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Original Article |
Metabolism Unit, National Research Council Institute of Clinical Physiology and Department of Internal Medicine, University of Pisa (A.G., M.P., E.S., E.F.), I-56100 Pisa, Italy; and Diabetes Division, Department of Medicine, University of Texas Health Science Center (Y.M., M.M., S.M., R.A.D., E.F.), San Antonio, Texas 78284
Address all correspondence and requests for reprints to: Ele Ferrannini, M.D., Department of Internal Medicine, University of Pisa, Via Savi, I-56100 Pisa, Italy. E-mail: ferranni{at}ifc.cnr.it.
Abstract
Visceral fat (VF) excess has been associated with decreased peripheral insulin sensitivity and has been suggested to contribute to hepatic insulin resistance. However, the mechanisms by which VF impacts on hepatic glucose metabolism and the quantitative role of VF in glycemic control have not been investigated. In the present study 63 type 2 diabetic subjects (age, 55 ± 1 yr; fasting plasma glucose, 5.5–14.4 mmol/liter; hemoglobin A1c, 6.1–11.7%) underwent measurement of 1) fat-free mass (3H2O technique), 2) sc and visceral abdominal fat area (magnetic resonance imaging), 3) insulin sensitivity (euglycemic insulin clamp), 4) endogenous glucose output ([3H]glucose infusion technique), and 5) gluconeogenesis (2H2O method). After adjustment for sex, age, body mass index, diabetes duration, ethnicity, and sc fat area, VF area was positively related to fasting hyperglycemia (partial r = 0.46; P = 0.001) as well as to hemoglobin A1c (partial r = 0.50; P = 0.0003). Insulin sensitivity was reciprocally related to VF independently of body mass index (partial r = 0.33; P = 0.01). In contrast, the relation of basal endogenous glucose output to VF was not statistically significant. This lack of association was explained by the fact that VF was positively associated with gluconeogenesis flux (confounder-adjusted, partial r = 0.45; P = 0.003), but was reciprocally associated with glycogenolysis (partial r = 0.31; P < 0.05). We conclude that in patients with established type 2 diabetes, VF accumulation has a significant negative impact on glycemic control through a decrease in peripheral insulin sensitivity and an enhancement of gluconeogenesis.
A DIRECT RELATIONSHIP between degree of fasting hyperglycemia and increased endogenous glucose output (EGO) has been demonstrated in most studies (1, 2, 3, 4, 5, 6). In absolute terms EGO begins to rise when the fasting plasma glucose (FPG) exceeds 140 mg/dl (1, 2), although some investigators have suggested a higher FPG threshold (180 mg/dl) (7). At FPG levels below 140 mg/dl, fasting hyperinsulinemia, due to peripheral insulin resistance, exerts a restraining effect to maintain EGO within normal limits. We (8) and others (9) have reported that gluconeogenesis (GNG) is enhanced in type 2 diabetic patients, and that insulin is less potent in suppressing GNG than glycogenolysis (GLY) (10, 11).
Several lines of evidence have suggested a role for visceral fat (VF) accumulation in the pathogenesis of insulin resistance. Thus, VF excess has been associated with 1) decreased sensitivity of glucose uptake to insulin stimulation as measured by the euglycemic insulin clamp technique (12), 2) reduced rate of free fatty acids (FFA) reesterification (13), and 3) increased resistance of lipolysis to the inhibitory effect of insulin in both visceral and peripheral adipocytes (14, 15). It has been postulated that preferential influx of FFA (and other molecules produced by visceral adipocytes) via the portal circulation into the liver can induce or augment hepatic insulin resistance, in particular by enhancing GNG. However, direct evidence bearing on such hepatic effects is not, to our knowledge, available, nor is it clear whether such putative effects are great enough to influence fasting hyperglycemia and overall glycemic control in diabetic patients. In addition, VF accumulation is strongly related to overall adiposity (16), and this makes it mandatory to account for obesity when attempting to establish an independent role for VF in metabolic control.
The present study was undertaken to explore the relationship between VF [quantitated by magnetic resonance imaging (MRI)] and the severity of fasting hyperglycemia in a large group of type 2 patients, independently of confounders such as sex, age, and obesity. We also examined potential mechanisms (insulin-mediated glucose disposal, endogenous glucose output, GNG, and GLY) underlying such a relationship by employing the insulin clamp technique in combination with tracers.
Subjects and Methods
Subjects
The present series included 63 subjects with type 2 diabetes (37 Mexican-Americans and 26 Caucasians) with a wide range of FPG (5.5–14.4 mmol/liter) and hemoglobin A1c (HbA1c; 6.1–11.7%) concentrations, who were recruited at the Clinical Research Center of University of Texas Health Science Center (San Antonio, TX). None of the patients was treated with insulin, metformin, or thiazolidinediones. For subjects who were taking sulfonylureas (n = 25), the medication was stopped 2 d before the study. Subjects were not taking any other drugs known to affect glucose tolerance. The study protocol was approved by the institutional review board of the University of Texas Health Science Center, and informed written consent was obtained from each subject before participation.
Study design
Within a 5- to 7-d interval, all subjects received 1) measurement of fat-free mass (FFM) with the use of an iv bolus of 3H2O, 2) quantitation of sc and intraabdominal VF content using MRI, and 3) a euglycemic hyperinsulinemic clamp (to measure insulin sensitivity) combined with a primed-constant infusion of [3-3H]glucose (for measurement of EGO) and 2H2O ingestion (in 48 of the 63 study subjects) to measure the contribution of GNG and GLY to EGO.
Body composition and fat distribution
On the day of the study subjects were admitted to the Clinical Research Center at 0800 h. Height and weight were recorded, arterial blood pressure was measured, and waist and hip circumferences were measured to the nearest centimeter. A catheter was placed into an antecubital vein, and subjects received a 100-µCi iv bolus of 3H2O. Blood samples were drawn at 90, 105, and 120 min for the determination of plasma 3H2O radioactivity. FFM was calculated as described previously (17), and fat mass was determined as the difference between body weight and FFM. Intraabdominal VF and sc fat (SF) depots were measured by MRI, using imaging procedures previously described (18). Briefly, images were acquired on a 1.9 T Elscint Prestige MRI system (GE Medical System, Milwaukee, WI), using a T1-weighted spin echo pulse sequence with a TR of 500 msec and a TE of less than 20 msec. A sagittal localizing image was used to center transverse sections on the line through the space between L4 and L5. Ten 5.0-mm thick sections were acquired with a gap of 1.0 mm to prevent signal cross-over from adjacent sections. The field of view ranged from 30–50 cm depending on body size. Phase encoding was in the antero-posterior direction to minimize the effects of motion-induced phase artifacts that might otherwise be distributed laterally through a large portion of the abdomen. The field of view was adjusted for body size to ensure a 2-mm pixel spacing. Signal averaging (four-signal average) was used to reduce the effect of motion-related artifacts. Additionally, respiratory gating was used to combat motion-induced artifacts and to reduce the blurring of fat boundaries in the anterior region of the abdomen. Images were processed using Alice Software (Perceptive Systems, Inc., Boulder, CO) to determine abdominal sc and intraabdominal VF areas. The SF area was analyzed by selecting the outer and inner margins of sc adipose tissue as the region of interest from the cross-sectional images and counting the number of pixels between the outer and inner margins of sc adipose tissue. The visceral (intraabdominal) fat area was determined using histograms specific to the visceral regions. The histograms were summed over the range of pixel values designated as fat by fitting two normal analysis distribution curves to them.
Metabolic measurements
In the morning on the day before the study, a blood sample for the determination of background 2H2O enrichment was taken. At 2200 h on the evening before admission, subjects drank 2H2O (Isotec, Miamisbug, OH; 5 g/kg FFM). The following morning, subjects were admitted to the Clinical Research Center at 0700 h after a 13-h overnight fast. A polyethylene cannula was inserted into an antecubital vein for the infusion of all test substances. A second catheter was inserted retrogradely into an ipsilateral wrist vein on the dorsum of the hand for blood sampling, and the hand was kept in a heated box at 65 C. A primed (20-µCi)-constant infusion of 3-[3H]glucose (NEN Life Science Products, Boston, MA) was started at 0700 h and continued (at a rate of 0.20 µCi/min) throughout the duration of the study. The prime was adjusted in proportion to the elevation of FPG as follows: 20 µCi x FPG/5. During the last 30 min of the basal equilibration period (150–180 min after the start of 3-[3H]glucose), plasma samples were taken at 5- to 10-min intervals for the determination of plasma glucose, FFA, and insulin concentrations and [3H]glucose specific activity. After the 180-min basal equilibration period, insulin was administered as a primed-continuous infusion at the rate of 280 pmol/min·m-2 for 120 min as previously described (19). After the start of the insulin infusion, the plasma glucose concentration was allowed to decline to 5.0 mmol/liter, at which level it was maintained (with a coefficient of variation <5%) by measuring the plasma glucose concentration every 5 min and appropriately adjusting a variable infusion of 20% glucose based on the negative feedback principle. Plasma samples were collected every 15 min from 0–90 min and every 5–10 min from 90–120 min for the determination of plasma glucose and insulin concentrations and [3H]glucose specific activity. Plasma samples for the determination of GNG (see below) were taken before starting the [3H]glucose infusion and at the end of the basal period.
Analytical methods
The glucose concentration was determined by the glucose oxidase method (Beckman II Glucose Analyzer, Beckman, Fullerton, CA). The plasma insulin concentration was measured by RIA (Diagnostic Products, Los Angeles, CA). The serum HbA1c concentration was measured by affinity chromatography (biochemical methodology, Drower 4350, Isolab, Akron, OH). The plasma FFA concentration was measured spectrophotometrically (Wako Chemicals GmbH, Neuss, Germany). 3-[3H]Glucose specific activity was measured on barium hydroxide/zinc sulfate-deproteinized plasma samples (Somogyi’s procedure).
The pattern of 2H incorporation into plasma glucose after 2H2O ingestion was determined according to the method developed by Landau and recently modified (20, 21). Briefly, the fraction of glucose produced via GNG from all precursors can be quantified from the ratio of 2H enrichment of carbon 5 (C5) to that of water. The precursor of the hydrogen bound to C5 of glucose is the hydrogen bound to carbon 2 of glyceraldehyde-3-phosphate. That hydrogen equilibrates with the hydrogen of body water in the isomerization of glyceraldehyde-3-phosphate with dihydroxyacetone phosphate, an intermediate in the conversion of glycerol to glucose, and binds in the hydration of phosphoenolpyruvate (formed in the conversion of pyruvate to glucose). Because during glycogen breakdown there is no binding of hydrogen from body water to C5 of the glucose formed, enrichment at C5 in blood glucose vs. water reflects the fractional contribution of total GNG, i.e. from both phosphoenolpyruvate precursors and glycerol.
Plasma samples were first deproteinized using the Somogyi procedure. The supernatant was then passed through a mixed column of AG1-X8 in the formate form and AG50W-X8 in the H+ form; the eluate was dried in a Speed-Vac (Savant Instruments, Farmingdale, NY). Samples were then reconstituted with 220 µl distilled water and injected into a high performance liquid chromatograph (Waters Corp., Milford, MA) for further purification. Deuterium enrichment at C5 was obtained by converting glucose to xylose by the removal of carbon in position 6. Xylose was purified by HPLC; the C5 group was cleaved by oxidation with periodic acid, and formaldehyde was collected by distillation. Formaldehyde was incubated with ammonia overnight. In the presence of ammonia, six molecules of formaldehyde react to form one molecule of hexamethylenetetramine. This step is used to increase the sensitivity of the method. Enrichment of hexamethylenetetramine obtained from C5 was determined by gas chromatography-mass spectrometry (GCMS) by monitoring peaks of mass 140 and 141. The precision and accuracy of C5 have been reported previously (8).
Water enrichment in the body water pool was monitored by reacting a sample of plasma or urine with calcium carbide (CaC2), thereby obtaining acetylene (C2H2). The enrichment of acetylene was then determined by GCMS by monitoring peaks with masses of 26 and 27 (22). All samples were run through the GCMS processing in duplicate or triplicate.
Data analysis
Glucose fluxes and plasma clearance rates were expressed per kilogram of FFM. During the baseline period of the study (0–180 min), both the plasma glucose concentration and [3H]glucose specific activity were stable during the last 30 min of tracer infusion in all subjects. Therefore, total EGO was calculated as the ratio of the [3H]glucose infusion rate to the plasma [3H]glucose specific activity (mean of five determinations). During the clamp, total glucose rates of appearance (Ra) and disappearance (Rd) were calculated using Steele’s equations (23). At low rates of insulin-stimulated glucose disposal (similar to those observed in the diabetic subjects in the present study), we have shown that the tracer-derived rates of Ra and Rd closely approximate the independently measured rates of whole body glucose disposal and glucose appearance (24). Therefore, [3H]glucose was not added to the exogenously infused glucose during the insulin clamp (25). EGO during the insulin clamp was obtained as the difference between Ra and the exogenous glucose infusion rate. Fasting plasma glucose clearance was calculated as the ratio between EGO and FPG, whereas insulin-mediated plasma glucose clearance was obtained as the ratio of Rd to plasma glucose concentration during the clamp.
Data are given as the mean ± SE. A comparison of group values was performed using ANOVA with Bonferroni-Dunn post hoc testing. To factor out confounding variables, multivariate analysis was performed with the use of mixed models, including both continuous [age and body mass index (BMI)] and nominal (ethnicity, sex, and sulfonylurea treatment) variables as independent variables; contrasts were used to estimate differences among levels of a nominal variable (i.e. tertiles of fasting glycemia or VF area). The strength of confounder-adjusted associations between the two variables of interest was expressed as the partial correlation coefficient.
Results
To examine the association between VF and metabolic control, the study cohort was divided into tertiles of fasting hyperglycemia. Thus, group 1 included mildly hyperglycemic subjects, group 2 consisted of patients with moderate hyperglycemia, and group 3 included severely hyperglycemic patients (Table 1
). Except for a slight imbalance in sex distribution, the three groups were well matched for age, obesity (BMI and percent fat mass), body fat distribution (as determined by waist circumference and waist to hip ratio), and previous sulfonylurea treatment. The serum lipid profile and arterial blood pressure levels were not significantly different among groups.
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). In a multiple regression model adjusting for confounding variables (ethnicity, sex, age, diabetes duration, and BMI) as well as SF, VF was still significantly higher in groups 2 and 3 than in group 1 (partial r = 0.48; P = 0.003). When group was replaced by FPG in this model, VF was directly related to FPG (partial r = 0.46; P = 0.001). Even stronger was the independent association of VF with HbA1c (partial r = 0.50; P = 0.0003). In the latter model, Mexican-American ethnicity and diabetes duration also were significant positive correlates of HbA1c.
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). As expected, FPG was positively related to EGO (r = 0.51; P < 0.0001). Insulin-mediated glucose clearance was inversely related to VF in a nonlinear fashion, and this relationship remained statistically significant after adjusting for BMI (partial r = 0.33; P = 0.01). In contrast, the relation of EGO to VF was weak and not statistically significant (Fig. 1). Plasma insulin and FFA concentrations were similar in the three groups both at baseline and during the clamp.
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). To examine whether VF contributed to enhance GNG, the percent GNG was regressed against VF, first singly and then after adjustment for confounders. In both models the association between percent GNG and VF was positive (r = 0.28; P < 0.03 and partial r = 0.30; P = 0.04, respectively). When GNG and GLY fluxes were calculated, the former was found to be strongly associated with VF in a direct fashion (partial r = 0.45; P = 0.003), whereas GLY was weakly related to VF in a reciprocal fashion (partial r = -0.31; P < 0.05; Fig. 2). The inverse relationship between GLY and VF explains the lack of relationship between total EGO and VF.
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Discussion
In this cohort of type 2 diabetic patients with an average disease duration of 5 yr and a wide range of fasting plasma glucose and HbA1c levels, VF accumulation was clearly associated with poor metabolic control (Table 1
). Upon stratifying the subjects by fasting glycemia, the resulting clinical phenotype was quite homogeneous, not only in terms of age, serum lipids and blood pressure, but also in terms of overall body size and fat distribution. Only increased VF and, to a smaller extent, diabetes duration paralleled the increase in FPG. In a multiple regression model, which accounted for sex, age, BMI, and SF, only VF, diabetes duration, and Mexican-American ethnicity, in that order, were significant positive correlates of FPG. Thus, if every other measured factor is the same, the selective accumulation of fat in the visceral area is a predictor of the severity of fasting hyperglycemia. Most importantly, VF is associated not only with the degree of fasting hyperglycemia, but even more strongly and independently with HbA1c. There also was a significant positive interaction between VF and Mexican-American ethnicity (P = 0.05). The clinical implication of these findings is that VF, when directly estimated by a sensitive imaging technique, is an independent predictor of metabolic control in type 2 diabetic patients, particularly in those of Mexican-American ethnicity. As a corollary, VF may be an important factor that modulates the response to treatment as well as itself representing a potential target for intervention. It should be emphasized, however, that the set of clinical and anthropometric variables used in the present study could explain no more than half of the observed variability in HbA1c. Clearly, other determinants of glycemic control went unmeasured.
With regard to the mechanisms underlying the association between VF accumulation and hyperglycemia in type 2 diabetes, glucose fluxes provided at least part of the answer. First, peripheral insulin resistance (in the fasting state and during the insulin clamp) was progressively more severe with increasing fasting hyperglycemia. This result stands in contrast with the observation that currently available therapeutic interventions (sulfonylurea, metformin, and thiazolidenidiones) bring about only a small to modest improvement in insulin resistance, yet glycemic control improves considerably (26, 27, 28). Whether the reciprocal relationship between glucose clearance and FPG is the expression of glucose toxicity or the inherent severity of the disease (or both) cannot be distinguished, but the strong and BMI-independent relationship between insulin-mediated glucose clearance and VF supports the idea that peripheral insulin resistance (and hence hyperglycemia) is related in part to a constitutional, anatomical trait, i.e. visceral adiposity. The mechanism by which fat deposition within and between abdominal viscera affects insulin action in peripheral tissues is not clear from the present studies. Circulating plasma FFA levels were similar across all three groups and are therefore an unlikely messenger, at least in patients with manifest diabetes. However, it is now well established that the fat cell can produce a variety of cytokines that can exert profound effects on insulin sensitivity and glucose metabolism (29).
EGO, which primarily represents hepatic glucose production (30), rose with increasing fasting glycemia, but was only weakly related to VF. The components of EGO, however, showed a revealing pattern. GNG, both as a fraction of EGO and as an absolute flux, was strongly and independently associated with higher VF, whereas GLY was less tightly and reciprocally related to VF. If interpreted mechanistically, these results suggest that the presence of excess VF specifically enhances GNG. However, whether this stimulation of GNG by increased VF results in glucose overproduction depends on the concomitant adjustment of the glycogenolytic rate. Because GNG is less sensitive to insulin inhibition than GLY (10), the increased fasting plasma insulin concentrations in mildly hyperglycemic patients (98 ± 21 and 119 ± 14 pmol/liter in groups 1 and 2, respectively; P < 0.05 for both vs. 70 ± 7 pmol/liter in 20 nondiabetic subjects; data not shown) down-regulate GLY, thereby maintaining EGO within normal limits. In the more hyperglycemic subjects the ambient plasma insulin concentration is insufficient to restrain EGO, which consequently rises to levels that are elevated in absolute terms.
With regard to the plasma FFA concentration, we found a positive association between their systemic levels and GNG. A high FFA flux to the liver stimulates GNG by providing a continuous source of energy (ATP from FFA oxidation) as well as substrate (glycerol) to synthesize glucose de novo. Conversely, a decrease in FFA levels inhibits GNG in both diabetic and control subjects (31, 32). Visceral obesity would be expected to directly increase the delivery of FFA from intraabdominal fat depots to the liver via the portal vein. Although we found no association between VF area and circulating FFA levels, it must be remembered that the systemic FFA concentration underestimates prehepatic FFA levels because of the larger VF mass, which drains directly into the portal vein, and the higher lipolytic rate of visceral compared with sc adipocytes (14). VF mass, however, represents a small portion (
18%) of the total body fat mass, even in abdominally obese individuals (33). In addition, hepatic FFA extraction is high. Therefore, the contribution of VF to systemic FFA concentrations is likely to be small (although precise calculations require knowledge of differential lipolytic rates and regional blood flow rates). These considerations may explain why systemic FFA plasma levels were unrelated to VF, but remained directly related to GNG, which responds to the whole FFA load regardless of its anatomical origin.
Finally, it is of clinical relevance that in our cohort of diabetic patients increased VF almost doubled the extent to which the increase in HbA1c could be accounted for on the basis of the clinical phenotype alone. Thus, ethnicity, sex, age, duration of diabetes, and obesity (as the BMI) together explained only 25% of HbA1c variability, whereas the inclusion of VF in the model raised the explicable HbA1c variability to 45%. According to this model, HbA1c is predicted to be 0.8% higher for each 50-cm2 increment in VF area. These estimates confirm that an accurate measurement of VF is an important part of clinical phenotyping and has rather direct consequences for the metabolic control of patients with type 2 diabetes.
Acknowledgments
We thank Magda Ortiz, Dianne Frantz, Socorro Mejorado, Janet Shapiro, John Kinkaid, John King, Norma Diaz, and Patricia Wolf for their assistance with performing the insulin clamp studies, and S. Frascerra, Ph.D.; S. Baldi, Ph.D.; D. Ciociaro; and N. Pecori for their technical assistance with the measurement of GNG.
Footnotes
This work was supported by NIH Grant DK-24092, General Clinical Research Center Grant M01-RR-01346, a V.A. Merit Award, and funds from the V.A. Medical Research Service.
Abbreviations: BMI, Body mass index; C5, carbon 5; EGO, endogenous glucose output; FFA, free fatty acids; FFM, fat-free mass; FPG, fasting plasma glucose; GCMS, gas chromatography-mass spectrometry; GLY, glycogenolysis; GNG, gluconeogenesis; HbA1c, hemoglobin A1c; MRI, magnetic resonance imaging; Ra, rate of appearance; Rd, rate of disappearance; SF, sc fat; VF, visceral fat.
Received May 3, 2002.
Accepted August 13, 2002.
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