patlak demonstrated that the PET
measurement plotted against the normalized integrated tracer
concentration in arterial plasma increases linearly with a slope
directly proportional to K:
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Statistics
Data are expressed as the mean ± SEM. Linear regression was used to examine the statistical significance of correlation of metabolic variables with skeletal muscle IR determined by PET imaging. Variables that were not normally distributed were log transformed. P < 0.05 was considered significant. In addition to performing regression analysis, group comparisons were conducted to examine the relationship of FFA and obesity with skeletal muscle IR. Volunteers were categorized as insulin sensitive (IS) or insulin resistant (IR) based on a priori criteria for skeletal muscle IR. The a priori criteria were taken from our recently published data on PET parameters of skeletal muscle insulin sensitivity measured in lean healthy nondiabetic volunteers studied at the same rate of insulin infusion as that used in the current study (i.e. 120 mU/min·m2). In that study (25) the lean volunteers had a mean K value of 0.01173 ± 0.00156 ml/min·g tissue. Subjects in the current study who had a K value more than 2 SD below this value (i.e. K < 0.00861 ml/min·g tissue) were categorized as IR. The two groups (IS and IR) were then compared for clinical, metabolic, and body composition characteristics using ANOVA.
Results
Insulin-stimulated glucose metabolism
On the morning of the study, after 4-wk washout of any prior antidiabetic pharmacological treatment, the mean value for fasting plasma glucose was 226 ± 15 mg/dl, with a fasting value for plasma insulin of 13 ± 2 µU/ml. During insulin infusion at 120 mU/min·m2, the mean steady state plasma insulin concentration was 261 ± 10 µU/ml, which was approximately 20-fold greater than basal, and euglycemia (98 ± 1 mg/dl) was achieved in all subjects. The mean fasting level of plasma fatty acids was 847 ± 37 pmol/liter and decreased to 155 ± 18 pmol/liter during insulin infusion, with a range for insulin-suppressed plasma FFA from 74–374 pmol/liter. The mean rate of glucose infusion needed to maintain euglycemia was 7.5 ± 0.8 mg/min·kg FFM, with a range from 2.1–14.0 mg/min·kg FFM. There was also a wide range in the values for K, the PET parameter reflecting insulin-stimulated uptake of FDG into skeletal muscle, with nearly a 10-fold difference across the range, from 0.0006–0.053 ml/min·g tissue. Rates of glucose infusion (GINF) were correlated with K (r = 0.84; P < 0.001). There was not a significant effect of gender on K or GINF or on the correlation between these variables.
Association of IR with metabolic variables
Variance in IR of skeletal muscle was examined with respect to
metabolic parameters, including HbA1c, fasting
insulin, and C peptide, and basal and insulin-suppressed plasma FFA as
well as with clinical characteristics (Table 2). In these analyses there was not a
significant effect of gender, so the correlation for the entire group
is presented. Age, known duration of type 2 DM, fasting plasma glucose,
and HbA1c were not significantly correlated with
values for K (P = 0.2–0.4). However, K was
significantly and negatively related to fasting plasma C peptide
(r = -0.71; P < 0.01) and fasting plasma insulin
(r = -0.62; P < 0.01). The insulin sensitivity
of skeletal muscle was even more strongly correlated with
insulin-suppressed concentrations of plasma FFA attained during the
insulin infusion (r = -0.81; P < 0.001), as
shown in Fig. 1. There was also a
significant, though weaker, correlation of insulin resistance with
fasting concentrations of plasma FFA (r = -0.45;
P = 0.03), fasting plasma triglyceride (r =
-0.53; P < 0.01), and plasma HDL-C (r = 0.44;
P = 0.03). There was not a significant correlation
between skeletal muscle IR and low density lipoprotein cholesterol.
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Data on body composition are shown in Table 3. As a group, these subjects with type 2
DM were moderately obese, with a mean BMI of 32.1 ± 1.0
kg/m2, but there was a fairly broad range of
values for BMI, from 21.5–40.4 kg/m2. Despite
similar mean values for BMI in men and women, men had a higher FFM
(59 ± 2 vs. 49 ± 3 kg; P <
0.05), and women had a greater percentage of weight as fat mass
(29 ± 3 vs. 42 ± 2%, men and women,
respectively; P < 0.05). With respect to visceral
adiposity, there was a 10-fold variance across the group, with a mean
value of 207 ± 20 cm2. Mean values for VAT
were greater in women (174 ± 15 vs. 243 ± 36
cm2, men and women, respectively;
P < 0.05) despite the similarity in mean BMI. Visceral
adiposity was correlated with BMI and FM (r = 0.59 and r =
0.57, respectively; P < 0.01). The amount of AT in the
deep sc layer was 189 ± 15 cm2, and there
was no gender difference in this parameter. The amount of AT in the
superficial layer was 172 ± 21 cm2, but
there were strong gender differences, with women having 244 ± 22
and men having 108 ± 17 cm2
(P < 0.001).
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Relation of IR to AT distribution
The correlation between the insulin sensitivity of skeletal
muscle, expressed by the PET parameter K, and systemic or regional
measures of adiposity are shown in Table 4. There was not an effect of gender
differences in these correlations. The correlation between K and VAT
was the strongest simple correlation between insulin sensitivity and
body composition (Fig. 2). However, the
association of K with FM or BMI was only moderately less robust than
that for VAT. The simple correlations between and K for deep sc AT and
superficial SAT of the abdomen were r = -0.21 and r =
-0.48, respectively, and therefore were not as robust for VAT in this
cohort with type 2 DM. The correlation of GINF with overall or regional
adiposity was weaker than the correlation between adiposity and the
PET-derived determination of skeletal muscle insulin sensitivity, as
also shown in Table 2
, demonstrating the greater precision of measuring
insulin action in muscle with this tissue-specific modality. With
regard to AT in the lower extremities, thigh sc adiposity was not
significantly correlated with K, whereas the correlation with thigh
subfascial adiposity was statistically significant (P =
0.02). Muscle attenuation was positively related to K, but the
association was of borderline statistical significance
(P = 0.08).
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. In multivariate analysis, plasma FFA was not only a more robust
simple correlate than any measure of adiposity in relation to muscle
IR, but adiposity did not contribute independent significance after
adjusting for plasma FFA. Comparison of IS and IR subgroups
Using the a priori criteria previously described in
Subjects and Methods, subjects were categorized as IS or IR
on the basis of insulin-stimulated PET data, and these data are shown
in Table 5. The two groups, IS and IR,
respectively, were of similar mean age (57 ± 2 vs.
55 ± 2 yr; P = NS) and had a similar known
duration of type 2 DM (8 ± 2 vs. 7 ± 1 yr;
P = NS). According to the criteria, the IS group had a
higher value for K, which was nearly 6-fold higher than that in the IR
group (P < 0.001). There was a corresponding
difference in values for steady state GINF (P <
0.001). The IS group tended to be less obese, have less VAT
(P = 0.13), and have lower FM and percent FM
(P = 0.18), although these differences did not achieve
statistical significance. With respect to thigh composition, the IS
group tended to have less subfascial AT in the thigh (P
= 0.11) and a higher value for muscle attenuation (P =
0.06). The IS group did have significantly less low density lean tissue
in the thigh muscle (P = 0.05) and a lower percentage
of low density lean tissue in the thigh muscle (P =
0.05). IS subjects also tended to have lower values for
HbA1c (P = 0.06) and lower
fasting values for plasma C peptide (P = 0.013). The
strongest group difference between IS and IR was insulin-suppressed
plasma FFA, which was lower in the IS group (P =
0.001), as was the percent suppression of plasma FFA (baseline to
insulin-stimulated conditions) with values of 83 ± 2%
vs. 71 ± 2%, in IS and IR, respectively
(P = 0.003). Fasting levels of plasma FFA did not
differ significantly in IS compared with IR groups (781 ± 49
vs. 891 ± 54 pmol; P = 0.15).
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The current study was undertaken to examine whether the extent to which insulin suppresses plasma FFA is a determinant of the interindividual differences in the severity of skeletal muscle IR in type 2 DM. The findings strongly support this hypothesis. Across a cohort of men and women with type 2 DM, variance in insulin-suppressed levels of plasma FFA accounted for nearly two thirds of the group variance in the severity of skeletal muscle insulin resistance. These findings indicate that insulin-regulated suppression of plasma FFA probably modulates the severity of IR in type 2 DM.
Several methodological aspects of this study fortify the conclusion that plasma FFA modulates the severity of IR in type 2 DM. First, a tissue-specific measure of skeletal muscle insulin action was obtained using PET imaging with the glucose analog [18F]FDG. In the setting of marked IR, as occurs in type 2 DM, it can be problematic to quantify the role of muscle from low systemic rates of insulin-stimulated glucose metabolism, and PET imaging makes this feasible (13). Second, in the current study an extensive array of body composition determinations were obtained, including overall FM, CT determinations of visceral and sc abdominal adiposity, and CT determinations of muscle lipid content and AT distribution in the thigh. Not unexpectedly, adiposity and, more specifically, the distribution of AT were related to the severity of IR in type 2 DM. This is consistent with prior data (14, 15, 16, 28, 29). However, these different measures of adiposity accounted for approximately 25–40% of the variance in the severity of skeletal muscle IR among these volunteers with type 2 DM, and in multivariate analysis, after adjusting for plasma FFA, the effect of adiposity or any subdivision of adiposity was not significant.
Visceral adiposity was the measure of AT distribution that was most strongly related to skeletal muscle IR (r = -0.63). This finding is consistent with some (16), but not all (15), prior reports in subjects with type 2 DM. It is noteworthy that in the current study the mean value for VAT among the group of women with type 2 DM was greater than that in the men, although these groups had a similar BMI. In general, for a given BMI, nondiabetic men usually have more VAT than women (28), and we are not aware of prior data suggesting that this gender effect is not present in type 2 DM.
More directly pertinent to the hypothesis of the study was the finding that VAT was the single measure of adiposity that was significantly related to insulin-suppressed levels of plasma FFA. These data suggest that plasma FFA levels may be a link mediating the relationship between VAT and skeletal muscle IR. Adipocytes within omental and mesenteric fat are more resistant to suppression of lipolysis by insulin than are sc depots of AT (30). Therefore, the data on body composition in the current study integrate well with the data on muscle glucose metabolism in supporting that IR of lipolysis, and of VAT in particular, with plasma FFA as the circulating mediator is a key aspect of the link between obesity and IR in glucose metabolism in skeletal muscle.
The hypothesis of glucose-fatty acid substrate competition as a modulator of insulin action in skeletal muscle was articulated by Randle and colleagues (1) more than 4 decades ago. Contemporary with Randle’s original presentation of the concepts on substrate competition in skeletal muscle, Zierler and colleagues (31) demonstrated in humans that skeletal muscle relied on oxidation of plasma fatty acids during fasting conditions. In lean, healthy volunteers, the reliance on fat oxidation during fasting conditions is substantially suppressed by insulin (32). Suppression of fat oxidation by insulin is due substantially to an inhibition of lipolysis and suppression of plasma FFA, as fractional extraction of plasma FFA by skeletal muscle continues at a high rate during insulin-stimulated conditions, albeit in the face of greatly reduced plasma FFA concentrations (4, 33). More recently, our laboratory has found that in obesity and type 2 DM, skeletal muscle manifests metabolic inflexibility in the transitions between fasting and insulin-stimulated patterns of fatty acid and glucose utilization (34), and that this inflexibility, which includes impaired suppression of lipid oxidation during insulin-stimulated conditions, is a component of the IR phenotype of skeletal muscle.
There are convincing experimental findings that acute manipulations of plasma FFA levels can modulate skeletal muscle insulin sensitivity. Using arterio-venous limb balance, our laboratory found that merely maintaining fasting levels of plasma FFA, by infusion of a triglyceride emulsion, during euglycemia and moderate hyperinsulinemia induced skeletal muscle IR in lean healthy volunteers (4). This is strongly supportive of the concept that insulin action to stimulate glucose utilization is mediated indirectly, through inhibition of lipolysis and reduction of plasma FFA. Boden (2) demonstrated a time dependence of the induction of IR by FFA and showed that glycogen formation and activation of the enzyme glycogen synthase are adversely affected (8). Roden and colleagues, using phosphorous magnetic resonance spectroscopy of human skeletal muscle, found an adverse effect of plasma FFA on insulin-stimulated glucose transport or phosphorylation (9). Reductions in glucose transport and glucose phosphorylation have been found by several methods to be the proximal metabolic impairments of skeletal muscle IR in type 2 DM (13, 35, 36, 37). Cellular mechanisms include altered insulin signaling, impaired glucose transport, and inhibition of hexokinase (4, 6, 7).
In addition to these important prior studies that provide a conceptual framework for the current investigation, there are two prior studies that are even more directly pertinent. One of these is the earlier application of PET methodologies for the study of substrate competition in skeletal muscle by Nuutila (38), who reported that elevated plasma FFA inhibited insulin-stimulated FDG uptake in skeletal muscle in healthy volunteers. Recent studies by our laboratory and others have defined the analog effect of FDG in skeletal muscle and have shown that this is not altered by insulin or insulin resistance (39). Thus, the approach of using PET imaging to obtain a high fidelity, tissue-specific measurement of insulin action in skeletal muscle has become well supported, and the current study demonstrates the usefulness of this method to examine differences in insulin action even within a cohort characterized by severe IR. The second study of great relevance to the current work is the recent report by Sanomauro et al. (11), who examined whether reductions in plasma FFA reduce IR in type 2 DM. Using acipimox to suppress lipolysis and thereby lower plasma FFA, it was found that peripheral IR was improved (11). The results of the current study suggest that variance in levels of plasma FFA within a relatively narrow range in response to a standardized insulin infusion protocol accounted for nearly two thirds of the variance in skeletal muscle IR. The data reported by Sanomauro (11) are consistent with this, in that their study indicates that relatively modest reductions lead to discernible changes in the severity of IR.
Another novel aspect of the relationship between regional adiposity and IR that was addressed in the current study, in addition to that of insulin-suppressed levels of plasma FFA and VAT, concerns the distribution of AT in the lower extremity. Goodpaster (40) found that AT located beneath the fascia lata of the thigh, although representing only approximately 10% of adiposity in the thigh, was significantly associated with IR, although the larger depot of thigh sc adipose tissue was only weakly associated with IR. In that study, which included lean and obese nondiabetic subjects and those with type 2 DM, the group with the largest amount of subfascial thigh adiposity were the subjects with type 2 DM (40). In the current study with the analyses restricted solely to a separate cohort comprised only of subjects with type 2 DM, a significant relation between subfascial thigh adiposity and IR was also observed. These observations further broaden the concept that location of adiposity, even within the lower extremity, is a key factor mediating obesity-related IR. Whether this might be mediated by local impairment of suppression of lipolysis or through production of other factors by AT, such as cytokines, is an important area for future research.
A number of research groups have been investigating the role of lipid content of skeletal muscle as a determinant of IR. Various approaches, ranging from lipid extraction from muscle biopsy, histological staining, and estimation of myocyte lipid content to proton spectroscopy of muscle triglyceride using in vivo magnetic resonance spectroscopy, have found that muscle lipid content correlates with IR (41). In the current study the association between muscle lipid content and IR was present, but was not as robust as had been found in prior studies. This may reflect in part that muscle lipid content is substantially increased in type 2 DM (42), and the current study was comprised solely of individuals with type 2 DM, thereby limiting variance for this parameter. In the group comparison of IS and IR, the body composition parameter that did reveal significant differences was the amount of low density lean tissue, a measure of fat-laden skeletal muscle (43).
Among other metabolic and clinical factors assessed in the current
study as potential determinants of variance of skeletal muscle IR,
those related to glycemic control (e.g.
HbA1c and fasting plasma glucose) were only
nominally associated with skeletal muscle IR. Also, the duration of
type 2 DM, admittedly an imprecise determination, was not a significant
determinant. However, in addition to insulin-suppressed plasma FFA,
other markers related to lipid metabolism were strongly related to
skeletal muscle IR. Fasting levels of plasma FFA, fasting plasma
triglyceride levels, and plasma HDL-C concentrations were correlated
significantly with skeletal muscle IR. In addition, fasting plasma
insulin and fasting plasma C peptide had fairly strong correlations
with skeletal muscle IR (correlation coefficients of 
0.6–0.7).
In summary, in the current study we observed that variations in several aspects of regional adiposity, namely subfascial AT in the thigh and abdominal adiposity, contribute substantially to the interindividual variance in the severity of skeletal muscle IR in type 2 DM. Among the depots of regional and overall adiposity, visceral adiposity was the depot of AT that was most strongly related to skeletal muscle IR. The mechanism for the association between VAT and skeletal muscle IR appears, in turn, to be an association between VAT and resistance to the suppression of plasma fatty acids by insulin. These findings point to the potential therapeutic importance of reducing adiposity and particularly visceral adiposity as a means of improving IR in type 2 DM. As an adjunct to weight loss or as an alternative if weight loss cannot be achieved, the current findings suggest that treatment targeted at improved insulin suppression of lipolysis could be an effective means to lessen skeletal muscle IR in type 2 DM.
Acknowledgments
We are grateful to our research volunteers and for the support of the nurses and research technicians at the General Clinical Research Center and the Positron Emission Tomography Center of the University of Pittsburgh. We also acknowledge the technical expertise of Janice Beattie, R.N.; Sue Andreko, M.S.; and the assistance of Cristy Matan with the analysis of the PET data.
Footnotes
This work was supported by University of Pittsburgh General Clinical Research Center Grant 5-MO1-RR-00056, the Medical Research Service of the Pittsburgh V.A. Medical Center, NIH Mentored Patient-Oriented Research Career Development Award DK-02647-02 (to K.V.W.), NIH K-24 Award 5-K24-DK-02782-02), and Career Development Award KO1-AG-00851 (to B.H.G.).
Abbreviations: AT, Adipose tissue; BMI, body mass index; CT, computed tomography; DM, diabetes mellitus; [18F]FDG, [18F]2-fluoro-2-deoxyglucose; FM, fat mass; FFM, fat-free mass; GINF, glucose infusion rate; HbA1c, hemoglobin A1c; HDL-C, high density lipoprotein cholesterol; HU, Hounsfield units; IS, insulin-sensitive; IR, insulin resistance, insulin-resistant; PET, positron emission tomography; ROI, region of interest; SAT, sc adipose tissue; VAT, visceral adipose tissue.
Received March 7, 2001.
Accepted July 31, 2001.
References
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B. Ukropcova, O. Sereda, L. de Jonge, I. Bogacka, T. Nguyen, H. Xie, G. A. Bray, and S. R. Smith Family History of Diabetes Links Impaired Substrate Switching and Reduced Mitochondrial Content in Skeletal Muscle Diabetes, March 1, 2007; 56(3): 720 - 727. [Abstract] [Full Text] [PDF]
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 M. A. Tarnopolsky, C. D. Rennie, H. A. Robertshaw, S. N. Fedak-Tarnopolsky, M. C. Devries, and M. J. Hamadeh Influence of endurance exercise training and sex on intramyocellular lipid and mitochondrial ultrastructure, substrate use, and mitochondrial enzyme activity Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2007; 292(3): R1271 - R1278. [Abstract] [Full Text] [PDF]
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 S. R. Smith and P. W. F. Wilson Free Fatty acids and atherosclerosis--guilty or innocent? J. Clin. Endocrinol. Metab., July 1, 2006; 91(7): 2506 - 2508. [Full Text] [PDF]
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C. Hadigan, D. Kamin, J. Liebau, S. Mazza, S. Barrow, M. Torriani, R. Rubin, S. Weise, A. Fischman, and S. Grinspoon Depot-specific regulation of glucose uptake and insulin sensitivity in HIV-lipodystrophy Am J Physiol Endocrinol Metab, February 1, 2006; 290(2): E289 - E298. [Abstract] [Full Text] [PDF]
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B.-S. Cha, T. P. Ciaraldi, K.-S. Park, L. Carter, S. R. Mudaliar, and R. R. Henry Impaired fatty acid metabolism in type 2 diabetic skeletal muscle cells is reversed by PPAR{gamma} agonists Am J Physiol Endocrinol Metab, July 1, 2005; 289(1): E151 - E159. [Abstract] [Full Text] [PDF]
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Y. Tamura, Y. Tanaka, F. Sato, J. B. Choi, H. Watada, M. Niwa, J. Kinoshita, A. Ooka, N. Kumashiro, Y. Igarashi, et al. Effects of Diet and Exercise on Muscle and Liver Intracellular Lipid Contents and Insulin Sensitivity in Type 2 Diabetic Patients J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3191 - 3196. [Abstract] [Full Text] [PDF]
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 Y.-H. Yu and H. N. Ginsberg Adipocyte Signaling and Lipid Homeostasis: Sequelae of Insulin-Resistant Adipose Tissue Circ. Res., May 27, 2005; 96(10): 1042 - 1052. [Abstract] [Full Text] [PDF]
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A. Bertoldo, J. Price, C. Mathis, S. Mason, D. Holt, C. Kelley, C. Cobelli, and D. E. Kelley Quantitative Assessment of Glucose Transport in Human Skeletal Muscle: Dynamic Positron Emission Tomography Imaging of [O-Methyl-11C]3-O-Methyl-D-Glucose J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1752 - 1759. [Abstract] [Full Text] [PDF]
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A. M. Poynten, S. K. Gan, A. D. Kriketos, L. V. Campbell, and D. J. Chisholm Circulating Fatty Acids, Non-High Density Lipoprotein Cholesterol, and Insulin-Infused Fat Oxidation Acutely Influence Whole Body Insulin Sensitivity in Nondiabetic Men J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 1035 - 1040. [Abstract] [Full Text] [PDF]
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S. D. Driscoll, G. E. Meininger, K. Ljungquist, C. Hadigan, M. Torriani, A. Klibanski, W. R. Frontera, and S. Grinspoon Differential Effects of Metformin and Exercise on Muscle Adiposity and Metabolic Indices in Human Immunodeficiency Virus-Infected Patients J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2171 - 2178. [Abstract] [Full Text] [PDF]
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 D. E. Kelley, L. H. Kuller, T. M. McKolanis, P. Harper, J. Mancino, and S. Kalhan Effects of Moderate Weight Loss and Orlistat on Insulin Resistance, Regional Adiposity, and Fatty Acids in Type 2 Diabetes Diabetes Care, January 1, 2004; 27(1): 33 - 40. [Abstract] [Full Text] [PDF]
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D. E. Kelley, T. M. McKolanis, R. A. F. Hegazi, L. H. Kuller, and S. C. Kalhan Fatty liver in type 2 diabetes mellitus: relation to regional adiposity, fatty acids, and insulin resistance Am J Physiol Endocrinol Metab, October 1, 2003; 285(4): E906 - E916. [Abstract] [Full Text] [PDF]
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Z. T. Bloomgarden Fat Metabolism and Diabetes: 2003 American Diabetes Association Postgraduate Course Diabetes Care, July 1, 2003; 26(7): 2198 - 2203. [Full Text] [PDF]
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K. V. Williams, A. Bertoldo, P. Kinahan, C. Cobelli, and D. E. Kelley Weight Loss-Induced Plasticity of Glucose Transport and Phosphorylation in the Insulin Resistance of Obesity and Type 2 Diabetes Diabetes, July 1, 2003; 52(7): 1619 - 1626. [Abstract] [Full Text] [PDF]
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D. Kim, S. Nam, C. Ahn, K. Kim, S. Yoon, J. Kim, B. Cha, S. Lim, K. Kim, H. Lee, et al. Correlation Between Midthigh Low- Density Muscle and Insulin Resistance in Obese Nondiabetic Patients in Korea Diabetes Care, June 1, 2003; 26(6): 1825 - 1830. [Abstract] [Full Text] [PDF]
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A. D. Kriketos, S. M. Furler, S. K. Gan, A. M. Poynten, D. J. Chisholm, and L. V. Campbell Multiple Indexes of Lipid Availability Are Independently Related to Whole Body Insulin Action in Healthy Humans J. Clin. Endocrinol. Metab., February 1, 2003; 88(2): 793 - 798. [Abstract] [Full Text] [PDF]
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