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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 9 3155-3160
Copyright © 2000 by The Endocrine Society

Original Studies

Codon-54 Polymorphism of the Fatty Acid-Binding Protein 2 Gene Is Associated with Elevation of Fasting and Postprandial Triglyceride in Type 2 Diabetes1

Angeliki Georgopoulos, Omer Aras and Michael Y. Tsai

Minneapolis Veterans Affairs Medical Center (A.G.) and the Departments of Medicine (A.G.) and Laboratory of Medicine and Pathology (O.A., M.Y.T.), University of Minnesota, Minneapolis, Minnesota 55417

Address correspondence and requests for reprints to: Angeliki Georgopoulos, M.D., Medicine Service 111 M, Veterans Affairs Medical Center, One Veterans Drive, Minneapolis, Minnesota 55417. E-mail: georg003{at}tc.umn.edu


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Patients with type 2 diabetes are frequently dyslipidemic or hypertriglyceridemic. To assess whether increased intestinal triglyceride input leads to elevated fasting and postprandial triglycerides in type 2 diabetes, we used the codon 54 polymorphism of the fatty acid-binding protein 2 gene, which results in the substitution of threonine (Thr) for alanine and is associated with increased intestinal input of triglyceride. Of the 287 diabetic patients screened, 108 (37.6%) were heterozygous and 31 (10.8%) were homozygous for the Thr-54 allele. Mean (±SEM) fasting plasma triglyceride levels in patients with the wild-type (n = 80), those heterozygous for the Thr-54 allele (n = 57), and those homozygous for it (n = 18) were 2.0 ± 0.09, 2.7 ± 0.20, and 3.8 ± 0.43 mmol/L, respectively. A linear relationship of mean fasting plasma triglyceride levels (r2 = 0.97) between the 3 groups was found. After fat ingestion, the postprandial area under the curve of plasma triglyceride (P = 0.025) and chylomicrons (Sf > 400, P = 0.013) was higher in the Thr-54/Thr-54 (n = 6) than in the wild-type (n = 9). Our results are consistent with the hypothesis that, in type 2 diabetes, increased intestinal input of triglyceride can lead to elevated fasting and postprandial plasma triglycerides.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
FATTY ACID-BINDING protein (FABP)2 is an intracellular protein expressed only in the intestine (1). The gene for FABP2 is located in the long arm of chromosome 4 (NIH Online Mendelian Inheritance in Man gene map). The G to A polymorphism of codon 54 of the FABP2 gene results in the substitution of a threonine (Thr) for an alanine (Ala) in the FABP2. This substitution is not silent; as shown in vitro experiments, it increases the affinity of FABP2 for long-chain fatty acids and is associated with increased triglyceride secretion of a human intestinal cell line (2, 3).

The Thr-54 allele has been associated with increased fat oxidation and insulin resistance in the Pima Indians (2), presumably by increasing the absorption and processing of fatty acids. Subsequent studies reported an association of the allele with insulin resistance in Native Canadians (4), Mexican-Americans (5), and some (6) [but not all (7, 8, 9)], Japanese. There was no such association in Finnish individuals (10, 11). However, some abnormalities in lipid metabolism were detected in Finnish subjects with this allele. Specifically: 1) dyslipidemic changes were reported in individuals with familial combined hyperlipidemia (12); and 2) elevated postprandial triglyceride-rich lipoprotein levels were reported in nondiabetic patients homozygous for the Thr-54 allele, compared with the wild-type (Ala-54/Ala-54) (13).

Type 2 diabetes is associated with insulin resistance, obesity, and frequently with elevation of plasma fasting and postprandial triglyceride levels (14, 15). It has been known for several years that in type 2 diabetes, triglyceride is an independent risk factor for atherosclerosis (16). We hypothesized that in type 2 diabetes, where there is very-low-density lipoprotein (VLDL) overproduction and decreased clearance of triglyceride-rich lipoproteins (15, 17), the codon 54 polymorphism of the FABP2 gene can further raise both fasting and postprandial triglyceride-rich lipoprotein levels by increasing the intestinal input of chylomicrons in the circulation. The present study tested this hypothesis.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
All study participants were patients with type 2 diabetes, as defined using criteria of the American Diabetes Association. Our study subjects had established diabetes by both the old and the new criteria. To assess the prevalence of the polymorphism, 287 diabetic patients, who responded to an announcement placed at the blood drawing room of the Minneapolis Veterans Affairs Medical Center (VAMC), were screened. The announcement solicited volunteer patients with type 2 diabetes to be screened for our study. All patients signed consent forms approved by our institutional review board. Study participants were male, and 98% were Caucasians. Patients on lipid-lowering drugs or steroids, and patients with secondary causes of hyperlipidemia except diabetes, were excluded from the study. Subjects included in the study were in good health, as determined by review of their history and physical examination and by routine laboratory studies (normal hematologic, liver, renal, and thyroid studies). Fasting and postprandial lipid measurements were carried out as outlined below. After a 12-h fast, blood was drawn for a lipid profile. In a smaller number of study participants (n = 15), who were not homozygous for the apo E2 or apo E4 allele, postprandial studies were carried out. Subjects ingested a shake containing egg white, Sweet-and-low, fruit flavor, and 55 g of corn oil/M2 of body surface. We decided not to include sucrose or other carbohydrates in the meal, because they can increase the production of hepatic triglycerides. Blood was drawn before the study and every 2 h, for a period of 8 h, for measurements of plasma triglyceride and isolation of 2 triglyceride-rich lipoprotein subfractions: Svedberg flotation (Sf) > 400 (chylomicrons) and Sf 20–400 (VLDL and remnants). Subjects were sitting or lying in the Special Diagnostic Testing Unit during the duration of the study. The triglyceride level of the 2 isolated lipoprotein subfractions was determined over time. No other meal was consumed until the study was completed. Subjects were encouraged to drink water after each blood drawing.

Detection of the polymorphism

DNA isolation was carried out from 10 ml of blood drawn in EDTA tubes, using a commercially available kit from Puregene (Gentra Systems, Minneapolis MN).

DNA amplification and digestion by restriction enzyme was done according to the method described by Baier et al. (2), using digestion by HhaI, to detect the Ala 54 Thr polymorphism, which disrupts an HhaI site. DNA was amplified by PCR, using primers 5'-ACAGGTGTTAATATAGTGAAAAG-3'and 5'-TACCCTGAGTTCAGTTCCGTC-3' from exon 2. The PCR buffer contained 2.5 mmol/L MgCl2, 0.2 mmol/L of each deoxynucleotide triphosphate, and 1.25 U of Amplitaq DNA polymerase. Temperature was cycled 30 times (60 sec at 95 C, 60 sec at 55 C, and 2 min at 72 C, followed by a 3-min extension at 72 C). The PCR product was digested by HhaI at 37 C for 3.5 h or overnight, applied to a 3% agarose gel containing 1 mg/mL ethidium bromide, electrophoresed for 40 min at 120 volts, and photographed under ultraviolet light. The PCR products that lack the HhaI site migrate as one 180-bp fragment (those carrying the Thr-54), but PCR products containing the HhaI site are cleaved to two fragments (a 99-bp and an 81-bp).

Apolipoprotein E genotyping

DNA samples were genotyped using PCR amplification followed by restriction enzyme digestion (18). Each amplification reaction contained PCR buffer with 15 mmol/L MgCl2, ng amounts of genomic DNA, 20 pmol Apo E forward (5N TAA GCT TGG CAC GGC TGT CCA AGG A 3N) and reverse (5N ATA AAT ATA AAA TAT AAA TAA CAG AAT TCG CCC CGG CCT GGT ACA C 3N) primers, 1.25 mmol/L of each deoxynucleotide triphosphate, 10% dimethylsulfoxide, and 0.25 µL Amplitaq DNA polymerase. Reaction conditions in a thermocycler included an initial denaturing period of 3 min at 95 C, 1 min at 60 C, and 2 min at 72 C; followed by 35 cycles of 1 min at 95 C, 1 min at 60 C, and 2 min at 72 C; and a final extension of 1 min at 95 C, 1 min at 60 C, and 3 min at 72 C. PCR products were digested with HhaI and separated on a 10% polyacrylamide nondenaturing gel and stained with silver nitrate. Known apo E isoform standards were included in the analysis.

Handling of blood samples

To avoid lipoprotein degradation, blood samples for lipoprotein analysis were collected in tubes containing EDTA (1 mg/mL), chloramphenicol (0.02 mg/mL), e-aminocaproic acid (1.3 mg/mL), gentamycin (0.05 mg/mL), benzamidine 0.01 mg/mL), and Trasylol (10 U/mL) (19). Plasma was separated by centrifugation at 4 C; triglyceride-rich lipoprotein subfractions were separated and analyzed within 5–7 days.

Determination of fasting lipoprotein parameters

Plasma triglyceride and total cholesterol was measured enzymatically by commercially available kits (Boehringer Mannheim Diagnostics). The coefficient of variation of these assays is 3.5% for the former and 4% for the latter. High-density lipoprotein (HDL) cholesterol was measured by heparin-manganese precipitation, according to the Lipid Research Centers protocol. These measurements are currently performed in the Veterans Affairs laboratory and are under quality control testing with the Northwest Lipid Research Laboratory in Seattle.

Isolation of lipoprotein subfractions

All isolations were performed under aseptic conditions within 48 h from harvesting of plasma. We used salt density gradient ultracentrifugation, according to the method of Lindgren, as modified by Redgrave (20), to isolate the triglyceride-rich lipoprotein subfractions, as published previously (21). Two subfractions were isolated: Sf > 400 at 4.5 x 106 g x min and Sf 20–400 at 183.2 x 106 g x min.

Statistical analysis

Standard statistical methods (22) were used to display and analyze the data. The BMDP/Dynamic statistical package (BMDP Statistical Software, Inc., Los Angeles, CA, 1992) was used for these analyses. Comparisons between groups were assessed using the nonparametric Mann-Whitney rank-sum test. The effect of FABP2 Thr-54 allele was assessed using an ANOVA (program 2V of BMDP), where this qualitative factor was entered at three levels (0 = absent, 1 = heterozygous, 2 = homozygous); in a separate analysis, this effect was assessed using the same program in an analysis of covariance in which the level of glycohemoglobin was added as a covariate.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Two hundred eighty-seven patients with type 2 diabetes were screened for the Thr- 54 polymorphism of the FABP2 gene. The population consisted of approximately 98% white men, which is typical of the population served by the Minneapolis VAMC. One hundred forty-eight individuals (51.6%) had the wild-type (Ala-54/Ala-54); 108 (37.6%) were heterozygotes (Ala-54/Thr-54), and 31 (10.8%) were homozygotes (Thr-54/Thr-54). As mentioned above, we excluded patients on lipid lowering medications or steroids and those with abnormal liver, kidney, or thyroid function tests. We then assessed whether dyslipidemia or elevated fasting plasma triglyceride levels were associated with the Thr-54 allele, by comparing the lipid profile of the patients who lacked the Thr-54 allele (wild-type) with that of the patients who were heterozygous or homozygous for it. As shown in Table 1Go, fasting plasma triglyceride levels were higher in both the heterozygotes and the homozygotes, compared with the wild-type. But total and non-HDL cholesterol were significantly elevated only in the homozygotes, whereas the heterozygotes had levels similar to the levels of the wild-type. There were no significant differences in mean age, body mass index (BMI), and glycohemoglobin levels among the three groups. However, because the mean glycohemoglobin levels tended to be higher in the heterozygous group, we performed analysis of covariance to adjust the plasma triglyceride levels for the effect of glycemic control. The adjusted plasma triglyceride means were very similar to the unadjusted ones. The respective values were as follows: 2.01 vs. 2.00 for the wild-type; 2.67 vs. 2.69 for the heterozygotes; and 3.84 vs. 3.83 mmol/L for the homozygotes. A regression analysis of these values showed a linear correlation of r2 = 0.97 (Fig. 1).


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  		Table 1. Characteristics of type 2 diabetic study patients grouped by FABP2 genotype (mean ± SEM)

 
To address the question of whether postprandial triglyceride levels were affected by the Thr-54 allele of the FABP2 in patients with type 2 diabetes, we gave a fatty meal to 9 patients with the wild-type (group A) and 6 homozygous for the Thr-54 allele (group B). The apo E allele distributions for group A were: 4 apo E3/E3, 2 apo E3/E4, 2 apo E2/E3, and 1 apo E2/E4; for group B, they were: 4 apo E3/E3, 1 apo E3/E4, and 1 apo E2/E3. The patients who underwent the postprandial studies were a representative sample of the groups they belonged to, with regard to confounding factors, because they were all male Caucasians whose age, BMI, and glycemic control were similar to the rest of the subjects in their corresponding group (data not shown). As expected, because of the lack of both within-group and between-group differences in age, BMI, and glycemic control, shown in Table 1Go, these parameters were similar between the two groups of representative subjects included in the postprandial studies (data not shown). The levels of postprandial triglyceride in plasma were higher in the Thr-54 homozygotes, compared with the wild-type (Fig. 2Go, top). The increased levels were not caused only by the elevated fasting baseline, as shown by the persistent differences in postprandial triglyceride levels after subtraction of the baseline (Fig. 2Go, bottom). The area under the curve (AUC) of the plasma triglyceride levels, after subtracting the baseline, was significantly different between the two groups (P = 0.025, Fig. 3Go). To assess which of the two isolated triglyceride-rich postprandial lipoprotein subfractions accounted for the observed plasma triglyceride differences between the two groups, we compared the AUC of the triglyceride levels in the chylomicron subfraction (Sf > 400) and the VLDL/chylomicron remnant subfraction (Sf 20–400). As shown in Fig. 3Go, only the AUC of the chylomicron subfraction was significantly different between the two groups (P = 0.013).



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  		Figure 2. Effect of the Thr-54 allele of the FABP2 gene on mean (± SEM) plasma triglycerides after a fat load. Top, Actual values; bottom, values calculated after subtracting the baseline.

 


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  		Figure 3. AUC of postprandial triglycerides in plasma, chylomicrons (Sf > 400), and VLDL (Sf 20–400) after subtracting baseline. Hatched bars, Diabetic patients with the wild-type (Ala-54/Ala-54); solid bars: diabetic patients homozygous for the Thr-54 allele. NS, Not significant.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
As reported by others, the frequency of the FABP2 polymorphism is similar in obese and nonobese individuals and diabetic and control subjects (4, 10). However, it varies, to some extent, between different ethnic groups, i.e. from 22% in the African Americans (23) to 36–41% in Japanese (7), and approximately 30% in Caucasians (10). Our results are within the range reported in the literature. The population we screened consisted almost completely (~98%) of Caucasian males, which is typical of the population served by the Minneapolis VAMC.

Our results show that the presence of the Thr-54 allele of the FABP2 is associated with elevated fasting plasma triglyceride levels in patients with type 2 diabetes. This is in contrast to reported findings in nondiabetic individuals (8, 11, 13). The only study reporting differences in fasting plasma triglycerides between individuals carrying the Thr-54 allele vs. the wild-type was done in Canadian Aboriginals. In that study, diabetic and nondiabetic subjects were pooled together (4). We believe that the higher fasting plasma triglyceride levels in diabetic patients with the Thr-54 allele is not attributable to any confounding factors like obesity, age, or the degree of glycemic control, because these factors were similar in the three groups. Moreover, as mentioned above, the mean values of fasting plasma triglycerides, adjusted for the effect of glycemic control, were very close to the unadjusted values. It is of interest that the level of plasma triglyceride in the homozygotes was approximately twice that present in the wild-type. This is similar to the in vitro findings of a 2- to 3-fold increase in intestinal triglyceride secretion by Caco-2 cells transfected with the codon 54 Thr allele (3). A linear dose response effect (r2 = 0.97) of the mean plasma triglyceride level was seen in our population, with the levels in heterozygotes being intermediate between those present in the homozygotes and in the wild-type (Fig. 1Go).



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  		Figure 1. Relationship of the Thr-54 allele of the FABP2 on mean (± SEM) fasting plasma triglycerides.

 
Elevated total cholesterol levels were associated only with the higher plasma triglyceride elevations present in the homozygous state (Table 1Go) and were attributable to dyslipidemic elevations of non-HDL cholesterol. Because the low-density lipoprotein (LDL) and HDL levels were similar in all study groups, cholesterol carried by the VLDL/remnant lipoproteins must have accounted for the observed differences in total cholesterol between homozygotes and the wild-type.

As hypothesized, the differences we observed in postprandial plasma triglyceride levels between the homozygotes and the wild-type were significant, even after adjusting for the baseline effect (Fig. 2Go). The observed differences were not attributable to confounding factors like glycemic control, age, BMI, or the presence of the apo E2 or the apo E4 alleles. They were attributable to differences in the chylomicron, but not the VLDL, triglyceride levels (Fig. 3Go). Again, a 2-fold or greater difference was seen between the two groups. Our results are in agreement with the only reported study carried out in nondiabetic individuals, which showed similar elevations of postprandial plasma triglyceride levels in the Thr-54 homozygotes (13). However, in that study, both chylomicron and VLDL triglyceride contributed to the observed postprandial plasma triglyceride differences. The discrepancy between our results and that study is most likely attributable to technical differences. The isolation of the two subfractions in the reported study (13) was carried out with a fixed rotor after layering the plasma with saline. This technique does not completely separate the VLDL and the chylomicrons, and therefore, the isolated VLDL subfraction could have included some residual chylomicron particles (24). Our isolation method included the creation of a density gradient and the use of a swinging rotor, measures known to decrease chylomicron contamination of VLDL (19, 24). An alternative explanation is that the observed discrepancy between the two studies is attributable to differences in the types of study subjects included in the studies, i.e. diabetic vs. nondiabetic individuals, or in differences in the type of fatty meal. Our meal did not include any carbohydrates, whereas their meal included a small amount of carbohydrates (7.6 g).

The authors cannot exclude the possibility that linkage of the FABP2 gene to another (as yet unidentified) gene could have contributed to the observed results. However, they find such a possibility unlikely, because the Thr-54 polymorphism of the FABP2 gene is not a silent marker; it results in a functional alteration of the FABP2 that is consistent with the reported observations of increased intestinal fatty acid transport and triglyceride secretion in vitro (3) and elevated triglyceride-rich lipoprotein levels in vivo (13, and present data).

In conclusion, our data are consistent with the hypothesis that increased intestinal input of triglycerides affects both fasting and postprandial plasma triglyceride levels in patients with type 2 diabetes. It is possible that the Thr-54 allele, in conjunction with the VLDL overproduction and decreased clearance of triglyceride-rich lipoproteins present in type 2 diabetes (15, 17), further increases plasma triglyceride levels. Fasting apo B48, originating from intestinal triglyceride-rich particles, has been described previously in individuals with types I, III, and V hyperlipidemia (25). However, we believe that this is the first clinical study that has described the occurrence of type IV hyperlipidemia driven by increased intestinal triglyceride input.


   Acknowledgments
 
We acknowledge the expert technical help of Laura Salvati, of the staff of the Special Diagnostic Treatment Unit and of the staff of the blood drawing room at the Minneapolis VAMC.


   Footnotes
 
1 This research was supported by Veterans Affairs funds. Back

Received February 29, 2000.

Revised May 18, 2000.

Accepted May 24, 2000.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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