Fatty acid and very low density lipoprotein metabolism in obese African American and Caucasian women with type 2 diabetes

Type 2 diabetes mellitus (T2DM) is associated with increased plasma triglyceride (TG) concentrations, but African Americans (AA) have lower plasma TG than Caucasians (CC). We evaluated the hypothesis that obese AA women have lower plasma TG than obese CC women do because of differences in lipid kinetics. Eleven AA and 11 CC obese women with T2DM, matched on body mass index (BMI) (AA = 37 ± 1, CC = 37 ± 1 kg/m2), age, duration of diabetes, percentage body fat, and insulin sensitivity (SI, determined by an intravenous glucose tolerance test), were studied. Plasma TG concentration (AA = 1.14 ± 0.11, CC = 1.88 ± 0.18 mmol/l), FFA rate of appearance (Ra) into plasma (AA = 419 ± 27, CC = 503 ± 31 µmol·min−1), and total VLDL-TG secretion rate (AA = 18 ± 2, CC = 29 ± 4 µmol·min−1) were lower in AA than CC women (all P < 0.05). In contrast, plasma total apolipoprotein (apo)B-100 concentration (AA = 1,542 ± 179, CC = 1,620 ± 118 nmol/l) and VLDL-apoB-100 secretion rate (AA = 1.3 ± 0.1, CC = 1.3 ± 0.1 nmol·min−1) were similar in both groups, so the molar ratio of VLDL-TG secretion rate to VLDL-apoB-100 secretion rate was lower in AA women than in CC women. VLDL-TG concentration was lower in AA women due to lower total VLDL-TG secretion rate. However, the VLDL-apoB-100 secretion rate was the same in both groups, demonstrating that AA women secrete smaller VLDL particles containing less TG than do CC women. Type 2 diabetes mellitus (T2DM) is associated with increased plasma triglyceride (TG) concentrations, but African Americans (AA) have lower plasma TG than Caucasians (CC). We evaluated the hypothesis that obese AA women have lower plasma TG than obese CC women do because of differences in lipid kinetics. Eleven AA and 11 CC obese women with T2DM, matched on body mass index (BMI) (AA = 37 ± 1, CC = 37 ± 1 kg/m2), age, duration of diabetes, percentage body fat, and insulin sensitivity (SI, determined by an intravenous glucose tolerance test), were studied. Plasma TG concentration (AA = 1.14 ± 0.11, CC = 1.88 ± 0.18 mmol/l), FFA rate of appearance (Ra) into plasma (AA = 419 ± 27, CC = 503 ± 31 µmol·min−1), and total VLDL-TG secretion rate (AA = 18 ± 2, CC = 29 ± 4 µmol·min−1) were lower in AA than CC women (all P < 0.05). In contrast, plasma total apolipoprotein (apo)B-100 concentration (AA = 1,542 ± 179, CC = 1,620 ± 118 nmol/l) and VLDL-apoB-100 secretion rate (AA = 1.3 ± 0.1, CC = 1.3 ± 0.1 nmol·min−1) were similar in both groups, so the molar ratio of VLDL-TG secretion rate to VLDL-apoB-100 secretion rate was lower in AA women than in CC women. VLDL-TG concentration was lower in AA women due to lower total VLDL-TG secretion rate. However, the VLDL-apoB-100 secretion rate was the same in both groups, demonstrating that AA women secrete smaller VLDL particles containing less TG than do CC women. African American body mass index Caucasian fractional catabolic rate fat-free mass fat mass intrahepatic triglyceride rate of appearance insulin sensitivity index subcutaneous abdominal adipose tissue type 2 diabetes mellitus triglyceride tracer-to-tracee ratio visceral adipose tissue Obesity is a major cause of multiorgan insulin resistance, which is associated with increased plasma triglyceride (TG) concentration, increased intrahepatic triglyceride (IHTG) content, and type 2 diabetes mellitus (T2DM). The relationships among obesity, plasma TG concentration, IHTG content, and T2DM, however, are influenced by race (1Cook C.B. Erdman D.M. Ryan G.J. Greenlund K.J. Giles W.H. Gallina D.L. El-Kebbi I.M. Ziemer D.C. Ernst K.L. Dunbar V.G. et al.The pattern of dyslipidemia among urban African-Americans with type 2 diabetes.Diabetes Care. 2000; 23: 319-324Crossref PubMed Scopus (50) Google Scholar–6Sharma M.D. Pavlik V.N. Dyslipidaemia in African Americans, Hispanics and whites with type 2 diabetes mellitus and hypertension.Diabetes Obes. Metab. 2001; 3: 41-45Crossref PubMed Scopus (25) Google Scholar). Although obesity and T2DM are associated with an increase in plasma TG concentration, obese African American (AA) women who have T2DM usually have lower plasma TG concentrations than do Caucasian (CC) women (1Cook C.B. Erdman D.M. Ryan G.J. Greenlund K.J. Giles W.H. Gallina D.L. El-Kebbi I.M. Ziemer D.C. Ernst K.L. Dunbar V.G. et al.The pattern of dyslipidemia among urban African-Americans with type 2 diabetes.Diabetes Care. 2000; 23: 319-324Crossref PubMed Scopus (50) Google Scholar, 2Cowie C.C. Howard B.V. Harris M.I. Serum lipoproteins in African Americans and whites with non-insulin-dependent diabetes in the US population.Circulation. 1994; 90: 1185-1193Crossref PubMed Scopus (72) Google Scholar, 6Sharma M.D. Pavlik V.N. Dyslipidaemia in African Americans, Hispanics and whites with type 2 diabetes mellitus and hypertension.Diabetes Obes. Metab. 2001; 3: 41-45Crossref PubMed Scopus (25) Google Scholar). The mechanisms responsible for the racial differences in TG concentration are not known but must involve an alteration in very low density lipoprotein-triglyceride (VLDL-TG) metabolism, because most TG in plasma circulates within VLDL particles produced by the liver (7Barter P.J. Nestel P.J. Precursors of plasma triglyceride fatty acids in obesity.Metabolism. 1973; 22: 779-783Abstract Full Text PDF PubMed Scopus (34) Google Scholar). The availability of fatty acids derived from the lipolysis of subcutaneous adipose tissue, visceral adipose tissue (VAT), and IHTG, as well as from de novo lipogenesis, are important regulators of VLDL-TG production within hepatocytes (8Lewis G.F. Fatty acid regulation of very low density lipoprotein production.Curr. Opin. Lipidol. 1997; 8: 146-153Crossref PubMed Scopus (247) Google Scholar). Obese AA women have a reduced whole-body adipose tissue lipolytic rate (9Racette S.B. Horowitz J.F. Mittendorfer B. Klein S. Racial differences in lipid metabolism in women with abdominal obesity.Am. J. Physiol. Regul. Integr. Comp. Physiol. 2000; 279: R944-R950Crossref PubMed Google Scholar, 10Albu J.B. Curi M. Shur M. Murphy L. Matthews D.E. Pi-Sunyer F.X. Systemic resistance to the antilipolytic effect of insulin in black and white women with visceral obesity.Am. J. Physiol. 1999; 277: E551-E560PubMed Google Scholar), less VAT (11Després J.P. Couillard C. Gagnon J. Bergeron J. Leon A.S. Rao D.C. Skinner J.S. Wilmore J.H. Bouchard C. Race, visceral adipose tissue, plasma lipids, and lipoprotein lipase activity in men and women: the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) family study.Arterioscler. Thromb. Vasc. Biol. 2000; 20: 1932-1938Crossref PubMed Scopus (313) Google Scholar, 12Albu J.B. Murphy L. Frager D.H. Johnson J.A. Pi-Sunyer F.X. Visceral fat and race-dependent health risks in obese nondiabetic premenopausal women.Diabetes. 1997; 46: 456-462Crossref PubMed Google Scholar), and lower IHTG content (4Guerrero R. Vega G.L. Grundy S.M. Browning J.D. Ethnic differences in hepatic steatosis: an insulin resistance paradox?.Hepatology. 2009; 49: 791-801Crossref PubMed Scopus (272) Google Scholar, 13Solga S.F. Clark J.M. Alkhuraishi A.R. Torbenson M. Tabesh A. Schweitzer M. Diehl A.M. Magnuson T.H. Race and comorbid factors predict nonalcoholic fatty liver disease histopathology in severely obese patients.Surg. Obes. Relat. Dis. 2005; 1: 6-11Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar) than do obese CC women. These differences in FFA kinetics and body fat distribution could reduce substrate availability for VLDL-TG particle assembly and secretion in AA women. The purpose of the present study was to test the hypothesis that the VLDL-TG secretion rate is lower in obese AA women with T2DM than in obese CC women with T2DM because of a lower contribution of fatty acids derived from both systemic sources (primarily from the lipolysis of subcutaneous adipose tissue) and nonsystemic sources (primarily from the lipolysis of VAT and IHTG). We evaluated VLDL-TG, VLDL-apolipoprotein B-100, and FFA kinetics in vivo in obese AA and CC women with T2DM, who were matched on percentage body fat and measures of insulin sensitivity, using stable isotopically labeled tracer infusions in conjunction with mathematical modeling. Eleven AA and 11 CC obese women with T2DM, matched on age, duration of diabetes, body weight, body mass index (BMI), whole-body fat mass, fat-free mass, and insulin sensitivity participated in this study. Written informed consent was obtained from all subjects before their participation, which was approved by the Human Studies Committee of Washington University School of Medicine in St. Louis, MO. Potential subjects completed a comprehensive medical evaluation that included a history and physical examination, standard blood and urine tests, and an electrocardiogram. Subjects who had markedly increased fasting plasma TG concentrations (>300 mg/dl), who smoked tobacco, or who took diabetes medications (other than sulfonylureas and biguanides) or medications/dietary supplements that can affect plasma lipids were excluded. All subjects had been weight stable (<2% change in body weight) and sedentary (regular exercise <1 h/week) for >2 months before the beginning of the study. Body fat mass (FM) and fat-free mass (FFM) were determined by using dual-energy X-ray absorptiometry (Delphi W-densitometer; Hologic, Waltham, MA) (14Genton L. Hans D. Kyle U.G. Pichard C. Dual-energy X-ray absorptiometry and body composition: differences between devices and comparison with reference methods.Nutrition. 2002; 18: 66-70Crossref PubMed Scopus (130) Google Scholar). Subcutaneous abdominal adipose tissue (SAT) and visceral adipose tissue (VAT) volumes were determined using magnetic resonance imaging (Siemens, Iselin, NJ) (15Abate N. Burns D. Peshock R.M. Garg A. Grundy S.M. Estimation of adipose tissue mass by magnetic resonance imaging: validation against dissection in human cadavers.J. Lipid Res. 1994; 35: 1490-1496Abstract Full Text PDF PubMed Google Scholar). Eight 10 mm thick axial images were obtained beginning at the L4–L5 interspace and analyzed for SAT and VAT content using Analyze 6.0 software (Mayo Foundation, Biomedical Imaging Resource, Rochester, MN); the volumes of fat were calculated for each slice, and the sum of these values was determined. The product of the fat volumes and the density of adipose tissue (0.9096 kg·L−1) was used to determine adipose tissue masses. Proton magnetic resonance spectroscopy (1.5 T Siemens Magneton Vision scanner; Siemens, Erlanger, Germany) was used to measure IHTG content as previously described (16Frimel T.N. Deivanayagam S. Bashir A. O'Connor R. Klein S. Assessment of intrahepatic triglyceride content using magnetic resonance spectroscopy.J. Cardiometab. Syndr. 2007; 2: 136-138Crossref PubMed Scopus (37) Google Scholar). Three 2 × 2 × 2 cm3 voxels were examined in each subject, and the values were averaged to determine IHTG content. A frequently sampled insulin intravenous glucose tolerance test (IVGTT) was performed to determine insulin sensitivity (SI) using the minimal model approach (17Saad M.F. Steil G.M. Riad-Gabriel M. Khan A. Sharma A. Boyadjian R. Jinagouda S.D. Bergman R.N. Method of insulin administration has no effect on insulin sensitivity estimates from the insulin-modified minimal model protocol.Diabetes. 1997; 46: 2044-2048Crossref PubMed Scopus (30) Google Scholar). Subjects were instructed to adhere to their regular diets and to refrain from exercise for 3 days before the study. Diabetes medications were discontinued 48 h before the IVGTT. At subjects was into a to glucose and insulin and a was into a which was to with a to blood blood were obtained at and to determine plasma glucose and insulin concentrations, an intravenous of glucose body was at and a of insulin was at were at 2, and to determine plasma glucose and insulin The insulin sensitivity was determined by using the plasma glucose and insulin concentrations and the minimal model of glucose kinetics the using Bergman R.N. a to insulin sensitivity and from the frequently sampled intravenous glucose tolerance 23: PubMed Scopus Google Scholar), is as the fractional glucose insulin concentration The insulin sensitivity index A. insulin sensitivity a for insulin sensitivity in Metab. 2000; PubMed Scopus Google Scholar) was calculated as measure of insulin Subjects were instructed to adhere to their regular diets and to refrain from exercise for 3 days before the study. Diabetes medications were discontinued 48 h before the kinetics study. Subjects were to the at Washington University School of Medicine in the a standard containing of total from from fat, and from at and for of the study the At h the was into a to stable isotopically labeled and a was into a in the which was to with a and blood were At a of in was the in the and infusions of to human and in were and for were obtained before tracer administration = and at and and h tracer administration to determine and tracer-to-tracee in plasma and in VLDL-TG and to determine in plasma and in VLDL-apolipoprotein Plasma insulin concentration was by St. Louis, Plasma FFA molar and concentrations were by acid to plasma as an standard N. D.L. Klein S. of a to determine plasma fatty acid concentration and Lipid Res. 1999; Full Text Full Text PDF PubMed Google Scholar). plasma TG and VLDL-TG concentrations were determined with a St. Louis, plasma and VLDL-apoB-100 concentrations were by using a blood were plasma was by within of of plasma were in the for of VLDL and of total plasma and VLDL-apoB-100 The VLDL was as previously described B. Klein S. of weight on and kinetics in women with abdominal obesity.Am. J. Physiol. Metab. PubMed Scopus Google Scholar). of plasma was into with a and at for h at in an with a type The which was by Plasma and the of and in VLDL-TG, and the of in VLDL-apoB-100 were determined by using mass as previously described N. D.L. Klein S. of a to determine plasma fatty acid concentration and Lipid Res. 1999; Full Text Full Text PDF PubMed Google Mittendorfer B. N. R. Klein S. of stable isotopically labeled to measure very low density lipoprotein-triglyceride Lipid Res. 2002; Full Text Full Text PDF PubMed Google Scholar). rate of appearance (Ra) in plasma was calculated by the tracer rate by the plasma between and and total FFA was calculated by by the contribution of to total plasma FFA concentration B. J.M. Klein S. the of whole-body fatty acid rate of appearance in plasma by using a fatty acid tracer PubMed Scopus Google Scholar). Plasma FFA were calculated by total FFA by total FFA concentration was for VLDL-TG and VLDL-apoB-100 because plasma VLDL-TG and VLDL-apoB-100 concentrations the h The fractional catabolic rate of VLDL-TG was determined by the of in plasma and VLDL-TG to a model Mittendorfer B. N. R. Klein S. of stable isotopically labeled to measure very low density lipoprotein-triglyceride Lipid Res. 2002; Full Text Full Text PDF PubMed Google Scholar). The VLDL-TG secretion rate of which the of VLDL-TG by the liver of was calculated by the of VLDL-TG by the concentration of VLDL-TG in plasma VLDL-TG secretion rate µmol·min−1), which the total of VLDL-TG by the was calculated by the rate in of by plasma at B. Klein S. of weight on and kinetics in women with abdominal obesity.Am. J. Physiol. Metab. PubMed Scopus Google Scholar). The contribution of systemic plasma fatty acids and nonsystemic fatty acids to total VLDL-TG production was calculated by in plasma and VLDL-TG to a model that for between plasma and VLDL-TG B. Klein S. of weight on and kinetics in women with abdominal obesity.Am. J. Physiol. Metab. PubMed Scopus Google Scholar). Systemic sources isotopically labeled fatty acids from the systemic that are by the liver and into VLDL-TG or into TG in VAT and the liver before into sources are derived from of fatty acids that are not labeled with tracer the these sources fatty acids from TG in the liver or into the as and fatty acids derived from hepatic de novo (8Lewis G.F. Fatty acid regulation of very low density lipoprotein production.Curr. Opin. Lipidol. 1997; 8: 146-153Crossref PubMed Scopus (247) Google Scholar). The of systemic fatty acids used in the production of VLDL-TG was calculated as × VLDL-TG secretion rate derived from systemic fatty acid sources FFA The of VLDL-apoB-100 was calculated by the of in plasma and in VLDL-apoB-100 to a model B. Klein S. of weight on and kinetics in women with abdominal obesity.Am. J. Physiol. Metab. PubMed Scopus Google Scholar). The rate of secretion was calculated on plasma VLDL-apoB-100 concentration and VLDL-apoB-100 as described for A mass of for was used for S.M. A. N. Human liver apolipoprotein acid and derived acid PubMed Scopus Google Scholar). The molar ratio of VLDL-TG secretion rate to VLDL-apoB-100 secretion rate was calculated to the of TG in VLDL A was used to test for differences between AA and CC women in with A was used for with A test was performed in with was used to test for of race and for between race and of on that subjects in each to a in the rate of VLDL-TG secretion or VLDL-apoB-100 secretion between with a = and an of Mittendorfer B. of stable tracer measures of and VLDL-apolipoprotein Lipid Res. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). were used to the relationships between of with distribution were as the ± with distribution were as the A P was for all All were performed with (AA = ± 2 and CC = ± 3 duration of T2DM (AA = ± 1 and CC = ± 1 blood (AA = ± CC = ± body weight, body fat, total and were similar in AA and CC women In contrast, body fat distribution was between VAT mass and IHTG content were lower in AA than CC women. of glucose plasma and and total were similar in both groups, but plasma total VLDL-TG, and concentrations were lower in AA than in CC women The of subjects with was similar in the AA = and CC = in obese Caucasian and African American subjects with American weight, ± ± ± ± fat, ± ± mass, ± ± mass, ± ± ± ± ± ± from Caucasian women at P < ± ± from Caucasian women at P < are ± from Caucasian women at P < from Caucasian women at P < in a in obese Caucasian and African American subjects with American ± ± from CC at P < ± ± from CC at P < from CC at P < ± ± from CC at P < ± ± ± ± ± ± ± ± are ± or insulin sensitivity from CC at P < from CC at P < in a are ± are ± or insulin sensitivity FFA was lower in AA than in CC plasma FFA were similar in both plasma FFA concentrations were lower in AA than in CC women Plasma FFA concentration was with FFA in both AA and CC women not VLDL-TG secretion rate was lower in AA than in CC women < The of VLDL-TG that was derived from nonsystemic fatty acids was lower in AA than in CC women < the of VLDL-TG derived from systemic fatty acids was in AA than in CC women < 0.05). The total of VLDL-TG derived from nonsystemic fatty acids derived from fatty acids lipolysis of IHTG and visceral adipose tissue, was lower in AA than in CC women < The of VLDL-TG derived from nonsystemic fatty acids was with IHTG content = P < was no between VLDL-TG production rate and visceral adipose tissue mass = The percentage of total FFA into the from the lipolysis of adipose tissue TG systemic FFA into VLDL-TG was similar in AA and CC women (AA = ± and CC = ± P = VLDL-TG secretion rate with total TG concentration P < with a race < but a secretion rate = VLDL-TG (AA = ± CC = ± P = and rate from plasma (AA = ± CC = ± P = were similar in AA and CC women. VLDL-apoB-100 secretion rate was not between groups, but VLDL-apoB-100 was in AA ± than in CC ± P < women plasma VLDL-apoB-100 concentration was lower in AA than in CC and the molar ratio of VLDL-TG secretion rate to VLDL-apoB-100 secretion rate was lower in AA than in CC women < 0.05). T2DM is associated with an dyslipidemia that is by an increase in TG and a in concentration on and of in of the on and of in Scholar). Although the of T2DM is C.C. C. D.E. et of diabetes and in the US in and Care. 2009; PubMed Scopus Google Scholar), TG concentrations are lower in AA than in CC women with T2DM (1Cook C.B. Erdman D.M. Ryan G.J. Greenlund K.J. Giles W.H. Gallina D.L. El-Kebbi I.M. Ziemer D.C. Ernst K.L. Dunbar V.G. et al.The pattern of dyslipidemia among urban African-Americans with type 2 diabetes.Diabetes Care. 2000; 23: 319-324Crossref PubMed Scopus (50) Google Scholar, 2Cowie C.C. Howard B.V. Harris M.I. Serum lipoproteins in African Americans and whites with non-insulin-dependent diabetes in the US population.Circulation. 1994; 90: 1185-1193Crossref PubMed Scopus (72) Google Scholar, 6Sharma M.D. Pavlik V.N. Dyslipidaemia in African Americans, Hispanics and whites with type 2 diabetes mellitus and hypertension.Diabetes Obes. Metab. 2001; 3: 41-45Crossref PubMed Scopus (25) Google Scholar). In the present evaluated the mechanisms responsible for the racial differences in plasma lipids by FFA and VLDL kinetics in obese AA and CC women with T2DM who were matched on percentage body fat, and measures of insulin that both FFA and VLDL-TG secretion rate were lower in AA than in CC which to the lower plasma FFA and VLDL-TG concentrations in the AA women. Plasma VLDL-apoB-100 concentrations were lower in AA however, this was due to a VLDL-apoB-100 not a lower VLDL-apoB-100 secretion rate. In VLDL-apoB-100 secretion were the same in AA and CC women and in similar total plasma concentrations in both race has on FFA and lipoprotein metabolism that are of insulin sensitivity in women with Although FFA increased with in all FFA was lower at in the AA than in CC women. The lower rate of lipolysis of adipose tissue triglyceride in the AA than in the CC women was responsible for the lower plasma FFA concentrations in the AA because plasma FFA was similar in both The effect of race on FFA kinetics has been before (9Racette S.B. Horowitz J.F. Mittendorfer B. Klein S. Racial differences in lipid metabolism in women with abdominal obesity.Am. J. Physiol. Regul. Integr. Comp. Physiol. 2000; 279: R944-R950Crossref PubMed Google Scholar, 10Albu J.B. Curi M. Shur M. Murphy L. Matthews D.E. Pi-Sunyer F.X. Systemic resistance to the antilipolytic effect of insulin in black and white women with visceral obesity.Am. J. Physiol. 1999; 277: E551-E560PubMed Google by demonstrating that FFA is lower in obese AA women who have T2DM than is in obese CC women who have The responsible for the in lipolytic activity in AA women is to a adipose tissue lipase content J. J. A. in the lipolytic of adipose tissue from American and Caucasian 2002; Full Text PDF PubMed Scopus Google Scholar) and TG lipase A. M. N. resistance in and Caucasian women: differences in and in adipose tissue and Metab. PubMed Scopus Google Scholar). The rate of hepatic secretion of VLDL-TG was lower in AA than in CC due to a reduced contribution of fatty acids derived from nonsystemic fatty acid the lower of and intrahepatic TG the availability of fatty acids from these sources for hepatic VLDL-TG was a a lower contribution of systemic fatty acids to VLDL-TG secretion in AA than in CC which is with the lower availability of systemic plasma FFA by whole-body lipolytic rate in AA women. These that lower VLDL-TG not VLDL-TG was responsible for the lower plasma VLDL-TG concentration in the AA women because VLDL-TG and were the same in both The secretion rate of VLDL particles with IHTG content M. C. A. J. S. A. et of VLDL particles is by increased liver fat content in 49: PubMed Scopus Google Scholar). AA women have smaller VLDL particles and lower concentrations of than do CC women J.D. and of and VLDL particle among the 2000; Full Text Full Text PDF PubMed Scopus Google J.S. J.A. and racial differences in lipoprotein the Full Text Full Text PDF PubMed Scopus Google Scholar). are with these because the molar ratio of VLDL-TG secretion rate to VLDL-apoB-100 secretion rate was lower in obese AA women than was in obese CC demonstrating the of smaller VLDL particles containing less TG in AA women than in CC women. In VLDL-apoB-100 was in AA women than in CC VLDL-TG and plasma were the same in both These that the of TG from VLDL a of from VLDL to and because of the lower TG content of VLDL particles in AA women than in CC women. In plasma FFA and VLDL-TG concentrations were lower in obese AA women with T2DM than in obese CC women with T2DM who were matched on percentage body fat, and insulin that lower adipose tissue lipolytic activity and hepatic VLDL-TG secretion rate were responsible for the racial differences in plasma The the of the for their in the and for their and the study subjects for their