FGF21 is a Hormonal Mediator of the Human "Thrifty" Metabolic Phenotype

Fibroblast growth factor 21 (FGF21) regulates energy expenditure (EE) and influences weight change after low-protein overfeeding in rodent models. The change in EE after low-protein overfeeding diet is a predictor of weight change in humans and a feature of the "thrifty" metabolic phenotype. However, there are no studies showing an association between circulating FGF21 and EE in humans. We assessed the changes in plasma FGF21 concentrations after 24 hours of seven dietary interventions with different macronutrient content while in a whole-room indirect calorimeter in 64 healthy subjects with normal glucose regulation. Plasma FGF21 concentration consistently increased by 3-fold only after the two low-protein (3%) overfeeding diets, one high in carbohydrate (75%) and the other high in fat (46%), with larger increases in FGF21 being associated with greater increases in 24-h EE. Subjects with smaller increases in FGF21 after the low-protein high-fat diet gained more weight after six months in free-living conditions. Therefore, the individual predisposition to weight gain over time can be assessed by 24-h overfeeding a low-protein diet and measurements of plasma FGF21 concentrations. Individuals with a blunted FGF21 response to a low-protein diet have a thrifty metabolism and are at risk for future weight gain

Association Analyses of Variants in the DIO2 Gene with Early-Onset Type 2 Diabetes Mellitus in Pima Indians

Background: The type 2 deiodinase gene (DIO2) encodes a deiodinase that converts the thyroid prohormone, thyroxine, to the biologically active triiodothyronine. Thyroid hormones regulate energy balance and may also influence glucose metabolism. Therefore, we hypothesized that variations in DIO2 could contribute to obesity or type 2 diabetes mellitus (T2DM) in Pima Indians. Methods: Sequencing of the DIO2 gene in DNA from 83 Pima Indians identified 12 single-nucleotide polymorphisms (SNPs). Several of these SNPs were in perfect genotypic concordance among the 83 samples that were sequenced, and all 12 could be divided into five linkage disequilibrium groups. One representative SNP from each group (Thr92Ala, rs225011, rs225015, rs6574549, and a rare 5¢ flanking SNP) was selected for further genotyping for association analyses. In this study, the five selected variants in DIO2, as described above, were genotyped in three groups of Pima Indians: (i) a case (n = 150)/control (n = 150) group for early-onset T2DM (onset age \u3c 25 years); (ii) a case (n = 362)/control (n = 127) group for obesity; (iii) a large (n = 1,311, cases n = 810/ controls n = 501) family-based group, of which 256 nondiabetic subjects had undergone detailed metabolic phenotyping. Results: The Thr92Ala variant common in Pima Indians, rs225011, and rs225015 were modestly associated with early-onset T2DM ( p = 0.01–0.04) in the case–control study, but were not associated with obesity in the obesity case–control study, nor associated with T2DM (at any age) or body–mass index (BMI; as a quantitative trait) in the family-based analysis. Thr92Ala, rs225011, rs225015, and rs6574549 were also nominally associated with hepatic glucose output ( p = 0.02). rs6574549 was associated with fasting insulin ( p = 0.02), insulin action ( p = 0.04), and energy expenditure ( p = 0.02). None of these nominal associations remained statistically significant after corrections for multiple testing. Conclusions: We propose that variation in DIO2 may have a subtle role in altering metabolic processes that lead to early-onset T2DM, but this gene does not have a large impact on T2DM at older ages, nor does DIO2 influence BMI in the Pima Indian population. Introductio

Insulin resistance and insulin secretory dysfunction are independent predictors of worsening of glucose tolerance during each stage of type 2 diabetes development

WSTĘP. Chociaż wyniki prospektywnych prac wskazują, że zaburzenia działania i wydzielania insuliny zapowiadają wystąpienie cukrzycy typu 2, jednakże nie dostarczają one dostatecznych informacji o współudziale tych dwóch czynników w pogarszaniu tolerancji glukozy w różnych okresach rozwoju cukrzycy typu 2. Dlatego autorzy podjęli próbę niezależnej oceny wpływu zaburzeń wydzielania i działania insuliny na przejście od stanu prawidłowej tolerancji glukozy (NGT, normal glucose tolerance) do tolerancji nieprawidłowej (IGT, impaired glucose tolerance) i ze stanu IGT w cukrzycę. MATERIAŁ I METODY. U 254 Indian Pima z NGT i u 145 z IGT autorzy badali stymulowane insuliną usuwanie glukozy (M) (klamra hiperinsulinowa), wielkość wydzielania insuliny w fazie wczesnej (AIR, acute insulin secretory response) (25-gramowy dożylny test tolerancji glukozy) i zawartość składników ciała (hydrodensytometria lub ilościowa radiografia cyfrowa). Czas obserwacji tych osób wynosił 0,5&#8211;13 lat. WYNIKI. Po okresie obserwacji 4,4 &plusmn; 3,1 i 5,5 &plusmn; 3,4 lat u 79 (31%) osób, u których początkowo występowała NGT, rozwinęła się IGT, a u 64 (44%) osób z początkową IGT rozwinęła się cukrzyca. Analiza statystyczna przeprowadzona z uwzględnieniem wieku, płci i zawartości procentowej tłuszczu wskazała na niskie M i niskie AIR jako niezależne czynniki określające ryzyko przejścia od NGT do IGT (względne ryzyko [95% CI] dla 10. vs 90. percentyla: M 2,4 [1,2&#8211;4,7], p < 0,02; AIR 2,1 [1,1&#8211;4,1], p < 0,04), a dla przejścia IGT w cukrzycę (M 2,5 [1,3&#8211;5,0], p < 0,01; AIR 1,8 [0,99&#8211;3,3], p = 0,055). WNIOSKI. Zarówno zaburzenia w działaniu, jak i upośledzenie wydzielania insuliny są niezależnymi czynnikami zapowiadającymi pogorszenie tolerancji glukozy na każdym etapie rozwoju cukrzycy i oba powinny stanowić cel prewencji pierwotnej cukrzycy typu 2.OBJECTIVE. Although prospective studies indicate that insulin resistance and insulin secretory dysfunction predict type 2 diabetes, they provide limited information on the relative contributions of both abnormalities to worsening glucose tolerance at different developmental stages of the disease. We therefore assessed the predictive effect of insulin resistance and insulin secretory dysfunction separately for the progression from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) and from IGT to diabetes. RESEARCH DESIGN AND METHODS. Insulin-stimulated glucose disposal (M) (hyperinsulinemic clamp), acute insulin secretory response (AIR) (25-g intravenous glucose tolerance test), and body composition (hydrodensitometry or dual-energy X-ray absorptiometry) were measured in 254 Pima Indians with NGT and in 145 Pima Indians with IGT, who were then followed for 0.5&#150;13 years. RESULTS. After follow-ups of 4.4 &#177; 3.1 and 5.5 &#177; 3.4 years, 79 (31%) of the subjects with initial NGT had developed IGT, and 64 (44%) of the subjects with initial IGT had developed diabetes. In proportional-hazards analyses with adjustment for age, sex, and percent body fat, low M and low AIR were independent predictors of both the progression from NGT to IGT (relative hazards [95% CI] for 10th vs. 90th percentile: M2.4 [1.2&#150;4.7], P < 0.02; AIR 2.1 [1.1&#150;4.1], P < 0.04) and from IGT to diabetes (M2.5 [1.3&#150;5.0], P < 0.01; AIR 1.8 [0.99&#150;3.3], P = 0.055). CONCLUSIONS. During each stage of the development of type 2 diabetes, insulin resistance and insulin secretory dysfunction are independent predictors of worsening glucose tolerance and are, therefore, both targets for the primary prevention of the disease

Bimodal distribution of RNA expression levels in human skeletal muscle tissue

<p>Abstract</p> <p>Background</p> <p>Many human diseases and phenotypes are related to RNA expression, levels of which are influenced by a wide spectrum of genetic and exposure-related factors. In a large genome-wide study of muscle tissue expression, we found that some genes exhibited a bimodal distribution of RNA expression, in contrast to what is usually assumed in studies of a single healthy tissue. As bimodality has classically been considered a hallmark of genetic control, we assessed the genome-wide prevalence, cause, and association of this phenomenon with diabetes-related phenotypes in skeletal muscle tissue from 225 healthy Pima Indians using exon array expression chips.</p> <p>Results</p> <p>Two independent batches of microarrays were used for bimodal assessment and comparison. Of the 17,881 genes analyzed, eight (<it>GSTM1, HLA-DRB1, ERAP2, HLA-DRB5, MAOA, ACTN3, NR4A2</it>, and <it>THNSL2</it>) were found to have bimodal expression replicated in the separate batch groups, while 24 other genes had evidence of bimodality in only one group. Some bimodally expressed genes had modest associations with pre-diabetic phenotypes, of note <it>ACTN3 </it>with insulin resistance. Most of the other bimodal genes have been reported to be involved with various other diseases and characteristics. Association of expression with <it>cis </it>genetic variation in a subset of 149 individuals found all but one of the confirmed bimodal genes and nearly half of all potential ones to be highly significant expression quantitative trait loci (eQTL). The rare prevalence of these bimodally expressed genes found after controlling for batch effects was much lower than the prevalence reported in other studies. Additional validation in data from separate muscle expression studies confirmed the low prevalence of bimodality we observed.</p> <p>Conclusions</p> <p>We conclude that the prevalence of bimodal gene expression is quite rare in healthy muscle tissue (<0.2%), and is much lower than limited reports from other studies. The major cause of these clearly bimodal expression patterns in homogeneous tissue appears to be <it>cis</it>-polymorphisms, indicating that such bimodal genes are, for the most part, eQTL. The high frequency of disease associations reported with these genes gives hope that this unique feature may identify or actually be an underlying factor responsible for disease development.</p

VO₂max is associated with measures of energy expenditure in sedentary condition but does not predict weight change

Background/Objectives Energy expenditure measured under sedentary conditions predicts weight change but evidence that directly measured VO2max is associated with weight change is lacking. The aim of this study was to determine the associations of VO2max with measures of predominantly sedentary 24-h thermogenesis, and subsequent weight change. Subjects/Methods Three hundred fifty-seven individuals (162 females; 27 Blacks, 72 Caucasians, and 258 American Indians) had measures of body composition, resting metabolic rate (RMR), and intermittent treadmill run test for assessment of VO2max. On a separate day, 24-h energy expenditure (EE), diet-induced thermogenesis (DIT) expressed as “awake and fed” thermogenesis (AFT), sleeping metabolic rate (SMR), and spontaneous physical activity (SPA) were measured in a whole-room indirect calorimeter. Follow-up weight for 217 individuals was available (median follow-up time, 9.5 y; mean weight change, 12.4 ± 14.9 kg). Results After adjustment for fat free mass, fat mass, age, sex, and race, a higher VO2max was associated with a higher RMR (β = 68.2 kcal/day per L/min, P &lt; 0.01) and 24-h EE (β = 62.2 kcal/day per L/min, P &lt; 0.05) and including additional adjustment for energy intake higher AFT (β = 66.1 kcal/day per L/min, P = 0.01). Neither SMR (P &gt; 0.2) nor SPA (P &gt; 0.8) were associated with VO2max. VO2max at baseline did not predict follow-up weight after adjustment for baseline weight, follow-up time, sex, and race (P &gt; 0.4). Conclusion VO2max is associated with measures of EE including 24-h EE, RMR and DIT implying a common mechanism regulating the energetics of skeletal muscle during exercise and thermogenesis. However, this did not translate to VO2max as a predictor of weight change