Increased Left Ventricular Torsion in Uncomplicated Type 1 Diabetic Patients: The role of coronary microvascular function

We used speckle tracking echocardiography to study the early changes in left ventricular (LV) torsion in young patients with uncomplicated type 1 diabetes and stress magnetic resonance imaging (MRI) to assess its interrelationships with coronary microangiopathy

The prion-like RNA-processing protein HNRPDL forms inherently toxic amyloid-like inclusion bodies in bacteria

BACKGROUND: The formation of protein inclusions is connected to the onset of many human diseases. Human RNA binding proteins containing intrinsically disordered regions with an amino acid composition resembling those of yeast prion domains, like TDP-43 or FUS, are being found to aggregate in different neurodegenerative disorders. The structure of the intracellular inclusions formed by these proteins is still unclear and whether these deposits have an amyloid nature or not is a matter of debate. Recently, the aggregation of TDP-43 has been modelled in bacteria, showing that TDP-43 inclusion bodies (IBs) are amorphous but intrinsically neurotoxic. This observation raises the question of whether it is indeed the lack of an ordered structure in these human prion-like protein aggregates the underlying cause of their toxicity in different pathological states. RESULTS: Here we characterize the IBs formed by the human prion-like RNA-processing protein HNRPDL. HNRPDL is linked to the development of limb-girdle muscular dystrophy 1G and shares domain architecture with TDP-43. We show that HNRPDL IBs display characteristic amyloid hallmarks, since these aggregates bind to amyloid dyes in vitro and inside the cell, they are enriched in intermolecular β-sheet conformation and contain inner amyloid-like fibrillar structure. In addition, despite their ordered structure, HNRPDL IBs are highly neurotoxic. CONCLUSIONS: Our results suggest that at least some of the disorders caused by the aggregation of human prion-like proteins would rely on the formation of classical amyloid assemblies rather than being caused by amorphous aggregates. They also illustrate the power of microbial cell factories to model amyloid aggregation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12934-015-0284-7) contains supplementary material, which is available to authorized users

Relationship between coronary microvascular dysfunction and cardiac energetics impairment in type 1 diabetes mellitus

BACKGROUND: Asymptomatic subjects with diabetes mellitus have an impaired cardiac energetics status that may play a significant role in the development of heart failure. In the present study, we assessed the role of microvascular dysfunction in the development of impaired cardiac energetics in subjects with type 1 diabetes mellitus. METHODS AND RESULTS: Twenty-five asymptomatic subjects with type 1 diabetes mellitus (mean age +/-1 SD 33+/-8 years) and 26 age-, sex-, and body mass index-matched healthy control subjects (32+/-8 years old) were recruited into the study. The type 1 diabetes mellitus subjects were divided into 2 age-matched groups (newly diagnosed [10 years] diabetes) to assess the impact of microvascular disease. All subjects had an echocardiogram and an exercise ECG performed, followed by magnetic resonance spectroscopy and stress magnetic resonance imaging. Compared with healthy control subjects, the phosphocreatine/gamma-ATP ratio was reduced significantly both in subjects with longer-term (2.1+/-0.5 versus 1.5+/-0.4, P<0.000) and newly diagnosed (2.1+/-0.5 versus 1.6+/-0.2, P<0.000) diabetes. The phosphocreatine/gamma-ATP ratio was similar in newly diagnosed diabetes subjects and those with longer-term disease (1.6+/-0.2 versus 1.5+/-0.4, P=0.32). The mean myocardial perfusion reserve index in the longer-term type 1 diabetes mellitus subjects was significantly lower than in healthy control subjects (1.7+/-0.6 versus 2.3+/-0.4, P=0.005). On univariate analysis, there was no significant correlation of phosphocreatine/gamma-ATP ratio with myocardial perfusion reserve index (r=0.21, P=0.26). CONCLUSIONS: We demonstrate that young subjects with uncomplicated type 1 diabetes mellitus have impaired myocardial energetics irrespective of the duration of diabetes and that the impaired cardiac energetics status is independent of coronary microvascular function. We postulate that impairment of cardiac energetics in these subjects primarily results from metabolic dysfunction rather than microvascular impairment