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Of 98 adult-onset diabetic patients selected at random from an ambulatory clinic, 37.8 per cent were found to have hyperlipidemia. In follow-up examination of the hyperlipidemic patients, 23 per cent had hyper-β-lipoproteinemia (Type II), 58 per cent had hyper-pre-β-lipoproteinemia (Type IV), 13 per cent had increased plasma β-and pre-β-lipoproteins (combined type) and 6 per cent had reverted to normal values. Type IV patients, as a group, were distinguished by greater hyperglycemia and relative body weight. Chylomicronemia was not observed in this study group. Hyperlipoproteinemia was frequent in this adult-onset diabetic population and differed in several respects from similar data in untreated juvenile-onset diabetes reported by others.

The mechanism responsible for the accumulation of chylomicrons in mixed hyperlipoproteinemia (Type 5) is not known. Assays of the plasma-clearing factor, lipoprotein lipase, with artificially prepared substrates have been normal or only mildly depressed in this condition. The recent report of a patient in whom there was marked depression of activity against native chylomicrons despite normal activity against an artificial substrate suggested, however, that there might exist a qualitative defect in the function of lipoprotein lipase undisclosed by assays with the artificial substrate in general use. Accordingly, the lipolytic activity of post-heparin plasma from five diabetic patients with mixed hyperlipoproteinemia was measured against two artificial substrates and two preparations of human chylomicrons. There was good correlation between activity against coconut oil and each of the three other substrates over a wide range of plasma glyceride concentrations and post-heparin lipolytic activities. The data support the conclusion that plasma post-heparin lipolytic activity in diabetic patients with mixed hyperlipoproteinemia is qualitatively normal.

The plasma post-heparin lipolytic activity (PHLA) and post-heparin monoglyceridase activity (PHMA) were determined in patients with Graves's disease and treated toxic nodular goiter. Both enzymes were markedly reduced in patients with active Graves's disease. Fasting serum triglycerides were normal or slightly below normal despite low post-heparin lipases. In these patients, restudied after propranolol therapy or within six months of euthyroid control with 131l, propylthiouracil or methimazole, PHLA and PHMA remained below normal. A separate group of patients with treated Graves's disease, who were euthyroid for as long as six years, also had low post-heparin lipases. Enzyme activity did not correlate with the presence of the long acting thyroid stimulator. In contrast, patients with treated toxic nodular goiter had normal PHLA and PHMA. Control subjects made hypermetabolic with tri-iodothyronine or thyroxine had normal post-heparin enzyme activities. Persistently low PHLA and PHMA may be a marke...

The influence of clofibrate on cholesterol metabolism in patients with hyperlipidemia was studied by means of sterol balance and isotope kinetic techniques and by measurements of flow rates of cholesterol through the biliary tract. Long-term balance studies were carried out on a metabolic ward in 24 patients with all currently recognized types of hyperlipidemia; in five other patients with hypercholesterolemia, pool sizes and turnover rates of cholesterol were defined by compartmental analysis before and after three years' daily administration of the drug. Except in fat-induced hypertriglyceridemia (two patients), clofibrate caused reduced plasma levels of triglycerides and cholesterol in all categories of hyperlipidemia. As a general rule, excretion of cholesterol into bile and feces was significantly increased and fecal bile acid excretion was decreased, regardless of the type of lipoprotein abnormality. Despite a net increase in steroid excretion in most patients with hyperlipidemia, cholesterol synthesis was not increased; indeed, in many patients synthesis appeared to be decreased. While the data obtained in 29 patients were not always consistent, the bulk of the evidence suggests that, in all forms of hyperlipidemia except fat-induced hyperglyceridemia, the drug causes an increased output of cholesterol while simultaneously inhibiting any compensatory increase in cholesterol synthesis. Therefore, it appeared that the increased excretion of steroids was most likely derived from cholesterol stored in tissues. This conclusion was strengthened by finding that long-term administration of the drug can cause marked reduction in body pools of cholesterol. These findings are reflected clinically by resolution of skin and tendon xanthomatosis. However, it is not yet known whether the accumulation of cholesterol in arterial walls that is part of the process of atherogenesis can be inhibited or reversed by the drug.

An experiment was undertaken to test whether in severe obesity cholesterol production rates obtained by isotope kinetic analysis (two-pool compartmental analysis) are comparable to those measured by chemical sterol balance techniques. Eight severely obese but normocholesterolemic patients were studied by the balance method, and five of these eight were studied by compartmental analysis. Cholesterol turnover was 10% higher by compartmental analysis. In the entire group of eight patients cholesterol turnover was greater than twice that found previously in nonobese patients studied under similar conditions with bile acids and neutral sterols both participating in the increase. This increment was directly related to excess body fat and to adipose cellularity, with correlation co-efficients of 0.66 and 0.72, respectively. The amount of cholesterol in the slowly turning over pool B was related to degree of adiposity, but that in plasma and in pool A did not differ from values in nonobese patients.

Adipocyte triglyceride, cholesterol, and tocopherol contents were examined in three human obese subjects, all over 150% of ideal weight, who were placed on weight reduction formula diets for 11, 21, and 25 wk, respectively. Body weight decreased from 77 to 63 kg, 188 to 147 kg, and 147 to 99 kg, respectively. All subjects had normal serum cholesterol and triglyceride levels, and these did not vary greatly during weight reduction. Subcutaneous fat was obtained at frequent intervals by needle aspiration from the buttocks before and during weight reduction. Adipocyte size was measured by osmium tetroxide fixation technique, tissue cholesterol content by GLC, tissue triglyceride content by lipid extraction, and tissue tocopherol by thin-layer chroma- tography. Initial adipocyte size was 0.54, 1.06, and 0.96 zg of lipid per cell, respectively (normal 0.60), and the mean cell size decrease during weight reduction was 40%, all due to triglyceride mobilization. Adipocyte cholesterol and tocopherol content did not change significantly during weight reduction. These data are consistent with the concepts that triglycerides but not cholesterol or tocopherol are mobilized from the fat cell during up to 6 months of weight reduction and that independent mechanisms control the efflux of these adipocyte constituents. Am J Clin Nutr 1983;37:749-754.

A method for measuring the rate of total daily cholesterol synthesis in man has been developed through isotope kinetic studies of squalene biosynthesis after intravenous administration of [14C]mevalonic acid. Plasma squalene becomes rapidly labeled, reaching maximal specific activity approximately 100 min after mevalonate administration and then decays exponentially to reach undetectable levels in 12 hr. The rate of daily squalene synthesis equals the percent dose of mevalonate converted to cholesterol divided by the area under the specific activity curve of squalene; the fraction of the dose of mevalonate converted to cholesterol is calculated by the simultaneous injection of [3H]- and [14C] cholesterol in plasma. The premise that squalene and cholesterol synthetic rates are equivalent was tested. In seven patients it was found that the mean daily cholesterol synthesis rates estimated simultaneously by sterol balance and by sqyalene kinetic methods agreed within 8%. In addition, fractional conversions of mevalonic acid to cholesterol were highly correlated with cholesterol synthesis rates. Maximum estimates of the pool sizes and half-lives of metabolically "active" squalene also were obtained. This measurement of daily cholesterol synthesis by squalene kinetics minimizes patient inconvenience, is suitable for outpatient studies, and yields results in 4 weeks or less. Because of the rapidity of the rate of squalene synthesis, the results obtained reflect cholesterol synthesis over a period of less than 10 hr and are therefore uniquely applicable to unsteady state situations.

The lipolytic effect of cyclic 3′, 5′-adenosine monophosphate (cAMP) is inhibited by the beta-adrenergic blocker propranolol. This is demonstrated on both isolated fat cells and intact epididymal fat pad preparations. A cell-free extract of either rat or human adipose tissue contains a lipase system which can be activated by cAMP. This activation is also prevented by propranolol as well as the alpha-adrenergic blocker, phentolamine, in a dose-related fashion. Because of this nonspecific action, pharmacologic differentiation of alpha- or beta-adrenergic receptor sites should be based upon direct measurements of cyclic nucleotide, adenyl cyclase or phosphodiesterase, and not target enzyme activity.

A 5-yr old male proband and his sister have had hypertriglyceridemia and hepatosplenomegaly since birth. When studied on a metabolic ward, they demonstrated rapid decreases in serum triglycerides on 3 g fat/day diets. Oral glucose tolerance tests were normal. Postheparin lipolytic activity (PHLA) against chylomicrons was virtually absent in both children whereas the mother and a normolipemic sister had levels approximately 50% normal. However, all four had a normal PHLA against commercial triglyceride emulsion (Intralipid). Two unrelated children from different kindreds of typical type 1 hyperlipoproteinemia and two patients with acquired type V hyperlipoproteinemia had deficient PHLA against both substrates. No inhibitors of PHLA could be demonstrated in the proband's plasma, and his own PHLA could not be enhanced by either normal concentrated plasma or pooled d > 1.063 lipoprotein fraction. The proband's postheparin plasma required almost 20 times the normal chylomicron-triglyceride concentration to reach one-half maximal lipase velocity. Both affected siblings showed heavy pre-beta lipoprotein electrophoretic bands plus chylomicrons in their fasting plasmas while ingesting a 33% carbohydrate, 30% fat diet. Incubation of their postheparin plasma with S(f) > 400 chylomicrons in vitro produced a smaller S(f) 20-400 "remnant" with pre-beta electrophoretic mobility that was not seen under the same conditions when normal postheparin plasma was used. Postheparin monoglyceridase and phospholipase activities were either normal or only moderately decreased when determined with appropriate artificial substrates. These data are consistent with either (a) a mutant gene producing a lipoprotein lipase with unusual substrate specificities or (b) an absolute deficiency of normal lipoprotein lipase with a compensatory increase in some other postheparin triglyceridase.

A 17-year-old girl with asymptomatic hyperlipemia was found to have a Type IV hyperpre-beta-lipoproteinemia. The diagnosis was established by measurement of fasting triglycerides and plasm...

SummaryProlonged fasting in man causes a significant decrease in post-heparin lipolytic and monoglyceridase activities. Activity is restored after refeeding. Plasma triglycerides declined in the face of diminished clearing factor lipase.

Hyperglycemic, nonketotic coma developed in an individual with a family background of diabetes mellitus who suffered severe second and third degree burns. Treating the patient with a formula high in carbohydrate content and covering the burned area with mafenide acetate, an ointment known to enhance the insensible water loss in burned patients, apparently precipitated the hyperosmolar state. Coma developed when the plasma glucose was 900 mg. per 100 ml., the plasma immunoreactive insulin 10 μU per ml. and free fatty acid level 655 μEq. per liter. A hereditary tendency for diabetes, high carbohydrate diets, dehydration and beta cell failure all have a role in the pathogenesis of hyperglycemic, nonketotic coma in the patient with burns.