[Hyperglycemia in critically ill]. / Therapie der Hyperglykämie bei erwachsenen, kritisch kranken PatientInnen (Update 2023).

In critical illness hyperglycemia is associated with increased mortality. Based on the currently available evidence, an intravenous insulin therapy should be initiated when blood glucose is above 180 mg/dl. After initiation of insulin therapy blood glucose should be maintained between 140 and 180 mg/dl.

[New AHA and ACC guidelines on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk : Statement of the D•A•CH Society for Prevention of Cardiovascular Diseases, the Austrian Atherosclerosis Society and the Working Group on Lipids and Atherosclerosis (AGLA) of the Swiss Society for Cardiology]. / Neue AHA- und ACC-Leitlinie zur Risikoreduktion von Herz-Kreislauf-Erkrankungen durch Cholesterinsenkung : Stellungnahme der D•A•CH-Gesellschaft Prävention von Herz-Kreislauf-Erkrankungen e. V., der Österreichischen Atherosklerose Gesellschaft und der Arbeitsgruppe Lipide und Atherosklerose (AGLA) der Schweizer Gesellschaft für Kardiologie.

Guidelines for the reduction of cholesterol to prevent atherosclerotic vascular events were recently released by the American Heart Association and the American College of Cardiology. The authors claim to refer entirely to evidence from randomized controlled trials, thereby confining their guidelines to statins as the primary therapeutic option. The guidelines derived from these trials do not specify treatment goals, but refer to the percentage of cholesterol reduction by statin medication with low, moderate, and high intensity. However, these targets are just as little tested in randomized trials as are the cholesterol goals derived from clinical experience. The same applies to the guidelines of the four patient groups which are defined by vascular risk. No major statin trial has included patients on the basis of their global risk; thus the allocation criteria are also arbitrarily chosen. These would actually lead to a significant increase in the number of patients to be treated with high or maximum dosages of statins. Also, adhering to dosage regulations instead of cholesterol goals contradicts the principles of individualized patient care. The option of the new risk score to calculate lifetime risk up to the age of 80 years in addition to the 10-year risk can be appreciated. Unfortunately it is not considered in the therapeutic recommendations provided, despite evidence from population and genetic studies showing that even a moderate lifetime reduction of low-density lipoprotein (LDL) cholesterol or non-HDL cholesterol has a much stronger effect than an aggressive treatment at an advanced age. In respect to secondary prevention, the new American guidelines broadly match the European guidelines. Thus, the involved societies from Germany, Austria and Switzerland recommend continuing according to established standards, such as the EAS/ESC guidelines.

Plasma amine oxidase: a postulated cardiovascular risk factor in nondiabetic obese patients.

Increased activity of semicarbazide-sensitive plasma amine oxidase (SSAO), an enzyme converting various amines, has been implicated in the generation of endothelial damage through formation of cytotoxic reaction products. We investigated if SSAO activity is elevated in morbidly obese patients, which might contribute to the increased cardiovascular risk associated with obesity. SSAO activity was determined in 74 nondiabetic, obese patients (median body mass index [BMI]: 42.9 kg/m(2)) and in 32 healthy, non-obese controls (median BMI: 23.3 kg/m(2)) using a radiometric assay based on the conversion of [(14)C]benzylamine. SSAO and parameters of glucose and lipid metabolism were compared for subgroups of obese patients with normal (n = 49) and impaired (n = 25) glucose tolerance using nonparametric statistical tests. Median SSAO activity was 434 microU/mL in obese patients, which was significantly higher than in healthy, non-obese controls (median SSAO activity: 361 microU/mL). Median SSAO activity in patients with normal and impaired glucose tolerance was 423 and 464 microU/mL, respectively. SSAO activity was not correlated with any other clinical or laboratory parameters characteristic of the metabolic alterations associated with obesity. Elevated SSAO activity is found in nondiabetic, morbidly obese patients and might be an interesting independent risk factor for obesity-related cardiovascular morbidity. Long-term follow-up of SSAO and its possible role in pathogenic events is warranted since intervention with specific SSAO inhibitors is available.

Pronounced postprandial lipemia impairs endothelium-dependent dilation of the brachial artery in men.

OBJECTIVE: Pronounced postprandial lipemia has been established as a risk factor for cardiovascular disease, but reports regarding its effect on endothelial function have been controversial. In the present study the influence of a standardized fatty meal with its ensuing postprandial lipemia of highly varying magnitude on endothelium-dependent dilation (EDD) was investigated. METHODS: In 17 healthy, normolipidemic men EDD of the brachial artery was quantified in two series of three measurements each. In both series initial measurements were performed at 08:00 h after an overnight fast followed by measurements at 12:00 and 16:00 h, in the first series with continued fasting and in the second following the ingestion of a standardized fatty test meal 4 and 8 h postprandially. RESULTS: Measurements of EDD in the fasting state revealed the recently appreciated diurnal variation with higher values in noon and afternoon hours compared with morning values (2.5+/-1.6% at 08:00, 7.5+/-2.7% at 12:00, and 7.0+/-2.1% at 16:00 h, P<0.001 by analysis of variance). Postprandial EDD values measured at 12:00 h were, at the average, lower than fasting EDD values measured at 12:00 h and correlated inversely with the magnitude of postprandial triglyceridemia (r=-0.81, P<0.001). In multivariate analysis, higher postprandial lipemia was associated with impaired postprandial EDD (P<0.001) independent of fasting triglycerides, low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol, insulin, age and body mass index. CONCLUSION: We conclude that pronounced postprandial lipemia is associated with transient impairment of endothelial function. Our findings support the notion that impaired triglyceride metabolic capacity plays an important role in atherogenesis.

Influence of leptin and insulin on lipid transfer proteins in human hepatoma cell line, HepG2.

AIM: Phospholipid transfer protein (PLTP) and cholesteryl ester transfer protein (CETP) are key enzymes in lipoprotein metabolism facilitating the transfer and exchange of cholesteryl esters, triglycerides and phospholipids between lipoproteins. In the study presented here, we investigated the influence of two hormones-the adipocyte-derived hormone leptin as well as insulin on the hepatic secretion of both, PLTP and CETP. METHODS: PLTP activity and CETP concentration-measured by exogenous substrate assay and enzyme-linked immunosorbent assay-were determined in supernatant of human hepatoma cell line HepG2 after single or combined exposure to leptin and insulin at physiological and supraphysiological concentrations, respectively. Messenger-RNA of PLTP and CETP was quantified by Northern blot analysis. RESULTS: Leptin suppressed PLTP activity and CETP-concentration by up to 33% and 23%, respectively. Insulin also suppressed PLTP activity by up to 11% and CETP-concentration by up to 16%. In combination, the two hormones had additive suppressive effects for both, PLTP activity and CETP-concentration. Northern blot analysis showed no difference in m-RNA levels after exposure to leptin or insulin. CONCLUSIONS: Leptin and insulin, both known to increase with body fat mass, suppress production of PLTP and CETP in HepG2 cells. When extrapolated to the in vivo situation, this suppressive effect may constitute a mechanism counteracting the potentially harmful action of lipid transfer proteins, particularly reduction of HDL-cholesterol, in conditions frequently associated with increased plasma triglyceride levels such as obesity and insulin resistance.

Influence of obesity and insulin sensitivity on phospholipid transfer protein activity.

AIMS/HYPOTHESIS: Phospholipid transfer protein plays a key role in lipoprotein metabolism by catalysing the transfer of phospholipids from triglyceride-rich lipoproteins to high-density lipoproteins and, also, within the high-density lipoprotein family, from particle to particle. This transfer results in a change of HDL particle size and the generation of pre-beta-high-density lipoproteins which function as initial lipid acceptors in the process of reverse cholesterol transport. Because adipose tissue is a source of phospholipid transfer protein we investigated the influence of obesity and insulin sensitivity on phospholipid transfer protein activity. METHODS: Using an exogenous substrate assay phospholipid transfer protein activity was measured in plasma specimens of 190 normolipidaemic, non-diabetic subjects with BMI ranging from 19 to 43 kg/m2. Insulin sensitivity was measured by the short insulin tolerance test. RESULTS: Phospholipid transfer protein activity was associated with BMI (r = 0.46, p < 0.01), body fat mass (r = 0.39, p < 0.01), subcutaneous fat area (r = 0.32, p < 0.01) and plasma leptin concentration (r = 0.24, p < 0.01) but not with insulin sensitivity expressed as the k(s) of the insulin tolerance test (kITT value) (r = -0.14, p = 0.40). Accordingly, phospholipid transfer protein activity was higher in obese than in nonobese subjects. As determined by linear regression analysis, BMI was the sole predictor of phospholipid transfer protein activity in plasma explaining 22.2% of the activity (p< 0.01). CONCLUSIONS/INTERPRETATIONS: This data suggests that increased phospholipid transfer protein activity in obese subjects is a consequence of obesity itself without the contribution of insulin resistance and can be explained by increased synthesis of phospholipid transfer protein from the enlarged mass of adipose tissue.

Flow-mediated, endothelium-dependent vasodilatation is impaired in male body builders taking anabolic-androgenic steroids.

Self-administration of anabolic-androgenic steroids to increase muscular strength and lean body mass has been used widely among athletes. Flow mediated dilatation (FMD) determined by ultrasound of the brachial artery is accepted as both an in vivo index of endothelial function and an indicator for future atherosclerosis. FMD was calculated in 20 male non-smoking body builders in different phases of their training cycle and in six male non-smoking control athletes. Ultrasound studies of the brachial artery were performed according to the protocol of Celermajer et al. Of the entire training cycle, work-out phase was training phase without actual intake of anabolic-androgenic steroids over 8 weeks; build-up phase included actual intake of anabolic-androgenic steroids; and competition phase consisted of 8 weeks post intake of anabolic-androgenic steroids. Baseline characteristics did not differ between body builder groups except for a higher weight in competition phase body builders. Hormonal analysis revealed suppressed luteinizing hormone and follicle stimulating hormone levels in build-up phase body builders. The lipid profiles showed a marked reduction of HDL-C in build-up phase body builders. FMD was reduced in body builders of all phases when compared to control athletes (work-out phase: 2.5+/-2.7%; build-up phase: 2.1+/-3.0%; competition phase: 0.4+/-2.9% vs. 10.9+/-4.4%, P<0.05 by pairwise comparison using Scheffe's test for work-out phase, build-up phase and competition phase vs. control athletes). The glyceryl trinitrate-induced vasodilatation was diminished, though not statistically significantly, in body builders when compared with control athletes. The differences in FMD persisted after adjustment for vessel size. Our data indicate that intake of anabolic-androgenic steroids is associated with both an atherogenic blood lipid profile and endothelial dysfunction and thus may pose an increased risk of atherosclerosis.

Transjugular intrahepatic portosystemic shunt (TIPS) augments hyperinsulinemia in patients with cirrhosis.

BACKGROUND/AIMS: Cirrhosis of the liver is characterized by glucose intolerance and hyperinsulinemia. Both increased insulin secretion and decreased insulin clearance appear to contribute to hyperinsulinemia in cirrhotic patients. A decrease in hepatic insulin extraction rate may be due either to hepatocellular dysfunction or to portosystemic shunting with decreased first-pass insulin clearance. METHODS: To specifically address the contribution of portosystemic shunting to the pathogenesis of hyperinsulinemia in cirrhotic patients, we analyzed glycemic control and insulin levels in fasting serum in 23 cirrhotic patients before and after transjugular intrahepatic portosystemic shunt (TIPS). RESULTS: Compared to respective values in healthy controls, C-peptide, insulin and proinsulin concentrations at baseline were increased by 340%, 120% and by 100% in cirrhotic patients (all p<0.05). In cirrhotic patients insulin levels before TIPS averaged 104+/-73 pmol/l and increased by more than 50% to 163+/-118 pmol/l after TIPS (p<0.01), whereas levels of C-peptide and proinsulin showed no significant change. Glucose and fructosamin levels also remained unchanged after TIPS. CONCLUSION: Our data demonstrate that TIPS does not impair glycemic control in cirrhotic patients and that an increase in portosystemic shunting augments hyperinsulinemia, most likely by decreasing hepatic insulin clearance.

Postprandial lipemia and coronary risk.

A number of cross-sectional studies have demonstrated that the magnitude of postprandial lipemia or single postprandial triglyceride values predict asymptomatic and symptomatic atherosclerosis, independent of risk factors measured in the fasting state. Postprandial lipemia reflects an integrated measure of an individual's triglyceride metabolic capacity. Numerous genetic and environmental factors that are known or suspected to affect triglyceride transport contribute to the magnitude of postprandial lipemia. In this article, mechanisms linking postprandial lipemia with the development and progression of atherosclerosis are described, and determinants of the extent and duration of postprandial lipemia are discussed.

Fetal leptin and insulin levels only correlate inlarge-for-gestational age infants.

OBJECTIVE: To determine whether fetal leptin levels correlate with fetal weight and whether such correlation is direct or indirect via insulin or human placental lactogen (hPL), respectively. DESIGN: Cross-sectional study of offspring at term (n=175) with over-representation of large-for-gestational age (LGA; n=70) and small-for-gestational age (SGA; n=23) cases in a population of Caucasian women with no pregnancy pathology. METHODS: Fetal cord blood was collected after delivery. In several cases (n=62) paired mother-fetus blood samples were obtained. Leptin, insulin and hPL levels were measured by RIA. Anthropometric data (birth weight, body mass index, placental weight) were recorded. RESULTS AND CONCLUSIONS: Maternal insulin, hPL and leptin levels were higher than fetal concentrations. Cord blood leptin levels positively correlated with the anthropometric data with stronger correlations in female (0.54

Hepatic lipase deficiency decreases the selective uptake of HDL-cholesteryl esters in vivo.

Recent in vitro studies have provided evidence that hepatic lipase (HL) facilitates the selective uptake of HDL cholesteryl esters (CE), but the in vivo physiological relevance of this process has not been demonstrated. To evaluate the role that HL plays in facilitating the selective uptake of HDL-CE in vivo, we studied the metabolism of [(3)H]CEt, (125)I-labeled apolipoprotein (apo) A-I, and (131)I-labeled apoA-II-labeled HDL in HL-deficient mice. Kinetic analysis revealed similar catabolism of (125)I-labeled apoA-I (as well as (131)I-labeled apoA-II) in C57BL controls and HL deficient mice, with fractional catabolic rates (FCR) of 2.17 +/- 0.15 and 2.16 +/- 0.11 d(-)(1) (2.59 +/- 0.14 and 2.67 +/- 0.13 d(-)(1), respectively). In contrast, despite similar hepatic scavenger receptor BI expression, HL-deficient mice had delayed clearance of [(3)H]CEt compared to controls (FCR = 3.66 +/- 0.29 and 4.41 +/- 0.18 d(-)(1), P < 0.05). The hepatic accumulation of [(3)H]CEt in HL-deficient mice (62.3 +/- 2.1% of total) was significantly less than in controls (72.7 +/- 3.0%), while the [(3)H]CEt remaining in the plasma compartment increased (20.7 +/- 1.8% and 12.6 +/- 0.5%) (P < 0.05, all). In summary, HL deficiency does not alter the catabolism of apoA-I and apoA-II but decreases the hepatic uptake and the plasma clearance of HDL-CE. These data establish for the first time an important role for HL in facilitating the selective uptake of HDL-CE in vivo.

Cholesteryl ester transfer protein corrects dysfunctional high density lipoproteins and reduces aortic atherosclerosis in lecithin cholesterol acyltransferase transgenic mice.

Expression of human lecithin cholesterol acyltransferase (LCAT) in mice (LCAT-Tg) leads to increased high density lipoprotein (HDL) cholesterol levels but paradoxically, enhanced atherosclerosis. We have hypothesized that the absence of cholesteryl ester transfer protein (CETP) in LCAT-Tg mice facilitates the accumulation of dysfunctional HDL leading to impaired reverse cholesterol transport and the development of a pro-atherogenic state. To test this hypothesis we cross-bred LCAT-Tg with CETP-Tg mice. On both regular chow and high fat, high cholesterol diets, expression of CETP in LCAT-Tg mice reduced total cholesterol (-39% and -13%, respectively; p < 0.05), reflecting a decrease in HDL cholesterol levels. CETP normalized both the plasma clearance of [(3)H]cholesteryl esters ([(3)H]CE) from HDL (fractional catabolic rate in days(-1): LCAT-Tg = 3.7 +/- 0.34, LCATxCETP-Tg = 6.1 +/- 0.16, and controls = 6.4 +/- 0.16) as well as the liver uptake of [(3)H]CE from HDL (LCAT-Tg = 36%, LCATxCETP-Tg = 65%, and controls = 63%) in LCAT-Tg mice. On the pro-atherogenic diet the mean aortic lesion area was reduced by 41% in LCATxCETP-Tg (21.2 +/- 2.0 micrometer(2) x 10(3)) compared with LCAT-Tg mice (35.7 +/- 2.0 micrometer(2) x 10(3); p < 0.001). Adenovirus-mediated expression of scavenger receptor class B (SR-BI) failed to normalize the plasma clearance and liver uptake of [(3)H]CE from LCAT-Tg HDL. Thus, the ability of SR-BI to facilitate the selective uptake of CE from LCAT-Tg HDL is impaired, indicating a potential mechanism leading to impaired reverse cholesterol transport and atherosclerosis in these animals. We conclude that CETP expression reduces atherosclerosis in LCAT-Tg mice by restoring the functional properties of LCAT-Tg mouse HDL and promoting the hepatic uptake of HDL-CE. These findings provide definitive in vivo evidence supporting the proposed anti-atherogenic role of CETP in facilitating HDL-mediated reverse cholesterol transport and demonstrate that CETP expression is beneficial in pro-atherogenic states that result from impaired reverse cholesterol transport.

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 (HDL(2)) 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.

Hepatic lipase facilitates the selective uptake of cholesteryl esters from remnant lipoproteins in apoE-deficient mice.

We have investigated the role of hepatic lipase (HL) in remnant lipoprotein metabolism independent of lipolysis by using recombinant adenovirus to express native and catalytically inactive HL (HL-145G) in apolipoprotein (apo)E-deficient mice characterized by increased plasma concentrations of apoB-48-containing remnants. In the absence of apoE, the mechanisms by which apoB-48-containing remnants are taken up by either low density lipoprotein (LDL)-receptor or LDL-receptor-related protein (LRP) remain unclear. Overexpression of either native or catalytically inactive HL in apoE-deficient mice led to similar reductions (P > 0.5) in the plasma concentrations of cholesterol (41% and 53%) and non high density lipoprotein (HDL)-cholesterol (41% and 56%) indicating that even in the absence of lipolysis, HL can partially compensate for the absence of apoE in this animal model. Although the clearance of [3H]cholesteryl ether from VLDL was significantly increased (approximately 2-fold; P < 0. 02) in mice expressing native or inactive HL compared to luciferase controls, the fractional catabolic rates (FCR) of [125I-labeled] apoB- very low density lipoprotein (VLDL) in all three groups of mice were similar (P > 0.4, all) indicating selective cholesterol uptake. Hepatic uptake of [3H]cholesteryl ether from VLDL was greater in mice expressing either native HL (87%) or inactive HL-145G (72%) compared to luciferase controls (56%). Our combined findings are consistent with a role for HL in mediating the selective uptake of cholesterol from remnant lipoproteins in apoE-deficient mice, independent of lipolysis. These studies support the concept that hepatic lipase (HL) may serve as a ligand that mediates the interaction between remnant lipoproteins and cell surface receptors and/or proteoglycans. We hypothesize that one of these pathways may involve the interaction of HL with cell surface receptors, such as scavenger receptor (SR)-BI, that mediate the selective uptake of cholesteryl esters.

Influence of hyperinsulinemia on lipoproteins after pancreas transplantation with systemic insulin drainage.

Successful pancreas transplantation with systemic drainage is followed by a normalization of carbohydrate and lipid metabolism with low levels of plasma cholesterol and triglycerides. HDL cholesterol concentration and CETP plasma levels were found to be increased and the composition of lipoproteins altered in that LDL and HDL2/HDL3 were enriched in UC, HDL2 enriched in PL, and LDL depleted in PL. The mechanisms by which hyperinsulinemia may cause the observed changes in surface composition of plasma lipoproteins are unknown, as is their clinical relevance. It remains to be seen whether these changes counterbalance the favorable effects of an increased triglyceride clearance capacity on the cardiovascular risk of diabetic patients.

Plasma phospholipid transfer protein. Adenovirus-mediated overexpression in mice leads to decreased plasma high density lipoprotein (HDL) and enhanced hepatic uptake of phospholipids and cholesteryl esters from HDL.

In vitro studies have shown that plasma phospholipid transfer protein (PLTP) converts isolated human high density lipoprotein-3 (HDL3) into larger HDL particles and generates lipid-poor apoA-I containing nascent HDL. To evaluate the role of PLTP in vivo we generated recombinant adenovirus vectors containing either human PLTP cDNA (rPLTP.AdV) or the reporter luciferase cDNA as a control. After intravenous infusion of 4 x 10(7) plaque-forming units (low dose) and 4 x 10(8) plaque-forming units (high dose) of rPLTP.AdV into mice, PLTP activity in plasma increased from base-line levels of 8.4 +/- 0.2 to 108 +/- 17 and from 8.9 +/- 0.6 to 352 +/- 31 micromol/ml/h, respectively, on day 4 (both p < 0.001). Thus, both low and high doses of rPLTP.AdV led to pronounced overexpression of human PLTP in mice. On day 4 after treatment, mice treated with low and high doses of rPLTP.AdV showed decreased HDL cholesterol (-54% and -91%) and apoA-I (-64% and -98%) (all p < 0.05). Kinetic studies revealed that the fractional catabolic rates of HDL labeled with [3H]phosphatidylcholine, [14C]phosphatidylcholine ether, [3H]cholesteryl ether, and 125I-labeled mouse apoA-I were increased by 8.5-, 8.7-, 3.8-, and 2.8-fold, respectively, in mice treated with low dose rPLTP.AdV (all p < 0.001). After injection of labeled HDL, mice treated with rPLTP.AdV showed an increased accumulation of labeled PC ether (+304%) and cholesteryl ether (+92%) in the liver (both p < 0.05). Two-dimensional gel electrophoresis of plasma 5 min after injection of HDL labeled with 125I-apoA-I demonstrated increased levels of newly generated pre-beta-HDL in mice overexpressing PLTP. In conclusion, HDL remodeling mediated by PLTP generates nascent, lipid-poor apoA-I in vivo and accelerates the hepatic uptake of HDL surface and core lipids in mice treated with rPLTP.AdV. Accelerated catabolism of HDL in mice overexpressing PLTP leads to low HDL levels. Our data indicate an important role for PLTP in modulating reverse cholesterol transport in vivo.

High plasma HDL concentrations associated with enhanced atherosclerosis in transgenic mice overexpressing lecithin-cholesteryl acyltransferase.

A subset of patients with high plasma HDL concentrations have enhanced rather than reduced atherosclerosis. We have developed a new transgenic mouse model overexpressing human lecithin-cholesteryl acyltransferase (LCAT) that has elevated HDL and increased diet-induced atherosclerosis. LCAT transgenic mouse HDLs are abnormal in both composition and function. Liver uptake of [3H]cholesteryl ether incorporated in transgenic mouse HDL was reduced by 41% compared with control HDL, indicating ineffective transport of HDL-cholesterol to the liver and impaired reverse cholesterol transport. Analysis of this LCAT-transgenic mouse model provides in vivo evidence for dysfunctional HDL as a potential mechanism leading to increased atherosclerosis in the presence of high plasma HDL levels.

Relationship of plasma cholesteryl ester transfer protein to HDL cholesterol. Studies in normotriglyceridemia and moderate hypertriglyceridemia.

To evaluate the independent effect of cholesteryl ester transfer protein (CETP) on HDL concentrations in humans, we measured lipids, lipoproteins, postprandial lipemia after an oral fat load, CETP mass, and the activities of CETP, lipoprotein lipase (LPL), and hepatic lipase in 16 healthy, normotriglyceridemic men and in 23 men with moderate, primary hypertriglyceridemia on an American Heart Association Step I diet. Fasting triglycerides and postprandial lipemia were increased and HDL cholesterol (HDL-C) was decreased in hypertriglyceridemic men compared with control subjects (P < .001). In the normotriglyceridemic group, CETP mass (P < .001) and activity (P < .005) were directly related to LPL activity After statistical adjustment for this close association, no significant relationship of CETP to HDL-C independent of LPL activity could be demonstrated in the normotriglyceridemic subjects. In contrast, CETP was unrelated to LPL activity in the hypertriglyceridemic subjects, but CETP concentrations showed a close inverse relationship to HDL-C (r = -.504, P = .014). Structural equation modeling of the association structures between HDL and fasting and postprandial triglycerides, endothelial lipases, and CETP in both groups indicated that the overall regression models for the two groups differed (P < .05). Specifically, the associations between CETP mass and activity and HDL-C differed between both groups (both P < .01). We conclude that high-normal CETP levels lower HDL-C in nonsmoking, nonobese men with moderate, primary hypertriglyceridemia on a hypolipidemic diet, but not in healthy, normotriglyceridemic men on an unrestricted diet. Thus, variation in CETP plasma concentrations may contribute to the high-triglyceride, low-HDL phenotype.

Effects of pancreas transplantation on distribution and composition of plasma lipoproteins.

In type I (insulin-dependent) diabetic patients, peripheral hyperinsulinemia due to subcutaneous insulin treatment is associated with increased high-density lipoprotein (HDL) cholesterol, and also with an altered surface composition of HDL. Pancreas grafts also release insulin into the systemic rather than into the portal venous system, giving rise to pronounced peripheral hyperinsulinemia. We hypothesized that if peripheral hyperinsulinemia is responsible for high HDL cholesterol and/or altered surface composition of HDL in diabetic subjects, similar changes in the lipid profile should be present in pancreas-kidney transplant recipients (PKT-R). Using zonal ultracentrifugation, we isolated HDL2, HDL3, very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) from fasting plasma of 14 type I diabetic PKT-R, eight nondiabetic kidney transplant recipients (KT-R), and 14 healthy control subjects and determined the level and composition of the above lipoproteins. HDL2 cholesterol was increased in PKT-R as compared with KT-R and healthy controls (both P < .05), whereas HDL3 cholesterol was unchanged. However, an altered lipoprotein surface composition was evident in PKT-R: HDL2, HDL3, and LDL were enriched in unesterified cholesterol ([UC] PKT-R v KT-R, P=.13, P < .005, and P < .05, respectively; PKT-R v controls, all P < .005); HDL2 was enriched in phospholipids; and LDL was depleted of phospholipid. KT-R, in contrast, showed no changes in lipoprotein surface composition but a substantial triglyceride enrichment of HDL2 as compared with PKT-R and healthy controls (both P < .05). LDL size as determined by gradient gel electrophoresis was increased in PKT-R compared with controls (P < .005). The plasma concentration of cholesteryl ester (CE) transfer protein (CETP), involved also in phospholipid transfer, was increased in both transplant groups compared with healthy controls (both P < .05). Insulin concentrations in fasting plasma were directly related to CETP levels and to the weight-percentage of UC in HDL3, and inversely to the weight-percentage of phospholipids in LDL (all P < .05). We explain the increase in HDL2 cholesterol and LDL size in PKT-R by their high lipoprotein lipase (LPL) activity conferring an excellent capacity to clear chylomicron triglycerides. Effective handling of postprandial triglycerides, high HDL2 cholesterol, and predominance of LDL pattern A, respectively, are established indicators of a low risk of atherosclerosis. However, it is presently unclear what effects the compositional changes on the surface of HDL and LDL may have on cardiovascular risk in clinically stable PKT-R.