Dysregulation of Glucagon Secretion by Hyperglycemia-Induced Sodium-Dependent Reduction of ATP Production

© 2018 The Author(s). Published by Elsevier Inc.Diabetes is a bihormonal disorder resulting from combined insulin and glucagon secretion defects. Mice lacking fumarase (Fh1) in their β cells (Fh1βKO mice) develop progressive hyperglycemia and dysregulated glucagon secretion similar to that seen in diabetic patients (too much at high glucose and too little at low glucose). The glucagon secretion defects are corrected by low concentrations of tolbutamide and prevented by the sodium-glucose transport (SGLT) inhibitor phlorizin. These data link hyperglycemia, intracellular Na+ accumulation, and acidification to impaired mitochondrial metabolism, reduced ATP production, and dysregulated glucagon secretion. Protein succination, reflecting reduced activity of fumarase, is observed in α cells from hyperglycemic Fh1βKO and β-V59M gain-of-function KATP channel mice, diabetic Goto-Kakizaki rats, and patients with type 2 diabetes. Succination is also observed in renal tubular cells and cardiomyocytes from hyperglycemic Fh1βKO mice, suggesting that the model can be extended to other SGLT-expressing cells and may explain part of the spectrum of diabetic complications.Peer reviewe

A randomized trial involving a multifunctional diet reveals systematic lipid remodeling and improvements in cardiometabolic risk factors in middle aged to aged adults

BackgroundA multifunctional diet (MFD) combining foods and ingredients with proven functional properties, such as fatty fish and fiber-rich foods, among others, was developed and shown to markedly reduce cardiometabolic risk-associated factors.ObjectiveHere, we aim at examining metabolic physiological changes associated with these improvements.MethodsAdult overweight individuals without other risk factors were enrolled in an 8-week randomized controlled intervention following a parallel design, with one group (n = 23) following MFD and one group (n = 24) adhering to a control diet (CD) that followed the caloric formula (E%) advised by the Nordic Nutritional Recommendations. Plasma metabolites and lipids were profiled by gas chromatography and ultrahigh performance liquid chromatography/mass spectrometry.ResultsWeight loss was similar between groups. The MFD and CD resulted in altered levels of 137 and 78 metabolites, respectively. Out of these, 83 were uniquely altered by the MFD and only 24 by the CD. The MFD-elicited alterations in lipid levels depended on carbon number and degree of unsaturation.ConclusionAn MFD elicits weight loss-independent systematic lipid remodeling, promoting increased circulating levels of long and highly unsaturated lipids.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT02148653?term=NCT02148653&draw=2&rank=1, NCT02148653

The mosaic oat genome gives insights into a uniquely healthy cereal crop

Cultivated oat (Avena sativa L.) is an allohexaploid (AACCDD, 2n = 6x = 42) thought to have been domesticated more than 3,000 years ago while growing as a weed in wheat, emmer and barley fields in Anatolia1,2. Oat has a low carbon footprint, substantial health benefits and the potential to replace animal-based food products. However, the lack of a fully annotated reference genome has hampered efforts to deconvolute its complex evolutionary history and functional gene dynamics. Here we present a high-quality reference genome of A. sativa and close relatives of its diploid (Avena longiglumis, AA, 2n = 14) and tetraploid (Avena insularis, CCDD, 2n = 4x = 28) progenitors. We reveal the mosaic structure of the oat genome, trace large-scale genomic reorganizations in the polyploidization history of oat and illustrate a breeding barrier associated with the genome architecture of oat. We showcase detailed analyses of gene families implicated in human health and nutrition, which adds to the evidence supporting oat safety in gluten-free diets, and we perform mapping-by-sequencing of an agronomic trait related to water-use efficiency. This resource for the Avena genus will help to leverage knowledge from other cereal genomes, improve understanding of basic oat biology and accelerate genomics-assisted breeding and reanalysis of quantitative trait studies

EHD2 regulates plasma membrane integrity and downstream insulin receptor signalling events

Adipocyte dysfunction is a crucial driver of insulin resistance and type 2 diabetes. We identified EH domain-containing protein 2 (EHD2) as one of the most highly upregulated genes at the early stage of adipose tissue expansion. EHD2 is a dynamin-related ATPase influencing several cellular processes, including membrane recycling, caveolae dynamics and lipid metabolism. Here, we investigated the role of EHD2 in adipocyte insulin signalling and glucose transport. Using C57BL6/N EHD2 knockout mice under short-term high-fat diet conditions and 3T3-L1 adipocytes we demonstrate that EHD2 deficiency is associated with deterioration of insulin signal transduction and impaired insulin-stimulated GLUT4 translocation. Furthermore, we show that lack of EHD2 is linked with altered plasma membrane lipid and protein composition, reduced insulin receptor expression, and diminished insulin-dependent SNARE protein complex formation. In conclusion, these data highlight the importance of EHD2 for the integrity of the plasma membrane milieu, insulin receptor stability, and downstream insulin receptor signalling events, involved in glucose uptake and ultimately underscore its role in insulin resistance and obesity

Nanoparticle-based capillary electrochromatography

This thesis concerns a highly efficient nanoparticle-based capillary electrochromatography separation technique and its coupling with mass spectrometric detection. From chromatographic theory, it is well known that the separation efficiency increases with decreasing particle size. However, as the particle size decreases, the pressure required to push a liquid through the column also increases. This increase in back pressure results in problems both in packing and use of the columns. Therefore, there is a limitation on how small the particles used in traditional chromatography can be. In this thesis, a method is described that is based on capillary electrochromatography using a suspension of nanoparticles as a pseudostationary phase. With these nanoparticle suspensions, separation efficiencies as high as 1.1 million plates per meter were obtained. The technique can be used with very small particles, and there is rather an upper limit on particle sizes due to loss of suspension stability. The nanoparticles have a charge-to-size ratio that is different from that of the analytes. Consequently, the velocity of the nanoparticles is different from the velocity of the analytes under an applied electric field. The analytes are thus separated due to the difference in their partitioning between the liquid phase and the nanoparticle phase. In the thesis, three fundamentally different nanoparticle types have been synthesised and used. Molecularly imprinted polymer nanoparticles have been used for enantiomer separations, highly charged nanoparticles have been used for ion chromatographic separations, and hydrophobic nanoparticles have been used for reversed-phase separations. Thus, the technique can be applied to a broad range of different separation problems, and some examples are demonstrated here. The presented technique has several advantages over traditional chromatography performed with immobilised interaction phases. The nanoparticle suspension is exchanged after every separation, and thus, problems due to adsorption of sample components to the interaction phase are absent. Also, inexpensive bare fused silica capillaries are used and clogging or other damage to the capillary does not result in high costs. Therefore, the technique has great potential for analysis of complex samples such as blood plasma and urine. Determination of theophylline in spiked blood plasma was performed. Also, changes in interaction phase, in terms of type and amount, can be made without changing the column or capillary. Combinations of different nanoparticles can be used to resolve complex samples in a novel multimode fashion. This technique was used for simultaneous separation of the enantiomers of two different analytes. Compared to other separation techniques that employ relatively low molecular weight pseudostationary phases, such as proteins, surfactants and cyclodextrins, the nanoparticle-based interaction phases was shown to have improved compatibility with mass spectrometric detection. With an orthogonal electrospray ionisation interface, the analytes could be separated from the nanoparticles prior to mass spectrometric detection. Sensitive detection of the analytes without degradation of analyte signal intensity was achieved

A new approach to capillary electrochromatography: Disposable molecularly imprinted nanoparticles

Nanoparticle phases have provided a new technique for CEC that avoids the time-consuming procedure for packing capillary columns. Frits are not required in the separation channel, and because the pseudo-stationary phase is discarded after every separation, each run proceeds with an entirely new phase. Moreover, the monolithic molecularly imprinted polymer permits a high sample load to be used

A comparative study of the fatty acid profile of common fruits and fruits claimed to confer health benefits

This study aims to verify the nutritional value of the fatty acid (FA) profile of three fruits claimed to confer health benefits (goji berry, white mulberry, and cranberry), often referred to as “superfruits”, over three common fruits (banana, apple, and strawberry). Nineteen different FAs, ranging in concentrations between 0.018 and 9.4 mg/g dry sample were detected. Levels of very long-chained FAs were highest in cranberries, oleic acid was most abundant in goji berries, alpha-linolenic acid showed high levels in strawberries and linoleic acid showed high levels in goji berries and white mulberries. The ratio of unsaturated to saturated FAs was highest in strawberries and goji berries, and the ratio of odd-carbon to even carbon saturated FAs was high in all common fruits, whereas among the superfruits both goji- and white mulberries showed very low ratios. Finally, the ratio of very long-chain to long-chain FAs showed the highest levels in cranberries and apples. A composite measure of the FA profile suggests apples and cranberries to show the most beneficial lipid profile. However, a common and beneficial lipid profile was not found in the superfruits as compared to more common fruits

Metabolomics Analysis of Nutrient Metabolism in β-Cells

The islets of Langerhans harbor multiple endocrine cell types that continuously respond to circulating nutrient levels in order to adjust their secretion of catabolic and anabolic hormones. Stimulus–secretion coupling in these cells is largely of metabolic nature; that is, metabolism of nutrient fuels yields signals that trigger and amplify secretion of hormones. Hence, metabolism in this micro-organ is in a major way in control of whole-body metabolism. Therefore, insights into islet metabolism are critical to understand how secretion of insulin is regulated and why it is perturbed in type 2 diabetes. Metabolomics aims at characterizing a wide spectrum of metabolites in cells, tissues and body fluids. For this reason, this technique is well suited to supply information on stimulus–secretion coupling. Here, we summarize metabolomics studies in islets and β-cells, highlight important discoveries that would have been difficult to make without this technology but also raise awareness of challenges and bottlenecks that curtail its use in metabolic research

Selectivity toward multiple predetermined targets in nanoparticle capillary electrochromatography.

Two unique methods to achieve selectivity toward multiple predetermined targets employing molecular imprinting technology have been developed. Partial filling capillary electrochromatography (CEC) was utilized to evaluate and compare the two techniques. The first approach, the mixed singly templated molecularly imprinted polymer (MIP) nanoparticle approach, is based on the mixing of two types of MIP nanoparticles with inherently different selectivity. The second approach, the multiply templated MIP nanoparticle approach, is based on the incorporation of two different templates during the preparation of the MIP nanoparticles. The use of MIPs in analytical chemistry applications has been extensively investigated during the past years. However, MIP nanoparticles with tailored multiple selectivity toward predetermined enantiomers has not yet been explored. The relative amounts of the two templates studied, i.e., (S)-ropivacaine and (S)-propranolol, were found to strongly affect the affinity of the multiply templated MIP nanoparticles for the predetermined targets. The amount of (S)-propranolol template had to be decreased to concentrations rarely applied in MIP synthesis in order to achieve 2-fold selectivity. Even though strongly decreased to 10% of the usual concentration employed, the MIP could efficiently separate the enantiomers of propranolol when applied in partial filling CEC. This opens up for new possibilities to decrease the need for an initial high amount of template in order to be able to produce an efficient MIP. The multiple enantiomer separation ability of the multiply templated MIP nanoparticles was compared with that of singly templated MIP nanoparticles that were mixed prior to analysis. It was concluded that the multiply templated MIP potentially can offer many new and interesting applications in chromatography as well as in sensor technology and solid-phase extraction