Plasma phospholipid transfer protein activity is lowered by 24-h insulin and acipimox administration: blunted response to insulin in type 2 diabetic patients.

Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from HDL to VLDL and LDL. Phospholipid transfer protein (PLTP) transfers phospholipids between lipoproteins, converts HDL3 into larger and smaller particles, and is involved in pre-beta-HDL generation. We examined the effects of 24-h hyperinsulinemia (30 mU x kg(-1) x h(-1)) and 24-h Acipimox (250 mg/4 h) on plasma lipids as well as CETP and PLTP activities (measured with exogenous substrate assays) in eight healthy and eight type 2 diabetic subjects. After 24 h of insulin, plasma free fatty acids (FFAs), HDL cholesterol, and plasma apolipoprotein AI decreased in healthy subjects and type 2 diabetic patients (P < 0.05). Plasma triglycerides did not significantly change in either group. After 24 h of Acipimox, all parameters, including plasma triglycerides, decreased in both groups (P < 0.05). Insulin decreased plasma PLTP activity by 17.6% after 24 h in healthy subjects (P < 0.05) and 10.2% in diabetic patients (P < 0.05 vs. baseline; P < 0.05 vs. healthy subjects). Acipimox lowered PLTP activity by 10.3% in healthy subjects (P < 0.05) and 11.3% in diabetic patients (P < 0.05). When insulin was infused for 3 h after Acipimox, a further decrease was found only in healthy subjects. Plasma CETP activity decreased by 9.5% after 24 h of insulin in healthy subjects (P < 0.05), but not in diabetic patients. Acipimox did not decrease plasma CETP activity in either group. In healthy subjects, the PLTP responses with insulin and Acipimox were larger than the changes in CETP activity (P < 0.05). These findings suggest that there is a metabolic link between the regulation of plasma FFA and PLTP, but not CETP. The PLTP response to insulin is blunted in type 2 diabetes.

Cholesteryl ester transfer protein gene polymorphism is a determinant of HDL cholesterol and of the lipoprotein response to a lipid-lowering diet in type 1 diabetes.

The TaqIB cholesteryl ester transfer protein (CETP) gene polymorphism (B1B2) is a determinant of HDL cholesterol in nondiabetic populations. Remarkably, this gene effect appears to be modified by environmental factors. We evaluated the effect of this polymorphism on HDL cholesterol levels and on the lipoprotein response to a linoleic acid-enriched, low-cholesterol diet in patients with type 1 diabetes. In 44 consecutive type 1 diabetic patients (35 men), CETP polymorphism, apolipoprotein (apo) E genotype, serum lipoproteins, serum CETP activity (measured with an exogenous substrate assay, n = 30), clinical variables, and a diet history were documented. The 1-year response to diet was assessed in 14 type 1 diabetic patients, including 6 B1B1 and 6 B1B2 individuals. HDL cholesterol was higher in 10 B2B2 than in 14 B1B1 homozygotes (1.63 +/- 0.38 vs. 1.24 +/- 0.23 mmol/l, P < 0.01). HDL cholesterol, adjusted for triglycerides and smoking, was 0.19 mmol/l higher for each B2 allele present. CETP activity levels were not significantly different between CETP genotypes. Multiple regression analysis showed that VLDL + LDL cholesterol was associated with dietary polyunsaturated:saturated fatty acids ratio (P < 0.02) and total fat intake (P < 0.05) in the B1B1 homozygotes only and tended to be related to the presence of the apo E4 allele (P < 0.10). In response to diet, VLDL + LDL cholesterol fell (P < 0.05) and HDL cholesterol remained unchanged in 6 B1B1 homozygotes. In contrast, VLDL + LDL cholesterol was unaltered and HDL cholesterol decreased (P < 0.05) in 6 B1B2 heterozygotes (P < 0.05 for difference in change in VLDL + LDL/HDL cholesterol ratio). This difference in response was unrelated to the apo E genotype. Thus, the TaqIB CETP gene polymorphism is a strong determinant of HDL cholesterol in type 1 diabetes. This gene effect is unlikely to be explained by a major influence on the serum level of CETP activity, as an indirect measure of CETP mass. Our preliminary data suggest that this polymorphism may be a marker of the lipoprotein response to dietary intervention.

[Pneumocystis pneumonia during infliximab treatment for active Crohn's colitis]. / Pneumocystis-pneumonie tijdens behandeling met infliximab voor actieve Crohn-colitis.

A 51-year-old man with Crohn's disease for 22 years presented with a dry cough, dyspnoea, fever and diarrhoea. He had steroid-resistant Crohn's disease. Because of nausea complaints, azathioprine was switched to methotrexate with concomitant infliximab induction therapy. During infliximab therapy, symptoms occurred for which the patient was hospitalised and Pneumocystis pneumonia (PCP) was diagnosed by examination of bronchoalveolar lavage fluid; it was successfully treated with co-trimoxazole and prednisolone. The exacerbation of the Crohn's colitis diminished. This is the first Dutch case history of PCP during combination therapy with prednisolone, methotrexate and infliximab. Infliximab treatment has been associated with an increased risk for infectious complications. For patients with Crohn's disease, one should consider giving PCP prophylaxis for the duration of lymphocytopenia on an individual basis, weighing the adverse effects ofco-trimoxazole against the risk of PCP. A CD4-cell count < 0.2 x 10(9)/l or a lymphocyte count < 0.6 x 10(9)/l may be used as a guide.

Elevated plasma cholesteryl ester transfer in NIDDM: relationships with apolipoprotein B-containing lipoproteins and phospholipid transfer protein.

Lecithin:cholesteryl acyl transferase (LCAT) and cholesteryl ester transfer protein (CETP) are key factors in the esterification of cholesterol and the subsequent transfer of cholesteryl ester from high density lipoproteins (HDL) towards very low and low density lipoproteins (VLDL + LDL). Phospholipid transfer protein (PLTP), lipoprotein lipase (LPL) and hepatic lipase (HL) are involved in plasma phospholipid and triglyceride metabolism and also affect HDL. Equivocal changes in plasma cholesteryl ester transfer have been reported in non-insulin-dependent diabetes mellitus (NIDDM). In 16 NIDDM men with plasma triglycerides < or = 4.5 mmol/l and cholesterol < or = 8.0 mmol/l. plasma cholesteryl ester transfer (CET), cholesterol esterification rate, LCAT and PLTP activity levels were higher (P < 0.05 to P < 0.02) in conjunction with higher plasma triglycerides (P < 0.01) and lower HDL cholesterol and cholesteryl ester levels (P < 0.05) compared to 16 matched healthy men. Multiple stepwise regression analysis demonstrated that CET was positively related to VLDL + LDL cholesterol (P < 0.001), triglycerides (P = 0.001), PLTP activity (P = 0.007) and CETP activity (P = 0.008, multiple r = 0.94). NIDDM had no effect on CET, independently from these parameters. HDL cholesteryl ester was negatively related to CET (P= 0.017), HL activity (P = 0.033) and NIDDM (P = 0.047) and positively to LCAT activity levels (P = 0.034, multiple r = 0.68). It is concluded that the elevated CET in plasma from NIDDM patients is associated with higher plasma triglycerides and PLTP activity levels. Furthermore, our data suggest that in normo- and moderately dyslipidaemic subjects PLTP and CETP activity levels per se may influence the rate of cholesteryl ester transfer in plasma. Plasma cholesteryl ester transfer appears to be a determinant of HDL cholesteryl ester, but other factors are likely to contribute to lower HDL cholesteryl ester levels in NIDDM.

Hyperglycemia-induced hyperinsulinemia acutely lowers plasma apolipoprotein B but not lipoprotein (a) in man.

Acute hyperinsulinemia lowers plasma apolipoprotein B (apo B) and triglycerides by suppressing hepatic lipoprotein secretion and probably by enhancing catabolism of triglyceride-rich lipoproteins, but the effect of acute hyperinsulinemia on the plasma lipoprotein(a) (Lp(a)) level is unclear. We measured plasma triglycerides, cholesterol, apo B and Lp(a) in response to 3 h hyperglycemia-induced hyperinsulinemia (blood glucose clamped at 10 mmol/l) in 16 subjects (eight women and eight men). In a control experiment saline was infused in another group of seven men. After 3 h of hyperinsulinemia plasma triglycerides decreased by 29 +/- 14% (mean +/- S.D., P < 0.001) and this fall differed from the unchanged triglyceride level during saline infusion (P < 0.001). Plasma cholesterol fell by 8 +/- 5% (P < 0.001), which was different from the unchanged cholesterol during saline infusion (P < 0.02). Plasma apo B decreased by 9 +/- 8% (P < 0.001), which was again different from the minor fall in apo B (3 +/- 2%) during saline infusion (P < 0.02). However, plasma Lp(a) remained unchanged during hyperinsulinemia (change 8 +/- 15%, n.s.), as well as during saline infusion (change 5 +/- 15%, n.s.). The % change in apo B exceeded the % change in Lp(a) during hyperinsulinemia (P < 0.01). Baseline Lp(a) was inversely correlated with first phase insulin secretion (P < 0.05), but its level during the clamp was not related to insulin sensitivity. This study demonstrates that acute hyperglycemia-induced hyperinsulinemia has a different effect on plasma apo B and Lp(a) in healthy subjects. The present data support the notion that Lp(a) is metabolized differently from triglyceride-rich lipoproteins.

Higher high density lipoprotein cholesterol associated with moderate alcohol consumption is not related to altered plasma lecithin:cholesterol acyltransferase and lipid transfer protein activity levels.

Lecithin:cholesterol acyltransferase (LCAT), cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP) are important factors involved in HDL metabolism. Altered plasma activity levels of these factors could play a role in the increase in high density lipoprotein (HDL) cholesterol associated with moderate alcohol consumption. We measured plasma LCAT, CETP and PLTP activities with exogenous substrate assays, as well as lipoproteins and HDL lipids in 6 alcohol-abstaining men, 18 matched men who used < or = 1 and 18 men who used > or = 1 alcohol-containing drinks per day. Plasma cholesterol and triglycerides were similar in the three groups. HDL total cholesterol, HDL cholesteryl ester, HDL free cholesterol and HDL triglycerides were higher in the alcohol drinkers compared to the abstainers (all P < 0.05). No differences in plasma LCAT, CETP and PLTP activity levels were observed between the three groups. Analysis of covariance also demonstrated that the use of alcohol was associated with higher HDL cholesterol (P < 0.04), whereas plasma LCAT, CETP and PLTP activity levels were not related to alcohol consumption. Furthermore, HDL cholesteryl ester was positively associated with LCAT activity (P < 0.001), PLTP activity (P < 0.01) and alcohol intake (P < 0.04) and negatively with plasma triglycerides (P < 0.001) and CETP activity (P < 0.03); indicating that alcohol influenced HDL cholesteryl ester independently from these biochemical parameters. The higher HDL cholesterol associated with moderate alcohol consumption is, therefore, unlikely to be caused by and effect on plasma LCAT, CETP or PLTP activity levels.

Plasma semicarbazide-sensitive amine oxidase is moderately decreased by pronounced exogenous hyperinsulinemia but is not associated with insulin sensitivity and body fat.

OBJECTIVE: Semicarbazide-sensitive amine oxidase (SSAO) is widely expressed in adipose tissue, where it may contribute to stimulation of glucose transport via GLUT4 recruitment. We tested the relationships of soluble SSAO, as reflected by its plasma activity, with insulin sensitivity and indices of body fat, and determined whether insulin is involved in regulating plasma SSAO activity. MATERIAL AND METHODS: In 24 non-diabetic subjects, the relationships of plasma SSAO activity with insulin sensitivity (M-value and free fatty acid (FFA) suppression during a 3-h hyperinsulinemic (8.3 microU kg-1 s-1), euglycemic clamp), body mass index (BMI 25.5 +/- 3.1 kg m-2), waist-hip ratio and fat mass were assessed. In 16 subjects, the effect of insulin infusion, administered at a rate of 8.3 microU kg-1 s-1 during 3 h, followed by 3-h insulin infusion at a high rate of 41.7 microU kg-1 s-1 on plasma SSAO activity was determined. In the other 8 subjects, the response of plasma SSAO activity to 24-h insulin infused at 8.3 microU kg-1 s-1 was assessed. RESULTS: There were no relationships (all p > 0.10) of plasma SSAO activity (215 +/- 60 mU L-1) with the M-value or with any indices of body fat and FFA before and after insulin suppression. Plasma SSAO activity changed by -7.2 (95% CI, -14.5 to +0.2)% after 3 h (NS) and decreased by 10.1 (95% CI, 19.2 to 1)% after 6 h of insulin infusion (p < 0.05). Plasma SSAO activity did not significantly change after 8 h (change 0.4 (95% CI, -15.3 to +16.2)%, NS) and after 24 h (change -8.8 (95% CI, -27.4 to +9.7)%, NS) of insulin infusion. CONCLUSIONS: It is unlikely that circulating SSAO is a clinically important marker of insulin sensitivity on glucose and fatty acid metabolism. The reduction in plasma SSAO activity in response to pronounced hyperinsulinemia suggests that insulin is involved in the regulation of the soluble form of this enzyme.

Plasma adiponectin is modestly decreased during 24-hour insulin infusion but not after inhibition of lipolysis by Acipimox.

OBJECTIVE: Plasma adiponectin is associated with insulin resistance and atherosclerosis. Adiponectin expression in adipose tissue is up-regulated by peroxisome proliferator-activated receptor (PPAR)-gamma agonist treatment and its plasma level may be affected by insulin. We tested the hypothesis that prolonged exogenous insulin infusion decreases plasma adiponectin, and examined whether a possible effect of insulin on plasma adiponectin is attributable to inhibition of lipolysis. MATERIAL AND METHODS: The effect of insulin infusion on plasma adiponectin (Linco enzyme-linked immunosorbent assay) was evaluated during a 24-h moderately hyperinsulinemic clamp (8.3 microU kg(-1) s(-1)) in 8 male type 2 diabetic patients and in 8 healthy men. On a separate day, acipimox (250 mg/4 h for 24 h) was administered to inhibit lipolysis. Insulin and acipimox were administered in random order with 1 week between study days. RESULTS: In type 2 diabetic patients, insulin infusion decreased plasma adiponectin from 7.74+/-2.53 mg/l to 6.76+/-2.41 mg/l after 24 h (p<0.05). In healthy subjects, the change in plasma adiponectin after 24 h of insulin was not significant (8.10+/-2.76 and 7.55+/-2.41 mg/l at baseline and after 24 h of insulin, respectively). The change in plasma adiponectin after 24 h insulin in healthy subjects was not different from the change in diabetic patients. Plasma adiponectin did not decrease after 24 h acipimox administration in either group (type 2 diabetic patients: 6.84+/-2.19 and 6.54+/-2.93 mg/l at baseline and after 24 h, respectively (NS); healthy subjects; 7.35+/-2.52 and 8.31+/-3.37 mg/l, at baseline and after 24 h, respectively (NS)). When the results from diabetic and healthy subjects were combined, the decrease in plasma adiponectin after 24 h of insulin infusion (-0.76+/-1.08 mg/l, equivalent to a -9% change from baseline, p<0.05) was different (p = 0.05) from the change after 24 h acipimox (+0.33+/-1.74 mg/l, equivalent to a +4% change from baseline). Plasma free fatty acids decreased during insulin infusion (p<0.01 for both groups after 24 h) as well as in response to acipimox (p<0.05 for healthy subjects; p<0.01 type 2 diabetic patients after 24 h). After administration of acipimox, plasma insulin did not change in either group. CONCLUSIONS: Plasma adiponectin is modestly decreased during 24 h of insulin infusion. It is unlikely that this response to exogenous insulin is attributable to inhibition of lipolysis, since plasma adiponectin did not decrease after acipimox.

Twenty-four hours of insulin infusion does not lower plasma lipoprotein(a) in healthy men.

The effect of 24-h exogenous hyperinsulinaemia on the plasma level of the atherogenic lipoprotein(a) (Lp(a)) is unknown. We evaluated the responses of plasma cholesterol, triglycerides, apolipoprotein (apo) B and Lp(a) during 24-h insulin infusion (180 pmol/kg/h) in 6 healthy men. Plasma total cholesterol (p < 0.01) and triglycerides (p < 0.05) decreased after 24 h of hyperinsulinaemia. Apo B was unchanged after 8 h (-2.4 +/- 3.0%, n.s.) and decreased by 10.9 +/- 4.8% (p<0.025) after 24 h of insulin. In contrast, Lp(a) did not decrease (+28.4 +/- 18.4%, n.s., and +/- 49.1 +/- 22.0%, n.s., after 8 and 24 h of insulin, respectively). This experiment supports the hypothesis that moderate hyperinsulinaemia has a different effect on the plasma level of triglyceride-rich lipoproteins compared to Lp(a).

Enhanced escape of non-esterified fatty acids from tissue uptake: its role in impaired insulin-induced lowering of total rate of appearance in obesity and Type II diabetes mellitus.

AIMS/HYPOTHESIS: To estimate non-esterified fatty acids kinetics in patients with Type II (non-insulin-dependent) diabetes mellitus and obese subjects in the postabsorptive state and during hyperinsulinaemia using non-equilibrium tracer conditions. METHODS: We evaluated the effect of hyperinsulinaemia [euglycaemic clamp with insulin infused at 30 mU x kg(-1) x h(-1) (3-4 h) and 150 mU x kg(-1) x h(-1) (3 h)] on non-esterified fatty acid kinetics, traced with [14C]-palmitate using non-equilibrium tracer conditions in non-obese and obese healthy subjects and Type II diabetic patients (10 per group). Michaelis-Menten kinetics were applied for total non-esterified fatty acid disposal, which was assumed to be composed of total arterial plasma non-esterified fatty acid rate of appearance (equalling the rate of disappearance) and tissue uptake of non-esterified fatty acids derived from intravascular triglyceride hydrolysis. A model was developed to calculate the rate of escape of non-esterified fatty acids from tissue uptake and the net rate of tissue lipolysis. RESULTS: Total arterial plasma non-esterified fatty acid rate of appearance was lower in non-obese healthy subjects than in the other groups at low insulin infusion (p < 0.05) and in obese Type II diabetic patients at high insulin infusion (p < 0.05). Plasma triglycerides were also lowest in non-obese healthy subjects during hyperinsulinaemia (p <0.05 from other groups). The rate of escape from tissue uptake decreased during hyperinsulinaemia (p < 0.05 for each group) but remained higher in obese Type II diabetic patients (p < 0.05 from non-obese healthy subjects). In contrast, net rate of tissue lipolysis was not different between the groups at baseline and its decline during hyperinsulinaemia (p < 0.05 for each group) was similar in all groups. CONCLUSION/INTERPRETATION: This study challenges the view that the antilipolytic effect of insulin is impaired in Type II diabetes and obesity. We suggest that a high plasma triglyceride concentration causes a higher escape of non-esterified fatty acids from tissue uptake, leading to an impaired suppression of total arterial plasma rate of appearance during a low degree of hyperinsulinaemia in obese subjects and Type II diabetic patients and during a high degree of hyperinsulinaemia in obese Type II diabetic patients.

Plasma cholesteryl ester transfer and hepatic lipase activity are related to high-density lipoprotein cholesterol in association with insulin resistance in type 2 diabetic and non-diabetic subjects.

We evaluated the hypothesis that plasma cholesteryl ester transfer (CET) and lipase activities are influenced by insulin sensitivity and contribute to the low high-density lipoprotein (HDL) cholesterol observed in type 2 diabetic patients and insulin-resistant non-diabetic subjects. Sixteen type 2 diabetic and 16 non-diabetic subjects participated. Diabetic and non-diabetic subjects were divided in equal groups of eight subjects with low or high insulin sensitivity, which was documented as the glucose infusion rate (M-value) during the last hour of a 3-h euglycaemic hyperinsulinaemic clamp (150 mU kg(-1) h(-1), blood glucose target 4.6 mmol L(-1)). Post-heparin plasma lipoprotein lipase (LPL) and hepatic lipase (HL) activities were measured in samples obtained 1-2 weeks before the clamp. Plasma CET was measured by a radioisotope method. Compared to non-diabetic men with high insulin sensitivity (n = 8) HDL cholesterol was lower in type 2 diabetic men (n=8, p<0.01) and non-diabetic men (n=8, p <0.05) with low insulin sensitivity, and the HDL cholesterylester content was lower in type 2 diabetic men with high insulin sensitivity (n=8, p<0.05). In non-diabetic subjects with high insulin sensitivity, plasma CET was lower than in the other groups (p<0.05 for all). Multiple regression analysis showed that plasma CET (p=0.001) and HL activity (p=0.02) were independently and negatively associated with the M-value. No association between the M-value and LPL activity was observed. Independent negative relationships of HDL cholesterol with plasma CET (p = 0.04) and HL activity (p=0.03) were observed. This study supports the hypothesis that a low HDL cholesterol associated with insulin resistance in type 2 diabetic and non-diabetic subjects is related to a high plasma CET and a high HL activity.

Acute and chronic effects of a 24-hour intravenous triglyceride emulsion challenge on plasma lecithin: cholesterol acyltransferase, phospholipid transfer protein, and cholesteryl ester transfer protein activities.

Lecithin:cholesterol acyltransferase (LCAT), phospholipid transfer protein (PLTP), and cholesteryl ester transfer protein (CETP) are key factors in remodeling of high density lipoproteins (HDL) and triglyceride-rich lipoproteins. We examined the effect of a large, 24 h intravenous fat load on plasma lipids and free fatty acids (FFA) as well as on plasma LCAT, PLTP, and CETP activity levels in 8 healthy men. The effect of concomitant insulin infusion was also studied, with 1 week between the study days. During Lipofundin(R) infusion, plasma triglycerides and FFA strongly increased after 8 and 24 h (P < 0.001), whereas HDL cholesterol decreased (P < 0.01). The increase in triglycerides was mitigated with concomitant insulin infusion (P < 0.05 from without insulin). Plasma LCAT activity increased by 17.7 +/- 7.7% after 8 h (P < 0.001) and by 26.1 +/- 11. 1% after 24 h (P < 0.001), PLTP activity increased by 19.7 +/- 15.6% after 24 h (P < 0.001), but CETP activity remained unchanged. Concomitant insulin infusion blunted the increase in plasma LCAT activity (P < 0.05 from without insulin), but not that in PLTP activity. One week after the first fat load, plasma non-HDL cholesterol (P < 0.02), and triglycerides (P = 0.05) were increased, whereas HDL cholesterol was decreased (P < 0.02). Plasma CETP and PLTP activity levels were increased by 34.8 +/- 30.4% (P < 0.02) and by 15.9 +/- 6.4% (P < 0.02), respectively, but LCAT activity was then unaltered. In summary, plasma LCAT, PLTP, and CETP activity levels are stimulated by a large intravenous fat load, but the time course of their responses and the effects of insulin coadministration are different. Changes in plasma LCAT and PLTP activities may be implicated in HDL and triglyceride-rich lipoprotein remodeling under the present experimental conditions.

Influence of insulin sensitivity and the TaqIB cholesteryl ester transfer protein gene polymorphism on plasma lecithin:cholesterol acyltransferase and lipid transfer protein activities and their response to hyperinsulinemia in non-diabetic men.

Lecithin:cholesteryl acyl transferase (LCAT), cholesteryl ester transfer protein (CETP), phospholipid transfer protein (PLTP), and lipoprotein lipases are involved in high density lipoprotein (HDL) metabolism. We evaluated the influence of insulin sensitivity and of the TaqIB CETP gene polymorphism (B1B2) on plasma LCAT, CETP, and PLTP activities (measured with exogenous substrates) and their responses to hyperinsulinemia. Thirty-two non-diabetic men without hyperlipidemia were divided in quartiles of high (Q(1)) to low (Q(4)) insulin sensitivity. Plasma total cholesterol, very low + low density lipoprotein cholesterol, triglycerides, and apolipoprotein (apo) B were higher in Q(4) compared to Q(1) (P < 0.05 for all), whereas HDL cholesterol and apoA-I were lowest in Q(4) (P < 0.05 for both). Plasma LCAT activity was higher in Q(4) than in Q(1) (P < 0. 05) and PLTP activity was higher in Q(4) than in Q(2) (P < 0.05). Insulin sensitivity did not influence plasma CETP activity. Postheparin plasma lipoprotein lipase activity was highest and hepatic lipase activity was lowest in Q(1). Insulin infusion decreased PLTP activity (P < 0.05), irrespective of the degree of insulin sensitivity. The CETP genotype exerted no consistent effects on baseline plasma lipoproteins and LCAT, CETP, and PLTP activities. The decrease in plasma PLTP activity after insulin was larger in B1B1 than in B2B2 homozygotes (P < 0.05). These data suggest that insulin sensitivity influences plasma LCAT, PLTP, lipoprotein lipase, and hepatic lipase activities in men. As PLTP, LCAT, and hepatic lipase may enhance reverse cholesterol transport, it is tempting to speculate that high levels of these factors in association with insulin resistance could be involved in an antiatherogenic mechanism. A possible relationship between the CETP genotype and PLTP lowering by insulin warrants further study.

Insulin decreases plasma cholesteryl ester transfer but not cholesterol esterification in healthy subjects as well as in normotriglyceridaemic patients with type 2 diabetes.

BACKGROUND: Plasma cholesterol esterification (EST) and subsequent cholesteryl ester transfer (CET) from high-density lipoproteins (HDLs) towards apolipoprotein (apo) B-containing lipoproteins are key steps in HDL metabolism. MATERIALS AND METHODS: The effects of exogenous hyperinsulinaemia on plasma CET and EST, measured with isotope methods, were evaluated in 10 male normotriglyceridaemic (plasma triglycerides <2.0 mmol L-1) patients with type 2 diabetes and 10 individually matched healthy subjects during a two-step hyperinsulinaemic euglycaemic clamp over 6-7 h. RESULTS: No between-group differences in baseline plasma lipid parameters were observed, but the HDL cholesteryl ester content was lower (P < 0.02) and the HDL triglyceride content was higher (P < 0.05) in diabetic patients. Baseline CET and EST were similar in the groups. In both groups, hyperinsulinaemia decreased plasma triglycerides (P < 0.01) and the HDL triglyceride content (P < 0.01) compared with saline infusion in healthy subjects, whereas the HDL cholesteryl ester content increased (P < 0.05 vs. saline infusion) in diabetic patients. CET was similarly decreased by hyperinsulinaemia in both groups (P < 0.01 vs. saline infusion). In contrast, the change in EST in either group was not different from that during saline administration. In the combined group, baseline CET was positively correlated with plasma triglycerides (Rs = 0.68, P < 0.01). The HDL cholesteryl ester content was negatively (Rs = -0.48, P < 0.05) and the HDL triglyceride content was positively (Rs = 0.64, P < 0.01) correlated with CET. CONCLUSION: Insulin infusion decreases plasma CET in conjunction with a fall in triglycerides but does not decrease cholesterol esterification in healthy and type 2 diabetic subjects, indicating that acute hyperinsulinaemia has a different effect on these processes involved in HDL metabolism. Despite unaltered fasting plasma CET, HDL core lipid composition was abnormal in diabetic patients, suggesting that additional mechanisms may contribute to changes in HDL metabolism in diabetes mellitus.

Plasma phospholipid transfer protein activity is related to insulin resistance: impaired acute lowering by insulin in obese Type II diabetic patients.

Cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP) have important functions in high density lipoprotein (HDL) metabolism. We determined the association of plasma CETP and PLTP activities (measured with exogenous substrate assays) with insulin resistance, plasma triglycerides (TG) and non-esterified fatty acids (NEFA), and assessed the lipid transfer protein response to insulin during a 6-7 h hyperinsulinaemic euglycaemic clamp in non-obese and obese healthy subjects and patients with Type II (non-insulin-dependent) diabetes mellitus (n = 8 per group). Plasma PLTP activity was higher in obese healthy subjects and obese Type II diabetic patients compared with non-obese healthy subjects (p < 0.05 to 0.01) and was correlated with insulin resistance, plasma TG and NEFA (p = 0.02 to < 0.01). In non-obese healthy subjects, insulin decreased plasma TG and increased the HDL cholesteryl ester (CE)/TG ratio (p < 0.01 compared with saline infusion). Plasma PLTP activity fell by 14% at the end of the clamp (p < 0.01 compared with saline) but CETP activity did not change. The decreases in plasma NEFA, TG and PLTP activity and the rise in HDL CE/TG were smaller in obese Type II diabetic patients than in non-obese healthy subjects (p < 0.01 for all). Baseline HDL CE/TG was negatively correlated with plasma TG (p < 0.001, n = 32) and PLTP activity (p < 0.01) but not with CETP activity. Likewise, the rise in HDL CE/TG during the clamp was related to the fall in plasma TG (p < 0.001) and in PLTP activity (p < 0.02). It is concluded that plasma PLTP, but not CETP, is regulated by insulin in an acute setting. High plasma PLTP activity is associated with insulin resistance in conjunction with altered NEFA and triglyceride metabolism. High plasma TG and PLTP activity have coordinate effects on HDL metabolism.

Lack of relationship between 11beta-hydroxysteroid dehydrogenase setpoint and insulin sensitivity in the basal state and after 24h of insulin infusion in healthy subjects and type 2 diabetic patients.

OBJECTIVES: To test whether insulin resistance in type 2 diabetes mellitus is associated with an altered overall setpoint of the 11beta-hydroxysteroid dehydrogenase (11betaHSD) mediated cortisol to cortisone interconversion towards cortisol, and to evaluate whether changes in insulin sensitivity induced by antecedent hyperinsulinaemia are related to changes in the 11betaHSD setpoint. PATIENTS AND MEASUREMENTS: The urinary ratio of (tetrahydrocortisol + allo-tetrahydrocortisol)/tetrahydrocortisone ((THF + allo-THF)/THE) and of free cortisol/free cortisone (UFF/UFE), as well as the plasma cortisol/cortisone ratio were measured in 8 male type 2 diabetic patients and 8 healthy male subjects without and after 24 h of insulin infusion. Insulin was infused at a rate of 30 mU/kg/h with blood glucose being clamped at euglycaemic levels in healthy subjects and at isoglycaemic levels in diabetic patients. Insulin sensitivity was assessed by measurement of whole body glucose uptake (M-value) during a 3-4 h euglycaemic clamp, directly after the 24 h insulin infusion and compared to the M-value on a control day, at least 1 week apart from the 24 h insulin infusion. RESULTS: Despite impaired insulin sensitivity (M-value, 11.6 +/- 7.7 vs. 28.5 +/- 11.6 micromol/kg/minutes, in type 2 diabetic and healthy subjects, respectively, P < 0.05), urinary (THF + allo-THF)/THE ratio and baseline plasma cortisol/cortisone ratio at 0800 h were similar in type 2 diabetic patients (0.82 +/- 0.07 and 3. 77 +/- 0.70, respectively) and healthy subjects (0.76 +/- 0.14 and 3. 81 +/- 0.88, respectively, ns). Insulin sensitivity was not correlated with urinary (THF + allo-THF)/THE ratio nor with baseline plasma cortisol/ cortisone. In type 2 diabetic patients, insulin sensitivity was further impaired by antecedent hyperinsulinaemia (P < 0.05), but the urinary (THF + allo-THF)/THE ratio (0.80 +/- 0.14, ns) and the plasma cortisol/cortisone at 0800 h (3.66 +/- 0.72, ns) did not change. In healthy subjects, insulin sensitivity did not change significantly (M-value, 22.5 +/- 9.7 micromol/kg/minutes, ns), although the urinary (THF + allo-THF)/THE ratio (0.92 +/- 0.25, P < 0.05) and the plasma cortisol/cortisone (4.59 +/- 0.63, P < 0.05) increased. Insulin did not affect the UFF/UFE ratio in either group. CONCLUSION: The present study does not support the hypothesis that insulin resistance in type 2 diabetes mellitus is associated with an overall change in the 11betaHSD set point towards cortisol. In view of the stimulatory effects of insulin and cortisol on adipogenesis, long-term stimulation of 11betaHSD reductase activity by insulin could aggravate visceral obesity.

Familial occurrence of membranous obstruction of the inferior vena cava: arguments in favor of a congenital etiology.

Membranous obstruction of the inferior vena cava is a rare disease. The etiology of the membrane is believed to be thrombotic or congenital. In three of 11 siblings from a single family, symptoms of membranous obstruction of the inferior vena cava developed during early adult life. All had signs of more long-standing disease, as judged by the presence of collaterals, cirrhosis and, in one case, hepatocellular carcinoma. On family screening no further cases of membranous obstruction of the inferior vena cava were found. There was also no evidence of inherited defects in the natural coagulation inhibitors (protein C, protein S and antithrombin III) and plasminogen deficiency. This familial occurrence of membranous obstruction of the inferior vena cava supports a congenital etiology, although a thrombotic etiology cannot be totally excluded.

Measurement of free fatty acid kinetics during non-equilibrium tracer conditions in man: implications for the estimation of the rate of appearance of free fatty acids.

BACKGROUND: This study aimed to document the applicability and variability of free fatty acid (FFA) kinetic parameters during non-equilibrium and equilibrium tracer conditions in man. METHODS: FFA kinetic parameters were assessed after an overnight fast in six healthy non-obese and three obese subjects as well as in three patients with non-insulin-dependent diabetes mellitus (NIDDM) by infusion of [14C]-palmitate of 60 min (study A) and 10 min duration (study B). RESULTS: The kinetic parameters estimated from the upstroke and downstroke of the plasma FFA specific activity curve (non-equilibrium) were not statistically different within studies A and B. Furthermore, there were no significant differences in any of the FFA kinetic parameters between studies A and B. The averaged plasma levels of FFA obtained during the up- and downstroke from studies A and B were higher in obese subjects and NIDDM patients than in non-obese subjects (P < 0.01). The averaged total rate of appearance (TRa) of FFA was higher in obese subjects than in non-obese subjects (P < 0.02). The TRa and metabolic clearance rate (MCR), estimated from non-equilibrium conditions, were about 25% higher than the apparent values obtained from steady-state measurement in all subjects combined (P < 0.01), suggesting considerable recirculation of label from hydrolysis of labelled esterified fatty acids. Indeed, in three non-obese subjects, the radiolabel in esterified fatty acids was approximately 50% of labelled FFA at 60 min of label infusion. The coefficients of variation of the kinetic parameters were consistently larger in study A than in study B. CONCLUSION: FFA kinetic parameters can be estimated with sufficient precision using non-equilibrium data from short-term labelled palmitate infusion. Short-term label infusion has the advantage that label recirculation is prevented and exposure to radiation is limited.

Lowering of plasma phospholipid transfer protein activity by acute hyperglycaemia-induced hyperinsulinaemia in healthy men.

Human plasma contains two lipid transfer proteins involved in the remodelling of plasma lipoproteins; cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP). CETP mediates the transfer/exchange of cholesterylesters, triglycerides and phospholipids between high-density lipoproteins (HDL) and chylomicron (remnants), very low-density lipoproteins (VLDL) and low density lipoproteins (LDL). The physiological function of PLTP is unknown. It is able to transfer phospholipids (but not neutral lipids) between lipoproteins and to modulate HDL particle size in vitro. The effects of acute endogenous hyperinsulinaemia on plasma CETP and PLTP activity, as well as on lipid and lipoprotein levels, were assessed in eight healthy men during a 3-h hyperglycaemic clamp. Another group of seven men received an infusion of an equal volume of saline in order to detect possible dilution effects or effects on lipoprotein changes over time (control group). Plasma cholesterol and triglyceride concentrations fell during the clamp and the decreases were significantly different from the minor changes during saline infusion in the control group (p < 0.05 and p < 0.01, respectively). Plasma CETP activity levels did not change, but plasma PLTP activity levels decreased by 7.7 and 5.1% after 2 and 3 h of hyperglycaemia (p < 0.01 for each time-point). The hyperglycaemia-induced mean percentage change in PLTP activity levels during the 3 h of the clamp was greater than the essentially absent change during the NaCl infusion (p < 0.05). Plasma PLTP activity during the clamp was related negatively to the insulin sensitivity index (p < 0.01 by analysis of covariance). It is concluded that acute hyperglycaemia-induced hyperinsulinaemia lowers plasma PLTP, but not CETP activity levels, either directly or in conjunction with an effect on plasma lipoproteins.