Comparison of Metabolic Risk Factors between Severely and Very Severely Obese Patients

Authors


Institute for Molecular Cell Biology, Center for Experimental Medicine, University Hospital Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany. E-mail: beisiegel@uke.uni-hamburg.de

Abstract

Objective: A prospective clinical intervention study was performed to estimate the metabolic risk factors in patients with very severe obesity (VSO) vs. severe obesity (SO).

Research Methods and Procedures: Two hundred twenty-eight VSO (BMI ≥ 50 kg/m2) and 221 SO patients (BMI = 40 to 49.9 kg/m2) participated in the study (367 women and 82 men). Metabolic measurements included plasma lipids, glucose and insulin, hemoglobin A1c, leptin, and sex hormones, as well as hepatic steatosis in a subgroup of patients. Subgroups of patients with non–insulin-dependent diabetes and hyperlipidemia (HLP) were examined.

Results: The most unexpected result of our study was that VSO men showed significantly better lipid profiles than SO men. Furthermore, 18% of VSO men had no metabolic aberrations, whereas all SO men did. The advantageous metabolic status of VSO men was associated with sex hormone changes that favor gynoid fat distribution. The beneficial metabolic situation with VSO seems to be sex specific for men.

Discussion: This study shows that the metabolic situation in VSO is not more severe than in the less obese cohort. These findings distinctly differ from the positive associations that have previously been reported between BMI, lipids, and other metabolic indices among individuals whose BMI is <40 kg/m2.

Introduction

Obesity is a major risk factor for a number of metabolic aberrations, i.e., hyperlipidemia (HLP),1 dyslipoproteinemia, hyperglycemia, insulin resistance, and steatosis, that give rise to associated metabolic diseases including non–insulin-dependent diabetes (type 2 diabetes), coronary artery disease, and non-alcoholic fatty liver disease. Based on positive associations that epidemiological studies have established between body size and obesity comorbidities, it is generally assumed that individuals with severe obesity, i.e., having a BMI of ≥40 kg/m2, have a substantially greater risk of metabolic aberrations and associated disease states than do their less obese counterparts (1, 2, 3, 4). To our knowledge, there are few studies that have examined the metabolic situation in individuals whose BMI exceeds 40 kg/m2.

Several investigators have examined differences in the comorbid disease states between individuals with very severe obesity (VSO) and those whose severe obesity (SO) is less pronounced (5, 6, 7, 8, 9, 10). A few investigators have also followed changes in various metabolic indices of SO persons across a wide range of body sizes (8, 11, 12). A recent study compared SO with moderately obese women and found the metabolic profile in the SO to be less deteriorated than expected (13). All these studies have generated conflicting results regarding metabolic status in response to increased obesity severity. The purpose of our study, therefore, was to examine the metabolic profiles of bariatric surgical candidates with VSO in an effort to determine their metabolic risk. The primary aim of this study was to test the hypothesis that persons with VSO have a higher metabolic disease risk than do their less severely obese counterparts.

Research Methods and Procedures

The study population included 449 bariatric surgical candidates with SO (BMI ≥ 40 kg/m2), 367 women and 82 men, at the Evangelische Krankenhaus Dinslaken. A subgroup of these patients was described in 1998 (14). Anthropometrics and metabolic indices were measured preoperatively. To qualify for the study, patients had to meet the guidelines of the American Society for Bariatric Surgery (15). Written informed consent to participate in this study was obtained preoperatively. All patients tested negative for hepatitis and human immunodeficiency virus.

Patients were divided into two study populations based on body size: VSO and SO. VSO was defined as a BMI ≥50 kg/m2 and SO as a BMI = 40 to 49.9 kg/m2. The SO and VSO study groups were sorted according to sex as follows: 188 SO and 179 VSO women and 33 SO and 49 VSO men.

Sex hormones, serum insulin, leptin, total triglyceride, low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol were measured preoperatively. Fasting blood glucose was determined with an enzymatic test using glucose-oxidase. Type 2 diabetes was defined as a fasting blood glucose level ≥126 mg/dL (16). Insulin was measured by microparticle enzyme immunoassay. In this test kit, the upper limit of the normal range is 15.6 μU/mL. Hemoglobin (Hb)A1c was assessed by hemolysate method established by the Diabetes Control and Complications Trial, with the range of normal values between 4.3% and 5.8%. Leptin levels were measured with the ELISA of E&D Systems of Abbott (Abbott Laboratories, Abbott Park, IL). With these assays, the normal mean for men was 6.5 ng/mL and for women was 18 ng/mL.

Estradiol, testosterone, and progesterone were measured with immunologic tests from Roche (electro chemiluminescence immunoassay; F. Hoffmann-La Roche Ltd., Basel, Switzerland). The normal range for men in these assays was 15 to 45 ng/L for estradiol, 3.5 to 10.7 μg/L for testosterone, and 0.3 to 2.2 μg/L for progesterone II. We show sex hormones only for the male group because, in women, they cannot be standardized due to the menstrual cycle. The term “gynoid habitus” is used for men when estrogen levels are in the high normal range and testosterone levels are low, i.e., <2.5 μg/L, a situation that often occurs in men in association with a lower waist-to-hip ratio (WHR).

Lipid status was determined using enzymatic diagnostic kits from Boehringer Mannheim (cholesterol oxidase phenol 4-aminoantipyrine peroxidase and glycerol phosphate oxidase-p-aminophenazone). HLP was defined according to the European Guidelines on Cardiovascular Disease Prevention (17), i.e., total cholesterol ≥190 mg/dL, total triglycerides ≥150 mg/dL, LDL-cholesterol ≥130 mg/dL, and HDL-cholesterol ≤40 mg/dL for men and ≤46 mg/dL for women.

Subcutaneous fat width was measured in the midline of the upper abdominal incision during bariatric surgery. Liver biopsies were taken intraoperatively by a small wedge resection in a subgroup of 179 patients. Liver histology was determined by two pathologists in the same private practice. The biopsies were processed routinely and stained by hematoxylin and eosin and Masson's trichrome stains. Steatosis was quantified as percentage of hepatocytes containing fat droplets and reported as follows: absent (0% of hepatocytes containing fat droplets), 1% to 10% containing fat droplets, 10% to 30%, and >30% (18). Fatty liver is defined as the appearance of fat droplets in >30% of hepatocytes.

Data were analyzed with the STATISTICA program (StatSoft, Inc., Tulsa, OK) and expressed as mean ± standard deviation. Differences between values of the SO and VSO patient groups were analyzed using the independent Student's t test, and differences between values for multiple groups were determined by ANOVA. Associations between parameters were assessed by linear regression analyses. Statistical significance with all analyses was defined as p ≤ 0.05.

Results

Because BMI is the major criteria of the study, patients were divided into VSO and SO groups. Because of significant sex differences in various metabolic parameters, i.e., fasting blood glucose, HbA1c, insulin, triglyceride, HDL-cholesterol, leptin, and percent steatosis, results are recorded according to sex (Tables 1and 2, respectively).

Table 1.  Metabolic status of the female patients divided by BMI groups
ParametersSO women (BMI = 40 to 50 kg/m2) (n = 188)VSO women (BMI ≥ 50 kg/m2) (n = 179)
  • SO, severely obese; VSO, very severely obese; WHR, waist-to-hip ratio; LDL, low-density lipoprotein; HDL, high-density lipoprotein; HbA1c, hemoglobin. Anthropometric measures are shown, as well as parameters to determine lipid and glucose metabolism. Numbers indicate mean ± standard deviation. Normal values are given parentheses.

  • *

    p < 0.05.

  • p < 0.01.

  • p < 0.001.

  • §

    p < 0.000001.

Age (years)38 ± 1039 ± 9
Waist circumference (<80 cm)121 ± 10137 ± 13§
WHR (<0.80)0.86 ± 0.080.86 ± 0.08
Subcutaneous fat layer (cm)5.2 ± 0.895.7 ± 1.19
Leptin (18 ng/mL)66 ± 2782 ± 33
Triglyceride (<150 mg/dL)155 ± 76161 ± 99
Total cholesterol (<190 mg/dL)205 ± 38200 ± 37
LDL-cholesterol (<130 mg/dL)130 ± 34126 ± 29
HDL-cholesterol (>45mg/dL)44 ± 1242 ± 9*
Fasting glucose (<126 mg/dL)108 ± 34110 ± 30
Insulin (<15.6 μU/mL)16 ± 1319 ± 14
HbA1c (4.3% to 5.8%)5.86 ± 1.335.99 ± 1.07
Steatosis30%42%*
Table 2.  Metabolic status of the male patients divided by BMI groups
ParametersSO men (BMI = 40 to 50 kg/m2) (n = 33)VSO men (BMI ≥ 50 kg/m2) (n = 49)
  • SO, severely obese; VSO, very severely obese; WHR, waist-to-hip ratio; LDL, low-density lipoprotein; HDL, high-density lipoprotein; HbA1c, hemoglobin. Anthropometric measures are shown, as well as parameters to determine lipid and glucose metabolism. Numbers indicate mean ± standard deviation. Normal values are given parentheses.

  • *

    p < 0.05.

  • p < 0.01.

  • p < 0.001.

  • §

    p < 0.000001.

Age (years)39 ± 839 ± 8
BMI (kg/m2)46 ± 259 ± 7§
Waist circumference (<94 cm)138 ± 8160 ± 14§
WHR (<0.95)1.02 ± 0.071.00 ± 0.11
Subcutaneous fat layer (cm)4.3 ± 1.035.5 ± 2.08
Leptin (7 ng/mL)35 ± 1554 ± 28
Triglyceride (<150 mg/dL)300 ± 197215 ± 117*
Total cholesterol (<190 mg/dL)228 ± 38206 ± 36
LDL-cholesterol (<130 mg/dL)139 ± 31128 ± 32
HDL-cholesterol (>40mg/dL)35 ± 835 ± 7
Fasting glucose (<126 mg/dL)124 ± 48134 ± 60
Insulin (<15.6 μU/mL)21 ± 1823 ± 13
HbA1c (4.3% to 5.8%)6.08 ± 1.487.07 ± 2.50
Estrogen (13 to 47 ng/liter)31 ± 1239 ± 14*
Testosterone (2.5 to 12 μg/liter)3.6 ± 1.52.5 ± 1.3

Table 1 reports the results of the metabolic status of the SO and VSO women. As can be seen, there were no significant differences between the study groups with regard to age or WHR. With greater BMI, the subcutaneous fat layers are significantly thicker for VSO patients and leptin levels are higher. HDL-cholesterol was significantly lower for VSO women, but there were no significant differences in levels of triglyceride, total cholesterol, or LDL-cholesterol. Metabolic indices that reflect glycemic status, i.e., fasting blood glucose, HbA1c, and insulin, also did not differ significantly between the SO and VSO female groups.

To relate the metabolic parameters to the disease state, we analyzed how many patients in the two groups suffered from metabolic aberrations or metabolic disease. The percentage of patients with HLP and type 2 diabetes were calculated. Approximately one third of SO and VSO women had no metabolic aberrations (33% and 34%, respectively). However, 16% of the SO and 17% of VSO female patients had type 2 diabetes, and 51% and 49% exhibited HLP. The VSO female patients, therefore, had no greater metabolic risk, with regard to the indices measured, than their less obese counterparts.

Hepatic steatosis was significantly (p < 0.01) higher for the VSO (42%) vs. SO (30%) women. In the VSO group, 38% of the women who had steatosis did not have any metabolic disease compared with 28% in the SO patients, indicating that VSO alone can induce fatty liver. This is independent of the fact that, in all patients, the percentage steatosis correlated significantly positive (p < 0.05) with age (r = 0.19), glucose levels (r = 0.36), insulin (r = 0.22), HbA1c (r = 0.36), WHR (r = 0.36), and triglyceride levels (r = 0.30), whereas HDL-cholesterol correlated inversely with degree of steatosis (r = 0.18, p < 0.03).

Table 2 reports the results of the metabolic status of the SO and VSO men. As can be seen, there were no significant differences between the male SO and VSO study groups with regard to age. The increase in BMI was accompanied by higher leptin levels. We also observed a trend toward a thicker subcutaneous fat layer in VSO men, but this value did not reach statistical significance. Triglyceride levels were significantly lower for VSO patients, but there were no significant differences between the groups for LDL- and HDL-cholesterol, although the mean LDL-cholesterol in the VSO group was below the desired level of 130 mg/dL. Total cholesterol was significantly (p < 0.01) lower than in the SO group. There were no significant differences between fasting blood glucose, insulin, or HbA1c values of the SO and VSO male patients, although all values were higher than would be expected in the absence of obesity. With regard to sex hormones, estrogen levels were significantly higher (p < 0.05) and testosterone values significantly lower in the VSO vs. SO men (p < 0.01).

Relating the metabolic parameters to disease, we saw striking differences between the SO and VSO men (Figure 1). According to the data, 76% of the SO men exhibited HLP, whereas in the VSO group, only 53% had a lipid abnormality. The size of the subgroups of patients with type 2 diabetes, in contrast, was relatively similar between the groups, i.e., 29% and 24% for the VSO and SO patients, respectively. Within the SO group, all patients had type 2 diabetes and/or HLP; whereas 18% of the VSO patients had neither type 2 diabetes nor HLP. This difference was statistically significant (p < 0.01). When the VSO patients having neither type 2 diabetes nor HLP were compared with their diseased counterparts (Table 3), we saw no difference in BMI. However, the non-diseased VSO patients had higher estrogen levels and a lower WHR, although neither of these parameters reached significance, possibly because of the small numbers.

Figure 1.

(A) Metabolic risk in SO men. All SO men suffered from metabolic risk factors: 24% from type 2 diabetes (without and with HLP) and 76% from HLP alone. (B) Metabolic risk in VSO men. Eighteen percent of VSO men showed no metabolic risk factors; 29% suffered from type 2 diabetes (without and with HLP) and 53% from HLP alone.

Table 3.  Characterization of the VSO men with and without metabolic disease
ParametersHealthy VSO men (n = 9)VSO men + hyperlipidemia (n = 23)VSO men + type 2 diabetes* (n = 14)
  • VSO, very severely obese; WHR, waist-to-hip ratio. Anthorpometric measures are given, as well as hormone levels. Numbers indicate mean ± standard deviation. Normal values are given parentheses.

  • *

    p < 0.05.

Age (years)34 ± 1040 ± 841 ± 6
BMI (kg/m2)62 ± 760 ± 857 ± 6
WHR (<0.95)0.93 ± 0.121.03 ± 0.11*0.98 ± 0.06
Subcutaneous fat layer (cm)6.0 ± 1.16.2 ± 2.64.6 ± 1.5
Leptin (7 ng/mL)67 ± 4161 ± 2344 ± 18
Estrogen (13 to 47 ng/liter)47 ± 936 ± 1541 ± 16
Testosterone (2.5 to 12 μg/liter)3.0 ± 1.22.5 ± 1.42.0 ± 1.3

Data on steatosis are available for only 33 men. The VSO group presented with 52% (n = 23) steatosis, whereas the SO group has a mean value of 56% (n = 10, p = 0.6). These numbers are too few for more definitive statistical assessments.

Discussion

The literature is relatively replete with regard to obesity-associated metabolic risk factors for obese individuals whose BMI is <40 kg/m2 (1, 2, 3, 4). There is little information, however, regarding the metabolic status of individuals whose BMI ≥40 kg/m2. Several studies (5, 6, 7, 8, 9, 10, 11, 12) have compared the metabolic status of individuals with varying stages of SO and VSO. Some of these studies reported that certain parameters of metabolic status worsen as the severity of SO increases, whereas others found that the metabolic situation remains the same or even improves with more severe stages of obesity. Interestingly, a recent study of ∼200 women showed that the metabolic profile in SO women is less deteriorated than expected compared with moderately obese women (13). Reasons for conflicting results in the various studies are unknown but may occur secondary to limited numbers of study subjects in some of these reports or to a failure to express the study findings according to sex. To verify the metabolic risk factors of SO patients according to severity of obesity, we studied the metabolic risk profiles and incidence rates for type 2 diabetes and HLP in 221 SO and 228 VSO patients, grouped according to sex.

Metabolic profiles of our study were more comprehensive than have been previously reported and included fasting blood glucose, HbA1c, insulin levels, leptin, lipid profiles, and degree of hepatic steatosis. According to our findings, male patients, regardless of degree of obesity, have higher values for factors of glycemic status than do women, i.e., higher fasting blood glucose, HbA1c, and insulin levels, corroborating the findings of others (19) who also reported greater defects in glycemic status for severely obese men than women. Male patients in our study, in comparison with women, also had more lipid abnormalities and a higher incidence of type 2 diabetes. For these reasons, all analyses relating metabolic status to body size were performed according to sex.

The gender-specific results have to be seen in the light of genetic differences (20, 21) and the fact that, in men, health concerns are more often the reason for seeking help in bariatric surgery.

The data show that male and female SO and VSO patients have a number of metabolic aberrations, including high insulin values and elevated fasting glucose, as well as elevated triglycerides and below normal levels of HDL-cholesterol. The incidence of type 2 diabetes and HLP in each of the study groups was also high in comparison to that expected for normal weight populations. However, increasing weight above an BMI of 40 kg/m2 does not seem to be a major contributor to the metabolic status of these massively obese patients.

The VSO and SO women in our study had similar metabolic profiles, i.e., glucose, HbA1c, insulin, and lipid profiles, and, in addition, exhibited nearly an identical incidence rate for type 2 diabetes and HLP, i.e., 67% and 66%, respectively. In the male population of our study, increasing degree of obesity was associated with a lower risk for type 2 diabetes and HLP. While all SO patients had either HLP or type 2 diabetes, 18% of VSO men had neither of these metabolic diseases. VSO men, therefore, have no significantly higher incidence of type 2 diabetes, nor do they have higher levels of fasting blood glucose, HbA1c, or insulin than do the SO men. These findings differ from those of other investigators who, in reporting differences in measures of glycemic status or incidence of type 2 diabetes, failed to group their patients according to sex (8, 11, 12).

Lipid profiles of the VSO men were much improved over those with SO. Total triglyceride and cholesterol levels of these patients were significantly less than in their SO counterparts. Further information on the quality of the lipid profile would have been obtained with measurement of LDL particle size. Such measurements, however, were not possible in the clinical setting. The percentage of patients with HLP among the SO cohort was considerably higher than for the more severely obese patients (76% vs. 53%, respectively). These findings suggest that, as severity of obesity increases in male patients with BMI above 40 kg/m2, lipid profiles might improve rather than worsen. This confirms other studies that have found that lipid defects peak at a BMI <40 kg/m2 and, thereafter, either remain unchanged or even tend to decline with greater obesity severity (10, 11, 12).

The lower metabolic risk of VSO men might be explained by information obtained from a subgroup of these patients that presented with no metabolic aberrations. In this group, there was a tendency toward higher estrogen levels and a lower WHR, favoring a more gynoid body habitus. This trend might be strengthened by a larger study group. Alagna et al. (22) just published data on gonadal function in severely obese men and found comparably low testosterone and relatively high estrogen levels, both being normalized 1 year after biliopancreatic diversion. In addition to a more favorable fat distribution and hormone pattern, we hypothesize that VSO men without metabolic aberrations may have a different genetic background, where the genetic predisposition affects genes involved in energy storage but not in metabolic pathways. Therefore, a genetic analysis of this group and other comparable cohorts should be performed.

In summary, the results of our study show that metabolic aberrations do not necessarily worsen with increasing BMI above 40 kg/m2. In fact, the metabolic status of severely obese men may improve as severity of obesity increases. This is an important fact that needs to be further evaluated and considered in clinical decisions.

Acknowledgments

We thank Sylvia Plöhn for handling the samples, Dr. Hans Werner Kuhlmann for support at the Evangelisches Krankenhaus Dinslaken, and PD Dr. Dubben for review of the statistical methods and critical reading of the manuscript. There was no funding/outside support for this study.

Footnotes

  • 1

    Nonstandard abbreviations: HLP, hyperlipidemia; VSO, very severe obesity; SO, severe obesity; LDL, low-density lipoprotein; HDL, high-density lipoprotein; Hb, hemoglobin; WHR, waist-to-hip ratio.

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