Delayed clearance of chylomicron remnants following vitamin-A-containing oral fat loads in broad-beta disease (type III hyperlipoproteinemia).

Chylomicron "remnants" are formed by the selective removal of triglyceride catalyzed by lipoprotein lipase. To investigate a possible defect in the clearance of these remnants in the pathophysiology of broad-beta disease (type III hyperlipoproteinemia), subjects with this disorder and comparison subjects with endogenous hypertriglyceridemia (and type IV lipoprotein patterns) ingested an oral fat load (corn oil: cocoa butter, 1:1, 50 g/sq M) containing retinyl ester, 100 mg, with or without 15 muCi 15-(14) C-retinol (43.7 mCi/mg). The content of triglyceride and vitamin A was sequentially determined in chylomicrons (Sf more than 400) and very low density lipoproteins (VLDS, Sf20-400) over the ensuing 24-72 hr. Vitamin A was chosen as a marker for exogenous sterol assimilation since, like cholesterol, it is absorbed in the small intestine and cosecreted in esterified form with triglyceride in the chylomicron core; however, unlike cholesterol, once having been removed by the liver, it cannot be recycled inot VLDL, but subsequently circulates only as a complex with the high density retinol binding protein. Thus measurements of the vitamin A/triglyceride ratio in Sf greater than 20 lipoproteins reflected the relative efficiency of vitamin A versus triglyceride removal within these lipoproteins. These studies confirmed the intital concentration of exogenous vitamin A in chylomicrons but invariably disclosed an increasing proportion of the remaining Sf greater than 20 vitamin A in VLDL 24 hr after its ingestion. The vitamin A/triglyceride ratio also invariably increased between 6 and 24 hr in the Sf20-30 subfraction, reflecting the formation of vitamin A-rich "remnants" as intermediate species in the catabolism of chylomicrons and VLDL. Among those with mild to moderate endogenous hypertriglyceridemia the Sf greater than 400 vitamin A/triglyceride ratio declined between 6 and 24 hr, reflecting the efficient passage of the vitamin A through this fraction and/or continued secretion of Sf greater than 400 particles rich in triglyceride. Among those with severe endogenous hypertriglyceridemia, both the peak and decline in the Sf greater than 400 vitamin A/triglyceride ratio were delayed. However, among those with broad-beta disease, an increasing vitamin A/triglyceride ratio between 6 and 24 hr was frequent within all VLDL subfractions and invariable among lipoproteins of Sf greater than 400 regardless of the degree of antecedent hypertriglyceridemia. Although additional experiments disclosed a similar delay in both vitamin A and triglyceride assimilation when basal triglyceride levels were high in these subjects, marked reduction of triglyceride levels did not correct the rise in the Sf greater than 400 vitamin A/triglyceride ratio between 6 and 24 hr. Experiments employing preparative electrophoresis confirmed the identity of VLDL containing a high vitamin A/triglyceride ratio with the beta-VLDL which accumulate in broad-beta disease...     

Genetic transmission of isoapolipoprotein E phenotypes in a large kindred: Relationship to dysbetalipoproteinemia and hyperlipidemia

The largest reported kindred of a proband with type III hyperlipoproteinemia was investigated by assessment of lipid and lipoprotein levels and very low density lipoprotein (VLDL) isoapolipoprotein E distributions in all accessible family members (56% of the 124 living blood relatives and 59% of the 37 spouses). The results confirm in this kindred a trimodal distribution of apoE₃/E₂ ratios, and segregation analysis of 16 informative matings classified according to $\text{E}{}_3\text{E}{}_2$ ratio demonstrated classical Mendelian inheritance of the autosomal codominant type: the $\text{E}{}_3\text{E}{}_2$ ratio is determined by two alleles, apoE₃^d and apoE₃ⁿ, which produce three phenotypes apoE₃-D, apoE₃-ND, and apoE₃-N, corresponding to the low, intermediate, and high modes, respectively. Vertical transmission of the apoE₃-D phenotype occurred in two branches of the second generation. In both instances this represented pseudodominance; i.e., products of heterozygous (apoE₃-ND) × homozygous (apoE₃-D) matings. Hyperlipidemia (defined as a low density lipoprotein cholesterol and/or plasma triglyceride level exceeding the respective age-, sex-, and sex-steroid-specific 95th percentiles derived from Lipid Research Clinics population studies) was present in 15 blood relatives in multiple lipoprotein patterns, consistent with the presence of familial combined hyperlipidemia in this kindred. Eight of nine members with the apoE₃-D phenotype had either type III hyperlipoproteinemia or, in the absence of hyperlipidemia, β-VLDL and at least marginally cholesterol-rich VLDL (VLDL-cholesterol/plasma triglyceride >0.25) (defined as dysbetalipoproteinemia). The ninth such member, the only child with this phenotype, was normal. β-VLDL and marginally cholesterol-rich VLDL was seen in but one of six hyperlipidemic family members of phenotype apoE₃-ND, in none of seven hyperlipidemic blood relatives of phenotype apoE₃-N, in no normolipidemic family members of phenotype apoE₃-ND or apoE₃-N, and in no spouses (three of whom were hyperlipidemic and nine of phenotype apoE₃-ND). Thus, among adult members of the O'D kindred the apo₃-D phenotype was nearly specifically associated with dysbetalipoproteinemia or, when hyperlipidemia was present, type III hyperlipoproteinemia.     

Quantitation of apolipoprotein A-I of human plasma high density lipoprotein.

High density lipoproteins (HDL) may be controlled via their major apolipoprotein, A-I. To study this apolipoprotein, a simple, precise, and accurate immunodiffusion assay for A-I was developed and applied in a sample of Bell Telephone Company employees. A-I showed a slight increase with age in men (r=0.11, n=263) and women (r=0.15, n=257). A-I correlated closely with HDL cholesterol (r=0.72). It was weakly related to total triglyceride in women (r=0.24) but was inversely related in men (r=-0.17). Women on estrogen had the highest A-I levels (149 mg/dl +/- 26, x +/- S.D., n=29, p is less than 0.05), followed by women on combination oral contraceptives (141 +/- 26, n=80) whereas women on no medication had lower levels (129 +/- 25, n=99, p is less than 0.01) but men had the lowest levels (120 +/- 20, p is less than 0.01) In a separate group of 14 women given estrogen for 2 wks (1 mug/kg/day), A-I increased by 24%. Thus A-I is increased by exogenous and, most likely, endogenous estrogen, Among hyperlipidemic referral subjects, those with hypercholesterolemia (n=43) and hypertriglyceridemic women (n=33) had normal A-I levels. Among hypertriglyceridemic men both A-I and HDL cholesterol values were decreased (115 +/- 20, p is less than 0.01 and 37 +/- 3, p is less than 0.01, respectively, n=68) but were significantly lower among a group of myocardial infarction survivors (107 +/- 16, p is less than 0.01, and 27 +/- 6, p is less than 0.01, respectively, n=24). High density lipoprotein levels and the content of cholesterol in HDL associated with A-I appear to be decreased in coronary heart disease.     

Effect of intravenous glucagon on urinary catecholamine excretion in normal man.

We have evaluated intravenous glucagon as pharmacologic stimulus to adrenal catecholamine secretion in normal human subjects. Urinary epinephrine and norepinephrine were measured at two hourly intervals before and after the intravenous injection of saline, 4 mg glucagon, or 0.1 mu/kg crystalline insulin. Urinary epinephrine was increased 2.3-fold over baseline after both saline and glucagon. By contrast, insulin hypoglycemia produced a 24-fold rise in urinary epinephrine. No rise in urinary norepinephrine was detected in any test. Under the conditions of this study, we conclude that epinephrine excreted after glucagon injection is due to the stress of the test itself. In normal man, glucagon either does not stimulate adrenal catecholamine secretion, or the effect is too small to measure. By contrast, in pheochromocytoma, glucagon may be specific for catecholamine secretion, based on data from the literature. In normal subjects, insulin hypoglycemia remains the only proved method for assessing adrenal catecholamine reserve.     

Lp(a) lipoprotein: relationship to sinking pre-beta lipoprotein hyperlipoproteinemia, and apolipoprotein B.

To assess the relationship between the Lp(a) and the "sinking pre-beta" (d smaller than 1.006) lipoprotein, the concentration of Lp(a) was quantified by radial immunodiffusion and the presence or absence of sinking pre-beta was assessed by agarose electrophoresis in overnight fasting plasma samples from 485 adults, comprised of 320 with normal lipid levels, 48 with type IIa, 40 with type IIb, and 77 with type IV lipoprotein phenotypes. The median Lp(a) level was 7.6 mg/100 ml, 89% (433 of 485) having detectable Lp(a) levels. Twenty-two per cent (107 of 485) had detectable pre-beta lipoprotein in the d greater than 1.006 plasma fraction (sinking pre-beta). Of the sinking pre-beta positive plasma samples, 96% (102 and 107) exceeded the median Lp(a) level, and sinking pre-beta was detected in all 44 samples with an Lp(a) concentration exceeding 40 mg/100 ml. The relationship of Lp(a) and sinking pre-beta to lipoprotein phenotype was assessed. Compared to the normolipidemic group, the type IIa group had higher Lp(a) percentile values (p smaller than 0.02), whereas the IIb and type IV groups had significantly lower Lp(a) values than the normolipidemic group. Ninety-two per cent (296 of 320) of the normolipidemic subjects had detectable levels of Lp(a) and 22% (70 of 320) had detectable sinking pre-beta lipoprotein. Ninety-four per cent (45 of 48) of the type IIa plasmas had detectable Lp(a) levels and 27% (13 of 48) had sinking pre-beta lipoproteins. Contrasted with the IIa group, only 80% (32 of 40) of the IIb plasmas had detectable Lp(a) levels and 18% (7 of 40) had sinking pre-beta lipoprotein. In the type IV plasmas 78% (60 of 77) had detectable Lp(a) and 22% (17 of 77) had sinking pre-beta lipoprotein. Lp(a) or log Lp(a) levels were not correlated with apolipoprotein B levels (n = 485, r = 0.002 or 0.037, respectively). Furthermore, Lp(a) levels remained essentially constant in three subjects whose aprptein B levels were altered in response to pharmacological and/or dietary manipulation. A fourth subject had a 50% increase in Lp(a) but this change did not correlate with apoprotein B changes. Thus, these findings suggest that Lp(a) is metabolically independnet of low density lipoprotein even though it shares the same structural protein, apoprotein B.     

High-density lipoproteins in myocardial infarction survivors.

Subjects with existing coronary heart disease and those with many of the conditions associated with increased risk of coronary disease have reduced levels of high-density lipoprotein (HDL) cholesterol. Since HDL cholesterol is only one index of HDL composition, a reduction of HDL cholesterol could reflect a change in HDL composition and/or a decrease in all HDL constituents. Therefore the present studies assessed the major apolipoproteins of HDL, A-I and A-II, in addition to HDL cholesterol in 90 male myocardial infarction (MI) survivors and their lipid-matched male controls. The MI survivors had significantly lower (p < 0.01) A-I (112 ± 2 mg/dl, mean ± SEM), A-II (29 ± 1 mg/dl), and HDL cholesterol (39 ± 1 mg/dl) than the lipid-matched control group (A-I, 121 ± 2; A-II, 33 ± 1; HDL cholesterol, 43 ± 1) and than a population-based male control group (n = 172; A-I, 121 ± 2; A-II, 33 ± 1; HDL cholesterol, 45 ± 1). The HDL cholesterol/A-I ratio in the MI survivors was slightly lower than the ratio in the lipidmatched control group but significantly lower (P < 0.02) than that in the population-based control group. The HDL cholesterol of both control groups was significantly negatively related to log triglyceride (r = ?0.43). Similarly the HDL cholesterol of the MI survivors was inversely correlated with log triglyceride (r = ?0.51), but the slope of this relationship was significantly steeper in the MI survivors. These results are consistent with a relative decrease of HDL in MI survivors over and above that attibutable to their increased triglyceride levels.     

Lipid metabolism in pregnancy. II. Postheparin lipolytic activity and hypertriglyceridemia in the pregnant rat

Plasma postheparin lipolytic activity (PHLA) has been measured in rat pregnancy to qualitatively assess mechanisms of triglyceride removal from the circulation. This assessment can be made if the larger plasma volume of pregnancy is considered. A supramaximal dose of heparin avoids dilution of the heparin stimulus to PHLA release. Dilution of the released PHLA is corrected using measurements of plasma volume. In addition, no evidence of circulating inhibitors is present, and timing of PHLA appearance is unaffected by pregnancy. Prior studies of postheparin lipolytic activity in human pregnancy have not taken the effect of plasma volume into account and must therefore be reconsidered in light of the present results. We observed a biphasic in PHLA over the course of gestation. Levels were increased in midgestation (day 12), declined to normal by day 19, and fell rapidly to one-half of control by day 21. Assuming a functional role for the triglyceride lipases represented in PHLA, the data suggest the following hypothesis: triglyceride removal is increased or normal for the greater part of gestation and is decreased only at term. If this hypothesis proves true, the hypertriglyceridemia of pregnancy should be due largely to overproduction, with decreased removal contributing only near term.     

Estrogen-induced increase in uptake of cholesterol-rich very low density lipoproteins in perfused rabbit liver

A nonrecirculating rabbit liver perfusion system was developed to test whether estrogen increases hepatic uptake of radio-iodinated normal and/or cholesterol-rich very low density lipoproteins (VLDL, d < 1.006 g/ml) from cholesterol-fed rabbits. When equal concentrations of VLDL protein from normal rabbits and from cholesterol-fed rabbits were perfused together through the same liver, there was a selectively higher (1.4-fold) uptake of cholesterol-rich VLDL. These particles were rich in apolipoprotein E, and the radioactivity bound to this apolipoprotein was selectively removed by the perfused normal rabbit liver relative to its uptake of apolipoproteins B and C. When livers from estrogen-treated rabbits were perfused under identical conditions as normal livers and with the same lipoproteins, the uptake of cholesterol-rich VLDL was increased by 76%, compared with 21% for normal VLDL.     

Adipose tissue lipoprotein lipase activity in type III hyperlipoproteinemia.

An impairment in the catabolism of chylomicron and very low density lipoprotein remnants appears to cause the lipid abnormalities in type III hyperlipoproteinemia. A reduction in the activity of lipoprotein lipase (LPL) has been suggested as the catabolic defect. Results in this study indicate that the activity of adipose tissue LPL measured in the fasted and fed states are in the normal range in type III hyperlipoproteinemia (fasted: type III = 2.7 +/- 1.8 mU/10(6) cells, N = 8; normals = 3.4 +/- 2.5, N = 23, p, not significant; fed: type III = 3.6 +/- 2.1, N = 7; normals = 4.8 +/- 1.8, N = 12, p, not significant). This suggests that perhaps another mechanism, such as the interaction between LPL and its lipid substrate, is abnormal, or that the activity of LPL derived from another tissue source is deficient.     

Thyrotropin levels in hyperlipidemic survivors of myocardial infarction.

In an earlier investigations, the prevalence of hyperlipidemia in a group of patients who survived myocardial infarction was determined, and family studies were performed to allow genetic classification of patients with hyperlipidemia. Radioimmunoassay for thyrotropin (TSH) has now been performed on plasmas from most of these hyperlipidemic survivors. Elevated TSH values were found in five of the 18 hyperlipidemic women over age 60, and in seven of the remaining 104 hyperlipidemic subjects. Among the various genetically defined types of hyperlipidemia, the highest prevalence of TSH elevations was seen in women with sporadic (nonfamilial) hypertriglyceridemia; four of the ten had an abnormal TSH level, and two of the remainder were receiving thyroid medication. Hypercholesterolemia was not strongly correlated with TSH abnormalities. These data support the hypothesis that clinically inapparent thyroid damage may be associated with coronary artery disease.     

Lipid metabolism in pregnancy. VIII. Effects of dietary fat versus carbohydrate on lipoprotein and hepatic lipids and tissue triglyceride lipases

We have asked, is hypertriglyceridemia in the fed state in pregnancy due to intolerance to exogenous fat, accumulation of endogenous triglycerides, or accumulation of remnants of d < 1.006 lipoprotein metabolism? To answer these questions, we fed rat-free diets high in starch or sucrose, or diets containing fat or fat plus cholesterol to pregnant and nonpregnant rats for 12 days until gestational day 21 (term = 22 days). Blood was obtained 0, 4, or 8 hr after removal of food from the cages. Lipid concentrations were determined in chylomicrons and very low, low, and high density lipoproteins. Hypertriglyceridemia in pregnancy exists on both starch and sucrose containing fat-free diets and is exaggerated 4 and 8 hr after food is removed from the cage. The triglyceride rise occurs in d < 1.006 lipoproteins. With fat feeding, chylomicron triglyceride concentrations are not significantly elevated in pregnant rats, 0 or 8 hr postabsorptively despite greater food intake in pregnancy. In contrast, very low density lipoprotein (VLDL) triglyceride concentrations are elevated at all times following fat feeding in pregnant compared to nonpregnant animals. A significant contribution of lipoprotein remnants to the triglyceride rise in d < 1.006 lipoproteins seems unlikely since an isolated increase in VLDL cholesterol is not observed. No statistically significant accumulation of hepatic triglycerides occurs on any diet in pregnancy. Diet induced shifts in adipose tissue and muscle lipoprotein lipase activity are exaggerated in pregnancy while hepase in unaffected. Fetal weight is similar on all diets except sucrose where weight is reduced. Conclusions: Hypertriglyceridemia in fed pregnant rats is due to an increase in endogenous triglycerides. Remnant lipid accumulation does not appear to contribute to the endogenous hypertriglyceridemia. There is no intolerance to exogenous (dietary) fat. The results are compatible with an unimpaired delivery of exogenous fat to fat oxidizing tissues thereby maximizing glucose availability for fetal growth.     

Metabolism of cholesteryl esters of very low density lipoproteins in the guinea pig.

Very low density lipoproteins from guinea pig plasma, endogenously labeled with 3H in both the esterified and free cholesterol moieties, were obtained from serum collected 20 hr after the intravenous injection of 3H-cholesterol into donor animals. When these lipoproteins were injected into recipient guinea pigs, the esterified 3H-cholesterol was rapidly cleared from the plasma; 24% was in the liver in 5 min and 54% in 15 min. A smaller fraction of the esterified cholesterol appeared in other plasma lipoprotein fractions, with 3H in the low density lipoproteins reaching a peak of 9%-18% of the injected esterified 3H-cholesterol between 30 and 60 min after the injection. The results indicate that most of the esterified cholesterol in very low density lipoproteins of guinea pig plasma is removed directly by the liver and a minor fraction is transferred to low density lipoproteins. The pattern of labeling of cholesteryl esters of high density lipoproteins in these experiments suggests that their low concentration in the guinea pig is accompanied by a rapid turnover rate.     

Glucocorticoids and triglyceride transport: effects on triglyceride secretion rates, lipoprotein lipase, and plasma lipoproteins in the rat.

In order to elucidate the mechanism(s) of hyperlipidemia following glucocorticoid administration, dexamethasone (0.125 mg/Kg) was administered daily intramuscularly for 2 wk to male Sprague-Dawley rats and the effects on plasma triglyceride (TG) and cholesterol (Chol), lipoprotein neutral lipids, hepatic triglyceride secretion rates (TGSR; Triton), and epididymal fat lipoprotein lipase (LPL) were determined. Special measures were taken to maintain positive caloric balance and keep the weights of control and dexamethasone-treated animals comparable. Significant increases (p less than 0.001) in TG and very-low density lipoprotein (VLDL) triglyceride associated with no change in Chol and actual reduction in both triglyceride and cholesterol in low density lipoprotein (ldl) were observed in the steroid-treated animals. Dexamethasone treatment was associated with increased basal insulin and glucose levels, an insignificant increment in TGSR, and a highly significant reduction (p less than 0.001) in LPL. These findings suggest that glucocorticoid treatment increases splanchnic triglyceride production rates, but the resulting hypertriglyceridemia is primarily a consequence of impaired VLDL removal due to low adipose tissue LPL activity.     

Observations on the untreated progeny of hypothyroid male rats

The untreated progeny (F₁) of hypothyroid male rats that were either radiothyroidectomized (Tx) or had the neo-T₄ syndrome (an endocrine disorder produced by large doses of thyroxine (T₄) injected during the neonatal period) were studied. The mother rats were all normal. The fathers never had any contact with their progeny.Unexpectedly, the progeny usually showed delayed eye opening, decreased weaning weights, and increased final body weight. The thyroid glands from F₁ offspring of both Tx and neo-T₄ fathers were enlarged significantly in all but F₁ males of Tx fathers. The F₁ of Tx fathers had significantly smaller uteri, both absolutely and relatively. The ovaries were significantly larger, whereas the testes were significantly smaller. Pituitary TSH, stalk-median eminence (SME) TSH, and serum TSH were all normal with the exception of an increase in SME TSH in F₁ males born of neo-T₄ fathers. The response to thyrotropin releasing hormone (TRH) stimulation of the F₁ adult progeny of neo-T₄ fathers was significantly blunted in the males, whereas the response was normal in the offspring of Tx fathers. The mechanisms by which hypothyroid fathers caused changes in their progeny is not known.     

Thyroid function and lipids in patients with chronic renal disease treated by hemodialysis: with comments on the "free thyroxine index".

It is known that hypertriglyceridemia and abnormal thyroid function tests are common in patients with chronic renal disease treated by hemodialysis, but a possible association between these abnormalities has not been investigated. We measured serum thyroid hormone and lipid levels in one hundred patients receiving chronic hemodialysis. There were ten patients with elevations in serum thyrotropin (TSH). In the remaining patients with normal TSH, those receiving no drugs known to affect thyroid function had low mean values for thyroxine (T₄) and triiodothyronine (T₃), while the mean T₃ resin uptake (fraction of T₃ bound to resin, T₃U) was normal, resulting in low mean values for free T₄ index (FT₄I = T₄ × T₃U) and free T₃ index (FT₃I = T₃ × T₃U). The depression in T₃ was greater than the depression in T₄, so that $\text{T}{}_3\text{T}{}_4$ ratios were also low. Androgen-treated male patients had the lowest T₃ and T₄ levels; their T₃Us were high, presumably reflecting androgen-induced depression of T₄-binding globulin, but their mean FT₄I and FT₃I were still lower than those of the other patients. Evidence is presented that the conventional T₃U underestimates the proportion of free hormone when binding protein levels are low, and that a “new T₃U,” the ratio of resin-bound T₃ to serum protein-bound T₃, more accurately reflects the proportion of free hormone. Computing a “new FT₄I,” as new T₃U × T₄, yielded values in the androgen-treated group similar to those of the other patients. Patients receiving propranolol had lower $\text{T}{}_3\text{T}{}_4$ ratios than the other patients, presumably due to propranolol's inhibitory effect on peripheral conversion of T₄ to T₃. No relationship was found between indexes of thyroid function and lipid levels. Subjects with high TSH levels had levels of triglyceride and cholesterol similar to the remaining patients. Among those with normal TSH levels, low levels of T₃ or T₄ did not correlate with abnormal lipid levels. It is concluded that thyroid hormone abnormalities do not explain the hypertriglyceridemia of patients on chronic hemodialysis. The frequency of low T₄ and T₃ values in such patients, in the absence of clinical evidence of hypothyroidism and, in most instances, in the absence of TSH hypersecretion, remains unexplained.     

Impaired very low density lipoprotein and triglyceride removal in broad beta disease: comparison with endogenous hypertriglyceridemia.

The removal rate of apoprotein-B (apo B) in very low density lipoprotein (VLDL) was decreased in individuals with broad beta disease when compared with endogenous hypertriglyceridemia. Following the injection of 125I-VLDL isolated from individuals with endogenous hypertriglyceridemia, both VLDL apo B fractional catabolic rate (0.058 +/- 0.029 hr-1) and VLDL apo-B turnover rate (0.300 +/- 0.070 mg/kg/hr) were lower in broad beta disease than in endogenous hypertriglyceridemia (fractional catabolic rate 0.112 +/- 0.046, p less than .05; turnover rate 0.640 +/- 0.199, p less than .005) despite equivalent plasma concentrations of VLDL-apo-B. Furthermore, conversion of VLDL apo-B to LDL was impaired in broad beta disease relative to endogenous hypertriglyceridemia. Differences in the kinetics of lipoprotein lipase-related triglyceride removal during a maximal heparin infusion were also demonstrated between these two disorders. These differences suggest an abnormality in the interaction of lipoprotein lipase with the lipoproteins of unusual composition in broad beta disease. This is further supported by the normalization of lipoprotein composition in broad beta disease by estrogen therapy, with a simultaneous change in the kinetics of lipoprotein lipase-related triglyceride removal towards those seen in endogenous hypertriglyceridemia.     

Myocardial infarction in the familial forms of hypertriglyceridemia.

Among 74 hypertriglyceridemic patients who were referred for study because of hypertriglyceridemia, family investigations detected 19 with familial hypertriglyceridemia and 24 with familial combined hyperlipidemia. The frequency of myocardial infarction among adult living hyperlipidemic relatives of patients with familial combined hyperlipidemia was 17.5% (10/57). Five of these relatives had their infarct between the ages of 40 and 50 yr of age, and five before the age of 40 yr. The frequency of myocardial infarction in living hyperlipedemic relatives with familial hypertriglyceridemia was 4.7% (2/43) and was similar to the frequency of myocardial infarction among normolipidemic relatives (4.5%) or among spouse controls (5.2%). Mortality data due to myocardial infarction among relatives of index patients failed to contribute meaningful information.     

Effect of phenformin on lipid transport in hypertriglyceridemia

The effect of phenformin on lipid metabolism was studied in nine hypertriglyceridemic subjects consuming isocaloric liquid formula diets. On a fat-free, 85% carbohydrate hydrate diet, phenformin reduced plasma triglyceride, cholesterol, and free fatty acid levels, the mean decreases being 14%, 13%, and 16%, respectively. The predominant effect of the drug was on very low density lipoprotein levels, with no change in low density lipoproteins. Plasma triglyceride and cholesterol levels were also reduced in the majority of subjects on a diet containing 40% of calories as fat and 45% as carbohydrate, but phenformin did not have any effect on the carbohydrate induction of triglyceride elevation. Basal insulin levels were reduced by the drug in all subjects (mean change, ?23%) and fasting glucose levels were lowered in the majority. The plasma lipolytic rate measured on endogenous substrate during a prolonged heparin infusion on the fat-free diet was reduced by phenformin (mean change, ?15%), although postheparin lipolytic activity on an artificial substrate was unchanged. Free fatty acid turnover, measured during the same procedure, fell in parallel with the fatty acid levels (mean change, ?27%). It is proposed that phenformin lowers plasma triglyceride levels in most subjects by reducing endogenous triglyceride production, and that the effects of the drug on glucose, insulin, and free fatty acid homeostasis contribute to this action. It is suggested that in some subjects the drug may also impair triglyceride clearance from plasma, and that this may account for the variable therapeutic response, since in three subjects phenformin did not decrease triglyceride levels on both diets.