Type 2 diabetes mellitus is characterized by 4 major metabolic abnormalities: obesity, impaired insulin action, insulin secretory dysfunction, and increased endogenous glucose output (EGO) (1-3). Although there is substantial evidence that the first 3 of these abnormalities are present in most individuals before the onset of diabetes, the sequence with which they develop and their relative contributions to the progression from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT), and ultimately to type 2 diabetes (4-6), remain unknown in the absence of a detailed longitudinal study (7)(8)(9)(10)(11)(12). Current understanding of the pathogenesis of type 2 diabetes is based on a large number of cross-sectional (13-25) and prospective (26-40) studies.In cross-sectional studies, subjects with IGT were on average more obese and more insulin-resistant than those with NGT. Basal EGO, largely reflecting hepatic glucose production, was not increased (3,7,8,(13)(14)(15). Whether insulin secretion is impaired in individuals with IGT is controversial. Some studies have found a lower early insulin secretory response (occurring within minutes of an intravenous or oral glucose load) in individuals with IGT compared with those with . Lower early insulin responses have also been demonstrated in first-degree relatives of individuals with type 2 diabetes, a population at high risk for developing diabetes (20)(21)(22). However, others have reported normal or increased early insulin secretion in both groups of individuals (13,14,23,24). Similarly, both lower (18) and higher (25) late insulin responses (2 hours after an oral glucose load) have been reported in subjects with IGT compared with those with NGT. With respect to the pathogenesis of diabetes, such cross-sectional findings must be interpreted with caution, because many individuals with IGT will never develop diabetes, and their metabolic characteristics may well differ from those who do.In recent years, several prospective studies, in which nondiabetic individuals are metabolically characterized on a single occasion and then followed for several years to determine who develops diabetes, have helped to identify metabolic abnormalities that predispose to diabetes. These studies have shown that obesity (27-29, 33-35, 39) and insulin resistance (30-35) predict the development of diabetes in many populations, whereas basal EGO was not predictive in the only study in which it was measured (30). A low early insulin response predicted diabetes in most (30,(35)(36)(37)(38)(39) but not all (31, 32) studies. Together, these results indicate that defects in both insulin action and insulin secretion predispose some individuals with NGT to diabetes, but they give little information about the time course with which these abnormalities change as glucose tolerance worsens.To determine the natural history of insulin secretory dysfunction and insulin resistance during the development of diabetes, and to understand how these factors interact with one another during the developm...

Insulin resistance is a major risk factor for the development of NIDDM: A low acute insulin response to glucose is an additional but weaker risk factor.

Type 2 or non-insulin-dependent diabetes mellitus (NIDDM) is the most common form of diabetes worldwide, affecting approximately 4% of the world's adult population. It is multifactorial in origin with both genetic and environmental factors contributing to its development. A genome-wide screen for type 2 diabetes genes carried out in Mexican Americans localized a susceptibility gene, designated NIDDM1, to chromosome 2. Here we describe the positional cloning of a gene located in the NIDDM1 region that shows association with type 2 diabetes in Mexican Americans and a Northern European population from the Botnia region of Finland. This putative diabetes-susceptibility gene encodes a ubiquitously expressed member of the calpain-like cysteine protease family, calpain-10 (CAPN10). This finding suggests a novel pathway that may contribute to the development of type 2 diabetes.

These results show that the nutrient load is a key variable that can influence the gut (fecal) bacterial community structure over short time scales. Furthermore, the observed associations between gut microbes and nutrient absorption indicate a possible role of the human gut microbiota in the regulation of the nutrient harvest. This trial was registered at clinicaltrials.gov as NCT00414063.

reproducible (coefficient of variation = 2.4%); and (c) even when adjusted for differences in FFM, there is still considerable interperson variability of the daily energy expenditure. A large portion of the variability of 24EE among individuals, independent of differences in body size, was due to variability in the degree of spontaneous physical activity, i.e., "fidgeting," which accounted for 100-800 kcal/d in these subjects.

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.

Reduced oxidation of fat leading to a positive fat balance could be a factor in the development of obesity. Twenty-four-hour respiratory quotient (RQ) was measured in 152 nondiabetic Pima Indians fed a weight-maintenance diet [87 males and 65 females; 27 +/- 6 yr (mean +/- SD); 93.9 +/- 22.9 kg; 32 +/- 9% fat]. Twenty-four-hour RQ varied from 0.799 to 0.903. Prior change in body weight, 24-h energy balance, sex, and percent body fat explained 18% of the variance in 24-h RQ (P less than 0.001). In a subgroup of 66 siblings from 28 families, family membership explained 28% of the remaining variance in 24-h RQ (P less than 0.05). In 111 subjects for whom follow-up data (25 +/- 11 mo) were available, 24-h RQ was correlated with subsequent changes in body weight and fat mass (r = 0.27, P less than 0.01 and r = 0.19, P less than 0.05, respectively). Subjects with higher 24-h RQ (90th percentile) independent of 24-h energy expenditure were at 2.5 times higher risk of gaining greater than or equal to 5 kg body weight than those with lower 24-h RQ (10th percentile). We conclude that in Pima Indians fed a standard diet 1) family membership is the principal determinant of the ratio of fat to carbohydrate oxidation, and 2) a low ratio of fat to carbohydrate oxidation is associated with subsequent weight gain independent of low energy expenditure and may contribute to the familial aggregation of obesity.

Energy expenditure varies among people, independent of body size and composition, and persons with a "low" metabolic rate seem to be at higher risk of gaining weight. To assess the importance of skeletal muscle metabolism as a determinant of metabolic rate, 24-h energy expenditure, basal metabolic rate (BMR), and sleeping metabolic rate (SMR) were measured by indirect calorimetry in 14 subjects (7 males, 7 females; 30±6 yr Jmean±SDJ 79.1±173 kg; 22±7% body fat), and compared to forearm oxygen uptake. Values of energy expenditure were adjusted for individual differences in fat-free mass, fat mass, age, and sex. Adjusted BMR and SMR, expressed as deviations from predicted values, correlated with forearm resting oxygen uptake (ml 02/liter forearm) (r = 0.72, P < 0.005 and r = 0.53, P = 0.05, respectively). These findings suggest that differences in resting muscle metabolism account for part of the variance in metabolic rate among individuals and may play a role in the pathogenesis of obesity. (J. Clin. Invest. 1990.