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Visceral Obesity, Hepatic Lipase Activity, and Dyslipidemia in Type 1 Diabetes

Division of Endocrinology and Diabetes, University of Minnesota, Minneapolis, Minnesota 55455; and Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle, Washington 98195-6426

Address all correspondence and requests for reprints to: Shalamar D. Sibley, Division of Endocrinology and Diabetes, University of Minnesota School of Medicine, Mayo Medical Code 101, 420 Delaware Street SE, Minneapolis, Minnesota 55455. E-mail: sible004{at}umn.edu.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Excessive weight gain in a subset of intensively treated Diabetes Control and Complications Trial (DCCT) subjects was associated with higher waist to hip ratio; higher triglyceride (TG), low-density lipoprotein (LDL) cholesterol, and apolipoprotein B (ApoB) in the presence of small-dense LDL; and decreased high-density lipoprotein 2 cholesterol (HDL2-C), suggesting that weight gain in these subjects resulted in higher intraabdominal fat (IAF), and an atherosclerotic dyslipidemia mediated through hepatic lipase activity (HL). Objectives were to investigate relationships between IAF, HL, and dyslipidemia and to relate IAF to previous body mass index change during the DCCT.

Sixty-one subjects were studied approximately 4 yr after DCCT closeout. IAF was positively related to HL (P < 0.001). IAF positively correlated with logTG (P < 0.001) and ApoB (P < 0.001), and negatively with LDL relative flotation rate (P < 0.001) and logHDL2-C (P = 0.001). HL accounted for most of the relationship between IAF with logHDL2-C and LDL relative flotation rate, and none of the relationship between IAF and logTG or ApoB. DCCT-related body mass index change accounted for a significant portion of logIAF variance measured 4 yr later (P < 0.001).

Elevated IAF in subjects with type 1 diabetes was related to an atherosclerotic dyslipidemia similar to that seen in individuals without diabetes who have metabolic syndrome. DCCT-related weight gain positively correlated with subsequent IAF.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
OBESE PEOPLE, ESPECIALLY those who are centrally obese, often have hypertension, and an atherogenic lipid profile with high triglyceride (TG) levels and small-dense (sd) low-density lipoprotein (LDL) particles, and low levels of high-density lipoprotein as part of the metabolic syndrome (1, 2, 3, 4, 5). High levels of intraabdominal fat (IAF) have been associated with high levels of hepatic lipase activity (HL) and may lead to this dyslipidemia (6, 7). In studies of a variety of subjects who do not have diabetes, higher IAF was associated with higher HL and an atherogenic dyslipidemia (7, 8, 9, 10). In one interventional study, obese subjects without diabetes who lost weight through calorie restriction had significant decreases in IAF and insulin resistance accompanied by decreased HL and improved dyslipidemia (11).

Central obesity in subjects with type 2 diabetes has been intensively studied and has been linked to a similar dyslipidemic profile characterized by high TG and low high-density lipoprotein cholesterol levels that can be worsened by poor glycemic control (12, 13, 14, 15). In addition to being associated with insulin resistance and type 2 diabetes, central obesity has been linked to development of hypertension and cardiovascular disease (16, 17, 18).

Historically, subjects with type 1 diabetes were often underweight. There are little data on the effects of weight gain on subjects with type 1 diabetes. Purnell et al. (19) reported that intensively treated Diabetes Control and Complications Trial (DCCT) subjects within the top quartile of change () in body mass index (BMI), on intensive therapy, gained an average of 14 kg during the course of this study. The magnitude of weight gain in these individuals was about twice that of subjects in the top quartile of weight gain, on conventional therapy, and twice that of intensively treated subjects in the third quartile of weight gain. These subjects with the greatest weight gain on intensive therapy had higher waist to hip ratios (WHRs) and blood pressure, and higher insulin requirements for the same degree of glycemic control than their intensively treated counterparts who did not gain as much weight. They also had a relatively atherogenic lipid profile, with elevations in TG, LDL cholesterol (LDL-C), and apolipoprotein B (ApoB) in the presence of sdLDL, and decreased high-density lipoprotein 2 cholesterol (HDL2-C), compared with intensively treated subjects who did not gain as much weight. These findings suggested that intensive therapy may have unmasked the central obesity or metabolic syndrome in susceptible individuals with type 1 diabetes.

A follow-up study addressing possible mechanisms for the observed dyslipidemic profile and examining the link between DCCT-related weight gain and IAF, a key component of central obesity syndrome, was indicated. Therefore, the primary objective of this current study was to examine IAF in relation to HL and dyslipidemia. We hypothesized that IAF would correlate with HL level. We postulated that the level of HL would explain components of the dyslipidemia, particularly the levels of sdLDL and HDL2-C that were seen with DCCT-related weight gain, building on the abnormalities previously reported in the national cohort (19). A secondary objective was to examine the relationship between -BMI during the DCCT and the subsequent amount of IAF, as measured by single-slice computed tomography (CT), in the same individuals.

	Subjects and Methods

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Subjects

Sixty-one subjects from the University of Washington cohort of the Epidemiology of Diabetes Intervention and Complications Study (EDIC) (36 males and 25 females) had measurement of IAF, postheparin plasma lipase activity, lipids, and apolipoprotein levels between November 19, 1997 and November 13, 1999. EDIC is an ongoing observational follow-up study of the DCCT, a clinical trial conducted between 1982 and 1993 that involved 1441 subjects with type 1 diabetes for 1–15 yr at study entry. The DCCT cohort was randomly assigned to intensive or conventional diabetes treatment and was followed for 6.5 yr, on average (20). Subjects were excluded from the DCCT at baseline if they had a total cholesterol level greater than 3 SDs above the mean for sex and age as defined by the Lipid Research Clinics Population Studies Data Book (21), a calculated LDL above 190 mg/dl, cardiovascular abnormalities such as major ECG abnormalities, peripheral vascular disease symptoms, a clinical history of CVD or hypertension, or a body weight greater than 30% above ideal body weight as defined by the 1983 Metropolitan Life Insurance norms (22). At the end of the DCCT in 1993, all surviving participants were eligible for EDIC. Ninety-six percent of DCCT participants continued in EDIC (23). Sixty-one of the 70 EDIC participants from the Seattle and Vancouver, British Columbia clinics, who had a lipid visit with bloodwork between November 1997 and November 1999, completed all additional lipid and CT measurements for this ancillary study. This study was approved by the University of Washington Institutional Review Board, and all participants received informed consent.

Body fat distribution

IAF and sc fat were determined by single-slice umbilical-level CT scan (General Electric, 120 KVP, variable milliamperes, 9.8 sec scan time, 10-mm slice thickness and whole-body calibration settings). IAF was separated from retroperitoneal fat by drawing a line to the pericolic gutters. Intraobserver variability, reading the same CT scan, was less than 1.5%; and all scans were read by the same single observer, masked to participant characteristics. Cross-sectional IAF area determined by this technique has been well studied; additional abdominal slices were not obtained because the additional radiation exposure was not justified by the additional information (5, 24, 25).

Chemical assays

The serum lipid profile (including plasma TG, total cholesterol, LDL-C, HDL2-C, HDL3 cholesterol, and ApoB) was measured, by standard techniques, at the Northwest Lipid Research Laboratory (26). Annual serum creatinine and hemoglobin A1c were measured by the DCCT/EDIC Core Laboratory in Minneapolis, Minnesota, according to standard techniques (20). Fasting blood glucose levels were determined by the University of Washington Clinical Laboratory.

Cholesterol distribution was measured by density gradient ultracentrifugation with a Beckman VTI-65 rotor (Beckman Instruments, Fullerton, CA) (27). In this procedure, 1.0 ml plasma was mixed with 1.5 ml NaCl solution (specific gravity = 1.006) and 1.5 ml potassium bromide solution (specific gravity = 1.21), for a final density of 1.080 g/ml, and then overlaid with an additional 9.5 ml 0.9-molar NaCl solution. Samples were ultracentrifuged for 70 min at 65,000 rpm at 10 C to separate the lipoproteins by flotation characteristics. An Isco fractionator (Isco, Lincoln, NE) was used to drain the tube from the bottom at a flow rate of 1.0 ml/min. Thirty-eight 0.35-ml fractions were collected. This procedure gives a continuous profile of lipoprotein distribution based on flotation characteristics (28, 29). A cholesterol assay kit (Roche Molecular Biochemicals, Indianapolis, IN) was used to measure the cholesterol content in each fraction. Relative flotation rate (Rf), a measure of buoyancy, was determined by dividing the fraction number containing the peak LDL-C level (among fractions 7–19) by the total number of fractions collected (n = 38).

HL and lipoprotein lipase activity (LpL) were measured by previously published methods (30). Plasma was drawn 10 min after an iv heparin (60 U/kg) bolus. Total lipolytic activity was determined by the ability of postheparin plasma to hydrolyze an artificial triolein-phospholipid emulsion. LpL was selectively blocked by the monoclonal antibody to LpL, 5D2, to determine HL, the lipolytic activity remaining after inhibition of LpL.

Statistical analysis

Descriptive statistics were used to characterize the cohort. The unpaired t test was used for comparison of means between groups with normal distributions; Mann-Whitney U analysis was used for comparisons between two nonparametric groups. The relationships between IAF and HL (nmol/ml·min), HL and the lipid parameters of interest, and IAF and the HL-adjusted lipid parameters were evaluated with linear regression analyses. TG (mg/dl) and HDL2-C (mg/dl) values were log transformed for these statistical analyses. Linear regression analysis was also used to examine the correlation between -BMI (kg/m²) during the DCCT and the subsequent IAF (cm² visceral adipose tissue area) in EDIC. IAF was log transformed for this analysis. SigmaStat (Jandel Scientific, version 2.0; now SPSS, Inc., Chicago, IL) and SAS (SAS Institute, Inc., Cary, NC) were used for these analyses.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The University of Washington EDIC subjects available at the DCCT closeout for study (n = 61), including 34 originally followed on intensive and 27 followed on conventional therapy, had a mean age of 35.3 yr and a mean diabetes duration of 11.8 yr. Mean hemoglobin A1c was 8.6% (Table 1), and BMI was 25.4. On average, these 61 subjects from this cohort had slightly higher blood pressures at the end of the DCCT and were slightly older, on average, than the total DCCT/EDIC cohort, but they did not differ significantly otherwise (Table 1). Weight at the end of the DCCT was highly predictive (r² = 0.91, P < 0.001) of EDIC weight 4–5 yr later, and subjects had a mean increase of 9% in weight over that time period.

In the 61 subjects from the University of Washington cohort, a significant positive correlation between IAF and HL was found (r² = 0.255, P < 0.001). HL was significantly correlated with all of the lipid parameters. It was negatively correlated with logHDL2-C (r² = 0.280, P < 0.001) and LDL-Rf (r² = 0.294, P < 0.001). It was positively associated with logTG (r² = 0.074, P = 0.037) and ApoB (r² = 0.096, P = 0.018). A significant positive relationship was found to exist between IAF and logTG (r² = 0.388, P < 0.001) and between IAF and ApoB (r² = 0.351, P < 0.001). A significant negative relationship existed between IAF and LDL-Rf (r² = 0.270, P < 0.001) and between IAF and logHDL2-C (r² = 0.219, P = 0.001). Using the Kolmogorov-Smirnov test, all regression residuals were normally distributed except LDL-Rf (P = 0.049) as a function of IAF.

We examined the possibility that sc fat, which correlated with IAF and with DCCT-related weight gain, might be more closely linked with this dyslipidemic process than IAF. Though both correlations were significant, the correlation between -BMI and logIAF was stronger (r = 0.422, P < 0.001) than that of -BMI and log sc fat (r = 0.311, P = 0.018); sc fat was not related to HL (r² = 0.032, P = 0.181). There was no relationship between sc fat with logHDL2-C (r² = 0.029, P = 0.211), Rf (r² = 0.006, P = 0.552), LogTG (r² = 0.033, P = 0.173), or ApoB (0.056, P = 0.078). In a related analysis, the possibility that some factor other than IAF accounted for the relationship between -BMI and the lipids was examined. A multiple linear regression model including IAF and -BMI was used to examine this possibility. -BMI during the DCCT did not show an IAF-independent relationship with any of the lipids (see Table 3).

Though similar lipid patterns were seen within the sexes, with respect to IAF and HL, it is possible that sex could have confounded the results of this study. Sex strongly relates to HL and IAF; both are higher in males, compared with females. Earlier studies have shown that IAF accounts for a significant amount of HL but that sex still relates to HL independent of IAF (10). There are also differences between the sexes, with respect to the lipids under study. To determine whether sex might have an independent, confounding influence on the relationships between IAF and HL with the lipids, multiple regression models including IAF, HL, and sex were examined for each dyslipidemic component. LogTG, ApoB, and Rf were not related to sex independent of IAF and HL. For logHDL2-C there was a modest relationship with sex independent of IAF and HL, but these other variables remained significantly related to logHDL2-C. At a given level of IAF and HL, males tended to have logHDL-2 C values that were 0.16 U lower than females (P = 0.035).

In studies of centrally obese subjects, there are often coexistent elevations of TG and sdLDL. Central obesity-related TG elevation could contribute to increases in sdLDL via cholesteryl-ester transport protein (CETP)-mediated transfer of TG from VLDL and LDL, a process distinct from elevated HL. This possibility was evaluated theoretically by examining the correlation between HL-adjusted TG and LDL-Rf. The correlation was found to be significant (r² = 0.161, P = 0.002), suggesting that CETP also might be a mediator of sdLDL elevation in these subjects.

A secondary objective of this study was to determine whether weight gain during the DCCT correlated with subsequent IAF in this local cohort of 61 subjects about 4–5 yr after the end of the DCCT. Bivariate correlations showed that sex, BMI at DCCT start, and -BMI during the DCCT were significantly related to subsequent logIAF (data not shown). A multiple linear regression model controlling for sex and BMI at the start of the DCCT showed that -BMI during the DCCT was highly correlated with subsequent logIAF (r² = 0.294, P < 0.001) (Table 2). -BMI during the DCCT correlated more strongly with logIAF (r = 0.422, P < 0.001) than with log sc abdominal fat (r = 0.311, P = 0.018). DCCT treatment group assignment (intensive or standard therapy) was not related to IAF independent of these other factors.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Overall, the DCCT and EDIC follow up have shown that intensive diabetes therapy results in a uniform, major reduction in (and significant protection from) microvascular disease (32, 33). Regarding cardiovascular disease, obesity, and insulin resistance in type 1 diabetes, Orchard et al. (34, 35), in the Epidemiology of Diabetes Complications Study, found that, if these subjects had a positive family history of type 2 diabetes, they were at greater risk for cardiovascular disease than those subjects who did not. This cohort had lower BMIs at baseline but a similar incidence of obesity, compared with the general population. Tighter glycemic control correlated with weight gain, and weight gain was associated with a more favorable lipid profile in the setting of improved glycemic control. However, in studies done by Purnell et al. (19), a subgroup of intensively treated DCCT subjects gained excess weight. These subjects had the greatest BMI and significantly higher WHR at the end of the DCCT, compared with other subjects, and more atherogenic lipid profiles than intensively treated subjects who did not gain weight. The lipid profiles of these subjects who gained the most weight on intensive therapy were more like those of subjects on conventional therapy than those of intensively-treated subjects who did not gain weight, suggesting that, in these individuals, some of the lipid benefits of intensive therapy were lost (19). The data presented here follow up on that earlier analysis with a more intensive study of a local subgroup of the national DCCT/EDIC cohort. These data suggest that: central obesity-related dyslipidemia, characterized by low levels of HDL and high levels of sdLDL, is present in subjects with type 1 diabetes who have elevated levels of IAF; and that high HL levels may mediate some of this dyslipidemia. These data also show that IAF level is related to the amount of weight gain 4–5 yr earlier.

In addition to the overall relationships established here for the first time in relation to IAF in subjects with type 1 diabetes, these data suggest that more than half of the positive statistical correlation between IAF with LDL-Rf and HDL2-C seen in these subjects can be accounted for by HL activity. The IAF-TG and IAF-ApoB relationships are not accounted for by HL activity (Table 2), suggesting two patterns of central obesity-related dyslipidemia that may be largely mediated through separate processes (Fig. 1). Because both processes, in part, relate to high IAF levels, there is an association between low HDL2-C and high TG levels. Although these variables change appreciably and synchronously after weight loss (11), the mechanisms that account for these changes are unknown.

View larger version (6K): [in this window] [in a new window]   FIG. 1. Relationships among IAF, HL, and dyslipidemia. There are residual relationships between IAF with sdLDL and HDL2 that may be mediated through CETP.

Two questions regarding these analyses are: whether IAF or sc fat was more strongly associated with DCCT-related weight gain; and which fat compartment was more strongly associated with this atherosclerotic dyslipidemia. DCCT-related -BMI correlated more strongly with logIAF than it did with log sc fat. IAF was strongly associated with HL and the dyslipidemic components; sc fat was not. In a similar analysis, -BMI during the DCCT did not show an IAF-independent relationship with any of the lipids (Table 3) consistent with a role for IAF-related processes accounting for the association between -BMI and lipids seen in these subjects. Taken together, all of these data suggest that, whereas DCCT-related weight gain was associated with higher levels of both IAF and sc fat, absolute IAF level is a more important mediator of dyslipidemia in these individuals than is sc fat.

One potential shortcoming of the analysis of the relationship between -BMI during the DCCT and subsequent IAF is that a significant amount of the variance in IAF remains unaccounted for. However, this study compares measures taken 5 yr apart, -BMI during the DCCT and subsequent IAF. Such a comparison across time would have been much more likely to result in a negative finding than a positive one and may suggest an even stronger relationship between -BMI in the DCCT and IAF than was seen in this analysis. Additional studies are needed to further address this relationship.

In conclusion, this study of the University of Washington DCCT/EDIC cohort suggests that weight gain in the DCCT is associated with higher IAF and HL-mediated dyslipidemia. How these factors relate to clinical outcomes, particularly cardiovascular outcomes, remains to be explored.

	Acknowledgments

 
We thank the participants and investigators involved with the DCCT and EDIC, and the members of the EDIC executive committee for critical review of the manuscript. We thank Chris Casazza for his time and effort in performing the density gradient ultracentrifugations.

	Footnotes

 
This work was supported, in part, by a grant from the Juvenile Diabetes Foundation International (New York), NIH Grant DK-02456, Clinical Nutrition Research Unit (DK-35816), and the Diabetes Endocrine Research Center (DK-17047). These studies were performed on the University of Washington General Clinical Research Center NIH Grant RR-37. Dr. Sibley was also supported by an American Diabetes Association Mentor-Based Postdoctoral Fellowship awarded to Dr. Brunzell, a National Institutes of Health Clinical Research Training in Renal Diseases Fellowship, and a K23 Mentored Patient-Oriented Research Career Development Award from the NIH (1K23-DK-59445).

Abbreviations: ApoB, Apolipoprotein B; BMI, body mass index; -BMI, change in BMI; CETP, cholesteryl-ester transport protein; CT, computed tomography; DCCT, Diabetes Control and Complications Trial; EDIC, Epidemiology of Diabetes Intervention and Complications Study; HDL2-C, high-density lipoprotein 2 cholesterol; HL, hepatic lipase activity; IAF, intraabdominal fat; LDL, low-density lipoprotein; LDL-C, LDL cholesterol; LpL, lipoprotein lipase activity; Rf, relative flotation rate; sd, small-dense; TG, triglyceride; WHR, waist to hip ratio.

Received October 29, 2002.

Accepted March 25, 2003.

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