Early-onset and classical forms of type 2 diabetes show impaired expression of genes involved in muscle branched-chain amino acids metabolism

Abstract The molecular mechanisms responsible for the pathophysiological traits of type 2 diabetes are incompletely understood. Here we have performed transcriptomic analysis in skeletal muscle, and plasma metabolomics from subjects with classical and early-onset forms of type 2 diabetes (T2D). Focused studies were also performed in tissues from ob/ob and db/db mice. We document that T2D, both early and late onset, are characterized by reduced muscle expression of genes involved in branched-chain amino acids (BCAA) metabolism. Weighted Co-expression Networks Analysis provided support to idea that the BCAA genes are relevant in the pathophysiology of type 2 diabetes, and that mitochondrial BCAA management is impaired in skeletal muscle from T2D patients. In diabetic mice model we detected alterations in skeletal muscle proteins involved in BCAA metabolism but not in obese mice. Metabolomic analysis revealed increased levels of branched-chain keto acids (BCKA), and BCAA in plasma of T2D patients, which may result from the disruption of muscle BCAA management. Our data support the view that inhibition of genes involved in BCAA handling in skeletal muscle takes place as part of the pathophysiology of type 2 diabetes, and this occurs both in early-onset and in classical type 2 diabetes

Early-onset and classical forms of type 2 diabetes show impaired expression of genes involved in muscle branched-chain amino acids metabolism

The molecular mechanisms responsible for the pathophysiological traits of type 2 diabetes are incompletely understood. Here we have performed transcriptomic analysis in skeletal muscle, and plasma metabolomics from subjects with classical and early-onset forms of type 2 diabetes (T2D). Focused studies were also performed in tissues from ob/ob and db/db mice. We document that T2D, both early and late onset, are characterized by reduced muscle expression of genes involved in branched-chain amino acids (BCAA) metabolism. Weighted Co-expression Networks Analysis provided support to idea that the BCAA genes are relevant in the pathophysiology of type 2 diabetes, and that mitochondrial BCAA management is impaired in skeletal muscle from T2D patients. In diabetic mice model we detected alterations in skeletal muscle proteins involved in BCAA metabolism but not in obese mice. Metabolomic analysis revealed increased levels of branched-chain keto acids (BCKA), and BCAA in plasma of T2D patients, which may result from the disruption of muscle BCAA management. Our data support the view that inhibition of genes involved in BCAA handling in skeletal muscle takes place as part of the pathophysiology of type 2 diabetes, and this occurs both in early-onset and in classical type 2 diabetes

A polymorphism in the gene encoding carnosinase (CNDP1) as a predictor of mortality and progression from nephropathy to end-stage renal disease in type 1 diabetes mellitus

Aims/hypothesis Homozygosity for a five leucine repeat (5L-5L) in the carnosinase gene (CNDP1) has been found to be cross-sectionally associated with a low frequency of diabetic nephropathy (DN), mainly in type 2 diabetes. We prospectively investigated in patients with type I diabetes whether: (1) 5L-5L is associated with mortality; (2) there is an interaction of 5L-5L with DN or sex for prediction of mortality; and (3) 5L-5L is associated with progression to end-stage renal disease (ESRD). Methods In this prospective study in white European patients with type 1 diabetes, individuals with DN were defined by persistent albuminuria >= 300 mg/24 h. Controls without nephropathy were defined by persistent (>15 years) normoalbuminuria Results The study involved 916 patients with DN and 1,170 controls. During follow-up for 8.8 years, 107 patients (14%) with 5L-5L died compared with 182 patients (13.8%) with other genotypes (p=0.99). There was no significant interaction of 5L-5L with DN for prediction of mortality (p=0.57), but a trend towards interaction with sex (p=0.08). In patients with DN, HR for ESRD in 5L-5L vs other genotypes was not constant over time, with increased risk for 5L-5L beyond 8 years of follow-up (p=0.03). Conclusions/interpretation CNDP1 polymorphism was not associated with mortality, and nor was there an interaction of this polymorphism with DN for prediction of mortality in patients with type 1 diabetes. CNDP1 polymorphism predicts progression to ESRD in patients with DN, but only late after baseline measurements

Temperature dependence of spin fluctuation scattering of neutrons on pyrrhotite

By means of the triple axis Cracow neutron spectrometer installed at Vinca (Yugoslavia), coherent inelastic scattering of monochromatic neutrons (λ0 = 1.376 Å) connected with τ = (001) was investigated at various temperatures above room temperature up to 400 °C, i.e. above the critical point (TN = 320 °C) of the spin alignment in pyrrhotite. The intensity of the (001) scattering cone increases with temperature but its magnon character does not change. Only at temperatures above 200 °C do the widths of the magnon peaks begin to increase. This temperature is not very sensitive to the energy of a given magnon group. The high degree of inelasticity is maintained over the critical point region and the mean energy transfer is close to the one for low temperatures. The results are discussed in terms of magnon lifetime and temperature dependence of effective exchange coupling.A l'aide du spectromètre à neutrons triple axe de Cracovie installé à Vinca (Yougoslavie), la diffusion cohérente inélastique des neutrons de longueur d'onde λ = 1,376 Å liée au point τ = (001) a été étudiée à différentes températures jusqu'à 400 °C, c'est-à-dire, bien au-dessus de la température critique (TN = 320 °C). L'intensité du cône de diffusion (001), augmente avec la température, mais son caractère « magnon » reste sans changement. Néanmoins, à partir de 200 °C, les raies « magnons » commencent à s'élargir. Cette température n'est pas très sensible à l'énergie d'un groupe de magnons donnés. Le degré élevé d'inélasticité se maintient au-dessus de la température critique, et le transfert moyen d'énergie reste très voisin de celui à basse température. Les résultats sont discutés en fonction de la durée de vie des magnons et de l'effet de la température sur le couplage d'échange effectif