Studies in hypertriglyceridaemia. VI: Serum lathosterol concentration is raised in hypertriglyceridaemic non-diabetic males with hyperinsulinaemia.

OBJECTIVES: To assess the cholesterol synthesis rate in primary hypertriglyceridaemia using the serum unesterified lathosterol concentration as an indicator. DESIGN: A cross-sectional, case-control study. SETTING: The Karolinska Hospital, Stockholm. SUBJECTS: Randomly selected hyper- (n = 53) and normotriglyceridaemic (n = 57) males, 40-50 years, with a fasting serum triglyceride concentration (mean +/- SD) of 3.81 +/- 1.65 and 1.28 +/- 0.53 mmol L-1, respectively. The exclusion criterion was diabetes mellitus, defined according to the World Health Organization (WHO) guidelines. MAIN OUTCOME MEASURES: To compare the fasting serum concentration distributions of lathosterol, a cholesterol precursor, in hyper- and normotriglyceridaemic groups. RESULTS: Thirty-six per cent of the hypertriglycerdaemic group had raised serum lathosterol concentrations, based on the 90th percentile of the lathosterol distribution of the normotriglyceridaemic group. In the hyper- but not in the normotriglyceridaemic group, lathosterol concentration was directly correlated with serum insulin responses to oral (r = 0.38; P = 0.007) and intravenous (r = 0.41; P = 0.005) glucose challenges. CONCLUSIONS: One-third of a randomly selected non-diabetic hypertriglyceridaemic population had an increased serum lathosterol concentration and this might indicate an increased cholesterol synthesis rate compatible with increased production of VLDL particles, possibly as the result of chronic hyperinsulinaemia.

Nicotinic acid treatment shifts the fibrinolytic balance favourably and decreases plasma fibrinogen in hypertriglyceridaemic men.

BACKGROUND: Nicotinic acid in gram doses decreases cholesterol and triglyceride concentrations in plasma, but the effect on haemostatic function is not known. METHODS: Twenty-three men with hypertriglyceridaemia were treated with 4 g nicotinic acid daily for 6 weeks. Tests for haemostatic function and serum lipoproteins were performed before and at the end of the period of treatment. RESULTS: Treatment with nicotinic acid had the expected effect on lipoprotein concentrations: it reduced the serum concentrations of triglyceride and the three major density fractions of triglyceride (very low density lipoprotein (VLDL), low density lipoprotein (LDL) and high density lipoprotein (HDL)). The VLDL cholesterol concentration was reduced, but that of HDL cholesterol was increased (all P<0.0001). The lipoprotein(a) (Lp(a)) concentration decreased significantly (P<0.01). The total fibrinolytic activity was increased by nicotinic acid treatment as indicated by decreases in plasminogen activator inhibitor-1 activity from 34.3 to 23.8 U/ml (P<0.01) and in alpha2-antiplasmin activity from 1.10 to 0.97 U/ml (P<0.01). The plasma fibrinogen concentration decreased from 3.55 to 3.01 U/ml (P<0.01). Multvariate analysis showed that the changes in alpha2-antiplasmin and Lp(a) concentrations could explain 53% of the change in plasma fibrinogen, suggesting that increased plasmin mobilization could be responsible for the decrease in plasma fibrinogen. CONCLUSION: This study of hypertriglyceridaemic men has shown that long-term treatment with nicotinic acid not only corrects serum lipoprotein abnormalities, but also reduces the fibrinogen concentration in plasma and stimulates fibrinolysis.

Effects of gemfibrozil therapy on glucose tolerance, insulin sensitivity and plasma plasminogen activator inhibitor activity in hypertriglyceridaemia.

BACKGROUND: Hypertriglyceridaemia (HTG), glucose intolerance, insulin resistance and elevated plasma activity of plasminogen activator inhibitor (PAI)-1 are risk factors for ischaemic heart disease. Because these conditions tend to cluster in the same individuals, the concerted action of gemfibrozil on all these parameters were investigated in a patient group with primary HTG. METHODS: Gemfibrozil was given as 600 mg tablets twice a day for 12 months to a group of middle-aged non-diabetic men with moderate HTG. Patients served as their own controls, because the treatment period was preceded by a single-blinded 2-month placebo phase. Gradient gel electrophoresis subfractionation of HDL was performed and glucose tolerance was defined according to World Health Organization criteria. The insulin sensitivity was assessed by the insulin-modified minimal model method. Plasma PAI-1 was assayed as activity. RESULTS: Serum triglyceride concentration was lowered by 49%. Serum high density lipoprotein (HDL) cholesterol concentration was raised by 11% with percentage shift towards the smaller HDL3c subfraction. The low-density lipoprotein cholesterol concentration remained unchanged. The proportion of glucose-intolerant subjects and insulin sensitivity were not altered by gemfibrozil. Plasma PAI-1 activity and fibrinogen levels were unaffected by gemfibrozil. The serum activity of gamma-glutamyltranspeptidase was lowered in all patients. CONCLUSION: Gemfibrozil is safe and effective with regard to its serum triglyceride-lowering potential. However, glucose intolerance, insulin resistance and elevated plasma PAI-1 activity, frequently seen in HTG patients, are not to be expected to be normalized by this drug.

Studies in hypertriglyceridaemia, III: Glucose tolerance, insulin sensitivity and indices of adipose tissue lipolysis in randomly selected non-diabetic hypertriglyceridaemic Swedish men.

Hypertriglyceridaemia, insulin resistance and glucose intolerance are conditions associated with an increased risk of coronary heart disease. In this study we have examined randomly selected nondiabetic hypertriglyceridaemic (HTG) males, 40-50 years (n = 65) and age-matched normotriglyceridaemic (NTG) controls (n = 61). The (mean +/- SD) insulin sensitivity index, as assessed by the Minimal Model method, was significantly lower in the HTG compared with the NTG group (3.69 +/- 2.96 vs. 6.29 +/- 3.38 x 10(-4) min-1 per mUL-1; P < 0.001). Thirty-eight per cent of the HTG group was glucose intolerant, compared with 8% in the NTG group (X2 = 13.16; P < 0.001). The glucose intolerant HTG sub-group had, when compared with the glucose tolerant one, significantly higher serum concentrations of apoB (1318 +/- 284 vs. 1094 +/- 312 mg L-1; P < 0.01) and glycerol (84 +/- 26 vs. 65 +/- 22 nmol L-1; P < 0.01). Serum FFA concentrations were, irrespective of glucose tolerance/intolerance, higher in the HTG than in the NTG group. By logistic regression analysis with the HTG/NTG state as the dichotomous variable, it was found that neither a low insulin sensitivity, nor glucose intolerance were independently linked with the HTG state. Instead, the lower insulin sensitivity of the HTG group was related to their higher body mass index. The higher frequency of glucose intolerance in the HTG group was explained by their higher mean serum apoB concentration, when compared with the NTG group. In conclusion, this study of a randomly selected of HTG group has confirmed the frequent coexistance of HTG, insulin resistance and glucose intolerance. The new important finding was that neither of these two latter conditions appear to be of direct pathogenetic importance for HTG.

A common variant in the gene for lipoprotein lipase (Asp9-->Asn). Functional implications and prevalence in normal and hyperlipidemic subjects.

Subjects with combined hyperlipidemia (CHL) were screened for mutations in the lipoprotein lipase (LPL) gene by single-strand conformational polymorphism, and a previously reported G-->A DNA sequence change in exon 2, causing substitution of Asp by Asn at position 9, was identified in 2 individuals. Because this substitution destroys a recognition site for Taq I, pooling of DNA samples, amplification, and digest with Taq I allowed the rapid screening of 1563 healthy individuals and patients of Dutch, Swedish, English, and Scottish origin. In the general populations of all four countries, healthy carriers of the mutation were detected at a frequency of 1.6% to 4.4% (mean, 3.0%; 95% confidence interval, 2.0% to 4.0%). The frequency of carriers was roughly twice as high (range, 4.0% to 9.8%) in selected patients with CHL or type IV hyperlipoproteinemia or in subjects with angiographically assessed atherosclerosis; the frequency was consistently higher in each patient group compared with its matched control group. In 773 healthy men from two general practices in the United Kingdom, 25 carriers and 2 homozygotes for the mutation were identified. In these 27, plasma triglyceride but not plasma cholesterol levels were significantly higher than in noncarriers (2.25 versus 1.82 mmol/L, P < .02), and this difference was maintained in three subsequent annual measurements. Postheparin LPL activity data were available for some carriers and for 7 of 9 individuals from the patient groups, and 6 of 6 individuals from the control groups had LPL activity that was lower than the respective group mean. In vitro mutagenesis and transient expression in COS cells showed that compared with the LPL-Asp9 construct, LPL-Asn9 activity and mass were reduced by 20% to 30% in the culture media. Overall however, LPL-Asn9 had only slightly reduced specific activity (by 18%). Thus, although the precise mechanism of the effect is unclear, the data strongly suggest that the LPL-Asn9 variant is associated with and may play a direct role in predisposing carriers to develop hypertriglyceridemia.

Studies in hypertriglyceridaemia. 1. Serum triglyceride distribution and its correlates in randomly selected Swedish middle-aged men.

OBJECTIVES: To obtain a randomly selected hypertriglyceridaemic population for detailed further characterization. DESIGN: Study of randomly selected males. SETTING: Subjects examined and blood sampled at Sollentuna Primary Health Care Centre. SUBJECTS: Men aged 40-50 years (n = 1564), living in the Stockholm area, who were screened for hypertriglyceridaemia, January 1990-June 1992. MAIN OUTCOME MEASURES: Fasting concentrations of serum triglycerides. RESULTS: The serum triglyceride concentration distribution showed the expected skew distribution with the 90th and the 95th percentile at 2.51 and 3.05 mmol L-1, respectively. The mean serum triglyceride level compared well with several population values reported from this laboratory over the last 30 years, indicating stable triglyceride levels over time. There was no significant age-trend for the triglyceride concentration. Lower mean values for triglyceride, insulin and waist-to-hip (W/H) ratio were observed during the summer, whilst apolipoprotein A-I levels were higher. There was a linear relation between the number of cigarettes smoked and the serum triglyceride concentration. In stepwise multiple linear regression analysis with the triglyceride concentration as the dependent variable the following variables appeared as significant (P < 0.01) contributors: insulin, cholesterol, glucose, apolipoprotein A-I, number of cigarettes smoked, BMI, W/H ratio and diastolic blood pressure. The regression coefficient for apolipoprotein A-I was negative; all the others were positive. The multiple regression (R) was 0.68, suggesting that up to 47% of the variation of the serum triglyceride concentration could be predicted by these factors. CONCLUSIONS: A group of randomly selected hypertriglyceridaemic men has been recruited for further clinical, metabolic and genetic studies. Basic characteristics of the population for their recruitment are described.

Relationship between plasma plasminogen activator inhibitor-1 activity and VLDL triglyceride concentration, insulin levels and insulin sensitivity: studies in randomly selected normo- and hypertriglyceridaemic men.

Impaired fibrinolytic function secondary to elevated plasma plasminogen activator inhibitor-1 activity, hypertriglyceridaemia and hyperinsulinaemia are frequent findings in patients with coronary heart disease. It has been debated whether VLDL or insulin is the major regulator of plasma plasminogen activator inhibitor-1 activity. This study examines the relationships between plasma plasminogen activator inhibitor-1 activity and VLDL triglyceride concentration, fasting and post-oral glucose load insulin levels and insulin sensitivity, as estimated by the minimal model method. Subjects studied were randomly selected hypertriglyceridaemic (n = 65) and age-matched normotriglyceridaemic (n = 61) men, aged 40-50 years, recruited in a population survey. Plasma plasminogen activator inhibitor-1 activity was higher in the hypertriglyceridaemic than in the normotriglyceridaemic group (21 +/- 14 vs 10 +/- 8 mU/l; p < 0.01). The hypertriglyceridaemic group had higher serum insulin, basal as well as 2 h after intake of the oral glucose load, and a lower insulin sensitivity index. In univariate analysis, plasma plasminogen activator inhibitor-1 activity correlated positively with VLDL triglycerides in both the hyper- and normotriglyceridaemic groups (r = 0.43 r = 0.60, respectively) and negatively with the insulin sensitivity index (r = -0.35 r = -0.44, respectively). In multivariate analysis, VLDL triglyceride levels were found to be independently related to plasma plasminogen activator inhibitor-1 activity in both groups, whereas insulin sensitivity/serum insulin levels were not. An unexpected finding was that the serum activity of the enzyme gamma glutamyl transpeptidase appeared to influence the relationships for plasma plasminogen activator inhibitor-1 in the hypertriglyceridaemic group.(ABSTRACT TRUNCATED AT 250 WORDS)