Hyperlipoproteinemic Subjects Research Articles

Effects of nicotinic acid therapy on high-density ldpoprotein metabolism in type II and type IV hyperlipoproteinaemia

This study investigates the influence of pharmacologie doses of nicotinic acid on HDL metabolism in six type II and four type IV hyperlipoproteinaemic subjects. Although the drug lowered the level of triacylglycerol and VLDL-cholesterol in the type II group, it produced no significant change in the plasma concentrations of LDL-cholesterol, HDL-cholesterol, HDL 2, HDL 3 and apolipoproteins A-I and A-II. However, separation of the group into IIa and IIb subtypes revealed a marked divergence in their response to treatment. The former exhibited a substantial reduction in plasma triacylglycerol and a striking rise in the HDL 2/HDL 3 ratio while in the latter these parameters were little affected by the drug. In the type IV subjects nicotinic acid lowered both cholesterol and triacylglycerol levels, the former deriving from a reduction in the level of that lipid associated with VLDL. In contrast, HDL-cholesterol rose significantly in this group, as did both HDL 2 and HDL 3. These changes were accompanied by an increase in plasma apolipoprotein A-I due to a fall in its fractional rate of catabolism. The plasma apolipoprotein A-II level was unaffected by treatment. These differing responses to nicotinic acid treatment may reflect a differential effect of the drug on triacylglycerol and VLDL metabolism in normoand hypertriglyceridaemic subjects.

Apolipoprotein B metabolism in normal, type IV, and type V hyperlipoproteinemic subjects

Apolipoprotein B (apoB) metabolism was investigated in four normal, three type IV, and three type V hyperlipoproteinemic subjects. Following injection of autologous radioiodinated very low density lipoprotein (VLDL) the rate of clearance of the apoprotein from this particle and its subsequent appearance in low density lipoprotein (LDL) was measured by frequent apoB specific activity determinations over an 11-day period. The resultant data were analyzed using the SAAM 27 computer program. In the normal subjects, more than 95% of the injected VLDL apoB was rapidly transferred to the LDL density range and accounted for all LDL apoB synthesis in that group. The plasma VLDL apoB concentration in the type IV group was, on average, five times the normal level. This resulted primarily from a doubling of the VLDL apoB synthetic rate associated with a defective or saturated catabolic mechanism. Only 60% of this material subsequently appeared in LDL, while the remainder was catabolized via an LDL-independent pathway. The turnover parameters of LDL apoB were normal in the type IV patients. Type V hyperlipoproteinemic subjects exhibited a 12- to 35-fold increase in plasma VLDL apoB concentration over normal. This again derived from increased VLDL apoB synthesis in the presence of defective removal of the apoprotein; the fractional catabolic rate of VLDL apoB in this group was 14% of the normal value. However, in contrast to the type IV patient data, more than 85% of the apoB in type V VLDL eventually appeared in LDL whose turnover rate was raised as a result of an increase in its catabolism; the fractional catabolic rate of LDL apoB in type V patients was four-fold above normal. The plasma LDL apoB pool size was substantially reduced in these subjects. This study shows that in hyperlipoproteinemic pheno-types IV and V there exist multiple anomalies of apoB metabolism affecting both VLDL and LDL.

The effects of cholestyramine on high density lipoprotein metabolism

This study on 4 type II hyperlipoproteinaemic subjects examines the effects of pharmacologic doses (8 g twice daily) of the bile acid sequestrant cholestyramine on the plasma distribution and chemical composition of the high density lipoprotein subfractions, HDL 2 and HDL 3, and describes the influence of the drug on the metabolism of the major HDL apoproteins, apolipoprotein A-I and A-II. Cholestyramine lowered plasma low density lipoprotein cholesterol (32%; P < 0.05) without affecting the level of that lipid in very low density or high density lipoproteins. However, the plasma HDL 2 HDL 3 ratio and apolipoprotein A-I concentration rose significantly on treatment, while apolipoprotein A-II remained unchanged. The rise in apolipoprotein A-I derived from an increase in its synthetic rate and produced a relative enrichment of the protein with respect to apolipoprotein A-II in both HDL subfractions. These results demonstrate the cholestyramine treatment affects HDL metabolism in a way which, according to current concepts, may prove beneficial to the recipient.

The results of animal studies with ciprofibrate, a new orally effective hypolipidemic drug

Findings are given to show that ciprofibrate, a new orally active phenoxyisobutyrate, is significantly more hypolipidemic than is the reference clofibrate. In hyperlipidemic rats ciprofibrate suppresses the increase in blood lipids 33% at a daily dosage of 0.6–3 mg/kg. The corresponding dosage for clofibrate is 125–460 mg/kg. Based on studies with cholesterol pools pre-labeled with [ 14C]mevalonate or with cholesterol-labeled pools in ciprofibrate-treated normolipidemic rats, ciprofibrate was shown to inhibit cholesterol biosynthesis. No evidence of the presence of 7- or 24-dehydrocholesterol was obtained in the sera of ciprofibrate-treated rats as shown by gas chromatography examination. The order of hypolipidemic effectiveness of ciprofibrate in hyperlipidemic rats provides a basis for anticipating that ciprofibrate will be hypolipidemic in hyperlipoproteinemic subjects who are considered at high risk of acquiring coronary artery disease.

Very low density and low density lipoprotein subfractions in type III and type IV hyperlipoproteinemia Chemical and physical properties

Subfractions of VLDL (VLDL 1, Sf 100–400; VLDL 2V Sf 60–100; VLDL 3, Sf 20–60) and LDL (LDL 1, Sf 12–20; LDL 2, Sf 6–12; LDL 3, Sf 3–6) were isolated from the plasma of three normal, three type in and four type IV hyperlipoproteinemic subjects. In the type IV group, all VLDL subspecies Were of normal composition but were increased in concentration in the order VLDL 1 > VLDL 2 > VLDL 3. In the same subjects, although LDL 1 was lowered and LDL 3 increased, the total plasma LDL concentration Was normal. All VLDL subfractions were elevated in the type III group, but in this ease VLDL 3 predominated. These subfractions were enriched in cholesteryl esters and depleted in triglyceride. In the LDL density range there was a shift of mass towards the least dense fraction, LDL 1, which was of normal composition. EPR studies of the VLDL and LDL subfractions in a type IV subject demonstrated a decrease in fluidity with increasing density. The major change occurred between VLDL 3 and LDL, and was attributed to a substantial alteration in the cholesteryl ester: triglyceride ratio in the particle. A similar argument was used to explain the reduced fluidity of type III VLDL 3 with respect to that of the same subfraction in normal or type IV subjects. Particle diameters, determined by laser light-scattering speetroscopy were-in good agreement with the values obtained by electron microscopy. This study provides a baseline for the examination of the relationship' between the physical and metabolic properties of VLDL and LDL subtractions in type in and IV hyperlipoproteinemia.

Influence of a hypolipemic drug (procetofene) on platelet functions and lipid composition in type II B hyperlipoproteinemia.

Platelet function was evaluated in platelet-rich plasma and in washed platelets in relation to their lipid composition, in 18 type II B hyperlipoproteinemic men treated with procetofene. The results were compared to those obtained in 15 young, healthy normolipemic controls and in 22 untreated male subjects with type II B hyperlipoproteinemia. In addition to completely normalizing platelet functions, procetofene was able to induce a 28-53% decrease in serum cholesterol and triglycerides. Solely, the aggregation to ADP (secondary), arachidonic acid and epinephrine was higher in the untreated hyperlipoproteinemic subjects. This increased susceptibility to aggregation does not appear to be related to the cholesterol or cholesterol-phospholipid content of platelets.

Evaluation of an automated immunoassay procedure for APO-LDL for phenotyping type II hyperlipoproteinemia

Apo-low density lipoproteins were determined by an automated immunoassay procedure on serum samples from 88 normolipidemic individuals and 84 hyperlipoproteinemic subjects, to establish whether this method was useful in the routine detection of type II hyperlipoproteinemia. The results obtained were compared with the cholesterol levels of the same specimens. In subjects with type II hyperlipoproteinemia, the apo low density lipoprotein levels, as well as the ratio of low density lipoprotein cholesterol/apo-low density lipoprotein were higher, as expected, than in normals or in subjects with other types of hyperlipoproteinemia. However, there was considerable overlap in individual values of both these parameters, between patients with type II hyperlipoproteinemia and normals or subjects with other types of hyperlipoproteinemia, suggesting that apo low density lipoprotein levels alone were not sufficiently discriminatory for the laboratory determination of type II hyperlipoproteinemia.

Lecithin: Cholesterol Acyl Transfer Rate in Plasma and its Relations to Lipoprotein Concentrations and to Kinetics of Bile Acids and Triglycerides in Hyperlipoproteinemic Subjects

Lecithin: Cholesterol Acyl Transfer Rate in Plasma and its Relations to Lipoprotein Concentrations and to Kinetics of Bile Acids and Triglycerides in Hyperlipoproteinemic Subjects

Lecithin: Cholesterol Acyl Transfer Rate in Plasma and its Relations to Lipoprotein Concentrations and to Kinetics of Bile Acids and Triglycerides in Hyperlipoproteinemic Subjects

The lecithin:cholesterol acyl transfer (LCAT) rate and the concentrations of lipids and lipoproteins in plasma were determined in 85 normolipidemic reference subjects and in 89 subjects with different types of hyperlipoproteinemia (38 type 11a, 9 type lib. 2 type III. 38 type IV and 2 type V). The mean molar LCAT rate was lower in the reference group than in all types of hyperlipoproteinemia. The type IV and type V subjects had the highest molar LCAT rates. The mean fractional LCAT rate was reduced in type Ha and elevated in type IV compared to the reference group. In the hyperlipoproteinemic subjects the molar LCAT rate correlated positively with the triglyceride (TG)or the very low density lipoprotein (VLDL) concentration in plasma and with the body weight. The fractional LC AT rate correlated negatively with the LDL-total cholesterol (TC) concentration in plasma. After two months on a weight-reducing diet the mean molar and fractional LCAT rates were reduced by 17% and 6% respectively in 39 hypertriglyceridemic subjects. The changes of the molar LCAT rate correlated positively with the changes of the TG. unesterified cholesterol, and phospholipid concentrations in plasma and with the changes of the body weight. The changes of the fractional LCAT rate correlated negatively with the changes of the LDL-TC concentration in plasma. The production rate of bile acids and the turnover of endogenous TG, which were determined in 7 type IV subjects, correlated positively with the molar LCAT rate. There was no correlation between the bile acid production and the molar LCAT rate in 12 type Ila subjects. The results indicate that there are close relations between the production rate of cholesteryl esters (CE)in plasma and the production rate of VLDL and bile acids in type IV subjects. It is suggested that the molar LCAT rate determined in vitro might reflect the turnover of CE in plasma in vivo.

Metabolsim of apoB and apoC lipoproteins in man: kinetic studies in normal and hyperlipoproteininemic subjects

The kinetics of apolipoproteins B and C were studied in 14 normal and hyperlipoproteinemic subjects after injection of exogenously (125)I-labeled very low density lipoprotein (VLDL) particles. Plasma radioactivities of apoB and apoC were determined over a period of 4 days in VLDL (d < 1.006) and total radioactivity in intermediate (IDL) (1.006 < d < 1.019), low (LDL) (1.019 < d < 1.063), and high (HDL) (1.063 < d < 1.21) density lipoproteins. The data were analyzed by the use of a model, developed mostly from these data, with the following results. The VLDL particle undergoes a series of incremental density changes, most likely due to a number of delipidation steps, during which apoB stays with the particle until the density reaches the IDL range. There is, however, a loss of apoC associated with these delipidation steps. In our normal subjects, all IDL apoB eventually becomes LDL. In our hyperlipemic subjects some of the apoB on IDL is also degraded directly. The apoC lost by VLDL and IDL recycles to HDL, and most of it is picked up again by newly synthesized VLDL. There is a slowdown of the stepwise delipidation process in all hyperlipemic individuals studied. Three additional features became apparent in the type III subjects. First, there is a significant increase (a factor of 2 compared to normal) in the apoB synthesis rate by way of VLDL; second, there is an induced direct apoB synthesis pathway by way of IDL (and/or LDL); third, a bypass of the regular stepwise VLDL delipidation pathway is induced by which VLDL particles lose apoC but none of their apoB, thereby forming a new particle with metabolic properties similar to LDL, but with a density still in the VLDL density range. Two type III patients treated with nicotinic acid and clofibrate showed a sharp decrease in their VLDL apoB synthesis rates. This was somewhat compensated by an increased IDL apoB synthesis rate. A type I patient on a medium chain triglyceride diet also showed a number of metabolic changes, including reduced VLDL apoB synthesis and the induction of considerable IDL and/or LDL apoB synthesis.

Macromolecular dispersion of human plasma low-density lipoproteins in hyperlipoproteinemia

Low-density lipoprotein (LDL) has previously been reported to exist in either a polydisperse or a monodisperse state. Using the techniques of analytical velocity sedimentation and/or equilibrium density-gradient ultracentrifugation, the macromolecular dispersion of LDL has been investigated in 139 subjects classified by their lipoprotein phenotypes as follows: 63 normal, 25 type IIA, 6 type IIB, and 45 type IV. LDL polydispersion was found in 78% of subjects with hypertriglyceridemia (type IIB or IV phenotypes), while only 9% of normotriglyceridemic subjects had polydisperse LDL. A study of LDL dispersion in two families, one with hyperpreβ-lipoproteinemia and one with combined hyperlipoproteinemia, also demonstrated the frequent association of LDL polydispersity with increased plasma very low density lipoprotein (VLDL) concentrations. LDL polydispersion results from the presence of higher molecular weight, lipid-enriched lipoproteins of the LDL class. Among hyperlipoproteinemic subjects with a type IV phenotype and with polydisperse LDL, the concentrations of these higher molecular weight subspecies of LDL appear to increase with severity of the hyperlipemia. In 6 subjects, reduction of VLDL concentration resulted in a decrease in the concentration of the higher molecular weight LDL; however, LDL remained polydisperse. By contrast, approximately one-third of subjects with hypertriglyceridemia were observed to have monodisperse LDL, even in the presence of high VLDL concentrations. This observation raises the possibility of two separate populations of subjects with hypertriglyceridemia arising from increased VLDL concentration.

Selective extraction of human serum very low density apolipoproteins with organic solvents

The ability of dioxane, trimethylphosphate, isopropanol, acetone, tetramethylurea, dimethylformamide, acetonitrile, methylsulfoxide and formamide to solubilise human serum very low density apolipoproteins has been investigated. The solvents, with the exception of isopropanol, solubilised only small amounts of cholesterol and phospholipids together with the apolipoproteins. Isopropanol solubilised all phospholipids and much cholesterol. No cholesterol ester or triacylglycerol was extracted. The protein content in the solvent extracts from different hyperlipoproteinaemic subjects has been determined. None of the solvents solubilised apolipoprotein B. The composition of the apolipoprotein mixtures in the different extracts was examined by means of polyacrylamide disc gel electrophoresis. The solvents showed selective properties in extracting the apolipoproteins. Methylsulfoxide solubilised the apoliproteins C-II and C-III but not C-I and the arginine-rich apolipoprotein, whereas acetone extracted the apolipoproteins C-I, C-II and C-III but not AR. Formamide solubilised predominantly the different forms of apolipoprotein C-III. Isopropanol generally extracted more of the apolipoproteins C and arginine-rich apolipoprotein than tetramethylurea, which has previously been reported to quantitatively solubilise these apolipoproteins. The solvents differed in their ability to solubilise the uncharacterised VLDL-apolipoproteins present in small amounts. In trimethylphosphate extracts of very low density lipoproteins, a weak band with slightly lower electrophoretic mobility than apolipoprotein C-II, could clearly be demonstrated.

Isolation and carbohydrate composition of glycopeptides of human apo low-density lipoprotein from normal and type II hyperlipoproteinemic subjects

Glycopeptides were prepared from the delipidized protein of low-density lipoprotein (LDL, d=1.019-1.063) of three normal and three familial heterozygous type II hyperlipoproteinemic (HLP) subjects. The glycopeptides of all subjects were resolved into three groups by gel filtration on Bio-Gel P6 following papain (EC 3.4.22.2) digestion and initial purification on Bio-Gel P2. In normal individuals the component of largest molecular weight (F-1) contained mannose (Man), N-acetyl glucosamine (GlcNAc) galactose (Gal), and N-acetyl neuraminic acid (NANA) in the respective amounts of 45.9 +/- 6.7, 37.3 +/- 5.9, 28.6 +/- 3.4, and 27.0 +/- 3.9 nmol/mg original apoprotein. The group of smallest molecular weight (F-3) contained essentially only Man (25.8 +/- 1.5 nmol/mg protein) and GlcNac (3.0 +/- 0.4 nmol/mg protein) with traces of Gal and NANA. A group of intermediate molecular weight (F-2) exhibited considerable heterogeneity and contained Man, GlcNAc, Gal, and NANA in the amounts of 45.9 +/- 5.1, 18.3 +/- 1.7, 11.0 %/- 1.7, and 7.7 %/- 1.2 nmol/mg protein. While the major portion of NANA (78%), Gal (71%), and GlcNAc (64%) was present in F-1, approximately 22% of the total Man was in F-3. No major differences were detected in the carbohydrate composition of the three glycopeptide fractions of LDL apoptotein from normal and Type II subjects.

The carbohydrate composition of human apo low density lipoprotein from normal and type II hyperlipoproteinemic subjects

The carbohydrate composition of the apoprotein from low density lipoprotein (LDL) of normal (average LDL cholesterol, 122 mg/100 ml) and type II hyperlipoproteinemic (average LDL cholesterol, 236 mg/100 ml) males was studied using gas-liquid chromatographic analysis of the methul glycoside derivatives. All samples containing detectable sinking pre-beta-lipoprotein were excluded from the study. The apo LDL from both groups of subjects contained mannose, galactose, N-acetyl-glucosamine and N-acetylneuraminic acid. Glucose and fucose were not found while trace quantities of galactosamine were detected. Although the quantities of galactose and N-acetylglycosamine were the same in the two groups, lower quantities of mannose (p less than or equal to 0.01) and N-acetylneuraminic acid (p less than or equal to 0.05) were found in the type II patients as opposed to normal subjects.

Purified postheparin plasma lipoprotein lipase in primary hyperlipoproteinemias.

Purified postheparin plasma lipoprotein lipase (LPL) of normolipidemic and primary hyperlipoproteinemic subjects was characterized by lipoprotein C polypeptide activation and specificity for triglycerides in chylomicrons and VLDL. Chromatography of normal LPL on Sephadex G-100 resulted in two protein peaks, LPLC-1 (activated by C-I but not C-II) and LPLC-II (activated by C-II but not C-I). LPL from type I hyperlipoproteinemic subjects was not activated by C-I and C-II activation was reduced to 40% of control. Hydrolysis of chylomicron and VLDL triglycerides was severely impaired. Although chromatography of type I LPL resulted in two protein peaks, the protein peak corresponding to LPLC-I did not exhibit lipolytic activity and LPLC-II was reduced to 50% of control in protein and enzyme specific activity. Type III LPL was normal in respect to LPLC-I while LPLC-II averaged 40% of control. Hydrolysis of chylomicron and VLDL was reduced to 50% and 10% of control, respectively. An etiological implication for LPLC-I and/or LPLC-II in type I and III hyperlipoproteinemias is suggested.

Differences among Hyperlipoproteinaemic Subjects in the Response of Lipoprotein Lipids to Resin Therapy

AbstractIt has been reported that cholesterol turnover is raised when hypercholesterolaemia occurs in association with elevated levels of very low density lipoprotein, but normal when hypercholesterolaemia reflects an increase in the concentration of low density lipoprotein alone. The relationship of plasma lipoprotein levels to cholesterol metabolism has been further investigated in the present experiments, in which the acute effects on lipoprotein lipids of stimulating cholesterol turnover with a bile acid‐sequestering resin, colestipol, have been compared in normal subjects and in patients with four types of hyperlipoproteinaemia.Very low density lipoprotein (VLDL) lipids increased in every subject. The increase was greatest in patients with type IV or type V hyperlipoproteinaemia, least in normal subjects and in those with type IIa hyperlipoproteinaemia, and intermediate in patients with type IIb hyperlipoproteinaemia. The induced increments in VLDL cholesterol and triglyceride mass were accordingly positively correlated with the pre‐treatment concentrations. Low density lipoprotein (LDL) lipids decreased during resin therapy in all subjects, except those with type IV or type V hyperlipoproteinaemia in whom there was a transient rise. The reductions in LDL cholesterol were significantly greater in patients with type II hyperlipoproteinaemia than in the normal volunteers, and in both groups of subjects were proportionately greater than those in LDL triglyceride.These findings demonstrate clear differences among the hyperlipoproteinaemias in the response of lipoprotein lipids to resin therapy, and provide further evidence for the heterogeneity of cholesterol metabolism in these conditions. The colestipol‐induced changes in type IV and type V patients could be partially reproduced in normal subjects during the consumption of high carbohydrate diets, which might expected to increase VLDL synthesis. It is suggested, therefore, that the synthesis of VLDL cholesterol may be enhanced in such patients, and that any rise in LDL cholesterol observed during resin therapy reflected subsequent metabolism of VLDL to LDL rather than diminished LDL cholesterol clearance.

Effect of cholestyramine on tissue pools of cholesterol a preliminary report.

Four Type II Hyperlipoproteinemic subjects were investigated before and after treatment with cholestyramine. Plasma cholesterol was significantly reduced (365 plus or minus 23 vs 273 plus or minus 34 mg/100 ml) and triglycerides significantly increased (149 plus or minus 55 vs 181 plus or minus 59 mg/100 ml) on cholestyramine treatment. The daily turnover of cholesterol, as determined by the method of Goodman and Nobel, was nearly doubled by the treatment (0.813 plus or minus 0.11 vs 1.595 plus or minus 0.176 g). Although previous workers have already suggested that cholestyramine does not decrease tissue cholesterol pools, we observed a significant increase in tissue pools in each of the three subjects given cholestyramine alone (10.1 plus or minus 1.4 vs 16.2 plus or minus 6.9 g) for Pool A - EXCLUDING PLASMA; AND 27.2 PLUS OR MINUS 4.6 VS 43.7 PLUS OR MINUS 6.4 G FOR Pool B). Treatment for the fourth subject consisted of a combination of cholestyramine and clofibrate. This combination appeared to prevent increases in the size of Pool B and in the size and production rate of Pool A. These preliminary observations suggest that the hypocholesterolemic effect of cholestyramine may be enhanced and its effects on tissue cholesterol prevented by giving it in combination with other agents such as clofibrate.

The use of nitroblue tetrazolium prestaining of serum lipoproteins on polyacrylamide disc electrophoresis

The use of Nitroblue tetrazolium as a prestain for the separation of serum lipoproteins by polyacrylamide disc electrophoresis is described. The lipoprotein patterns in the sera of 50 normal and 9 hyperlipoproteinaemic subjects were studied. The major lipoprotein bands were clearly visible, and additional α- and β3-lipoprotein bands were demonstrated.

Assay of total plasma apolipoprotein B concentration in human subjects.

We have developed a double antibody radioimmunoassay (RIA) for human apolipoprotein B (ApoB). The assay measures not only the ApoB content of beta-lipoproteins (low density lipoproteins [LDL]) but also that contained in the other lipoproteins in plasma. Purified lymph and plasma chylomicrons and plasma very low density lipoproteins (VLDL) produced displacement curves in the assay system which paralleled those produced by pure LDL. Thus, the ApoB found in chylomicrons, VLDL, and LDL were immunologically identical. ApoB accounted for about 25 and 35%, respectively, of the total protein of chylomicrons and VLDL by RIA. VLDL and LDL preparations from normal and hyperlipoproteinemic subjects also produced parallel displacement curves, suggesting that the ApoB of normal and hyperlipoproteinemic subjects were immunologically identical. High density lipoproteins and abetalipoproteinemic plasma displaced no counts, nor did the sera of several animal species produce any useful displacement curves in this system. The fasting total plasma ApoB concentration of normal subjects was 83+/-16 mg/dl (mean+/-SD). ApoB levels were high in Type II (162+/-16), and less so in Type IV (112+/-24) and Type V (105+/-17).When plasma ApoB concentration in Type IV patients was graphed against plasma glycerides, two subpopulations, which may represent different genetic or biochemical subgroups, were apparent.ApoB concentration in individuals on constant diet and drug regimen was stable over weeks to months. Greater than 90% of ApoB of normal and Type II subjects was in the d > 1.006 plasma fraction. By contrast, only 50-80% of ApoB was in the d > 1.006 fraction in Types IV and V. Thus, hypertriglyceridemia was associated primarily with a redistribution of ApoB to the lighter density fractions; by contrast, in hypercholesterolemia absolute ApoB concentration was markedly increased.

Effects of weight reduction on obesity. Studies of lipid and carbohydrate metabolism in normal and hyperlipoproteinemic subjects.

Considerable controversy exists over the purported role of obesity in causing hyperglycemia, hyperlipemia, hyperinsulinemia, and insulin resistance; and the potential beneficial effects of weight reduction remain incompletely defined. Hypertriglyceridemia is one of the metabolic abnormalities proposed to accompany obesity, and in order to help explain the mechanisms leading to this abnormality we have proposed the following sequential hypothesis: insulin resistance --> hyperinsulinemia --> accelerated hepatic triglyceride(TG) production --> elevated plasma TG concentrations. To test this hypothesis and to gain insight into both the possible role of obesity in causing the above metabolic abnormalities and the potential benefit of weight reduction we studied the effects of weight loss on various aspects of carbohydrate and lipid metabolism in a group of 36 normal and hyperlipoproteinemic subjects. Only weak to absent correlations (r = 0.03 - 0.46) were noted between obesity and the metabolic variables measured. This points out that in our study group obesity cannot be the sole, or even the major, cause of these abnormalities in the first place. Further, we have observed marked decreases after weight reduction in fasting plasma TG (mean value: pre-weight reduction, 319 mg/100 ml; post-weight reduction, 180 mg/100 ml) and cholesterol (mean values: pre-weight reduction, 282 mg/100 ml; post-weight reduction, 223 mg/100 ml) levels, with a direct relationship between the magnitude of the fall in plasma lipid values and the height of the initial plasma TG level. We have also noted significant decreases after weight reduction in the insulin and glucose responses during the oral glucose tolerance test (37% decrease and 12% decrease, respectively). Insulin and glucose responses to liquid food before and after weight reduction were also measured and the overall post-weight reduction decrease in insulin response was 48% while the glucose response was relatively unchanged. In a subgroup of patients we studied both the degree of cellular insulin resistance and the rate of hepatic very low density (VLDL) TG production before and after weight reduction. These subjects demonstrated significant decreases after weight reduction in both degree of insulin resistance (33% decrease) and VLDL-TG production rates (40% decrease). Thus, weight reduction has lowered each of the antecedent variables (insulin resistance, hyperinsulinemia, and VLDL-TG production) that according to the above hypothesis lead to hypertriglyceridemia, and we believe the overall scheme is greatly strengthened. Furthermore, the consistent decreases in plasma TG and cholesterol levels seen in all subjects lead us to conclude that weight reduction is an important therapeutic modality for patients with endogenous hypertriglyceridemia.