William G H Abbott

Reduced rate of energy expenditure as a risk factor for body-weight gain

The contribution of reduced energy expenditure to the development of obesity has been a point of controversy. We measured 24-hour energy expenditure (adjusted for body composition, age, and sex), in a respiratory chamber, in 95 southwestern American Indians. Energy expenditure correlated with the rate of change in body weight over a two-year follow-up period (r = -0.39, P less than 0.001). The estimated risk of gaining more than 7.5 kg in body weight was increased fourfold in persons with a low adjusted 24-hour energy expenditure (200 kcal per day below predicted values) as compared with persons with a high 24-hour energy expenditure (200 kcal per day above predicted values; P less than 0.01). In another 126 subjects, the adjusted metabolic rate at rest at the initial visit was also found to predict the gain in body weight over a four-year follow-up period. When the 15 subjects who gained more than 10 kg were compared with the remaining 111 subjects, the initial mean (+/- SD) adjusted metabolic rate at rest was lower in those who gained weight (1694 +/- 103 vs. 1764 +/- 109 kcal per day; P less than 0.02) and increased to 1813 +/- 134 kcal per day (P less than 0.01) after a mean weight gain of 15.7 +/- 5.7 kg. In a group of 94 siblings from 36 families, values for adjusted 24-hour energy expenditure aggregated in families (intraclass correlation = 0.48). We conclude that a low rate of energy expenditure may contribute to the aggregation of obesity in families.

Skeletal muscle capillary density and fiber type are possible determinants of in vivo insulin resistance in man.

We have compared the capillary density and muscle fiber type of musculus vastus lateralis with in vivo insulin action determined by the euglycemic clamp (M value) in 23 Caucasians and 41 Pima Indian nondiabetic men. M value was significantly correlated with capillary density (r = 0.63; P less than or equal to 0.0001), percent type I fibers (r = 0.29; P less than 0.02), and percent type 2B fibers (r = -0.38; P less than 0.003). Fasting plasma glucose and insulin concentrations were significantly negatively correlated with capillary density (r = -0.46, P less than or equal to 0.0001; r = -0.47, P less than or equal to 0.0001, respectively). Waist circumference/thigh circumference ratio was correlated with percent type 1 fibers (r = -0.39; P less than 0.002). These results suggest that diffusion distance from capillary to muscle cells or some associated biochemical change, and fiber type, could play a role in determining in vivo insulin action. The association of muscle fiber type with body fat distribution may indicate that central obesity is only one aspect of a more generalized metabolic syndrome. The data may provide at least a partial explanation for the insulin resistance associated with obesity and for the altered kinetics of insulin action in the obese.

Familial Dependence of the Resting Metabolic Rate

Human obesity is known to be a familial disorder. We studied 130 nondiabetic adult southwestern American Indians (74 men and 56 women) from 54 families to determine whether the resting metabolic rate, as measured by indirect calorimetry, is a familial trait that is independent of individual differences in fat-free mass (estimated mass of metabolically active tissue), age, and sex. We found that most of the variance in the resting metabolic rate (83 percent, P less than 0.0001) was accounted for by three covariates--fat-free mass, age, and sex--and that fat-free mass was the most important determinant. Family membership accounted for an additional 11 percent (P less than 0.0001) of the variance in the resting metabolic rate. Thus, resting metabolic rate is a familial trait in this population, and it is independent of differences in fat-free mass, age, and sex. We also found that persons from families with lower resting metabolic rates were no more obese than persons from families with higher metabolic rates. This finding may be partly explained by the close correlation between fat-free mass and percentage of body fat (r = 0.81, P less than 0.0001), which indicates that the resting metabolic rate, as adjusted for fat-free mass, is already partly adjusted for obesity. Only prospective studies will elucidate whether the familial dependence of the resting metabolic rate is a contributing mechanism to the familial predisposition to obesity.

In Vivo Insulin Action Is Familial Characteristic in Nondiabetic Pima Indians

Non-insulin-dependent diabetes mellitus (NIDDM) is a genetic disorder characterized by two major pathogenic processes: reduced insulin action and a relative or absolute decrease in plasma insulin concentrations. We studied 116 nondiabetic siblings from 45 families to determine if in vivo insulin action showed any aggregation among siblings. Subjects were Pima Indians from the Gila River Indian Community in Arizona who, as a group, have the highest reported incidence and prevalence of NIDDM in the world. In vivo insulin action was determined by the euglycemic-clamp technique at two rates of insulin infusion in each subject with resulting mean plasma insulin concentrations of 119 and 1938 μU/ml. After adjustment for age, sex, and degree of obesity, there was significant aggregation among siblings of in vivo insulin action at the high insulin infusion rate (P < .0001). Family membership independently accounted for ∼34% of the variance in this measure of insulin action. Glucose uptake at the lower insulin infusion rate also showed familial aggregation (P < .01), with family membership independently accounting for ∼15% of the variance of this measurement. We conclude that in vivo insulin action is a familial characteristic. The familial component of insulin action occurs in addition to the effects of obesity, age, and sex on insulin action. Therefore it is not sufficient to simply know that an individual is lean or obese to predict his/her in vivo insulin resistance, because it must also be known whether he/she is from an insulin-resistant or insulin-sensitive family. An alteration of insulin action may be an underlying and potentially genetically determined abnormality in Pima Indians that could help explain the familial aggregation of diabetes in this population. Such a genetic mechanism might also operate in populations with Native American admixture (e.g., Mexicans) as well as other populations.

Relationships between plasma lipoprotein concentrations and insulin action in an obese hyperinsulinemic population

Relationships have been observed between lipoprotein concentrations and insulin action. These relationships may be important in explaining the association of insulin resistance and abnormalities of lipoprotein metabolism found in obesity, diabetes, and hypertriglyceridemia. We have measured plasma lipoprotein concentrations and indices of insulin action in 85 men and 56 women, all of whom were normolipidemic and had normal glucose tolerance. The subjects were obese Southwestern American Indians (body mass index 34 ± 1). Insulin action was measured via the hyperinsulinemic clamp with simultaneous indirect calorimetry. Triglyceride concentrations were inversely related to rates of total insulin-mediated glucose disposal (in men and women, respectively, r = –.37, P < .01; r = –.24, P < .10), glucose storage (r = –.31, P < .01; r = –.25, P < .10), increase in glucose oxidation (r = –.29, P < .01; r = –.24, P < .10), and, in men only, suppression of endogenous glucose production (r = –.32, P < .01). High-density lipoprotein (HDL) cholesterol concentration was positively related to rates of total insulin-mediated glucose disposal (r –.35, P < .01; r = .33, P < .05), increase in carbohydrate oxidation (r = .40, P < .001; r = .39, P < .001), suppression of endogenous glucose production (r = .24, P < .05; r = .29, P < .05), and, in men only, glucose storage (r = .35, P < .001). The relationships between lipoprotein concentrations and insulin action were independent of adiposity and insulin concentrations (with the exception of HDL cholesterol in women), and the relationships of Triglyceride and HDL cholesterol with insulin action were independent of each other. These relationships indicate that there may be a link between the development of insulin resistance and the abnormalities in lipoprotein metabolism associated with obesity, non-insulin-dependent diabetes mellitus, and hypertriglyceridemia.

Integrated study of low density lipoprotein metabolism and very low density lipoprotein metabolism in non-insulin-dependent diabetes

The metabolisms of VLDL, IDL, and LDL and their interconversions have been studied in ten obese untreated male Pima Indian diabetics compared to 16 age-, sex-, and weight-matched nondiabetics. VLDL was elevated in the diabetics and had abnormal composition, as indicated by a significantly higher ratio of triglyceride/apo B. Fractional catabolic rates for both VLDL apoB and VLDL triglyceride were lower in diabetics, and diabetics had increased production of VLDL triglyceride but not VLDL apoB compared to obese nondiabetics. A higher proportion of VLDL apoB was removed without conversion to LDL in diabetics. LDL cholesterol and apoB were higher in diabetics, but production of LDL apoB was not different from nondiabetics. Fractional catabolic rate for LDL apoB, however, was significantly lower in the diabetics. The data indicate that the triglyceride-rich VLDL in non-insulin-dependent diabetics are less readily converted to LDL, whereas the elevated LDL in this group of diabetics is due to impaired clearance. Thus, decreased conversion of VLDL to LDL and impaired LDL clearance are two opposing phenomena which may influence the LDL concentration of diabetics in either direction. Thus, despite minimal changes in LDL concentration, there are multiple defects in the metabolism of LDL in non-insulin dependent diabetes which may contribute to the increased atherogenesis in this disorder.

Comparison of body composition, adipocyte size, and glucose and insulin concentrations in Pima Indian and Caucasian children☆☆☆

Pima Indian adults with normal glucose tolerance have higher plasma glucose and insulin concentrations than Caucasian adults. To estimate the age of onset of these differences, and to assess their relationship to abdominal and gluteal adipocyte size, we measured adiposity, adipocyte size, and glucose and insulin concentrations during a glucose tolerance test in lean (less than 20% body fat), prepubertal children from each race. The Pima (n = 13) and Caucasian (n = 10) groups were of similar age, percent body fat, and weight. Pima Indian children had higher fasting glucose (101 +/- 2 v 94 +/- 2 mg/dL, P = .01) and insulin (22 +/- 2 v 15 +/- 2 microU/mL, P less than .01) concentrations and larger abdominal adipocytes (0.49 +/- 0.03 v 0.37 +/- 0.04 microgram lipid/cell, P less than .05) than the Caucasian children. Postprandial glucose and insulin concentrations and gluteal adipocyte size were similar in the two races. The higher plasma glucose and insulin concentrations found in Pima adults are present in lean Pima children, and are associated with increased abdominal adipocyte size. These increases may precede the development of obesity in this racial group.

Evaluation of Metabolic Effects of Substitution of Complex Carbohydrates for Saturated Fat in Individuals with Obesity and NIDDM

Dietary recommendations for diabetic patients now generally include the reduction of total and saturated fat and an increase in complex carbohydrates. We conducted two series of studies on individuals with obesity and/or non-insulin-dependent diabetes mellitus (NIDDM) to assess the effects of this dietary recommendation on both lipoproteins and their metabolism as well as on insulin secretion and action and energy expenditure. Both series compared a diet high in saturated fat with a diet high in complex carbohydrates and fiber. Calories and proportion of protein were constant. In the first set of studies, we sought to examine the effect of replacement of saturated fat with complex carbohydrate in a regimen with conventional foods that would closely approximate foods expected to be used and recommended to diabetic patients. In the second regimen, we examined a more extreme difference between carbohydrate content and fat content using a dietary change that would approximate the contrasts between traditional diets of Native Americans or other cultures and a modern westernized diet. The effects on lipoproteins included consistent decreases in total and low-density lipoprotein (LDL) cholesterol (av 10%), minimum to no change in high-density lipoprotein cholesterol, and insignificant changes in total or very-low-density lipoprotein (VLDL) triglycerides or 24-h triglyceride profiles. Changes in total and LDL cholesterol required 3-4 wk to reach equilibrium. Metabolic studies used to elucidate the reasons for the decrease in LDL cholesterol confirmed no stimulation of VLDL triglyceride or apolipoprotein B (apoB) production on the high-carbohydrate diet. The decrease in LDL appeared to be due to decreases in mechanisms that convert VLDL to LDL and increased activity of LDL apoB clearance. There were no changes in fasting and 2- or 24-h glucose profiles or in fasting and 2-h insulin concentrations in individuals consuming a diet of 30% fat and 55% carbohydrate. However, in the study with traditional foods, where dietary carbohydrate was 70% and fat only 15%, there was an improvement in glucose tolerance. It was accompanied by an improvement in glucose-mediated glucose disposal and insulin secretion. Finally, with a whole-body calorimeter, we found no difference between the high-fat and high-carbohydrate diets in terms of 24-h energy expenditure. In individuals having a wide range of obesity and glucose tolerance, substitution of complex carbohydrates for saturated fat has beneficial effects of lowering LDL cholesterol and possibly improving glucose tolerance and insulin secretion but without having any adverse effects on lipoprotein metabolism or energy expenditure.

Effects of Replacing Saturated Fat With Complex Carbohydrate in Diets of Subjects With NIDDM

This study examined the safety of an isocaloric highcomplex carbohydrate low-saturated fat diet (HICARB) in obese patients with non-insulin-dependent diabetes mellitus (NIDDM). Although hypocaloric diets should be recommended to these patients, many find compliance with this diet difficult; therefore, the safety of an isocaloric increase in dietary carbohydrate needs assessment. Lipoprotein cholesterol and triglyceride (TG, mg/dl) concentrations in isocaloric high-fat and HICARB diets were compared in 7 NIDDM subjects (fat 32 ± 3%, fasting glucose 190 ± 38 mg/dl) and 6 nondiabetic subjects (fat 33 ± 5%). They ate a high-fat diet (43% carbohydrate; 42% fat, polyunsaturated to saturated 0.3; fiber 9 g/1000 kcal; cholesterol 550 mg/day) for 7–10 days. Control subjects (3 NIDDM, 3 nondiabetic) continued this diet for 5 wk. The 13 subjects changed to a HICARB diet (65% carbohydrate; 21% fat, polyunsaturated to saturated 1.2; fiber 18 g/1000 kcal; cholesterol 550 mg/day) for 5 wk. NIDDM subjects on the HICARB diet had decreased low-density lipoprotein cholesterol (LDL-chol) concentrations (107 vs. 82, P < .001), but their high-density lipoprotein cholesterol (HDL-chol) concentrations, glucose, and body weight were unchanged. Changes in total plasma TG concentrations in NIDDM subjects were heterogeneous. Concentrations were either unchanged or had decreased in 5 and increased in 2 NIDDM subjects. Nondiabetic subjects on the HICARB diet had decreased LDL-chol (111 vs. 81, P < .01) and unchanged HDL-chol and plasma TG concentrations). In summary, replacing dietary saturated fat with complexcarbohydrate, independent of cholesterol intake, lowered LDL-chol without an adverse effect on HDLchol, TG, and glucose in most obese Pima Indian NIDDM subjects. Before concluding that these diets are safe in obese NIDDM subjects who are unable to restrict their calorie intake, more data are needed on lipoprotein particle flux.

Coordination of very low-density lipoprotein triglyceride and apolipoprotein B metabolism in humans: Effects of obesity and non-insulin-dependent diabetes mellitus

To understand the relationship between very low-density lipoprotein (VLDL) triglyceride and VLDL apolipoprotein (apo) B, we studied their metabolisms simultaneously in 53 subjects with a range of obesity and glycemia. Obese subjects had increased production of both VLDL apo B and VLDL triglyceride and more VLDL of normal composition. Compared with nondiabetics, diabetic subjects had decreased clearance of both VLDL apo B and VLDL triglyceride, increased production of VLDL triglyceride but not of VLDL apo B, and more VLDL of abnormal composition. Production of both VLDL apo B and VLDL triglyceride were significantly correlated with plasma insulin concentrations, and rates of clearance of both were inversely correlated with plasma glucose. There was no direct correlation between total plasma free fatty acid concentration and production of either VLDL triglyceride or VLDL apo B, but VLDL triglyceride production was found to account for only a very small proportion of the nonoxidative component of free fatty acid turnover. We suggest that in obese subjects hyperinsulinemia induces overproduction of both VLDL apo B and VLDL triglyceride. In diabetes VLDL is increased in part because of decreased clearance; the altered composition is the result of the increase in VLDL-triglyceride production independent of apo B. The increase in VLDL triglyceride production may be mediated through plasma free fatty acids or glucose, although assessment of the relationship between these precursors and VLDL triglyceride is confounded by the fact that only a small portion of free fatty acids or glucose is converted to VLDL triglyceride.