Showing papers by "Scott M. Grundy published in 1982"

Plasma lipids and diabetes mellitus in an adult community

Abstract: Most previous studies of hyperlipidemia in diabetics are based on patients in specialty clinics or reflect an era when diabetics consumed a high-fat, low-carbohydrate diet. In this paper, data from a defined adult population aged 20-79 years in an upper middle class community in Southern California, 1972-1974, were used to ascertain the relationship of hyperlipidemia to diabetes in a current community-based population. All (n = 358) diabetics as defined by history and/or fasting hyperglycemia (fasting plasma glucose, greater than or equal to 140 mg/dl) were compared with all (n = 4387) nondiabetics defined as euglycemic (fasting plasma glucose, less than 110 mg/dl) with no personal or family history of diabetes. In both men and women 50 years of age and older, the mean cholesterol level and the prevelance of categorical hypercholesterolemia were not significantly different in diabetics vs. nondiabetics, whereas the mean triglyceride level and the prevalence of categorical hypertriglyceridemia were significantly higher in diabetics vs. nondiabetics. Case-control comparisons of 356 diabetics matched for age and obesity with 356 nondiabetics confirmed the significantly higher triglyceride levels in diabetes. Conversely, hypertriglyceridemia was associated with diabetes in 29 per cent of nonobese men and 25 per cent of obese men, and in 10 per cent of non-obese women and 21 per cent of obese women. The biologic mechanism of hypertriglyceridemia in diabetics is discussed.

Metabolism of Cholesterol and Plasma Triglycerides in Nonketotic Diabetes Mellitus

Abstract: The metabolism of cholesterol and plasma triglycerides (TG) was studied in 14 diabetic men: these patients did not have marked obesity nor did they develop ketoacidosis without insulin. Before insulin therapy, measurements were made of (1) plasma lipoproteins, (2) postheparin lipolytic enzymes, (3) turnover to TG in very-low-density lipoproteins (VLDL) and chylomicrons, (4) cholesterol balance, and (5) biliary lipids. After baseline measurements, the patients were treated with enough long-acting insulin to maintain their fasting plasma glucose in the range of 100–125 mg/dl. When plasma glucose and lipid levels reached a new steady state, all of the above measurements were repeated. Before insulin, most patients had fasting hypertriglyceridemia. This was due mainly to overproduction of VLDL-TG. Insulin therapy lowered both synthesis and concentrations of VLDLTG to near normal. Also, patients with normotriglyceridemia, both before and during insulin therapy, had essentially normal clearance of chylomicrons. Those with high fasting TG had delayed clearance of chylomicrons, but clearance returned to normal in most with insulin therapy. Postheparin lipolytic enzymes were not decreased. Before insulin, synthesis rates of cholesterol and bile acids usually were greater than normal, and bile commonly was supersaturated with cholesterol. During insulin therapy, synthesis of both cholesterol and bile acids remained elevated, possibly because of imperfect control of hyperglycemia. Furthermore, saturation of bile with cholesterol was accentuated by insulin therapy.

Rationale of the diet-heart statement of the American heart association. Report of the AHA nutrition committee

Abstract: A fundamental goal of the American Heart Association (AHA) is to prevent cardiovascular disease and, in particular, to reduce the incidence of coronary heart disease (CHD) and other atherosclerotic diseases in our society. A question of great concern to the AHA has been whether the American diet is a significant factor in the genesis of atherosclerosis. This question has been the subject of continuous dialogue within the Association for at least 25 years. Although many and frequently diverse opinions have been voiced within the several committees of the AHA, a concerted effort has been made to integrate the best available evidence on the subject. It is clear that the "diet-heart question" is complex, and new information is emerging continually. Still, a broad base of knowledge has been accrued, and because of the urgency engendered by the high incidence of CHD in the U.S., the AHA has felt a responsibility to provide the best possible guidance to the medical community and the American public on the diet question. For this reason the policy of the AHA has been to frequently update recommendations on the basis of the best currently available evidence. The rationale and documentation for particular recommendations of the AHA are discussed below.

Effects of interruption of the enterohepatic circulation of bile acids on the transport of very low density-lipoprotein triglycerides

Abstract: An increase in plasma very low density lipoprotein-triglycerides (VLDL-TG) is seen frequently during treatment with bile acid-binding resins. The purpose of this study was to determine whether this increment in VLDL-TG is due mainly to an increase in synthesis of VLDL, or to an enhanced catabolism. Three types of patients were studied: (1) 7 normotriglyceridemic subjects. (2) 4 obese patients, and (3) 9 hypertriglyceridemic patients. Before treatment they underwent a study of VLDL-TG kinetics that employed multicompartmental analysis of specific activity curves following injection of 3H-glycerol. The patients were then treated with a bile acid-binding resin, either cholestyramine or colestipol, for several weeks to several months. At the end of the treatment period, they were readmitted to the hospital for a second study of VLDL-TG kinetics. The patients showed a variable response to resin therapy. Many had an increase in concentrations of VLDL-TG, but others had no change or even a slight decrease. However, analysis of the data showed a high correlation between change in production rates of VLDL-TG and change in concentration. Also, when the data for the 20 patients were combined, there was a statistically significant increase in both synthetic rates and concentrations of VLDL-TG; in contrast, the fractional catabolic rate (FCR) was unchanged by therapy. Therefore, our data show that when treatment with bile acid sequestrants causes an increase in plasma VLDL-TG, the increase is due to an increment in production and not to a decrease in catabolism.

Pregnancy-associated Hypertriglyceridemia in Normal and Diabetic Women: Differences in Insulin-dependent, Non-insulin-dependent, and Gestational Diabetes

Abstract: In this study longitudinal observations of plasma lipo-proteins were made in pregnant diabetic women classified according to the National Diabetes Data Group. Sequential measurements at second trimester (25–27 wk), third trimester (34–37 wk), and 3 mo postpartum (control period) were carried out in 18 diabetic and 6 normal women. In 15 diabetic and 4 normal women from this group, 24-h plasma glucose, serum C-peptide levels, and HbA 1c concentrations were measured. Another group of 15 normal and 18 diabetic women underwent determinations of fasting plasma lipoproteine and other parameters at one or more of the test periods. Insulin-dependent diabetic patients (IDDM, type I) as a group did not differ from normal controls in mean plasma levels of total cholesterol (CHOL), triglyceride (TG), very-low-density lipoprotein triglyceride (VLDL TG), low-density lipoprotein cholesterol (LDL CHOL), high-density lipoprotein cholesterol (HDL CHOL), or ratios of TG:CHOL in LDL or HDL during mid or late pregnancy or 3 mo postpartum. In marked contrast, non-insulin-dependent diabetics (NIDDM, type II) had significantly higher total fasting TG at second trimester (P These results indicate that women with IDDM diabetes do not differ from normal women with respect to pregnancy-associated changes in lipid metabolism. On the other hand, women with NIDDM and GDM exhibit a pregnancy-associated hypertriglyceridemia.

Significance of low density lipoprotein production in the regulations of plasma cholesterol level in man.

Abstract: To determine whether production or catabolism of low density lipoprotein (LDL) is the major factor controlling LDL concentrations in subjects with plasma cholesterol levels from low-normal to mildly elevated, measurements of apoprotein of LDL (apoLDL) turnover were performed in 16 patients with various plasma cholesterol concentrations. Cholesterol balance studies were done simultaneously in 13 of these patients. Plasma concentrations of apoLDL and LDL-cholesterol were positively correlated with synthetic rates of apoLDL (r = 0.74, P less than 0.001; r = 0.50, P less than 0.05, respectively). No correlation was noted between the fractional catabolic rate for apoLDL and apoLDL levels (or LDL-cholesterol). For further analysis, the patients were divided into three groups with stepwise increases in apoLDL concentrations. When apoLDL levels rose significantly, from 83 +/- 5 SEM to 122 +/- 2 to 149 +/- 5 mg/dl, synthetic rates for apoLDL also increased significantly from 11.6 +/- 12. to 17.0 +/- 0.9 to 23.8 +/- 1.8 mg/d/kg ideal weight. In contrast, the fractional catabolic rate of apoLDL was not different among the three groups (0.32 +/- 0.03 vs. 0.29 +/- 0.02 vs. 0.33 +/- 0.03/d). No relation was noted between synthesis of total body cholesterol (or bile acids) and concentrations, production rates, or removal of apoLDL. Thus, concentrations of apoLDL and LDL-cholesterol in these subjects with plasma cholesterol levels from low-normal to mildly elevated were regulated mainly by synthetic rates of apoLDL and not by LDL catabolism.

Rationale of the diet-heart statement of the american heart association: Report of nutrition committee

Abstract: A FUNDAMENTAL GOAL of the American Heart Association (AHA) is to prevent cardiovascular disease and, in particular, to reduce the incidence of coronary heart disease (CHD) and other atherosclerotic diseases in our society. A question of great concern to the AHA has been whether the American diet is a significant factor in the genesis of atherosclerosis. This question has been the subject of continuous dialogue within the Association for at least 25 years. Although many and frequently diverse opinions have been voiced within the several committees of the AHA, a concerted effort has been made to integrate the best available evidence on the subject. It is clear that the \"diet-heart question\" is complex, and new information is emerging continually. Still, a broad base of knowledge has been accrued, and because of the urgency engendered by the high incidence of CHD in the U.S., the AHA has felt a responsibility to provide the best possible guidance to the medical community and the American public on the diet question. For this reason the policy of the AHA has been to frequently update recommendations on the basis of the best currently available evidence. The rationale and documentation for particular recommendations of the AHA are discussed below.

Triglyceride and cholesterol metabolism in primary hypertriglyceridemia.

Abstract: To determine mechanisms of elevated plasma triglycerides (TG) in patients with primary hypertriglyceridemias, simultaneous studies were carried out on kinetics of very low density lipoprotein-triglycerides (VLDL-TG) and synthesis of cholesterol and bile acids. Sixteen hypertriglyceridemic patients with familial combined hyperlipidemia (FCHL) and 12 patients with poorly classified, primary hypertriglyceridemia were studied, and their results were compared to a series of normal and obese subjects previously studied in our laboratory. The mean value for transport (synthesis) of VLDL-TG in patients with FCHL was about twice normal. Although the upper normal synthesis rates overlapped with transport rates of some patients with FCHL, it appeared that the major cause of hypertriglyceridemia in FCHL was an elevated production of VLDL-TG. However, the height of the plasma TG in FCHL patients also was influenced by individual clearance capacities for VLDL-TG, and fractional clearance rates in several seemed particularly low. Synthesis rates for cholesterol and/or bile acids were high in several patients with FCHL, suggesting simultaneous overproduction of VLDL-TG and sterols; however, increased synthesis of both was not observed in all the patients. Most patients with poorly classified hypertriglyceridemia had over-production of VLDL-TG, but an apparent reduction in clearance was common. In these patients, increased synthesis of cholesterol and bile acids was infrequent. Our results indicate that abnormally high production of VLDL-TG seemed to be the major factor in causing primary hypertriglyceridemia, but that clearance capacity can play an important role in determining the the severity of the TG elevation.

Very low density lipoprotein metabolism in non-ketotic diabetes mellitus: Effect of dietary restriction

Abstract: We have measured the turnover of very low density lipoprotein (VLDL) triglyceride as well as plasma glucose, insulin and non-esterified fatty acid levels in nine mildly obese non-ketotic, insulinopenic diabetic subjects before and during an energy restricted diet. During the baseline period, subjects were hypertriglyceridaemic, hyperglycaemic and insulinopenic. During dietary restriction (mean weight loss: 2.3±0.4 kg) plasma triglyceride fell from 8.4±3.0 to 3.4±0.89 mmol/l (mean±SEM; p<0.05), and plasma glucose fell from 13.9 ±1.7 to 9.8±1.4 mmol/l (p<0.01). Neither fasting plasma insulin nor the insulin response to an oral glucose load changed. Plasma non-esterified fatty acid concentrations remained constant as well. During the baseline period, the transport rate of VLDL-triglyceride in the diabetic subjects was more than twice that in an age-weighted matched control group (27.4±2.9 versus 12.1±0.8 mg/kg ideal body weight per h). The fractional catabolic rates were similar in the two groups (0.20±0.05 versus 0.21±0.02/h). During energy restriction of the diabetic subjects, the VLDL-triglyceride transport rate fell to 17.4±2.9 mg/kg ideal body weight per h (p<0.05 versus baseline) while the fractional catabolic rate remained constant at 0.21±0.06/h (NS versus baseline). These data indicate that the major abnormality in triglyceride metabolism in these non-ketotic, insulinopenic diabetic patients was over-production of VLDL-triglyceride.

Effects of AOMA on cholesterol metabolism in man.

Abstract: A new cholesterol-lowering agent, surfomer (AOMA), has been developed that blocks cholesterol absorption and lowers plasma cholesterol in animals. To evaluate AOMA in man, we studied its effects on plasma cholesterol, cholesterol absorption, fecal excretion of cholesterol and its bacterial degradation products, coprostanol and coprostanone, and percent saturation of gallbladder bile with cholesterol in 20 individuals chosen for hyperlipidemia. These patients had low density lipoprotein cholesterol (LDL-C) of 215 ± 29 mg/dl. Two dose levels of AOMA were compared (10.8 and 5.4 grams daily), each for 1 mo in a study that combined features of inpatient and outpatient investigation. AOMA was tolerated well by all volunteers. There was a statistically significant correlation between percent absorption and LDL-C in both the control and AOMA treated states. AOMA lowered mean plasma cholesterol and LDL-C by 9.1% and 12.9% at the high dose and by 6.4% and 8.3% at the low dose, respectively. Triglyceride (control = 223 ± 58 mg/dl, treatment = 232 ± 85 mg/dl), high density lipoprotein cholesterol (HDL-C: control = 50 ± 11 mg/dl, treatment = 50 ± 13 mg/dl), and other lipoprotein lipids were not affected. AOMA lowered cholesterol absorption by 25% on the high dose. For 1820 patients there was a statistically significant (p < 0.001) correlation (r = 0.74) between percent LDL-C reduction and percent absorption inhibition. For these patients, presumably, variable effectiveness of the agent in inhibiting absorption was the most important predictor of individual responsiveness although individual variation in other cholesterol regulatory mechanisms also played a role. Two other patients showed marked LDL-C reduction at unusually low levels of absorption inhibition. We also had the opportunity to compare the effects of AOMA with neomycin in 8 volunteers. Neomycin was 50% more effective in lowering LDL-C than AOMA; however, it was twice as effective in inhibiting absorption as well. AOMA dramatically reduced fecal excretion of cholesterol bacterial conversion products; whereas cholesterol per se accounted for only 50% of total neutral steroid excretion in the control state, it accounted for 93% of steroid excretion when patients were administered 10.8 grams of AOMA daily. In four patients studied there was no adverse effect of AOMA on gallbladder saturation with cholesterol; in fact, the percent saturation tended to decrease with AOMA in these four patients.

Effects of haem infusion on biliary secretion of porphyrins, haem and bilirubin in man

Abstract: Employing a continuous bile collection, we measured the bile secretion of porphyrins, haem (iron protoporphyrin IX regardless of oxidation state) and bilirubin in five healthy subjects. The baseline values for the flow of porphyrins in the bile were: 4.7 +/- 1.9 nmol/h uroporphyrin, 27.3 +/- 3.8 nmol/h coproporphyrin and 39.2 +/- 11.7 nmol/h protoporphyrin. Bile haem flow was 59.7 +/- 12.6 nmol/h, and that of bilirubin 23.8 +/- 8.2 mumol/h. Following haem injection (6.4 mumol/kg) the flow of protoporphyrin but not of the other porphyrins was reduced, and the bile haem flow increased (232 +/- 109.5 nmol/h), while the flow of bilirubin did not increase significantly. A few patients with representative porphyrias showed the expected increase in copro- and protoporphyrin in the bile. The patient with coproporphyria exhibited a bile flow of coproporphyrin of 1470 +/- 133 nmol/h and of protoporphyrin of 334 +/- 29 nmol/h; haem infusion significantly reduced the bile flow of both porphyrins (to 649 +/- 101 for copro- and 215 +/- 36 nmol/for protoporphyrin). The patient with protoporphyria had an increased protoporphyrin flow, yet haem infusion caused no reduction in protoporphyrin flow (106 +/- 7 after v. 81.4 +/- 13 nmol/h before haem). In conclusion, we found that haem and porphyrins are normal constituents of bile, and that injected haem appears in bile. Bile bilirubin did not rise within 12 h after haem infusion a finding which warrants further investigation.

The Effect of Chenodeoxycholic Acid on Lipoproteins and Apolipoproteins

Abstract: Northwest Lipid Research Clinic, Harborview Medical Center and Department of Medicine, University of Washington School of Medicine, Seattle, Washington: Department of Medicine, Veterans Administration Medical Center and University of California at San Diego, La Jolla, California: The Biostatistics Center of the George Washington University, Bethesda, Maryland; Department of Medicine, Boston University, Boston, Massachusetts; Cedars-Sinai Medical Center and University of California School of Medicine, Los Angeles, California