Are there persons who are obese, but metabolically healthy?

The aim of this article was to review the evidence for a metabolically normal subset of the obese and its implications for clinical and research work. The methods included literature review and correspondence with authors. Since 1947, when Vague described a relation between distribution of body fat and the risk factors for cardiovascular disease, much evidence has suggested that early onset of the obesity, hyperplasia of normal adipocytes, and normal quantities of visceral abdominal fat may be associated with a favorable metabolic response in obese subjects. Analyses in 1973 by Keyes and later by Reuben Andres in 1980 suggested that obesity for some was not a risk factor and might even be an asset. Recently, in the study by Bonora et al of the relation between insulin resistance and the 4 main disorders of the metabolic syndrome in the Bruneck epidemiologic study, a subgroup of obese individuals with a normal metabolic response was evident. In a current study by Brochu et al of an obese metabolically normal subgroup of postmenopausal women, visceral abdominal fat estimated by computed tomography (CT) scan and age of onset were significant variables. The obese, metabolically normal subgroup (OBMN) must be taken into consideration in both clinical and research work. Persons with OBMN and their parents may be wrongly blamed because of the obesity. Attempts at weight loss may be counterproductive. The criteria for selection of obese research subjects may favor inclusion of an OBMN subset, which may invalidate statistical analysis. Findings suggesting the OBMN subset include family members with uncomplicated obesity, early onset of the obesity, fasting plasma insulin within normal range, and normal distribution of the excess fat. Hormonal, genetic studies, and prospective studies will help to clarify the significance and underlying mechanisms of this subset.

What are the physical characteristics associated with a normal metabolic profile despite a high level of obesity in postmenopausal women?

Although obesity is often associated with insulin resistance and a cluster of metabolic disturbances, the existence of a subgroup of healthy but obese individuals has been postulated. It is unclear why some obese individuals fail to show traditional risk factors associated with the insulin resistance syndrome despite having a very high accumulation of body fat. To address this issue, we identified and studied a subgroup of metabolically normal but obese (MNO) postmenopausal women to gain insight into potential physiological factors that may protect them against the development of obesity-related comorbidities. We carefully examined the metabolic characteristics of 43 obese, sedentary postmenopausal women (mean +/- SD, 58.0 +/- 6.0 yr). Subjects were classified as MNO or as metabolically abnormal obese (MAO) based on an accepted cut-point for insulin sensitivity (measured by the hyperinsulinemic/euglycemic clamp technique). Thereafter, we determined 1) body composition (fat mass and lean body mass), 2) body fat distribution (abdominal visceral and sc adipose tissue areas, midthigh sc adipose tissue and muscle attenuation), 3) plasma lipid-lipoprotein levels, 4) plasma glucose and insulin concentrations, 5) resting blood pressure, 6) peak oxygen consumption, 7) physical activity energy expenditure, and 8) age-related onset of obesity with a questionnaire as potential modulators of differences in the risk profile. We identified 17 MNO subjects who displayed high insulin sensitivity (11.2 +/- 2.6 mg/min.kg lean body mass) and 26 MAO subjects with lower insulin sensitivity (5.7 +/- 1.1 mg/min.kg lean body mass). Despite comparable total body fatness between groups (45.2 +/- 5.3% vs. 44.8 +/- 6.6%; P: = NS), MNO individuals had 49% less visceral adipose tissue than MAO subjects (141 +/- 53 vs. 211 +/- 85 cm(2); P: < 0.01). No difference was noted between groups for abdominal sc adipose tissue (453 +/- 126 vs. 442 +/- 144 cm(2); P: = NS), total fat mass (38.1 +/- 10.6 vs. 40.0 +/- 11.8 kg), muscle attenuation (42.2 +/- 2.6 vs. 43.6 +/- 4.8 Houndsfield units), and physical activity energy expenditure (1060 +/- 323 vs. 1045 +/- 331 Cal/day). MNO subjects had lower fasting plasma glucose and insulin concentrations and lower insulin levels during the oral glucose tolerance test (P: values ranging between 0.01-0.001). No difference was observed between groups for 2-h glucose levels and glucose area during the oral glucose tolerance test. MNO subjects showed lower plasma triglycerides and higher high density lipoprotein cholesterol concentrations than MAO individuals (P: < 0.01 in both cases). Results from the questionnaire indicated that 48% of the MNO women presented an early onset of obesity (<20 yr old) compared with 29% of the MAO subjects (P: = 0.09). Stepwise regression analysis showed that visceral adipose tissue and the age-related onset of obesity explained 22% and 13%, respectively, of the variance observed in insulin sensitivity (total r(2) = 0.35; P: < 0.05 in both cases). Our results support the existence of a subgroup of obese but metabolically normal postmenopausal women who display high levels of insulin sensitivity despite having a high accumulation of body fat. This metabolically normal profile is associated with a lower accumulation of visceral adipose tissue and an earlier age-related onset of obesity.

Longitudinal changes in body composition and energy balance in lean women with normal and abnormal glucose tolerance during pregnancy.

OBJECTIVE: The objective of this study was to evaluate the longitudinal changes in energy expenditure and body composition in relationship to alterations in carbohydrate metabolism in women with normal and abnormal glucose metabolism. We hypothesized that women with decreased insulin sensitivity before conception would have less fat accretion and smaller increases in energy expenditure. STUDY DESIGN: Six women with normal glucose tolerance and 10 women with abnormal glucose tolerance were evaluated before conception, and in early (12 to 14 weeks) and late (34 to 36 weeks) gestation. Body composition was estimated by hydrodensitometry, resting energy expenditure, and glucose and fat metabolism by indirect calorimetry, endogenous glucose production by infusion of [6-6 2H2] glucose, and insulin sensitivity using a hyperinsulinemic-euglycemic clamp (40 mU/m2/min). RESULTS: There was a smaller increase in fat mass (1.3 kg [P = .04]) in early pregnancy in women with abnormal glucose tolerance before pregnancy. Indirect calorimetry measured gestational age-related increases in basal oxygen utilization, with or without correction for fat-free mass (VO2, P = .002), resting energy expenditure (expressed in kilocalories, P = .0001), and carbohydrate oxidation (P = .0003). The insulin-mediated elevation in VO2 increased in later gestation VO2 (P = .005), as did resting energy expenditure (P = .0001) and fat oxidation (P = 0.0001). However, there was a decrease in respiratory quotient (P = .0001), carbohydrate oxidation (P = .002), and nonoxidative carbohydrate metabolism (P = .0001) with advancing gestation during insulin infusion. In early pregnancy, changes in fat mass correlated inversely with changes in insulin sensitivity (r= -0.52, P = .04) and changes in basal VO2 correlated inversely with decreases in basal endogenous glucose production (r = -0.74, P = .01). CONCLUSION: In early gestation, the changes in maternal fat mass and basal oxygen consumption are inversely related to the changes in insulin sensitivity. This response in lean women with decreased insulin sensitivity before conception may have survival value by providing a larger amount of available substrate to meet fetoplacental needs during gestation.

Drug therapy for obesity in the elderly.

The prevalence of obesity is increasing rapidly in the US and other developed countries. Even though the percentage of older individuals is increasing worldwide, obesity has only recently become a recognised problem in this population. Obesity occurs when energy intake chronically exceeds energy expenditure. Moreover, advancing age is associated with an inability to couple energy intake with energy expenditure. Obesity contributes to many adverse health outcomes, including non-insulin-dependent (type II) diabetes mellitus, as well as to an increase in both cardiovascular and all-cause mortality. Only recently has the medical community begun to accept obesity as a disease with a multifactorial pathogenesis that requires systematic lifestyle changes and pharmacological treatment. Several groups of drugs are available for the pharmacotherapy of obesity; anorectic medications (e.g. fenfluramine, dexfenfluramine); substances affecting energy expenditure and body composition [e.g. chromium (chromium picolinate), ephedrine, anabolic steroids, beta 3-adrenoceptor agonists]; and drugs affecting the absorption of nutrients (e.g. orlistat). To date, few drugs have produced and sustained a significant bodyweight loss. However, some drugs induce a significant short term reduction in bodyweight compared with placebo. Moreover, there is a paucity of information regarding the effectiveness of these drugs in the treatment of obesity in the elderly. Furthermore, it is even debated whether obesity should be treated with drug intervention in the elderly. Clinicians prescribing medications for obesity treatment in the elderly need to carefully consider the benefit: risk ratio, given the high prevalence of polypharmacy in elderly patients. Furthermore, physiological changes that occur with aging may affect the pharmacokinetics of administered drugs and need to be taken into consideration.

Carbohydrate metabolism during pregnancy in control subjects and women with gestational diabetes.

The purpose of this study was to characterize carbohydrate metabolism associated with the development of gestational diabetes. Six control (Ctl) and ten women with gestational diabetes mellitus (GDM) were evaluated using an intravenous glucose tolerance test and hyperinsulinemic-euglycemic clamp with [6,6-2H2]glucose prior to conception (P) and at 12-14 (E), and 34-36 wk of gestation (L). There was an increase (P = 0.0001) in first-phase insulin response in Ctl (P 174 +/- 133, E 388 +/- 120, and L 587 +/- 303 microU/ml) and GDM (P 197 +/- 94, E 267 +/- 77, and L 376 +/- 162 microU/ml) but a significant (P = 0.02) lag in change in GDM with advancing gestation. Basal endogenous glucose production increased during gestation [Ctl: P 2.74 +/- 0.23, E 2.62 +/- 0.38, and L 3.14 +/- 0.36; GDM: P 2.68 +/- 0.51, E 2.78 +/- 0.45, and L 2.98 +/- 0.48 mg.kg fat-free mass (FFM)-1 x min-1; P = 0.02], but there was resistance to suppression by insulin infusion (P = 0.03) in late gestation (GDM: 0.61 +/- 0.44 vs. Ctl: 0.16 +/- 0.17 mg.kg FFM-1 x min-1). Insulin sensitivity decreased during gestation (Ctl: P 10.78 +/- 2.78, E 8.34 +/- 2.36, and L 4.75 +/- 1.22; GDM: P 7.49 +/- 2.13, E 7.40 +/- 1.45, and L 4.21 +/- 1.01 mg.kg FFM-1 x min-1; P = 0.0001) and was primarily decreased (P = 0.04) in GDM compared with Ctl from P through E. These findings closely resemble those of non-insulin-dependent, predominantly insulin-resistant diabetes, which is often a sequel of GDM.

Longitudinal changes in basal hepatic glucose production and suppression during insulin infusion in normal pregnant women.

OBJECTIVE: The purpose of this study was to evaluate basal endogenous glucose production and suppression during insulin infusion in normal pregnant women. STUDY DESIGN: This prospective, longitudinal study was conducted at the Medical Center Hospital of Vermont. Six healthy women were evaluated before conception and at 12 to 14 and 34 to 36 weeks' gestation. Body composition was estimated by hydrodensitometry. Basal endogenous glucose production was estimated with a primed constant infusion of 6-6 2H2 glucose, and suppression of endogenous glucose production was estimated with insulin infusion during a hyperinsulinemic-euglycemic clamp. RESULTS: There was a significant (p = 0.02) 65% increase in fasting insulin concentration by late gestation. Moreover, there was a significant 30% (p = 0.0005) increase in basal endogenous glucose production (mg/min) with advancing gestation, which remained significant (p = 0.05) when corrected for fat-free mass. During insulin infusion endogenous glucose production was almost completely suppressed (i.e., > 90%) throughout gestation. CONCLUSIONS: There is a significant increase in basal endogenous glucose production at 34 to 36 weeks' gestation in spite of a significant increase in fasting insulin concentration. However, endogenous glucose production remains sensitive to insulin infusion throughout gestation.

Longitudinal changes in insulin release and insulin resistance in nonobese pregnant women.

To assess the longitudinal changes in insulin release and insulin sensitivity in nonobese normal women during gestation, six women were evaluated with oral glucose tolerance testing, body composition analysis, intravenous glucose tolerance tests, and the hyperinsulinemic-euglycemic clamp before conception, at 12 to 14 weeks, and at 34 to 36 weeks' gestation. There was a significant increase in the insulin/glucose ratio (p = 0.028) during the oral glucose tolerance test during gestation. There was also a significant 3.0- to 3.5-fold increase throughout gestation in first-phase (p = 0.001) and second-phase (p = 0.0001) insulin release during the intravenous glucose tolerance test. Peripheral insulin sensitivity was estimated as the glucose infusion rate (in milligrams per kilogram fat-free mass per minute) during the hyperinsulinemic-euglycemic clamp. There was a significant (p = 0.0003) 56% decrease in insulin sensitivity through 36 weeks' gestation. These results are the first to prospectively evaluate the longitudinal changes in maternal carbohydrate metabolism from the time before conception through late gestation with newer methods such as the hyperinsulinemic-euglycemic clamp.

Incidence and significance of islet cell antibodies in women with previous gestational diabetes.

Islet cell antibodies (ICAs) are markers for patients at risk for insulin-dependent diabetes and are associated with progressive beta-cell destruction. This prospective study was performed to estimate the incidence of these antibodies in 187 women with previous gestational diabetes. With a specific protein A monoclonal antibody (MoAb) assay, the incidence of ICAs was only 1.6% (3 of 187). Oral and intravenous glucose tolerance tests were performed in these 3 women and compared with 6 women with previous gestational diabetes without ICAs and 5 control women. Glucose tolerance was impaired only in the 3 women with ICAs, who also had an increase (P less than 0.03) in fasting plasma glucose and a decrease (P less than 0.03) in early first-phase insulin response. We conclude that the more specific MoAb method indicates a lower incidence of ICA in women with a history of gestational diabetes than previously reported and that a decreased first-phase insulin response is associated with the presence of ICAs, suggesting progressive islet cell damage.

Storage and expenditure of energy in obesity and their implications for management.

We have seen in the past 20 years intensive investigation of the responses of the obese and the lean to caloric intake and to various environmental stresses. Although there is much discrepancy of results, the following are obvious: Obesity is not a clear-cut syndrome, and individuals differ significantly in their genetic subtypes and in the stages, type, and degree of their metabolic disturbances. A difference in the facultative component of the thermogenic effect of food can explain some of the variation. This in turn is closely related to insulin resistance, which bears a close relationship to subtypes of hypertension and hyperlipidemias. The greatest scope for clinical intervention lies in these fields. Both the obese and the lean subjects are adapted to retain dietary fat independently of the energy needs. The high ratio of fat to carbohydrate in the western diet and, increasingly in that of the east, is cause for concern.

1987 Herman award lecture. A plea for an integrated approach to characterization and management of obesity, type II diabetes, hyperlipidemias, and hypertension: a role for the personal computer?

In the Vermont study of experimental obesity, heterogeneity of the response to overfeeding was a striking finding in normal subjects. There is also poorly defined heterogeneity within the areas of obesity, noninsulin-dependent diabetes, hyperlipidemias, and so-called essential hypertension. These disorders may occur in the same individual and have important mechanisms in common. Thus it is logical to strive for an integrated approach to nutritional and medical management rather than an approach fragmented between medical specialties. The rapidly developing computer programs now adapted to microcomputers hold promise of facilitating an integrated approach both in the clinical and in the investigative field.

Subclinical abnormalities of glucose metabolism in subjects with previous gestational diabetes.

To investigate whether there are subclinical abnormalities of glucose metabolism in women with previous gestational diabetes that are consistent with a high incidence of diabetes mellitus in later life, eight patients with previous gestational diabetes and normal oral glucose tolerance were evaluated by means of body composition studies, intravenous glucose tolerance tests, and the hyperinsulinemic-euglycemic clamp coupled with 6-6 dideuterated glucose infusion, indirect calorimetry, and measurement of islet cell antibodies. Eight control subjects were matched for percent body fat and diet and studied in a similar fashion. Abnormalities of insulin response and insulin resistance were present in four (50%) of patients with previous gestational diabetes. Insulin resistance was significantly greater in the patients than in the control subjects. When compared with lean patients, obese patients with previous gestational diabetes had significantly greater insulin response to the intravenous glucose tolerance test and insulin resistance. These changes are consistent with reported findings of an early and progressive development of overt diabetes in patients who had gestational diabetes.

Effect of diet on energy expenditure and plasma norepinephrine in lean and obese Pima Indians.

To assess whether thermogenesis or sympathetic nervous system (SNS) function might differ between lean and obese human subjects, studies of thermic and sympathetic responses to standard stimuli were undertaken in Pima Indians, an ethnic group with a high prevalence of obesity. Plasma levels of norepinephrine (NE) and energy expenditure at rest and in response to feeding, exercise, and graded infusions of NE were compared in five lean and five obese Indians during a period of weight maintenance (WM), after 3 weeks of overfeeding (OF) and, in the obese, also after 6 weeks of underfeeding (UF). Basal energy expenditure, when adjusted for fat free mass, was equivalent during WM and increased 3% with OF (P less than 0.01) in both groups. Thermic responses to exercise or a test meal did not differ in lean and obese and did not change with OF, while thermic responses to NE infusion fell during OF to a greater degree in obese than lean (P less than 0.05). A similar pattern (decreased effect in obese with OF) was also noted in the glycemic response to infused NE (P less than 0.05). Although not quantitatively different in lean and obese, the plasma NE concentration appeared to vary more in response to feeding or dietary alteration in the obese than lean, a finding that may reflect lower plasma clearance of NE in the obese. These studies, therefore, raise the possibility that overfeeding in obese Pima Indians may limit the contribution of sympathetically mediated thermogenesis to energy expenditure, though the implications of this for body weight regulation are speculative.

Mood and appetite during minimal-carbohydrate and carbohydrate-supplemented hypocaloric diets.

After a baseline period of free-feeding, 20 obese outpatients alternated between four 2-wk periods of minimal-carbohydrate diet (800 kcal; 58% protein and 42% fat by weight) and of a carbohydrate-supplemented diet (1,000 kcal; 42% protein, 30% fat, and 28% carbohydrate). In a comparison of psychological adjustment during the baseline and low-calorie diets, the initial 2 wk of dieting was associated with a decrease in appetite and elevation of psychological well-being, regardless of the composition of the diet. Thereafter, appetite and mood approached basal levels. Further changes in these psychological reactions to dieting did not vary with the type of diet. There was no support for the idea that a minimal-carbohydrate, protein-supplemented fast decreases appetite and elevates mood more in comparison with a similar diet containing enough carbohydrate to minimize ketosis.