Showing papers by "Scott M. Grundy published in 1985"

Hyperglycaemia as an inducer as well as a consequence of impaired islet cell function and insulin resistance: implications for the management of diabetes.

Abstract: It is postulated that hyperglycaemia influences the natural history of Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes mellitus. Hyperglycaemia, even when mild, can attenuate the secretory response of pancreatic β and α cells to increments in glucose and can impair insulin-mediated glucose transport, thus impeding its own correction and initiating a cycle of progressive self-exacerbation and metabolic deterioration. Both reduced islet function and insulin action may be the consequence of a generalized down-regulation and/or occupation of glucose transporters by hyperglycaemia so that the islets respond less to further increments in glycaemia. The postulated hyperglycaemic cycle can be initiated by any environmental perturbation that increases insulin demand in previously normoglycaemic patients in whom insulin secretion has already reached a maximum level of compensation for peripheral insulin resistance (as in obese pre-Type 2 diabetes) or for a reduced β-cell mass (as in pre-Type 1 diabetes). Elimination of hyperglycaemia by any means can halt this cycle of progressive metabolic deterioration and may restore transiently metabolic recompensation both in Type 1 and Type 2 diabetes. There is experimental evidence that long-standing severe hyperglycaemia may irreversibly damage β cells.

Influence of obesity on the metabolism of apolipoprotein B in humans.

Abstract: The influence of obesity on the metabolism of apolipoprotein B (apo B) in very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), and low density lipoprotein (LDL) was investigated in nine obese and seven nonobese Pima Indian men. Kinetics of VLDL-apo B (VLDL-B), VLDL-triglycerides, IDL-B and LDL-B were studied after injection of autologous 131I-VLDL, [3H]glycerol, and autologous 125I-LDL. Specific activities were measured in apo B isolated from all lipoprotein fractions and in triglyceride isolated from VLDL. Transport rates and fractional catabolic rates for apo B in VLDL, IDL, and LDL and triglyceride in VLDL were determined by multicompartmental analysis. This method also allowed the estimation of rates of interconversions of the lipoproteins. The two groups had similar mean ages and heights, but the obese group had a higher total body weight (131 +/- 14 vs. 66 +/- 3 kg +/- SEM) and fat free mass (81 +/- 5 vs. 54 +/- 2 kg) than lean controls. Plasma total lipids were similar for the two groups, and apo B concentrations in VLDL, IDL, and LDL were similar in obese and lean subjects. In spite of similarity in concentrations, obese subjects compared to lean subjects had higher synthetic rates of VLDL-triglyceride (62.6 +/- 15 vs. 26.2 +/- 7 g/d, P less than 0.01), VLDL-B (2,241 +/- 215 vs. 1,113 +/- 72 mg/d, P less than 0.001), and LDL-B (1,234 +/- 87 vs. 802 +/- 83 mg/d, P less than 0.01). Furthermore, in obese subjects, significantly higher amounts of VLDL-B were removed from the circulation without conversion to LDL-B (1,078 +/- 159 vs. 460 +/- 34 mg/d, P less than 0.05), and obese subjects had a higher fractional catabolic rate for LDL than the lean controls (0.48 +/- 0.02 vs. 0.41 +/- 0.02 d-1, P less than 0.05). The rapid catabolism of LDL and increased metabolism of VLDL without conversion to LDL in obese individuals may be mechanisms for maintenance of LDL at normal levels despite the overproduction of its precursor.

Comparisons of metabolism of apolipoprotein B in normal subjects, obese patients, and patients with coronary heart disease.

Abstract: This study was designed to examine the integrated metabolism of apolipoprotein B (apo B) in very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), and low density lipoproteins (LDL) in normal subjects, obese patients, and a group of patients with coronary heart disease (CHD) Turnover rates of 131I-VLDL-B, 131I-IDL-B, 125I-LDL-B, and [3H]VLDL-triglycerides (TG) were determined by the multicompartmental analysis that used the model described in the preceding article (Beltz, WF, et al 1985 J Clin Invest 76: 575-585) Compared with five normal subjects, four obese subjects had increased synthesis rates of both VLDL-B and VLDL-TG Production of LDL-B was inconsistently raised in these same patients Five patients with CHD had enhanced production of both VLDL-B and LDL-B, but secretion rates of VLDL-TG were not increased Thus, in patients with obesity and in those with CHD, synthesis rates of VLDL particles may be abnormally high In the obese patients, the VLDL appeared to be of normal composition, but in patients with CHD, the VLDL were relatively poor in TG The study also showed that a significant fraction of VLDL-B is removed directly from the circulation and never reaches LDL regardless of the type of patients The fraction that does reach LDL is one factor that determines LDL concentrations

Influence of Combined Therapy with Mevinolin and Interruption of Bile-Acid Reabsorption on Low Density Lipoproteins in Heterozygous Familial Hypercholesterolemia

Abstract: Patients with heterozygous familial hypercholesterolemia have a 50% deficiency of receptors for plasma low density lipoproteins (LDL) that induces a marked increase in plasma LDL levels. T...

Kinetic mechanisms determining variability in low density lipoprotein levels and rise with age

Abstract: Levels of plasma low density lipoproteins (LDL) vary among individuals at any given age and frequently rise with increasing age. Both production rates and fractional clearance rates (FCRs) of LDL theoretically could affect the plasma levels of LDL. To evaluate the relative importance of these two factors, turnover rates of LDL apoprotein (apoLDL) were determined in two groups: 19 young adult men aged 23 to 29 years and 15 middle-aged men aged 40 to 60 years. Results were compared to a group of six healthy young adults (aged 22 to 28 years) who we previously studied and who were on a cholesterol-lowering diet. In both groups in the current study, a diet resembling the average American diet was consumed, and LDL levels ranged from low-to-high normal. On average, the 19 young adult men had lower levels of total cholesterol and LDL cholesterol than did the middle-aged men. The younger men also had significantly higher FCRs and lower production rates of apoLDL. When data from all subjects were pooled, apoLDL levels were negatively and significantly correlated with FCRs and positively and significantly correlated with production rates. Similar relations were found with LDL cholesterol levels. These results show that both FCRs and production rates of apoLDL are important regulators of plasma LDL levels; the correlation suggests that the FCR is more influential at lower LDL concentrations, and that production rates are more influential at higher LDL concentrations.

Development of an integrated model for analysis of the kinetics of apolipoprotein B in plasma very low density lipoproteins, intermediate density lipoproteins, and low density lipoproteins

Abstract: To quantify more precisely the metabolism of apolipoprotein B (apo B) in human beings, an integrated model was developed for the analysis of the isotope kinetics of apo B in very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), and low density lipoproteins (LDL). The experimental basis for model development was a series of 30 triple-isotope studies in which patients received autologous 131I-VLDL, 125I-IDL, and [3H]glycerol as a precursor of VLDL triglycerides. The currently proposed model contains the following components: (a) a VLDL delipidation cascade that has a variable number of subcompartments, (b) a slowly catabolized pool of VLDL, (c) an IDL compartment consisting of two closely connected subcompartments, one of which is outside the immediate circulation, and (d) a two-compartment subsystem for LDL. Because mass data indicate that not all VLDL were converted to LDL, the model allows for irreversible removal of apo B from VLDL (or IDL) subsystems. It accounts for apparent "direct" input of LDL by postulating an early, rapidly metabolized compartment of VLDL that is converted directly to IDL. The model appears to be consistent with specific activity curves from the current triple-isotope studies and with present concepts of lipoprotein physiology; it also can be used to quantify pathways of lipoprotein apo B transport in normal and abnormal states.

Gemfibrozil therapy in primary hypertriglyceridemia associated with coronary heart disease. Effects on metabolism of low-density lipoproteins.

Abstract: Certain primary hypertriglyceridemias cause abnormalities in lipoproteins that seemingly predispose patients to coronary heart disease. We examined metabolism of low-density lipoproteins (LDL) in 11 men with both hypertriglyceridemia and coronary heart disease and compared them with that of controls. The LDL turnover was measured during placebo and gemfibrozil therapy. With placebo, LDL-cholesterol level usually was normal, but production and fractional clearance of LDL were high. The LDL composition also was abnormal. Gemfibrozil reduced triglycerides, lowered production and fractional clearance of LDL, and normalized LDL composition. The LDL-cholesterol level usually rose, but generally not to abnormally high levels. Therefore, normalization of LDL metabolism and marked reduction of triglycerides by gemfibrozil suggest benefit to hypertriglyceridemic patients who are at high risk for coronary heart disease. However, when LDL-cholesterol level rises excessively, gemfibrozil may not be sufficient therapy.

Correction of hyperglycemia with phloridzin restores the glucagon response to glucose in insulin-deficient dogs: implications for human diabetes.

Abstract: In insulin-deprived alloxan-induced diabetic dogs with severe hyperglycemia and marked hyperglucagonemia, glucagon was not suppressed by intravenous infusion of glucose at a progressively increasing rate up to 24 mg/kg of body weight per min. However, when the hyperglycemia was corrected by phloridzin, a blocker of renal tubular glucose reabsorption, the hyperglucagonemia was readily suppressed by as little as 2 mg of glucose per kg/min. Direct perfusion of phloridzin into the isolated pancreas of nondiabetic dogs had no effect on the in vitro glucagon response to increments in glucose. However, in pancreata isolated from dogs whose glucose levels had been lowered by phloridzin pretreatment, in vitro glucagon suppression in response to glucose increments was more than twice that of controls. This enhancing effect of phloridzin treatment was completely abolished by giving an intravenous infusion of glucose for the 5 hr prior to surgery for isolation of the pancreas. It is concluded that (i) alpha cells have a glucose-sensing system that is independent of insulin and beta cells, and (ii) this system is reversibly attenuated by hyperglycemia. Thus, hyperglycemia, a metabolic consequence of islet cell dysfunction, may be a self-exacerbating inducer of further islet cell dysfunction, a possibility with implications for human diabetes.

Impaired catabolism of very low-density lipoprotein-triglyceride in a family with primary hypertriglyceridemia

Abstract: In this report, kinetic studies of plasma very low-density lipoprotein-triglyceride (VLDL-TG) were examined in five brothers (three affected and two unaffected) from a family with primary hypertriglyceridemia. Synthesis and catabolism of VLDL-TG were studied by in vivo labelling of plasma TG with 3 H-glycerol, and multicompartmental analysis of the plasma die-away curves. Results of the kinetic studies revealed the following information: (1) one brother, who had the highest plasma TG level and was obese, had both overproduction and a reduced fractional catabolic rate (FCR) of VLDL-TG; (2) second brother, who had moderate hypertriglyceridemia, had a low FCR and high-normal synthesis of VLDL-TG; (3) a third, who had only mildly elevated TG, had a low FCR and normal synthesis of VLDL-TG; and (4) the two normolipidemic brothers had neither overproduction nor decreased FCR of VLDL-TG. The composition of the soluble apoproteins of VLDL was normal. The apoprotein E phenotypes were E4 3 in four brothers, and E3 2 in the fifth. We have reached the following conclusions regarding this family: (1) the common kinetic abnormality of VLDL-TG metabolism in the hypertriglyceridemic brothers was a low clearance of VLDL-TG; (2) impaired catabolism of VLDL could not be explained by the apoprotein C or E patterns; and (3) the most severe hypertriglyceridemia occurred when the decreased FCR was present in conjunction with VLDL-TG overproduction due to obesity. Thus, a moderate defect in catabolism of plasma TG appears to be responsible for one familial form of primary hypertriglyceridemia.

NIH report on research challenges in nutrition and hypertension.

Abstract: O delineate the role of nutrition in the regulation of blood pressure and the pathogenesis of hypertension, the National Heart, Lung, and Blood Institute in conjunction with the National Institute on Aging and the National Institutes of Health Nutrition Coordinating Committee, sponsored a Workshop on Nutrition and Hypertension in Bethesda, Maryland, on March 12 to 14, 1984. The purpose of the workshop was to identify the research needed to strengthen the understanding of the relationships between nutrition, blood pressure regulation, and hypertension. This research is important for two reasons: first, there is still an enormous amount of knowledge to be gained about the pathogenesis of hypertension, and any insights that can be derived about nutritional influences are highly desirable. Second, because the majority of patients with elevated blood pressure fall in the borderline and mild hypertensive categories, there is a need to support research on nonpharmacological strategies for management of these patients, in particular, nutritional interventions. The format of the workshop consisted of two major activities: position papers on selected dietary nutrients that may influence blood pressure and working group sessions devoted to the specification of research objectives. In addition to touching on an overview of hypertension and nutrition research methods, the position papers expounded on the roles of sodium and other electrolytes; caloric intake and obesity; dietary proteins, amino acids, carbohydrates, alcohol, and trace metals; and dietary fats and prostaglandins. Nutritional considerations of special populations, including the young and the elderly,

Comparison of clofibrate and caloric restriction on kinetics of very low density lipoprotein triglycerides.

Abstract: This study of 12 patients with mild-to-moderate hypertriglyceridemia compares the mechanisms of triglyceride (TG) lowering by caloric restriction and by clofibrate. Turnover rates of very low density lipoprotein triglycerides (VLDL-TG) were determined by using 3H-glycerol as a precursor. Radioactivity-time curves of VLDL-TG were analyzed with a multicompartmental model. Hypertriglyceridemia in these patients was due mainly to overproduction of VLDL-TG. Clofibrate therapy for 1 month had a variable effect on VLDL-TG levels. A group of relatively poor responders to the drug had a mild increase in the fractional catabolic rate (FCR) of VLDL-TG, but no change in production rates. The remaining patients were relatively good responders; they had increased FCR and modest reductions in synthetic rates of VLDL-TG. However, clofibrate largely failed to correct the primary defect in this group of patients, namely, the overproduction of VLDL-TG. Almost all patients responded to 1 month of caloric restriction (1000 cal/day) with marked reductions in VLDL-TG levels. The major response to reduced caloric intake was a decrease in production of VLDL-TG, although FCR was also increased to some extent. Despite these differences in mechanisms for VLDL-TG lowering, both regimens tended to raise levels of LDL and HDL.

Kinetic Analysis of Lipoproteins-Reply

Abstract: In Reply.— The multicompartmental analysis of isotope kinetic curves of VLDL TGs, according to the method of Zech et al, 1 provides a value for FCR of VLDL TG. The transport rate (production rate) of VLDL TG is obtained by multiplying the FCR by the total plasma pool of VLDL TG. All interpretations about pathogenic mechanisms must be based on the FCR and transport rate of VLDL TG. We observed that patients with type 5 HLP had very low FCR of VLDL TG and a very high transport rate. They consequently had very high plasma levels of VLDL TG. Another group of patients with less severe hypertriglyceridemia (type 4 HLP) had a very high transport rate of VLDL TG and a relatively normal FCR. These individuals were called "overproducers" of VLDL TG. Another group with type 4 HLP had very low FCRs and normal transport rates. They were said to