Efficacy and safety of beloranib for weight loss in obese adults: a randomized controlled trial.

AIM: To assess the efficacy, safety and tolerability of beloranib treatment for obesity. METHODS: This phase II, double-blind, randomized study investigated the effects of beloranib suspension (0.6, 1.2 and 2.4 mg) or placebo, administered subcutaneously, for 12 weeks in 147 participants (primarily white women) with obesity. No diet or exercise advice was administered. RESULTS: At week 12, beloranib resulted in dose-dependent progressive weight loss of -5.5 ± 0.5, -6.9 ± 0.6 and -10.9 ± 1.1 kg for the 0.6, 1.2 and 2.4 mg beloranib doses, respectively, compared with -0.4 ± 0.4 kg with placebo (all p < 0.0001 vs placebo). Weight loss with beloranib was associated with corresponding reductions in waist circumference and body fat mass, as well as improvements in lipids, high-sensitivity C-reactive protein and blood pressure. Sleep disturbance and gastrointestinal adverse events were more common with beloranib than with placebo; these were generally mild to moderate, transient and dose-related, and led to more early study withdrawals in participants in the group with the highest dose of beloranib. CONCLUSIONS: In this 12-week phase II study, beloranib produced clinically and statistically significant weight loss and corresponding improvements in cardiometabolic risk factors. Beloranib appeared safe, and the 0.6 and 1.2 mg doses were generally well tolerated. The 2.4 mg dose was associated with increased sleep latency and mild to moderate gastrointestinal adverse events over the first month of treatment. These findings represent a novel mechanism for producing clinically meaningful weight loss.

Agreement among type 2 diabetes linkage studies but a poor correlation with results from genome-wide association studies.

AIMS/HYPOTHESIS: Little of the genetic basis for type 2 diabetes has been explained, despite numerous genetic linkage studies and the discovery of multiple genes in genome-wide association (GWA) studies. To begin to resolve the genetic component of this disease, we searched for sites at which genetic results had been corroborated in different studies, in the expectation that replication among studies should direct us to the genomic locations of causative genes with more confidence than the results of individual studies. METHODS: We have mapped the physical location of results from 83 linkage reports (for type 2 diabetes and diabetes precursor quantitative traits [QTs, e.g. plasma insulin levels]) and recent large GWA reports (for type 2 diabetes) onto the same human genome sequence to identify replicated results in diabetes genetic 'hot spots'. RESULTS: Genetic linkage has been found at least ten times at 18 different locations, and at least five times in 56 locations. All replication clusters contained study populations from more than one ethnic background and most contained results for both diabetes and QTs. There is no close relationship between the GWA results and linkage clusters, and the nine best replication clusters have no nearby GWA result. CONCLUSIONS/INTERPRETATION: Many of the genes for type 2 diabetes remain unidentified. This analysis identifies the broad location of yet to be identified genes on 6q, 1q, 18p, 2q, 20q, 17pq, 8p, 19q and 9q. The discrepancy between the linkage and GWA studies may be explained by the presence of multiple, uncommon, mildly deleterious polymorphisms scattered throughout the regulatory and coding regions of genes for type 2 diabetes.

Skeletal muscle triglyceride levels are inversely related to insulin action.

In animal studies, increased amounts of triglyceride associated with skeletal muscle (mTG) correlate with reduced skeletal muscle and whole body insulin action. The aim of this study was to test this relationship in humans. Subjects were 38 nondiabetic male Pima Indians (mean age 28 +/- 1 years). Insulin sensitivity at physiological (M) and supraphysiological (MZ) insulin levels was assessed by the euglycemic clamp. Lipid and carbohydrate oxidation were determined by indirect calorimetry before and during insulin administration. mTG was determined in vastus lateralis muscles obtained by percutaneous biopsy. Percentage of body fat (mean 29 +/- 1%, range 14-44%) was measured by underwater weighing. In simple regressions, negative relationships were found between mTG (mean 5.4 +/- 0.3 micromol/g, range 1.3-1.9 micromol/g) and log10M (r = -0.53, P < or = 0.001), MZ (r = -0.44, P = 0.006), and nonoxidative glucose disposal (r = -0.48 and -0.47 at physiological and supraphysiological insulin levels, respectively, both P = 0.005) but not glucose or lipid oxidation. mTG was not related to any measure of adiposity. In multiple regressions, measures of insulin resistance (log10M, MZ, log10[fasting insulin]) were significantly related to mTG independent of all measures of obesity (percentage of body fat, BMI, waist-to-thigh ratio). In turn, all measures of obesity were related to the insulin resistance measures independent of mTG. The obesity measures and mTG accounted for similar proportions of the variance in insulin resistance in these relationships. The results suggest that in this human population, as in animal models, skeletal muscle insulin sensitivity is strongly influenced by local supplies of triglycerides, as well as by remote depots and circulating lipids. The mechanism(s) underlying the relationship between mTG and insulin action on skeletal muscle glycogen synthesis may be central to an understanding of insulin resistance.

Impaired glucose tolerance in Pima Indians.

More than 50% of Pima Indians develop NIDDM. This disorder is preceded by impaired glucose tolerance (IGT) and we tested the hypothesis that the elevated glucose levels in IGT must be due to reduced beta-cell function. We first determined the plasma glucose/plasma insulin and plasma insulin/insulin resistance relationships in individuals with NGT, relationships which by definition must be normal, and determined if these relationships were intact in individuals with IGT. We also compared Pimas and Caucasians with NGT or IGT. Subjects were assessed with an OGTT, an IVGTT, underwater weighing (for body composition), and a euglycaemic clamp. The results showed that insulin concentrations in Pimas with IGT were not lower than the levels predicted by the relationships found in subjects with NGT. Compared to Caucasians, Pima Indians had elevated insulin concentrations at the same degree of insulin resistance. These studies indicate that insulin resistance, and not beta-cell failure, is the principal lesion determining IGT in Pimas. NIDDM occurs when beta-cell failure develops in the presence of insulin resistance. In some individuals of other races, beta-cell function may be less able to withstand insulin resistance, and presumably in these individuals beta-cell failure assumes a greater importance in the evolution to NIDDM.

Interrelationships between muscle morphology, insulin action, and adiposity.

There is evidence that insulin resistance and obesity are associated with relative increases in the proportion of glycolytic type IIb muscle fibers and decreases in the proportion of oxidative type I fibers. Futhermore, insulin resistance and obesity are associated with the fatty acid (FA) profile of structural membrane lipids. The present study was undertaken to define interrelationships between muscle fiber type and oxidative capacity, muscle membrane FA composition, and insulin action and obesity. Muscle morphology, insulin action, and body fat content were measured in 48 male nondiabetic Pima Indians. Percent body fat (pFAT, determined by hydrodensitometry) correlated negatively with percentage of type I fibers (r = -0.44, P = 0.002) and positively with percentage of type IIb fibers (r = 0.40, P = 0.005). Consistent with this finding, pFAT was also significantly related to oxidative capacity of muscle, as assessed by NADH staining (r = -0.47, P = 0.0007) and citrate synthase (CS) activity (r = -0.43, P = 0.008). Insulin action was correlated with oxidative capacity (CS; r = 0.41, P = 0.01) and weakly correlated with percentage of type IIb fibers (r = -0.29, P = 0.05). In addition, relationships were shown between muscle fiber type and FA composition (e.g., percentage of type I fibers related to n-3 FA; r = 0.37, P = 0.01). Thus leaness and insulin sensitivity are associated with increased oxidative capacity and unsaturation of membranes in skeletal muscle. Present studies support the hypothesis that muscle oxidative capacity and fiber type may play a genetically determined or an environmentally modified role in development of obesity and insulin resistance.

Growth hormone-binding protein in human lymph.

The high affinity GH-binding protein (GHBP) is a soluble circulating ectodomain of the GH receptor (GHR). In humans, it is thought to be released from the plasma membrane-bound GHR by proteolysis at or near the transmembrane domain. GHBP modulates GH action by 1) intravascular complex formation, and 2) competing with the GHR for ligand in tissues (interstitial complex formation). Little is known about the tissue source(s) of GHBP, the local regulation of GHBP generation, or its concentration in the interstitium. To begin addressing these questions, we studied GHBP levels in peripheral lymph, whose composition approximates that of interstitial fluid. Lymph was collected in 13 healthy adult men from cannulated lymphatic vessels in the calf. Venous and arterial blood samples were collected from the femoral vein and radial artery contemporaneously with lymph collection. Potential GHBP production by endothelial or blood cells was assessed by examining conditioned medium from in vitro cell cultures. GHBP activity was measured by standardized GH binding/column chromatography assay. GHBP was consistently and significantly lower in lymph (mean +/- SD, 4.6 +/- 1.2% GH bound/200 microL) than in venous (14.1 +/- 3.0%) or arterial (14.9 +/- 3.6%) plasma. Conditioned medium from endothelial or blood cell cultures did not contain detectable GHBP. We conclude that the level of GHBP in peripheral lymph is substantially lower than that in the peripheral circulation, and that components of the vasculature are not important sources of GHBP. These findings suggests that 1) the main tissue sources of GHBP in man are the central organs (especially liver); and 2) transcapillary diffusion of GHBP into the interstitial space is restricted.

Skeletal muscle membrane lipid composition is related to adiposity and insulin action.

The cellular basis of insulin resistance is still unknown; however, relationships have been demonstrated between insulin action in muscle and the fatty acid profile of the major membrane structural lipid (phospholipid). The present study aimed to further investigate the hypothesis that insulin action and adiposity are associated with changes in the structural lipid composition of the cell. In 52 adult male Pima Indians, insulin action (euglycemic clamp), percentage body fat (pFAT; underwater weighing), and muscle phospholipid fatty acid composition (percutaneous biopsy of vastus lateralis) were determined. Insulin action (high-dose clamp; MZ) correlated with composite measures of membrane unsaturation (% C20-22 polyunsaturated fatty acids [r= 0.463, P < 0.001], unsaturation index [r= -0.369, P < 0.01]), a number of individual fatty acids and with delta5 desaturase activity (r= 0.451, P < 0.001). pFAT (range 14-53%) correlated with a number of individual fatty acids and delta5 desaturase activity (r= -0.610, P < 0.0001). Indices of elongase activity (r= -0.467, P < 0.001), and delta9 desaturase activity (r= 0.332, P < 0.05) were also related to pFAT but not insulin action. The results demonstrate that delta5 desaturase activity is independently related to both insulin resistance and obesity. While determining the mechanisms underlying this relationship is important for future investigations, strategies aimed at restoring "normal" enzyme activities, and membrane unsaturation, may have therapeutic importance in the "syndromes of insulin resistance."

In vivo beta-cell function at the transition to early non-insulin-dependent diabetes mellitus.

Impaired insulin secretion occurs at some stage in the development of non-insulin-dependent diabetes mellitus (NIDDM), possibly during impaired glucose tolerance (IGT) or early NIDDM. To assess insulin secretion at these critical stages, we measured the first-phase insulin response (to glucose and arginine), maximal secretory capacity, and glucose potentiation slope for insulin secretion in Pima Indians with normal glucose tolerance (n = 20), IGT (n = 9), and mild (fasting glucose < 7.8 mmol/L) NIDDM (n = 7). We also measured oral glucose tolerance and insulin action. Subjects with IGT were more insulin-resistant (P < .05) than normals. A wide range of insulin secretion was noted, although as a group, no significant impairment was detected. Subjects with mild NIDDM were similarly insulin-resistant, but they also had impaired insulin secretion. The first-phase response to glucose was markedly reduced in absolute terms (P < .001), but all secretion indices were impaired relative to the degree of insulin resistance (P = .05 to P < .0001). These results suggest that in Pima Indians, impairment of insulin secretion, especially the first-phase response to glucose, is associated with mild NIDDM. Insulin secretion in IGT is variable and, overall, seems intact, although a subtle defect in the first-phase insulin response to glucose could not be ruled out in this study. Glucose sensing for first-phase secretion may be one of the early secretory defects in the progression of glucose intolerance and seems to be critical at the transition from IGT to early NIDDM.

Glycemic response to stress is altered in euglycemic Pima Indians.

The aim of this work was to study the effects of a computer-driven mental arithmetic task on blood glucose in a group of four male and four female euglycemic Caucasians and a group of seven male and six female euglycemic Pima Indians. Approximately 60% of euglycemic Pima Indian Native Americans eventually develop type 2 diabetes, while only 5% of Caucasians develop the disease. All subjects had normal glucose tolerance. Subjects were given a standard breakfast; 2 h later, they were given a computerized mental arithmetic stress test for 10 min. Before, during and after the test, several variables were analyzed, including serum concentrations of glucose, insulin, glucagon and plasma cortisol and catecholamines. Heart rate, systolic and diastolic blood pressure and all the stress hormones increased during stress and decreased during recovery in all subjects. Blood glucose consistently declined one hour after the meal in all subjects. However, while it continued to decline following stress in seven out of eight Caucasian subjects, it consistently increased during and following stress in 10 out of 13 Pima Indians. Fasting serum glucose in Pima Indians and Caucasians was respectively 5.07 + 0.08 mM and 5.04 + 0.09 mM. Two-hour post-prandial values were 5.63 + 0.22 mM and 5.48 + 0.19 mM respectively, whereas post-stress values were 6.15 + 0.19 mM for Pima Indians and 5.22 + 0.20 mM for Caucasians. Both serum glucose means following stress (t = 3.1, P < 0.005) and the direction of change in serum glucose in response to mental arithmetic (chi 2 = 8.2, P < 0.01) clearly differentiated Pimas from Caucasians.(ABSTRACT TRUNCATED AT 250 WORDS)

Hyperinsulinemia is associated with menstrual irregularity and altered serum androgens in Pima Indian women.

To determine whether hyperinsulinemia is associated with menstrual irregularity or hyperandrogenemia among Pima Indians, a population with a high prevalence of hyperinsulinemia, we retrospectively studied 20 hyperinsulinemic (higher insulin [HI ) and 20 relatively nonhyperinsulinemic (lower insulin [LI]) nondiabetic Pima women 18 to 45 years of age. Reproductive histories were obtained by review of medical records. Stored serum samples were used for measurement of total testosterone, androstenedione, and dehydroepiandrosterone sulfate (DHEAS) levels. Fifty percent (nine of 18) of HI women had irregular menses, as compared with none of the LI women (0 of 19, P = .0004). HI women were significantly more obese than LI women. Serum testosterone and androstenedione levels were similar in HI and LI women (median testosterone, 1.13 v 1.13 nmol/L, P = .55; median androstenedione, 3.79 v 3.26 nmol/L, P = .90). Serum DHEAS was lower in HI than in LI women (median, 2.85 v 4.55 mumol/L, P < .01). HI women with irregular menses had significantly higher testosterone levels than HI women with regular menses (median, 1.62 v 0.76, nmol/L, P = .04). Androstenedione and DHEAS levels were not different between these women. In conclusion, the association of obesity, hyperinsulinemia, irregular menstruation, and high testosterone concentration described in the polycystic ovarian syndrome (PCO) also occurs in Pima Indian women. Moreover, low concentrations of DHEAS are associated with hyperinsulinemia in these women.

Interstitial insulin concentrations determine glucose uptake rates but not insulin resistance in lean and obese men.

Insulin action and obesity are both correlated with the density of muscle capillary supply in humans. Since the altered muscle anatomy in the obese might affect interstitial insulin concentrations and reduce insulin action, we have cannulated peripheral lymphatic vessels in lean and obese males, and compared peripheral lymph insulin concentrations with whole body glucose uptake during a euglycemic, hyperinsulinemic clamp. Lymph insulin concentrations in the lower limb averaged only 34% of arterial insulin concentrations during 150 min of insulin infusion. Obese subjects had the highest arterial (P < or = 0.0001) and lymph insulin (P < 0.005) concentrations, but the lowest glucose uptake rates (P < 0.002). In contrast to the initial steep rise then plateau of arterial insulins, both lymph insulin and whole body glucose uptake rates rose slowly and did not consistently reach a plateau. In each individual, the glucose uptake closely correlated with peripheral lymphatic insulin concentrations (mean r2 = 0.95). The coupling between glucose uptake and lymph insulin (glucose uptake/pmol insulin) was much steeper in lean subjects than in the obese (P < or = 0.0001). These results indicate that even if insulin diffusion into tissues is rate limiting for insulin action, a tissue defect rather than an insulin diffusion defect causes insulin resistance in obese subjects.

Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians.

BACKGROUND: The relative roles of obesity, insulin resistance, insulin secretory dysfunction, and excess hepatic glucose production in the development of non-insulin-dependent diabetes mellitus (NIDDM) are controversial. We conducted a prospective study to determine which of these factors predicted the development of the disease in a group of Pima Indians. METHODS: A body-composition assessment, oral and intravenous glucose-tolerance tests, and a hyperinsulinemic--euglycemic clamp study were performed in 200 non-diabetic Pima Indians (87 women and 113 men; mean [+/- SD] age, 26 +/- 6 years). The subjects were followed yearly thereafter for an average of 5.3 years. RESULTS: Diabetes developed in 38 subjects during follow-up. Obesity, insulin resistance (independent of obesity), and low acute plasma insulin response to intravenous glucose (with the degree of obesity and insulin resistance taken into account) were predictors of NIDDM: The six-year cumulative incidence of NIDDM was 39 percent in persons with values below the median for both insulin action and acute insulin response, 27 percent in those with values below the median for insulin action but above that for acute insulin response, 13 percent in those with values above the median for insulin action and below that for acute insulin response, and 0 in those with values originally above the median for both characteristics. CONCLUSIONS: 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.

Linkage of chromosomal markers on 4q with a putative gene determining maximal insulin action in Pima Indians.

Insulin action in vivo varies widely in nondiabetic Pima Indians. Not all of this variance is attributable to individual differences in obesity, physical fitness, sex, or age, and after correcting for these co-variates, measures of insulin action aggregate in families. Insulin action at maximally stimulating insulin concentrations has a trimodal frequency distribution, particularly among obese individuals. This is consistent with the hypothesis that a codominantly inherited autosomal gene, unrelated to obesity, determines MaxM in the population. Preliminary sib-pair linkage analyses indicated the possibility of linkage between MaxM and the GYPA/B locus (encoding the MNSs red cell surface antigens) on chromosome 4q. To confirm and extend these findings, 10 additional loci on 4q were typed in 123 siblings and many of their parents from 46 nuclear families. The results indicate significant (P < 0.001) linkage of the FABP2 and ANX5 loci on 4q with MaxM, and of FABP2 with fasting insulin concentration. No linkage was found between the 4q markers and obesity. Our findings indicate that a gene on 4q, near the FABP2 and ANX5 loci, contributes to in vivo insulin action in Pima Indians.

Lower sedentary metabolic rate in women compared with men.

Since females have a greater prevalence of obesity compared with males, the question arises whether females have lower metabolic rate than males after adjusting for differences in body weight and composition. 24-h energy expenditure (24EE), basal metabolic rate (BMR), and sleeping metabolic rate (SMR) were measured in a respiratory chamber in 235 healthy, nondiabetic Caucasian subjects (114 males, 121 females). Body composition was determined by hydrodensitometry. 24EE was 124 +/- 38 kcal/d (P less than 0.002) higher in males than females after adjusting for differences in fat-free mass, fat mass, and age. Spontaneous physical activity was not significantly different between males and females. Since adjusted 24EE was 106 +/- 39 kcal/d (P less than 0.01) higher in females during the luteal phase of the menstrual cycle compared with females during the follicular phase, energy expenditure was analyzed in a subset (greater than 50 yr) to minimize the confounding effect of menstrual status. 24EE (160 +/- 66 kcal/d; P less than 0.03), BMR (116 +/- 45; P less than 0.02), and SMR (208 +/- 68 kcal/d; P less than 0.005) were higher in males compared with females of the older subset after adjusting for differences in body composition, age, and activity. In summary, sedentary 24EE is approximately 5-10% lower in females compared with males after adjusting for differences in body composition, age, and activity.

Twenty-four-hour energy expenditure in Pima Indians with type 2 (non-insulin-dependent) diabetes mellitus.

To assess the impact of Type 2 (non-insulin-dependent) diabetes mellitus on energy metabolism, 24-h energy expenditure, basal metabolic rate and sleeping metabolic rate were measured in a respiratory chamber in 151 Pima Indians, 102 with normal glucose tolerance (67 male/35 female, (mean +/- SD) 28 +/- 7 years, 99 +/- 24 kg, 32 +/- 9% body fat) and in 49 with Type 2 diabetes (22 male/27 female, 35 +/- 11 years, 107 +/- 33 kg, 39 +/- 7% body fat), after at least 3 days on a weight maintaining diet. After adjustment for differences in fat-free mass, fat mass, age and sex, 24-h energy expenditure, basal metabolic rate and sleeping metabolic rate were significantly higher in diabetic patients than in control subjects (72 kcal/day, p less than 0.05; 99 kcal/day, p less than 0.005; 99 kcal/day, p less than 0.001 respectively). Spontaneous physical activity was similar in both groups whereas the thermic effect of food, calculated as the mean energy expenditure corrected for activity throughout the day above sleeping metabolic rate and expressed as a percentage of energy intake, was significantly lower in Type 2 diabetic patients (17.1 +/- 7.1 vs 19.8 +/- 5.6%, p less than 0.05). Adjusted values of 24-h energy expenditure, basal metabolic rate and sleeping metabolic rate were correlated with hepatic endogenous glucose production (r = 0.22, p less than 0.05; r = 0.22, p less than 0.05; r = 0.31, p less than 0.01 respectively). Therefore, increased basal and sleeping metabolic rates, resulting in increased 24-h sedentary energy expenditure may play a role in the weight loss so often observed in Type 2 diabetic subjects in addition to the energy loss from glycosuria.

Pima Indians as a model to study the genetics of NIDDM.

More than half the Pima Indians over 35 years of age have non-insulin dependent diabetes mellitus (NIDDM). They have been the focus of prospective epidemiologic and metabolic studies for over two decades and the data collected during these studies are now proving invaluable in efforts to find genetic markers for NIDDM in humans. The Pima Indian model of this disease affords two major advantages. The population is genetically homogeneous compared to Caucasian populations, and therefore the causes of NIDDM are less heterogeneous, simplifying genetic linkage studies. Equally important, based on results from metabolic studies, two pre-diabetic phenotypes have been identified in the Pimas: insulin resistance and a low metabolic rate. Use of these phenotypes in genetic linkage analyses should greatly improve chances of finding genetic markers for NIDDM since these phenotypes may be more closely related to the putative abnormal gene products, and actual disease genes, than is the hyperglycemia of the fully developed phenotype of NIDDM.

Peripheral lymphatic cannulation for physiological analysis of interstitial fluid compartment in humans.

Analysis of peripheral interstitial concentrations of hormones or substrates in humans has undoubtedly been hampered by the difficulty in performing retrograde peripheral lymphatic cannulation and obtaining adequate flow rates of lymph. We now describe a technique for direct continuous sampling of peripheral lymph. A lymphatic vessel was cannulated in the lower legs of 14 males, and lymph was collected for 24-48 h. Adequate quantities of lymph were obtained basally and during physiological manipulations to make collections at 15-min intervals. Flow rates averaged 1.84 ml/h and ranged from 0.34 to 4.96 ml/h. We conclude that peripheral lymphatic vessels can be cannulated and flow rates are sufficient to measure interstitial concentration of hormones or substrates both at steady state and dynamically in adult humans.

Basal and insulin-mediated carbohydrate metabolism in human muscle deficient in phosphofructokinase 1.

Biopsies were obtained from the quadriceps femoris muscle of two male patients deficient in phosphofructokinase (PFK) 1. In the basal state the patients had markedly higher contents of UDP-glucose (approximately 5-fold), hexose monophosphates (approximately 7- to 13-fold), inosine monophosphate (IMP) (approximately 15-fold), and fructose 2,6-bisphosphate (F-2,6-P2; approximately 6-fold) than controls. Fructose 1,6-bisphosphate was not detectable, and phosphocreatine was lower (33 and 54 mmol/kg dry wt) than in controls [72 +/- 4 (SD)]. Patients had normal fasting plasma glucose and insulin levels and basal glucose turnover rates and responded normally to a 75-g oral glucose challenge. Patients were also studied during euglycemic hyperinsulinemia (approximately 95 mg/dl; 40 and 400 mU.m-2.min-1). Whole body glucose disposal rates were normal during both insulin infusion rates. Biopsies taken after the 400 mU insulin infusion showed decreases in acetylcarnitine and citrate and increases in the fractional activity of glycogen synthase. It is suggested that the high basal levels of F-2,6-P2 are, at least partly, a consequence of the high levels of fructose 6-phosphate, which will stimulate flux through PFK-2 and inhibit fructose-2,6-bisphosphatase. The low phosphocreatine and high IMP contents indicate that carbohydrate availability is important for control of high-energy phosphate metabolism, even in the basal state. The insulin-mediated decreases in acetylcarnitine and citrate suggest an activation of the tricarboxylic acid cycle in skeletal muscle but an absence of the normal response to replenish these intermediates.

Exaggerated early insulin release and insulin resistance in a diabetes-prone population: a metabolic comparison of Pima Indians and Caucasians.

Pima Indians have the highest reported prevalence rate of noninsulin-dependent diabetes mellitus (NIDDM) in the world, so that metabolic comparisons with caucasians, who have a much lower rate, should provide insights into the pathogenesis of NIDDM. We have compared 81 caucasians with 211 Pima Indian nondiabetic subjects similar in age, sex, degree of obesity, and glucose tolerance. During a hyperinsulinemic euglycemic clamp at physiological insulin concentrations, Pima Indians were 17% more insulin resistant than caucasians after accounting for any differences in degree of obesity (P less than 0.0001). During oral glucose tolerance testing, mean plasma insulin concentrations were 33% higher in the Pimas (P less than 0.0001), but these differences were largely explained by the greater insulin resistance in the Pimas. Insulin clearance did not differ between the races. However, early insulin responses were exaggerated in the Indians and not explained by insulin resistance. After accounting for differences in insulin action, plasma insulin concentrations in Pima Indians were 50% higher than those in caucasians 3-5 min after iv glucose (P less than 0.0001), 38% higher 10 min after the end of a meal (P less than 0.0001), and 20% higher 30 min after an oral glucose load (P less than 0.006). These data suggest that in addition to insulin resistance, Pima Indians have exaggerated early insulin release and either increased beta-cell mass or enhanced beta-cell sensitivity to glucose. The data argue against low or delayed insulin secretion as primary factors leading to NIDDM in Pima Indians and favor insulin resistance as the underlying and initiating cause of the disease.