Calpain-10 interacts with plasma saturated fatty acid concentrations to influence insulin resistance in individuals with the metabolic syndrome

Background: Calpain-10 protein (intracellular Ca2+-dependent cysteine protease) may play a role in glucose metabolism, pancreatic β cell function, and regulation of thermogenesis. Several CAPN10 polymorphic sites have been studied for their potential use as risk markers for type 2 diabetes and the metabolic syndrome (MetS). Fatty acids are key metabolic regulators that may interact with genetic factors and influence glucose metabolism. Objective: The objective was to examine whether the genetic variability at the CAPN10 gene locus is associated with the degree of insulin resistance and plasma fatty acid concentrations in subjects with MetS. Design: The insulin sensitivity index, glucose effectiveness, insulin resistance [homeostasis model assessment of insulin resistance (HOMA-IR)], insulin secretion (disposition index, acute insulin response, and HOMA of β cell function), plasma fatty acid composition, and 5 CAPN10 single nucleotide polymorphisms (SNPs) were determined in a cross-sectional analysis of 452 subjects with MetS participating in the LIPGENE dietary intervention cohort. Results: The rs2953171 SNP interacted with plasma total saturated fatty acid (SFA) concentrations, which were significantly associated with insulin sensitivity (P < 0.031 for fasting insulin, P < 0.028 for HOMA-IR, and P < 0.012 for glucose effectiveness). The G/G genotype was associated with lower fasting insulin concentrations, lower HOMA-IR, and higher glucose effectiveness in subjects with low SFA concentrations (below the median) than in subjects with the minor A allele (G/A and A/A). In contrast, subjects with the G/G allele with the highest SFA concentrations (above the median) had higher fasting insulin and HOMA-IR values and lower glucose effectiveness than did subjects with the A allele. Conclusion: The rs2953171 polymorphism at the CAPN10 gene locus may influence insulin sensitivity by interacting with the plasma fatty acid composition in subjects with MetS. This trial was registered at clinicaltrials.gov as NCT00429195.

Glucokinase Regulatory Protein genetic variant interacts with omega-3 PUFA to influence insulin resistance and inflammation in metabolic syndrome

Glucokinase Regulatory Protein (GCKR) plays a central role regulating both hepatic triglyceride and glucose metabolism. Fatty acids are key metabolic regulators, which interact with genetic factors and influence glucose metabolism and other metabolic traits. Omega-3 polyunsaturated fatty acids (n-3 PUFA) have been of considerable interest, due to their potential to reduce metabolic syndrome (MetS) risk. Objective To examine whether genetic variability at the GCKR gene locus was associated with the degree of insulin resistance, plasma concentrations of C-reactive protein (CRP) and n-3 PUFA in MetS subjects. Design Homeostasis model assessment of insulin resistance (HOMA-IR), HOMA-B, plasma concentrations of C-peptide, CRP, fatty acid composition and the GCKR rs1260326-P446L polymorphism, were determined in a cross-sectional analysis of 379 subjects with MetS participating in the LIPGENE dietary cohort. Results Among subjects with n-3 PUFA levels below the population median, carriers of the common C/C genotype had higher plasma concentrations of fasting insulin (P = 0.019), C-peptide (P = 0.004), HOMA-IR (P = 0.008) and CRP (P = 0.032) as compared with subjects carrying the minor T-allele (Leu446). In contrast, homozygous C/C carriers with n-3 PUFA levels above the median showed lower plasma concentrations of fasting insulin, peptide C, HOMA-IR and CRP, as compared with individuals with the T-allele. Conclusions We have demonstrated a significant interaction between the GCKR rs1260326-P446L polymorphism and plasma n-3 PUFA levels modulating insulin resistance and inflammatory markers in MetS subjects. Further studies are needed to confirm this gene-diet interaction in the general population and whether targeted dietary recommendations can prevent MetS in genetically susceptible individuals.

Insulin receptor substrate-2 gene variants in subjects with metabolic syndrome: association with plasma fatty acid levels and insulin resistance

Several insulin receptor substrate-2 (IRS-2) polymorphisms have been studied in relation to insulin resistance and type 2 diabetes. To examine whether the genetic variability at the IRS-2 gene locus was associated with the degree of insulin resistance and plasma fatty acid levels in metabolic syndrome (MetS) subjects. Methods and results: Insulin sensitivity, insulin secretion, glucose effectiveness, plasma fatty acid composition and three IRS-2 tag-single nucleotide polymorphisms (SNPs) were determined in 452 MetS subjects. Among subjects with the lowest level of monounsaturated (MUFA) (below the median), the rs2289046 A/A genotype was associated with lower glucose effectiveness (p<0.038), higher fasting insulin concentrations (p<0.028) and higher HOMA IR (p<0.038) as compared to subjects carrying the minor G-allele (A/G and G/G). In contrast, among subjects with the highest level of MUFA (above the median), the A/A genotype was associated with lower fasting insulin concentrations and HOMA-IR, whereas individuals carrying the G allele and with the highest level of ω-3 polyunsaturated fatty acids (above the median) showed lower fasting insulin (p<0.01) and HOMA-IR (p<0.02) as compared with A/A subjects. Conclusion: The rs2289046 polymorphism at the IRS2 gene locus may influence insulin sensitivity by interacting with certain plasma fatty acids in MetS subjects.

A gene variation (rs12691) in the CCAT/enhancer building α modulates glucose metabolism in metabolic syndrome

Background and aims CCAAT/enhancer-binding protein alpha (CEBPA) is a transcription factor involved in adipogenesis and energy homeostasis. Caloric restriction reduces CEBPA protein expression in patients with metabolic syndrome (MetS). A previous report linked rs12691 SNP in CEBPA to altered concentration of fasting triglycerides. Our objective was to assess the effects of rs12691 in glucose metabolism in Metabolic Syndrome (MetS) patients. Methods and results Glucose metabolism was assessed by static (glucose, insulin, adiponectin, leptin and resistin plasma concentrations) and dynamic (disposition index, insulin sensitivity index, HOMA-IR and acute insulin response to glucose) indices, performed at baseline and after 12 weeks of 4 dietary interventions (high saturated fatty acid (SFA), high monounsaturated fatty acid (MUFA), low-fat and low-fat-high-n3 polyunsaturated fatty acid (PUFA)) in 486 subjects with MetS. Carriers of the minor A allele of rs12691 had altered disposition index (p = 0.0003), lower acute insulin response (p = 0.005) and a lower insulin sensitivity index (p = 0.025) indicating a lower insulin sensitivity and a lower insulin secretion, at baseline and at the end of the diets. Furthermore, A allele carriers displayed lower HDL concentration. Conclusion The presence of the A allele of rs12691 influences glucose metabolism of MetS patients. Clinical Trials Registry number NCT00429195.

Not all sigmodontine rodents in the sugarcane fields in costal Veracruz, Mexico, are pests

Rats and mice have traditionally been considered one of the most important pests of sugarcane. However, "control" campaigns are rarely specific to the target species, and can have an effect on local wildlife, in particular non-pest rodent species. The objective of this study was to distinguish between rodent species that are pests and those that are not, and to identify patterns of food utilization by the rodents in the sugarcane crop complex. Within the crop complex, subsistence crops like maize, sorghum, rice, and bananas, which are grown alongside the sugarcane, are also subject to rodent damage. Six native rodent species were trapped in the Papaloapan River Basin of the State of Veracruz; the cotton rat (Sigmodon hispidus), the rice rat (Oryzomys couesi), the small rice rat (O. chapmani), the white footed mouse (Peromyscus leucopus), the golden mouse (Reithrodontomys sumichrasti), and the pigmy mouse (Baiomys musculus). In a stomach content analysis, the major food components for the cotton rat, the rice rat and the small rice rat were sugarcane (4.9 to 30.1 %), seed (2.7 to 22.9%), and vegetation (0.9 to 29.8%); while for the golden mouse and the pigmy mouse the stomach content was almost exclusively seed (98 to 100%). The authors consider the first three species to be pests of the sugarcane crop complex, while the last two species are not.

A period 2 genetic variant interacts with plasma SFA to modify plasma lipid concentrations in adults with metabolic syndrome

Genetic variants of Period 2 (PER2), a circadian clock gene, have been linked to metabolic syndrome (MetS). However, it is still unknown whether these genetic variants interact with the various types of plasma fatty acids. This study investigated whether common single nucleotide polymorphisms (SNPs) in the PER2 locus (rs934945 and rs2304672) interact with various classes of plasma fatty acids to modulate plasma lipid metabolism in 381 participants with MetS in the European LIPGENE study. Interestingly, the rs2304672 SNP interacted with plasma total SFA concentrations to affect fasting plasma TG, TG-rich lipoprotein (TRL-TG), total cholesterol, apoC-II, apoB, and apoB-48 concentrations (P-interaction < 0.001–0.046). Carriers of the minor allele (GC+GG) with the highest SFA concentration (>median) had a higher plasma TG concentration (P = 0.001) and higher TRL-TG (P < 0.001) than the CC genotype. In addition, participants carrying the minor G allele for rs2304672 SNP and with a higher SFA concentration (>median) had higher plasma concentrations of apo C-II (P < 0.001), apo C-III (P = 0.009), and apoB-48 (P = 0.028) compared with the homozygotes for the major allele (CC). In summary, the rs2304672 polymorphism in the PER2 gene locus may influence lipid metabolism by interacting with the plasma total SFA concentration in participants with MetS. The understanding of these gene-nutrient interactions could help to provide a better knowledge of the pathogenesis in MetS.

Obesity and body fat classification in the metabolic syndrome: impact on cardiometabolic risk metabotype

Obesity is a key factor in the development of the metabolic syndrome (MetS), which is associated with increased cardiometabolic risk. We investigated whether obesity classification by body mass index (BMI) and body fat percentage (BF%) influences cardiometabolic profile and dietary responsiveness in 486 MetS subjects (LIPGENE dietary intervention study). Anthropometric measures, markers of inflammation and glucose metabolism, lipid profiles, adhesion molecules and haemostatic factors were determined at baseline and after 12 weeks of 4 dietary interventions (high saturated fat (SFA), high monounsaturated fat (MUFA) and 2 low fat high complex carbohydrate (LFHCC) diets, 1 supplemented with long chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs)). 39% and 87% of subjects classified as normal and overweight by BMI were obese according to their BF%. Individuals classified as obese by BMI (± 30 kg/m2) and BF% (± 25% (men) and ± 35% (women)) (OO, n = 284) had larger waist and hip measurements, higher BMI and were heavier (P < 0.001) than those classified as non-obese by BMI but obese by BF% (NOO, n = 92). OO individuals displayed a more pro-inflammatory (higher C reactive protein (CRP) and leptin), pro-thrombotic (higher plasminogen activator inhibitor-1 (PAI-1)), pro-atherogenic (higher leptin/adiponectin ratio) and more insulin resistant (higher HOMA-IR) metabolic profile relative to the NOO group (P < 0.001). Interestingly, tumour necrosis factor alpha (TNF-α) concentrations were lower post-intervention in NOO individuals compared to OO subjects (P < 0.001). In conclusion, assessing BF% and BMI as part of a metabotype may help identify individuals at greater cardiometabolic risk than BMI alone.

An extreme case of plant-insect co-diversification: figs and fig-pollinating wasps

It is thought that speciation in phytophagous insects is often due to colonization of novel host plants, because radiations of plant and insect lineages are typically asynchronous. Recent phylogenetic comparisons have supported this model of diversification for both insect herbivores and specialized pollinators. An exceptional case where contemporaneous plant insect diversification might be expected is the obligate mutualism between fig trees (Ficus species, Moraceae) and their pollinating wasps (Agaonidae, Hymenoptera). The ubiquity and ecological significance of this mutualism in tropical and subtropical ecosystems has long intrigued biologists, but the systematic challenge posed by >750 interacting species pairs has hindered progress toward understanding its evolutionary history. In particular, taxon sampling and analytical tools have been insufficient for large-scale co-phylogenetic analyses. Here, we sampled nearly 200 interacting pairs of fig and wasp species from across the globe. Two supermatrices were assembled: on average, wasps had sequences from 77% of six genes (5.6kb), figs had sequences from 60% of five genes (5.5 kb), and overall 850 new DNA sequences were generated for this study. We also developed a new analytical tool, Jane 2, for event-based phylogenetic reconciliation analysis of very large data sets. Separate Bayesian phylogenetic analyses for figs and fig wasps under relaxed molecular clock assumptions indicate Cretaceous diversification of crown groups and contemporaneous divergence for nearly half of all fig and pollinator lineages. Event-based co-phylogenetic analyses further support the co-diversification hypothesis. Biogeographic analyses indicate that the presentday distribution of fig and pollinator lineages is consistent with an Eurasian origin and subsequent dispersal, rather than with Gondwanan vicariance. Overall, our findings indicate that the fig-pollinator mutualism represents an extreme case among plant-insect interactions of coordinated dispersal and long-term co-diversification.

Self-assembly studies of a chiral bisurea-based superhydrogelator

A chiral bisurea-based superhydrogelator that is capable of forming supramolecular hydrogels at concentrations as low as 0.2 mm is reported. This soft material has been characterized by thermal studies, rheology, X-ray diffraction analysis, transmission electron microscopy (TEM), and by various spectroscopic techniques (electronic and vibrational circular dichroism and by FTIR and Raman spectroscopy). The expression of chirality on the molecular and supramolecular levels has been studied and a clear amplification of its chirality into the achiral analogue has been observed. Furthermore, thermal analysis showed that the hydroACHTUNGTRENUNGgel- ACHTUNGTRENUNGation of compound 1 has a high response to temperature, which corresponds to an enthalpy-driven self-assembly process. These particular thermal characteristics make these materials easy to handle for soft-application technologies

Dietary quebracho tannins are not absorbed, but increase the antioxidant capacity of liver and plasma in sheep

A total of sixteen lambs were divided into two groups and fed two different diets. Of these, eight lambs were fed a control diet (C) and eight lambs were fed the C diet supplemented with quebracho tannins (C+T). The objective of the present study was to assess whether dietary quebracho tannins can improve the antioxidant capacity of lamb liver and plasma and if such improvement is due to a direct transfer of phenolic compounds or their metabolites, to the animal tissues. Feed, liver and plasma samples were purified by solid-phase extraction (SPE) and analysed by liquid chromatography–MS for phenolic compounds. Profisitinidin compounds were identified in the C+T diet. However, no phenolic compounds were found in lamb tissues. The liver and the plasma from lambs fed the C+T diet displayed a greater antioxidant capacity than tissues from lambs fed the C diet, but only when samples were not purified with SPE. Profisetinidin tannins from quebracho seem not to be degraded or absorbed in the gastrointestinal tract. However, they induced antioxidant effects in animal tissues.

Protease-activated receptor 2 sensitizes the transient receptor potential vanilloid 4 ion channel to cause mechanical hyperalgesia in mice

Exacerbated sensitivity to mechanical stimuli that are normally innocuous or mildly painful (mechanical allodynia and hyperalgesia) occurs during inflammation and underlies painful diseases. Proteases that are generated during inflammation and disease cleave protease-activated receptor 2 (PAR2) on afferent nerves to cause mechanical hyperalgesia in the skin and intestine by unknown mechanisms. We hypothesized that PAR2-mediated mechanical hyperalgesia requires sensitization of the ion channel transient receptor potential vanilloid 4 (TRPV4). Immunoreactive TRPV4 was coexpressed by rat dorsal root ganglia (DRG) neurons with PAR2, substance P (SP) and calcitonin gene-related peptide (CGRP), mediators of pain transmission. In PAR2-expressing cell lines that either naturally expressed TRPV4 (bronchial epithelial cells) or that were transfected to express TRPV4 (HEK cells), pretreatment with a PAR2 agonist enhanced Ca2+ and current responses to the TRPV4 agonists phorbol ester 4alpha-phorbol 12,13-didecanoate (4alphaPDD) and hypotonic solutions. PAR2-agonist similarly sensitized TRPV4 Ca2+ signals and currents in DRG neurons. Antagonists of phospholipase Cbeta and protein kinases A, C and D inhibited PAR2-induced sensitization of TRPV4 Ca2+ signals and currents. 4alphaPDD and hypotonic solutions stimulated SP and CGRP release from dorsal horn of rat spinal cord, and pretreatment with PAR2 agonist sensitized TRPV4-dependent peptide release. Intraplantar injection of PAR2 agonist caused mechanical hyperalgesia in mice and sensitized pain responses to the TRPV4 agonists 4alphaPDD and hypotonic solutions. Deletion of TRPV4 prevented PAR2 agonist-induced mechanical hyperalgesia and sensitization. This novel mechanism, by which PAR2 activates a second messenger to sensitize TRPV4-dependent release of nociceptive peptides and induce mechanical hyperalgesia, may underlie inflammatory hyperalgesia in diseases where proteases are activated and released.

Protease-activated receptor 2 sensitizes TRPV1 by protein kinase Cepsilon- and A-dependent mechanisms in rats and mice

Proteases that are released during inflammation and injury cleave protease-activated receptor 2 (PAR2) on primary afferent neurons to cause neurogenic inflammation and hyperalgesia. PAR2-induced thermal hyperalgesia depends on sensitization of transient receptor potential vanilloid receptor 1 (TRPV1), which is gated by capsaicin, protons and noxious heat. However, the signalling mechanisms by which PAR2 sensitizes TRPV1 are not fully characterized. Using immunofluorescence and confocal microscopy, we observed that PAR2 was colocalized with protein kinase (PK) Cepsilon and PKA in a subset of dorsal root ganglia neurons in rats, and that PAR2 agonists promoted translocation of PKCepsilon and PKA catalytic subunits from the cytosol to the plasma membrane of cultured neurons and HEK 293 cells. Subcellular fractionation and Western blotting confirmed this redistribution of kinases, which is indicative of activation. Although PAR2 couples to phospholipase Cbeta, leading to stimulation of PKC, we also observed that PAR2 agonists increased cAMP generation in neurons and HEK 293 cells, which would activate PKA. PAR2 agonists enhanced capsaicin-stimulated increases in [Ca2+]i and whole-cell currents in HEK 293 cells, indicating TRPV1 sensitization. The combined intraplantar injection of non-algesic doses of PAR2 agonist and capsaicin decreased the latency of paw withdrawal to radiant heat in mice, indicative of thermal hyperalgesia. Antagonists of PKCepsilon and PKA prevented sensitization of TRPV1 Ca2+ signals and currents in HEK 293 cells, and suppressed thermal hyperalgesia in mice. Thus, PAR2 activates PKCepsilon and PKA in sensory neurons, and thereby sensitizes TRPV1 to cause thermal hyperalgesia. These mechanisms may underlie inflammatory pain, where multiple proteases are generated and released.

Mast cell tryptase and proteinase-activated receptor 2 induce hyperexcitability of guinea-pig submucosal neurons

Mast cells that are in close proximity to autonomic and enteric nerves release several mediators that cause neuronal hyperexcitability. This study examined whether mast cell tryptase evokes acute and long-term hyperexcitability in submucosal neurons from the guinea-pig ileum by activating proteinase-activated receptor 2 (PAR2) on these neurons. We detected the expression of PAR2 in the submucosal plexus using RT-PCR. Most submucosal neurons displayed PAR2 immunoreactivity, including those colocalizing VIP. Brief (minutes) application of selective PAR2 agonists, including trypsin, the activating peptide SL-NH2 and mast cell tryptase, evoked depolarizations of the submucosal neurons, as measured with intracellular recording techniques. The membrane potential returned to resting values following washout of agonists, but most neurons were hyperexcitable for the duration of recordings (> 30 min-hours) and exhibited an increased input resistance and amplitude of fast EPSPs. Trypsin, in the presence of soybean trypsin inhibitor, and the reverse sequence of the activating peptide (LR-NH2) had no effect on neuronal membrane potential or long-term excitability. Degranulation of mast cells in the presence of antagonists of established excitatory mast cell mediators (histamine, 5-HT, prostaglandins) also caused depolarization, and following washout of antigen, long-term excitation was observed. Mast cell degranulation resulted in the release of proteases, which desensitized neurons to other agonists of PAR2. Our results suggest that proteases from degranulated mast cells cleave PAR2 on submucosal neurons to cause acute and long-term hyperexcitability. This signalling pathway between immune cells and neurons is a previously unrecognized mechanism that could contribute to chronic alterations in visceral function.

Social divisions in school participation and attainment in India: 1983-2004

This study documents the size and nature of “Hindu-Muslim” and “boy-girl” gaps in children’s school participation and attainments in India. Individual-level data from two successive rounds of the National Sample Survey suggest that considerable progress has been made in decreasing the Hindu-Muslim gap. Nonetheless, the gap remains sizable even after controlling for numerous socio-economic and parental covariates, and the Muslim educational disadvantage in India today is greater than that experienced by girls and Scheduled Caste Hindu children. A gender gap still appears within as well as between communities, though it is smaller within Muslim communities. While differences in gender and other demographic and socio-economic covariates have recently become more important in explaining the Hindu-Muslim gap, those differences altogether explain only 25 percent to 45 percent of the observed schooling gap.