Biomarkers associated with high-density lipoproteins in atherosclerotic kidney disease

High-density lipoproteins (HDL) originate as discoidal particles that are rapidly converted by lecithin:cholesterol acyltransferase (LCAT) into the spherical particles that predominate in normal human plasma. Spherical HDL consist of multiple populations of particles that vary widely in size, composition and function. Human population studies have established that high plasma HDL cholesterol levels are associated with a reduced incidence of cardiovascular disease. The mechanistic basis of this relationship is not well understood, but most likely involves a number of the cardioprotective functions of HDL. These include the ability of apolipoprotein (apo) A-I, the main apolipoprotein constituent of HDL, to remove cholesterol from macrophages in the artery wall. HDL also have antioxidant and anti-inflammatory properties that are potentially cardioprotective. Evidence that some of these beneficial properties are compromised in people with diabetes and renal disease is emerging. Persistently elevated plasma glucose levels in people with diabetes and poor glycemic control can lead to irreversible, non-enzymatic glycation of plasma proteins, including apoA-I. Non-enzymatically glycated proteins are also prevalent in people with diabetes and end-stage renal disease who are at high cardiovascular risk. Evidence that non-enzymatically glycated apoA-I inhibits the LCAT reaction and impairs some of the cardioprotective properties of HDL is also emerging. This review is concerned with how non-enzymatic glycation of apoA-I affects the ability of LCAT to convert discoidal HDL into spherical HDL, how it affects cholesterol efflux from macrophages and how it affects the anti-inflammatory and antioxidant properties of HDL.     

Elevated HDL cholesterol is functionally ineffective in cardiac transplant recipients: evidence for impaired reverse cholesterol transport

BACKGROUND: Cardiac transplant recipients frequently have high plasma HDL levels but it is unclear whether these promote a cardioprotective profile. METHODS: Parameters of reverse cholesterol transport and endothelial function were compared in 25 cardiac transplant recipients with low (<1.4 mmol/L; n=11) or high (>1.4 mmol/L; n=14) plasma levels of HDL and in a reference healthy group. RESULTS: Patients with high HDL had lower levels of triglyceride and prebeta1-HDL and a higher proportion of large HDL particles. When normalized to apoA-I content, non-ABCA1-dependent cholesterol efflux from RAW 264.7 macrophage cells to plasma from high HDL patients was 33% lower when compared to plasma from patients with low HDL, whereas ABCA1-dependent cholesterol efflux was not impaired. Forearm vascular responses to acetylcholine and sodium nitroprusside were not influenced by HDL levels in these patients. Compared to a reference healthy group (n=26), cardiac transplant recipients had higher levels of triglyceride, lower levels of prebeta1-HDL and LCAT, and lower activities of cholesteryl ester transfer protein and phospholipid transfer protein. CONCLUSIONS: Hyperalphalipoproteinaemia in cardiac transplant recipients is associated with the formation of partially dysfunctional HDL. We conclude that high levels of HDL may not confer cardioprotection in this group of patients.     

The ATP-binding cassette transporter A1 R230C variant affects HDL cholesterol levels and BMI in the Mexican population: association with obesity and obesity-related comorbidities

Although ATP-binding cassette transporter A1 (ABCA1) is well known for its role in cholesterol efflux and HDL formation, it is expressed in various tissues, where it may have different functions. Because hypoalphalipoproteinemia is highly prevalent in Mexico, we screened the ABCA1 coding sequence in Mexican individuals with low and high HDL cholesterol levels to seek functional variants. A highly frequent nonsynonymous variant (R230C) was identified in low-HDL cholesterol but not in high-HDL cholesterol individuals (P = 0.00006). We thus assessed its frequency in the Mexican-Mestizo general population, seeking possible associations with several metabolic traits. R230C was screened in 429 Mexican Mestizos using Taqman assays, and it was found in 20.1% of these individuals. The variant was significantly associated not only with decreased HDL cholesterol and apolipoprotein A-I levels but also with obesity (odds ratio 2.527, P = 0.005), the metabolic syndrome (1.893, P = 0.0007), and type 2 diabetes (4.527, P = 0.003). All of these associations remained significant after adjusting for admixture (P = 0.011, P = 0.001, and P = 0.006, respectively). This is the first study reporting the association of an ABCA1 variant with obesity and obesity-related comorbidities as being epidemiologically relevant in the Mexican population.     

Apolipoprotein E-containing lipoproteins and lipoprotein remnants in experimental canine diabetes

The effects of diabetes on plasma lipoproteins were examined in a cohort of control and streptozocin-alloxan diabetic beagles fed either standard rations or an atherogenic cholesterol-supplemented diet. Lipoprotein cholesterol, triglyceride, and retinyl ester concentrations were measured in fractions separated by density gradient ultracentrifugation. Individual lipoprotein classes and apolipoproteins were assessed by electrophoresis. Postheparin plasma lipoprotein triglyceride lipase activities were also examined. In the absence of added dietary cholesterol, diabetic animals became hypercholesterolemic with relatively increased low-density (LDL) and decreased high-density (HDL) lipoprotein cholesterol concentrations. Apolipoprotein E-containing beta- to alpha 2-migrating HDL1 (HDLc) appeared in rho = 1.020-1.080 g/ml subfractions, whereas alpha 1-migrating typical HDL (rho = 1.06-1.21 g/ml) was reduced. In comparison to nondiabetic cholesterol-fed animals, diabetic cholesterol-fed animals had increased cholesterol (but not triglyceride) concentrations in very-low- and intermediate-density classes. These classes contained retinyl esters and low-molecular-weight apolipoprotein B (components of intestinal lipoprotein remnants) as well as apolipoprotein E and high-molecular-weight apolipoprotein B. These findings could not be explained by decreased postheparin plasma lipoprotein lipolytic activities. Increased plasma concentrations of HDLc in poorly controlled diabetic dogs may reflect a pathologic disturbance in the excretory limb of cholesterol transport from peripheral cells to the liver. In addition, exaggerated retention of lipoprotein remnants in cholesterol-fed diabetic dogs may contribute to increased delivery of cholesterol to extrahepatic tissues. This model appears to be suitable for physiologic studies of the effects of diabetes on reverse cholesterol transport.     

miR-33a modulates ABCA1 expression, cholesterol accumulation, and insulin secretion in pancreatic islets

Changes in cellular cholesterol affect insulin secretion, and β-cell-specific deletion or loss-of-function mutations in the cholesterol efflux transporter ATP-binding cassette transporter A1 (ABCA1) result in impaired glucose tolerance and β-cell dysfunction. Upregulation of ABCA1 expression may therefore be beneficial for the maintenance of normal islet function in diabetes. Studies suggest that microRNA-33a (miR-33a) expression inversely correlates with ABCA1 expression in hepatocytes and macrophages. We examined whether miR-33a regulates ABCA1 expression in pancreatic islets, thereby affecting cholesterol accumulation and insulin secretion. Adenoviral miR-33a overexpression in human or mouse islets reduced ABCA1 expression, decreased glucose-stimulated insulin secretion, and increased cholesterol levels. The miR-33a-induced reduction in insulin secretion was rescued by cholesterol depletion by methyl-β-cyclodextrin or mevastatin. Inhibition of miR-33a expression in apolipoprotein E knockout islets and ABCA1 overexpression in β-cell-specific ABCA1 knockout islets rescued normal insulin secretion and reduced islet cholesterol. These findings confirm the critical role of β-cell ABCA1 in islet cholesterol homeostasis and β-cell function and highlight modulation of β-cell miR-33a expression as a means to influence insulin secretion.     

Early Postoperative Changes of HDL Subfraction Profile and HDL-Associated Enzymes After Laparoscopic Sleeve Gastrectomy

This study aimed to determine early postoperative changes of LDL/HDL subfraction profile and HDL-associated enzymes following laparoscopic sleeve gastrectomy (LSG). Thirteen obese patients (mean body mass index (BMI) 52.74?±?10.97 kg/m²) underwent LSG and normal weight control patients (mean BMI 23.56?±?1.92 kg/m²) underwent laparoscopic abdominal surgery. Fasting blood samples were collected prior to surgery, at day 1 after surgery, and after postoperation oral feeding. LDL and HDL subfraction analysis was done by continuous disk polyacrylamide gel electrophoresis. Plasma levels of cholesteryl ester transfer protein (CETP), lecithin–cholesterol acyltransferase (LCAT), and apolipoprotein A-1 (apoA-I) were determined by enzyme-linked immunosorbent assay. Measurement of CETP and LCAT activity was performed via fluorometric analysis. LDL subfraction profile showed no change in both LSG and control group patients. No significant difference was observed in HDL cholesterol, HDL-subfraction distribution, and apoA-I levels in the control group. LSG patients showed a significant increase in HDL-large and a significant decrease in HDL-small fractions at postoperation day 1 compared to preoperation. HDL cholesterol significantly decreased and apoA-I significantly increased in LSG patients after postoperation oral feeding compared to both preoperation and postoperation day 1. Changes in HDL subfraction profile at postoperation day 1 after LSG were accompanied by a significant decrease in CETP protein, LCAT protein, and LCAT activity as compared to preoperation levels. Early changes in HDL subfraction profile and HDL-associated enzymes following LSG suggest that the surgical procedure, irrespective of changes in body weight, affects reverse cholesterol transport.     

Abnormal HDL apolipoprotein A-I and A-II kinetics in hemodialysis patients: a stable isotope study

Low levels of HDL cholesterol and its major apoprotein constituents apoA-I and apoA-II are common in patients who have ESRD and are undergoing hemodialysis (HD), but the metabolic basis for the low HDL is poorly understood. This study aimed to investigate in vivo metabolism of apoA-I and apoA-II in five normotriglyceridemic ESRD-HD patients and compared it with five control subjects using endogenous stable isotope labeling methods coupled with a multicompartmental modeling. HDL cholesterol, apoA-I, and apoA-II levels were markedly decreased in the ESRD-HD patients by 39, 30, and 44%, respectively, in comparison with the control subjects. Fractional catabolic rate of apoA-I was found to be significantly increased by 59% to 0.360 +/- 0.084/d in ESRD-HD patients as compared with control subjects of 0.227 +/- 0.076/d (P = 0.028), whereas the production rates remained unchanged. Conversely, the apoA-II production rate significantly decreased by 31% to 1.50 +/- 0.61 mg/kg per d in the ESRD-HD patients in comparison with control subjects of 2.17 +/- 0.40 mg/kg per d (P = 0.047) with apoA-II fractional catabolic rate unchanged. These results revealed that the decreased levels of apoA-I are due solely to the increased rate of catabolism, whereas the reduced apoA-II levels are due primarily to the decreased rate of production in ESRD-HD patients. This differential regulation of apoA-I and apoA-II further supports the concept that apoA-I and apoA-II have distinct metabolic pathways.     

Pancreas transplantation modulates reverse cholesterol transport

Hyperinsulinemia secondary to insulin resistance in type-II diabetes or in the metabolic syndrome is associated with the “atherogenetic lipoprotein phenotype”: high triglycerides, small, dense low-density lipoprotein (LDL) cholesterol, and low high-density lipoprotein (HDL) cholesterol. In contrast, hyperinsulinemia in pancreas–kidney transplant recipients (PKT-R), secondary to systemic venous drainage of the heteropically implanted pancreas graft, leads to high lipoprotein lipase (LPL) activity and a presumably antiatherogenic lipoprotein profile with very attenuated postprandial lipemia, high HDL cholesterol, and a preponderance of large-sized HDL (HDL₂) and large buoyant LDL particles. We interpret these findings to suggest that in PKT-R, peripheral hyperinsulinemia upregulates LPL activity in peripheral tissues, which induces rapid clearance of chylomicron triglycerides from plasma and, thus, attenuates postprandial lipemia. Low postprandial lipemia allows little net cholesteryl ester transfer from HDL to triglyceride-rich lipoproteins, keeping the levels of the antiatherogenic lipoprotein HDL high and potentially increasing, thereby reverse cholesterol transport. The type of lipoprotein metabolism and pattern present in PKT-R is associated with a low cardiovascular risk in the general population; it cannot be excluded, however, that hyperinsulinemia as found in PKT-R may contribute to atherosclerosis by effects unrelated to lipoprotein metabolism. Received: 25 September 1998 Received after revision: 14 June 1999 Accepted: 12 July 1999     

Genetic predisposition to dyslipidemia and type 2 diabetes risk in two prospective cohorts

Dyslipidemia has been associated with type 2 diabetes, but it remains unclear whether dyslipidemia plays a causal role in type 2 diabetes. We aimed to examine the association between the genetic predisposition to dyslipdemia and type 2 diabetes risk. The current study included 2,447 patients with type 2 diabetes and 3,052 control participants of European ancestry from the Nurses' Health Study and the Health Professionals Follow-up Study. Genetic predisposition to dyslipidemia was estimated by three genotype scores of lipids (LDL cholesterol, HDL cholesterol, and triglycerides) on the basis of the established loci for blood lipids. Linear relation analysis indicated that the HDL cholesterol and triglyceride genotype scores, but not the LDL cholesterol genotype score, were linearly related to elevated type 2 diabetes risk. Each point of the HDL cholesterol and triglyceride genotype scores was associated with a 3% (odds ratio [OR] 1.03 [95% CI 1.01-1.04]) and a 2% (1.02 [1.00-1.04]) increased risk of developing type 2 diabetes, respectively. The ORs were 1.39 (1.17-1.65) and 1.19 (1.01-1.41) for type 2 diabetes by comparing extreme quartiles of the HDL cholesterol genotype score and triglyceride genotype score, respectively. In conclusion, genetic predisposition to low HDL cholesterol or high triglycerides is related to elevated type 2 diabetes risk.     

Loss of both ABCA1 and ABCG1 results in increased disturbances in islet sterol homeostasis, inflammation, and impaired β-cell function

Cellular cholesterol homeostasis is important for normal β-cell function. Disruption of cholesterol transport by decreased function of the ATP-binding cassette (ABC) transporter ABCA1 results in impaired insulin secretion. Mice lacking β-cell ABCA1 have increased islet expression of ABCG1, another cholesterol transporter implicated in β-cell function. To determine whether ABCA1 and ABCG1 have complementary roles in β-cells, mice lacking ABCG1 and β-cell ABCA1 were generated and glucose tolerance, islet sterol levels, and β-cell function were assessed. Lack of both ABCG1 and β-cell ABCA1 resulted in increased fasting glucose levels and a greater impairment in glucose tolerance compared with either ABCG1 deletion or loss of ABCA1 in β-cells alone. In addition, glucose-stimulated insulin secretion was decreased and sterol accumulation increased in islets lacking both transporters compared with those isolated from knockout mice with each gene alone. Combined deficiency of ABCA1 and ABCG1 also resulted in significant islet inflammation as indicated by increased expression of interleukin-1β and macrophage infiltration. Thus, lack of both ABCA1 and ABCG1 induces greater defects in β-cell function than deficiency of either transporter individually. These data suggest that ABCA1 and ABCG1 each make complimentary and important contributions to β-cell function by maintaining islet cholesterol homeostasis in vivo.     

Catabolism of lipoprotein-X (Lp-X) induced by infusion of 10% intralipid]

In order to clarify the metabolism of Lipoprotein X (Lp-X) induced by intravenous Intralipid 10%, in vitro experiments using purified Lp-X from the sera of the patients receiving Intralipid 10% were carried out. 1) Lp-X or high density lipoprotein (HDL) was incubated with J-774 macrophages laden with [3H] cholesterol. Marked extraction of cholesterol from macrophages by Lp-X as well as HDL was observed. 2) [3H] cholesterol labelled Lp-X or oxidized LDL (o-LDL) was incubated with J-774 macrophages. Incorporation of Lp-X into macrophages was negligible comparing to o-LDL. 3) [3H] cholesterol labelled Lp-X, low density lipoprotein (LDL), or HDL was incubated with Hep G2 cells was less than LDL, but similar to that of HDL. These results indicated that Lp-X extracted cholesterol from peripheral tissues during its formation, and it was not catabolized by the scavenger pathway, but catabolized by the LDL pathway of hepatocytes.     

Nonenzymatic glycosylation of HDL and impaired HDL-receptor-mediated cholesterol efflux.

Previous studies have shown that nonenzymatic glycosylation of high-density lipoprotein (HDL) inhibits high-affinity binding to cultured cells and the candidate HDL-receptor protein. Because binding of HDL to its receptor is required for HDL-receptor-mediated cholesterol efflux from cells, we hypothesized that glycosylated HDL3 would have reduced ability to remove cholesterol from cells. HDL3 was glycosylated in vitro to achieve up to 40-50% reductions in free-lysine residues. Glycosylated HDL3 had a slightly greater ability than control HDL3 to sequester cholesterol directly from the plasma membrane, as predicted by changes in lipid composition. This process is independent of HDL-receptor binding and should not be influenced by reduced binding of HDL3. In contrast, efflux of intracellular cholesterol from cells, which is HDL-receptor dependent, was reduced 25-40%. The ability of glycosylated HDL3 to diminish cholesterol esterification was significantly reduced, indicating reduced net cholesterol efflux. Steady-state efflux of LDL-derived cholesterol was also markedly reduced. These findings suggest that nonenzymatically glycosylated HDL is functionally abnormal and might contribute to the accelerated development of atherosclerosis in patients with diabetes mellitus.     

Carbamylated lipoproteins in diabetes

Diabetic dyslipidemia is characterized by quantitative and qualitative abnormalities in lipoproteins. In addition to glycation and oxidation, carbamylation is also a post-translational modification affecting lipoproteins in diabetes. Patients with type 2 diabetes(T2D) exhibit higher levels of carbamylated low-density lipoproteins(cLDL) and high-density lipoproteins(cHDL). Accumulating evidence suggests that cLDL plays a role in atherosclerosis in diabetes. cLDL levels have been shown to predict ...     

Isolated low HDL cholesterol: an insulin-resistant state only in the presence of fasting hypertriglyceridemia.

Individuals with isolated low HDL cholesterol are at increased risk of coronary artery disease. It has been reported previously that this is an insulin-resistant state. We analyzed data from the 1992 Singapore National Health Survey with the objective of defining the clinical and metabolic parameters associated with isolated low HDL cholesterol. A total of 3,568 individuals were selected by stratified random sampling. Subjects with low HDL cholesterol (<0.9 mmol/l) and "ideal" total cholesterol (<5.2 mmol/l) were identified. Data on anthropometry, blood pressure (BP), insulin resistance, glucose tolerance, sex, smoking habit, and ethnic group were examined. We found that this group was heterogeneous. Those with fasting triglyceride (TG) >1.7 mmol/l (low HDL/high TG) displayed features of the insulin resistance syndrome characterized by obesity, higher diastolic BP, greater insulin resistance, and a greater tendency to have diabetes or impaired glucose tolerance (IGT). If fasting TG was <1.7 mmol/l (isolated low HDL cholesterol), individuals were similar to the general population in terms of insulin resistance and obesity. Both groups were more commonly men and Asian Indian. The ethnic difference in prevalence could not be explained by differences in diet, exercise, alcohol ingestion, or smoking. Our data support the view that Asian Indians are genetically predisposed to isolated low HDL cholesterol as well as the insulin resistance syndrome. The higher prevalence of isolated low HDL cholesterol, the young age at which individuals exhibit this phenotype (mean age 32.5 years), along with the greater propensity for Asian Indians to develop insulin resistance and IGT contribute to the threefold increased incidence of myocardial infarction in those <65 years of age in this ethnic group.     

Cardiovascular disease risk factors in chronic renal insufficiency

BACKGROUND: Coronary heart disease (CHD) is an important cause of morbidity and mortality in end-stage renal disease (ESRD). Prevention of CHD in ESRD requires identification and treatment of coronary risk factors in chronic renal insufficiency (CRI). METHODS: We evaluated the prevalence of "traditional coronary risk factors" in CRI in 1,795 patients enrolled in the baseline period of Modification of Diet in Renal Disease (MDRD) Study. Using a cross-sectional design, we determined the relationship of these risk factors to the level of glomerular filtration rate (GFR) and proteinuria. We also predicted the CHD risk in the MDRD Study baseline cohort using the coronary point score. RESULTS: 64.0% had blood pressure > or = 130/85 mmHg despite antihypertensive therapy. 64.2% had LDL cholesterol > or = 130 mg/dl, while 38.3% had HDL cholesterol < 35 mg/dl. After adjustment for age, gender and the presence of diabetes, GFR was inversely associated with systolic blood pressure and positively associated with HDL cholesterol, but not associated with total or LDL cholesterol. After adjustment for age. gender and the presence of diabetes, proteinuria was positively associated with systolic and diastolic blood pressure, total serum cholesterol and LDL cholesterol, and inversely associated with HDL cholesterol. Nonetheless, the predicted CHD risk, even at a very low GFR, was similar to the risk in the general population and lower than the observed rate of de novo CHD in incident dialysis patients. CONCLUSIONS: "Traditional coronary risk factors" are highly prevalent in CRI and vary with the level of renal function. However, the coronary point score does not appear to explain the extent of increased CHD risk in ESRD. Non-traditional risk factors may also contribute to CHD in ESRD.     

ATP结合元件A1与肾间质泡沫细胞形成、小管间质损害及血清胆固醇的相关性

目的 研究肾小球肾病患者肾间质区域ATP结合元件A1（ABCA1）蛋白的表达及其与泡沫细胞形成、肾小管间质损害、血清胆固醇的相关性。方法 选取诊断明确的Alport综合征患者5例、膜增生性肾小球肾炎（MPGN）患者28例、局灶节段性肾小球硬化（FSGS）患者35例、特发性膜性肾病（IMN）患者36例、IgA肾病（IgAN）患者34例为研究对象。采用免疫组织化学法检测患者肾间质区域（除肾小管）ABCA1蛋白的表达;用直线相关分析其与肾间质区域泡沫细胞相对面积、肾小管间质损害积分、血清胆固醇的相关性。 结果 在各类肾小球疾病患者的肾间质区域中,浸润的单核巨噬细胞、泡沫细胞及肾小管上皮细胞均表达ABCA1蛋白。泡沫细胞浸润者肾间质区域ABCA1蛋白的阳性表达量显著高于无泡沫细胞浸润者（P < 0.05）,但ABCA1的阳性表达量与泡沫细胞相对面积无相关。MPGN、FSGS、IMN患者肾间质区域ABCA1表达量与肾小管间质损害积分呈正相关（P < 0.05）。血清胆固醇与肾间质区域ABCA1蛋白的阳性表达量呈正相关（P < 0.05）。 结论 在各种病理类型的肾小球疾病患者中,血清胆固醇可促进肾间质ABCA1的表达;ABCA1对胞内脂质的转运具有双向作用,其与泡沫细胞形成缺乏肯定关联;ABCA1可能参与了肾小管间质的损害。     

Insulin and leptin acutely regulate cholesterol ester metabolism in macrophages by novel signaling pathways

Leptin is produced in adipose tissue and acts in the hypothalamus to regulate food intake. However, recent evidence also indicates a potential for direct roles for leptin in peripheral tissues, including those of the immune system. In this study, we provide direct evidence that macrophages are a target tissue for leptin. We found that J774.2 macrophages express the functional long form of the leptin receptor (ObRb) and that this becomes tyrosine-phosphorylated after stimulation with low doses of leptin. Leptin also stimulates both phosphoinositide 3-kinase (PI 3-kinase) activity and tyrosine phosphorylation of JAK2 and STAT3 in these cells. We investigated the effects of leptin on hormone-sensitive lipase (HSL), which acts as a neutral cholesterol esterase in macrophages and is a rate-limiting step in cholesterol ester breakdown. Leptin significantly increased HSL activity in J774.2 macrophages, and these effects were additive with the effects of cAMP and were blocked by PI 3-kinase inhibitors. Conversely, insulin inhibited HSL in macrophages, but unlike adipocytes, this effect did not require PI 3-kinase. These results indicate that leptin and insulin regulate cholesterol-ester homeostasis in macrophages and, therefore, defects in this process caused by leptin and/or insulin resistance could contribute to the increased incidence of atherosclerosis found associated with obesity and type 2 diabetes.     

Loss-of-Function Mutations in ABCA1 and Enhanced β-Cell Secretory Capacity in Young Adults

Loss-of-function mutations affecting the cholesterol transporter ATP-binding cassette transporter subfamily A member 1 (ABCA1) impair cellular cholesterol efflux and are associated with reduced HDL-cholesterol (HDL-C) levels. ABCA1 may also be important in regulating β-cell cholesterol homeostasis and insulin secretion. We sought to determine whether loss-of-function ABCA1 mutations affect β-cell secretory capacity in humans by performing glucose-potentiated arginine tests in three subjects homozygous for ABCA1 mutations (age 25 ± 11 years), eight heterozygous subjects (28 ± 7 years), and eight normal control subjects pair-matched to the heterozygous carriers. To account for any effect of low HDL-C on insulin secretion, we studied nine subjects with isolated low HDL-C with no ABCA1 mutations (age 26 ± 6 years) and nine pair-matched control subjects. Homozygotes for ABCA1 mutations exhibited enhanced oral glucose tolerance and dramatically increased β-cell secretory capacity that was also greater in ABCA1 heterozygous subjects than in control subjects, with no differences in insulin sensitivity. Isolated low HDL-C subjects also demonstrated an increase in β-cell secretory capacity but in contrast to those with ABCA1 mutations, exhibited impaired insulin sensitivity, supporting β-cell compensation for increased insulin demand. These data indicate that loss-of-function mutations in ABCA1 in young adults may be associated with enhanced β-cell secretory capacity and normal insulin sensitivity and support the importance of cellular cholesterol homeostasis in regulating β-cell insulin secretion.