John W. Farquhar

Role of Insulin in Endogenous Hypertriglyceridemia

Dietary carbohydrate accentuation of endogenous triglyceride production has been studied in 33 patients. A broad and relatively continuous spectrum of steady-state plasma triglyceride concentrations was produced in 31 of the 33 subjects during 3 wk of a high carbohydrate (fat-free) liquid formula diet. Two patients developed plasma triglyceride concentrations in excess of 2000 mg/100 ml, and these were the only patients we have studied in which carbohydrate induction of hypertriglyceridemia seemed to be associated with a defect in endogenous plasma triglyceride removal mechanisms. In the remaining 31 patients the degree of hypertriglyceridemia was highly correlated with the insulin response elicited by the ingestion of the high carbohydrate formula (P < 0.005). No significant correlation existed between fasting plasma triglyceride concentration and either plasma glucose or free fatty acid concentrations after the high carbohydrate diet, nor was the degree of hypertriglyceridemia related to degree of obesity. It is suggested that hypertriglyceridemia in most subjects results from an increase in hepatic triglyceride secretion rate secondary to exaggerated postprandial increases in plasma insulin concentration.

Reappraisal of the role of insulin in hypertriglyceridemia

Abstract We have previously proposed a sequential hypothesis to help explain the genesis of endogenous hypertriglyceridemia in man. This scheme states that insulin resistance → hyperinsulinemia → increased very low density lipoprotein (VLDL)-triglyceride (TG) production rate → increased plasma TG levels. In this study we have measured each of these metabolic variables in 34 nonobese subjects all consuming the same isocaloric diet. We have found highly significant positive correlations between insulin resistance and insulin response (r = 0.74, p

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.

Increased exercise level and plasma lipoprotein concentrations: A one-year, randomized, controlled study in sedentary, middle-aged men☆

Eighty-one sedentary but healthy men aged 30-55 participated in a 1 yr randomized study of the effects of exercise on plasma lipoprotein concentrations. Forty-eight were assigned to a running program, while 33 remained as sedentary controls (an approximately 3:2 ratio). After 1 yr the running group had become significantly fitter and leaner than the control group. Lipoprotein concentration changes in the runners (vs. controls) uniformly favored reduced risk of coronary heart disease, but were not significant when all 46 participants with complete data were included. However, the 25 men who averaged at least eight miles (12.9 kilometers) per wk of running increased their plasma high-density-lipoprotein (HDL) cholesterol level by 4.4 mg/dl (p = 0.045) and their HDL2 mass level by 33 mg/dl (p = 0.059), vs. controls. Significant correlations were found for distance run per wk vs. change in plasma HDL-cholesterol (r = 0.48), HDL2 (r = 0.41), and low-density-lipoprotein cholesterol (r = -0.31). Changes in percent body fat and in HDL-cholesterol were correlated (r = -0.47) in runners. There appears to be a threshold at about 8 miles per wk above which a 1-yr running program leads to beneficial lipoprotein changes.

The distribution of plasma lipoproteins in middle-aged male runners*†

Stimulated by increasing evidence of an inverse relationship between plasma high-density lipoprotein cholesterol level and frequency of coronary heart disease, we determined concentrations of fasting plasma cholesterol, triglyceride, and lipoproteins in 41 very active men (running greater than 15 miles/wk for the previous year) 35-59 years of age (mean age, 47) and in a comparison group of men of similar age, randomly selected from three northern California communities. The runners had significantly (p less than 0.05) decreased mean plasma triglyceride (70 versus 146 mg/100 ml), total plasma cholesterol (200 versus 210 mg/100 ml), and low-density lipoprotein (LDL) cholesterol (125 versus 139 mg/100 ml) concentrations, and a higher mean level of high-density lipoprotein (HDL) cholesterol (64 versus 43 mg/100 ml) than the comparison group (n equals 147 for HDL and LDL; n equals 743 for total cholesterol and triglycerides). These very active men exhibited a plasma lipoprotein profile resembling that of younger women rather tan of sedentary, middle-aged men. This characteristic, and apparently advantageous, pattern could be only partially accounted for by differences in adiposity between runners and control subjects.

Psychosocial predictors of physical activity in adolescents

Regular physical activity consistently demonstrates an inverse relationship with coronary heart disease and has positive effects on quality of life and other psychological variables. Despite the benefits of exercise, many youth and adults maintain a sedentary lifestyle. Interventions are needed, particularly with youth, to increase levels of physical activity. A better understanding of the psychosocial predictors of physical activity will aid in structuring these interventions. Longitudinal data from a cohort of 743 10th-grade students from the control condition of the Stanford Adolescent Heart Health Program were analyzed. Regression analysis indicated that psychosocial variables were significantly related to physical activity after controlling for baseline levels of physical activity and BMI. Associations with physical activity were found for intention to exercise, self-efficacy, stress, and direct social influence. The designers of future interventions should consider including program components that target these variables.

Relationship Between Fasting Plasma Insulin Level and Resistance to Insulin-Mediated Glucose Uptake in Normal and Diabetic Subjects

We have previously shown that a significant inverse correlation exists between the height of the plasma insulin concentration and the efficiency of glucose uptake in the fasting state. Subsequently, we devised an infusion technic that provides a more specific measure of cellular resistance to insulin mediated glucose uptake. We have used this technic to study the relationship between fasting plasma insulin level and resistance to insulin mediated glucose uptake in twenty-two patients with normal oral glucose tolerance, fourteen patients with impaired glucose tolerance, and fourteen patients classified as having chemical diabetes mellitus. The results indicate a highly significant positive correlation between the degree of insulin resistance and fasting plasma insulin concentration (r = .69, p < .0001). A positive correlation (r = .43, p < .005) was also found between the degree of insulin resistance and the two hour plasma glucose level during an oral glucose tolerance test. However, no significant correlation was found between per cent adiposity and fasting insulin level, and the relationship between insulin resistance and fasting insulin level appeared to be independent of obesity or any other known cause of decreased insulin responsiveness. These studies indicate that: (1) increases in fasting insulin levels and increase in resistance to insulin mediated glucose uptake are closely related, and that these changes can occur in the absence of any of the “known” causes of decreased insulin responsiveness; (2) in the types of subjects we have studied, deterioration of glucose tolerance is closely related to increases in insulin resistance; and (3) the increases in fasting insulin levels which we have observed appear to be compensatory attempts to overcome the resistance to glucose uptake.

The cost-effectiveness of three smoking cessation programs.

This study analyzed the cost-effectiveness and distribution of costs by program stage of three smoking cessation programs: a smoking cessation class; an incentive-based quit smoking contest; and a self-help quit smoking kit. The self-help program had the lowest total cost, lowest per cent quit rate, lowest time requirement for participants, and was the most cost-effective. The most effective program, the smoking cessation class, required the most time from participants, had the highest total cost, and was the least cost-effective. The smoking contest was in-between the other two programs in total costs, per cent quit rate, and cost-effectiveness; it required the same time commitment from participants as the self-help program. These findings are interpreted within the context of community-based intervention in which the argument is made that cost-effectiveness is only one of several factors that should determine the selection of smoking cessation programs.

The Effect of a Plant-Based Diet on Plasma Lipids in Hypercholesterolemic Adults: A Randomized Trial

Context People can achieve recommended fat intake while consuming high or low amounts of vegetables, fruits, legumes, and whole grains. Contribution This 4-week randomized trial compared 2 diets with different vegetable, fruit, legume, and whole-grain content but identical total fat, saturated fat, protein, carbohydrate, and cholesterol content. The 59 adults who consumed high amounts of vegetables, fruits, legumes, and whole grains had greater improvements in total and low-density lipoprotein cholesterol levels than the 61 adults who ate low amounts of these foods. Implications At least over the short term, greater improvements in low-density lipoprotein and total cholesterol are an additional benefit of diets high in vegetables, fruits, legumes, and whole grains. The Editors It is well established that elevated low-density lipoprotein (LDL) cholesterol concentrations are a risk factor for cardiovascular diseases and that dietary modification is considered a first approach to their treatment and control (1, 2). For several decades, dietary modification for lipid management traditionally focused on avoiding saturated fat and cholesterol (3-5). Previous examples of dietary interventions targeting LDL cholesterol level often reported only modest lipid improvements, leading some to consider diet a relatively ineffective therapy (6). However, recent developments have suggested that the traditional focus of lipid management may have been overly simplistic and that diets might be more effective if more attention was focused on including certain foods or factors rather than just avoiding saturated fat and cholesterol. Effective refinements of dietary strategies for lipid management could decrease the gap in effectiveness between dietary approaches and drug therapy. Several dietary factors or foods, including soy protein, soy isoflavones, plant sterols, soluble fiber, oats, nuts, and garlic, have established or potential lipid benefits (7-13). Each is derived from plant food sources, and it is inclusion of these factors, rather than avoidance, that is reported to confer benefits. However, given that most plant foods contain low or negligible amounts of saturated fat and that all plant foods are devoid of cholesterol, it follows that a plant-based diet is inherently low in saturated fat and cholesterol. Therefore, it is difficult to distinguish between plasma lipid benefits derived from the actual plant-based dietary components and those derived from avoidance of saturated fat and cholesterol. Several studies have been designed to test the effects on plasma lipids of diets with identical saturated fat and cholesterol intake but varied amounts of 1 or 2 additional dietary components (14-16). Data are more limited on dietary approaches that hold saturated fat and cholesterol intake constant while modifying multiple other dietary components simultaneously (17). Modifying multiple dietary components simultaneously (for example, increasing intake of vegetables, fruits, and low-fat dairy) while holding sodium intake constant has been shown to effectively lower elevated blood pressure in the Dietary Approaches to Stop Hypertension trials (DASH I and II) (18, 19). Testing a parallel approach to refining dietary intervention for lipid management is warranted. In 2000, the American Heart Association (AHA) reported revised dietary guidelines that substantially modified its 1993 and 1996 guidelines (2, 4, 5). All 3 versions of the guidelines recommended keeping saturated fat intake at less than 10% of energy and cholesterol intake below 300 mg/d. A notable modification of the 2000 guidelines was to emphasize foods and overall eating patterns, including increased intakes of vegetables and whole grains (in general, a plant-based diet). It was our hypothesis that a plant-based diet consistent with the revised AHA 2000 guidelines would increase the LDL cholesterol-lowering benefits of the previous AHA Step I guidelines. We theorized that this improvement would be independent of the plant-based diets saturated fat and cholesterol content. Therefore, we designed 2 diets that had identical levels of total fat (30% of energy), saturated fat (10% of energy), and cholesterol (<300 mg/d) but differed substantially in content of nutrient- and phytochemical-dense plant-based foods. The purpose of the study was to determine whether LDL cholesterol-lowering benefits among adults with moderately elevated cholesterol levels would be greater under weight-stable conditions with a plant-based low-fat diet than with a more typical, convenience-oriented low-fat diet that was identical in intake of total fat, saturated fat, and cholesterol. Methods Participants Participants were recruited from the local community, primarily through newspaper advertisements, letters to previous study participants, and flyers sent to university employees. Men and women were invited to enroll if they were 30 to 65 years of age with fasting plasma LDL cholesterol levels of 3.3 to 4.8 mmol/L (130 to 190 mg/dL), fasting plasma triglyceride levels less than 2.83 mmol/L (< 250 mg/dL), body mass index between 19 and 31 kg/m2, and a current diet estimated to derive at least 10% of energy from saturated fat. Pregnant women, persons who smoked, persons with prevalent heart disease or diabetes, or persons who had been using lipid-lowering or blood pressure-lowering medications within the past month (all determined through self-report) were excluded. During the recruitment phase, 1096 individuals were screened by telephone interview and 345 who met the initial inclusion criteria were considered eligible for cholesterol testing. Of these 345 persons, 188 who were found to have eligible concentrations of LDL cholesterol and triglycerides attended an orientation meeting. Fifty-one persons decided not to participate (primarily because of the time commitment), and an additional 12 potential participants were excluded after a 3-day food record showed that their estimated average intake of saturated fat was already less than 10% of energy. One hundred twenty-five participants were randomly assigned to 1 of the 2 diet groups. The Stanford University Human Subjects Committee reviewed and approved the investigation, all participants signed an informed consent form before enrollment, and the study was performed according to Declaration of Helsinki guidelines (20). Design The trial used a parallel design. We randomly assigned participants in blocks of 20 by selecting, without replacement, from a set of indistinguishable envelopes containing 10 assignments to each of the 2 diet groups. Randomization of the envelopes was done by hand, without a computer algorithm. No stratification criteria were used. Each participant was provided with meals, snacks, and beverages on an outpatient basis for 28 days, as described later. Diets Both study diets were designed to provide 30% of energy from total fat, 10% of energy from saturated fat, and approximately 100 mg of cholesterol per 1000 kcal per day. During the menu-designing stage of the study, the nutrient composition of the diets was determined by using the database of Food Processor software, version 7.0 (ESHA Research, Salem, Oregon). Menus were designed by using commonly available foods from local markets. The Low-Fat diet was designed to include many reduced-fat prepared-food items (for example, reduced-fat cheeses, low-fat frozen lasagna, and low-fat and sugar-rich snack foods). In contrast, the Low-Fat Plus diet was designed to include considerably more vegetables, legumes, whole grains, and fruits. Butter, cheese, and eggs were added to the daily menus for the Low-Fat Plus diet, increasing the saturated fat and cholesterol content to match the Low-Fat diet. A 7-day menu cycle was designed for each of the 2 study diets; therefore, each menu was repeated 4 times during the 28 days. The diets included breakfast, lunch, dinner, beverages, and snacks for each day. Each weekday, the participants ate either lunch or dinner at the dining facility of the Stanford General Clinical Research Center. After their on-site meal, they were given coolers that contained meals and snacks to be consumed off-site. On Fridays, participants received weekend meals to be consumed off-site. Appendix Table 1 and Appendix Table 2 list the daily menus. One free-choice evening meal was allowed each weekend. For this meal, participants were given guidelines for choosing low-fat meals consistent with their diet assignments and were required to keep a record of foods consumed. These records were analyzed for nutritional content and were used to determine the impact of the free-choice meals on the overall study diets. Adherence was measured by using daily log sheets kept by participants that tracked incomplete consumption of study foods or consumption of any nonstudy foods. The 28 daily food logs for each participant were examined for deviations from the diets. The energy contribution of each deviation was determined and then totaled for the entire 28-day protocol period. Each of the 14 daily menus (7-day cycle 2 diets) was analyzed chemically for nutrient content before the study and then again during the study (Covance Laboratories, Madison, Wisconsin). The chemical analyses performed before the study confirmed that the average composition of the daily menus provided 30% of energy from total fat, 10% of energy from saturated fat, and approximately 100 mg of cholesterol per 1000 kcal per day. When the 2 diets were first designed, we attempted to match their mono- and polyunsaturated fat content. However, the database used in the design phase was missing values for these nutrients for approximately 20% of the foods. In addition, many of the specific products purchased locally for the study provided incomplete information for the content of these unsaturated fats. The first round of chemical analyses of the diets, performed before enrollment began, indicated a modest discrepancy b

Does weight loss cause the exercise-induced increase in plasma high density lipoproteins?

Studies showing an increase in plasma concentration of high density lipoprotein cholesterol (HDL-C) with moderate exercise have usually rejected the role of body weight change in the HDL-C raising process, ostensibly because the amount of weight lost has been negligible. To investigate HDL-C changes more thoroughly, we followed initially sedentary middle-aged men randomly assigned to either a moderate running (n = 36) or a sedentary control (n = 28) group for one year. Among runners, one-year changes in plasma HDL-C concentrations correlated strongly with their body weight changes (r = - 0.53, P less than 0.001). Curve-fitting procedures and regression analysis suggested that processes associated with weight change produce much of the plasma HDL-C changes induced by moderate exercise and that changes in HDL-C concentration predominantly reflect changes in the reputedly anti-atherogenic HDL2 sub-component. Further, the interaction between weight change and plasma HDL-C concentration was significantly different (P less than 0.001) in exercisers and controls suggesting that the metabolic consequences of exercise-induced weight change are different from the consequences of weight change in the sedentary state.