Diabetic Cardiomyopathy: An Immunometabolic Perspective.

The heart possesses a remarkable inherent capability to adapt itself to a wide array of genetic and extrinsic factors to maintain contractile function. Failure to sustain its compensatory responses results in cardiac dysfunction, leading to cardiomyopathy. Diabetic cardiomyopathy (DCM) is characterized by left ventricular hypertrophy and reduced diastolic function, with or without concurrent systolic dysfunction in the absence of hypertension and coronary artery disease. Changes in substrate metabolism, oxidative stress, endoplasmic reticulum stress, formation of extracellular matrix proteins, and advanced glycation end products constitute the early stage in DCM. These early events are followed by steatosis (accumulation of lipid droplets) in cardiomyocytes, which is followed by apoptosis, changes in immune responses with a consequent increase in fibrosis, remodeling of cardiomyocytes, and the resultant decrease in cardiac function. The heart is an omnivore, metabolically flexible, and consumes the highest amount of ATP in the body. Altered myocardial substrate and energy metabolism initiate the development of DCM. Diabetic hearts shift away from the utilization of glucose, rely almost completely on fatty acids (FAs) as the energy source, and become metabolically inflexible. Oxidation of FAs is metabolically inefficient as it consumes more energy. In addition to metabolic inflexibility and energy inefficiency, the diabetic heart suffers from impaired calcium handling with consequent alteration of relaxation-contraction dynamics leading to diastolic and systolic dysfunction. Sarcoplasmic reticulum (SR) plays a key role in excitation-contraction coupling as Ca(2+) is transported into the SR by the SERCA2a (sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a) during cardiac relaxation. Diabetic cardiomyocytes display decreased SERCA2a activity and leaky Ca(2+) release channel resulting in reduced SR calcium load. The diabetic heart also suffers from marked downregulation of novel cardioprotective microRNAs (miRNAs) discovered recently. Since immune responses and substrate energy metabolism are critically altered in diabetes, the present review will focus on immunometabolism and miRNAs

Catestatin induces glycogenesis by stimulating the phosphoinositide 3-kinase-AKT pathway

Aim: Defects in hepatic glycogen synthesis contribute to post-prandial hyperglycaemia in type 2 diabetic patients. Chromogranin A (CgA) peptide Catestatin (CST: hCgA 352-372) improves glucose tolerance in insulin-resistant mice. Here, we seek to determine whether CST induces hepatic glycogen synthesis. Methods: We determined liver glycogen, glucose-6-phosphate (G6P), uridine diphosphate glucose (UDPG) and glycogen synthase (GYS2) activities; plasma insulin, glucagon, noradrenaline and adrenaline levels in wild-type (WT) as well as in CST knockout (CST-KO) mice; glycogen synthesis and glycogenolysis in primary hepatocytes. We also analysed phosphorylation signals of insulin receptor (IR), insulin receptor substrate-1 (IRS-1), phosphatidylinositol-dependent kinase-1 (PDK-1), GYS2, glycogen synthase kinase-3β (GSK-3β), AKT (a kinase in AKR mouse that produces Thymoma)/PKB (protein kinase B) and mammalian/mechanistic target of rapamycin (mTOR) by immunoblotting. Results: CST stimulated glycogen accumulation in fed and fasted liver and in primary hepatocytes. CST reduced plasma noradrenaline and adrenaline levels. CST also directly stimulated glycogenesis and inhibited noradrenaline and adrenaline-induced glycogenolysis in hepatocytes. In addition, CST elevated the levels of UDPG and increased GYS2 activity. CST-KO mice had decreased liver glycogen that was restored by treatment with CST, reinforcing the crucial role of CST in hepatic glycogenesis. CST improved insulin signals downstream of IR and IRS-1 by enhancing phospho-AKT signals through the stimulation of PDK-1 and mTORC2 (mTOR Complex 2, rapamycin-insensitive complex) activities. Conclusions: CST directly promotes the glycogenic pathway by (a) reducing glucose production, (b) increasing glycogen synthesis from UDPG, (c) reducing glycogenolysis and (d) enhancing downstream insulin signalling

Impact of Chromogranin A deficiency on catecholamine storage, catecholamine granule morphology and chromaffin cell energy metabolism in vivo

Chromogranin A (CgA) is a prohormone and granulogenic factor in neuroendocrine tissues with a regulated secretory pathway. The impact of CgA depletion on secretory granule formation has been previously demonstrated in cell culture. However, studies linking the structural effects of CgA deficiency with secretory performance and cell metabolism in the adrenomedullary chromaffin cells in vivo have not previously been reported. Adrenomedullary content of the secreted adrenal catecholamines norepinephrine (NE) and epinephrine (EPI) was decreased 30–40 % in Chga-KO mice. Quantification of NE and EPI-storing dense core (DC) vesicles (DCV) revealed decreased DCV numbers in chromaffin cells in Chga-KO mice. For both cell types, the DCV diameter in Chga-KO mice was less (100–200 nm) than in WT mice (200–350 nm). The volume density of the vesicle and vesicle number was also lower in Chga-KO mice. Chga-KO mice showed an ~47 % increase in DCV/DC ratio, implying vesicle swelling due to increased osmotically active free catecholamines. Upon challenge with 2 U/kg insulin, there was a diminution in adrenomedullary EPI, no change in NE and a very large increase in the EPI and NE precursor dopamine (DA), consistent with increased catecholamine biosynthesis during prolonged secretion. We found dilated mitochondrial cristae, endoplasmic reticulum and Golgi complex, as well as increased synaptic mitochondria, synaptic vesicles and glycogen granules in Chga-KO mice compared to WT mice, suggesting that decreased granulogenesis and catecholamine storage in CgA-deficient mouse adrenal medulla is compensated by increased VMAT-dependent catecholamine update into storage vesicles, at the expense of enhanced energy expenditure by the chromaffin cell

Implications of recent solar neutrino observations: an analysis of charged current data

We have analysed the recent results from the observation of charged current \nu_e d \to e^- p p events from solar neutrinos by the Sudbury Neutrino Observatory SNO assuming neutrino oscillations with three active flavours. The data seem to prefer a low mass-squared difference and large mixing angle solution (the so-called LOW solution) in (12) parameter space. However, when combined with the Gallium charged current interaction data from Gallex and GNO, distinct (1\sigma) allowed regions corresponding to the large mixing angle (LMA) and small mixing angle (SMA) appear while the LOW solution is disfavoured upto 3\sigma standard deviation. The physical electron neutrino survival probability corresponding to these best fit solutions are then determined and analysed for their energy dependence.Comment: 16 pages Latex file, with 5 epsf figures; one reference adde

Muscle injury and impaired function, and insulin resistance in Chromogranin A knockout mice

Chromogranin A (CgA) is widely expressed in endocrine and neuroendocrine tissues as well as in the central nervous system. We observed CgA expression (mRNA and protein) in the gastrocnemius (GAS) muscle and found that performance of CgA-deficient Chga-KO mice in treadmill exercise was impaired. Supplementation with CgA in Chga-KO mice restored exercise ability suggesting a novel role for endogenous CgA in skeletal muscle function. Chga-KO mice display (i) lack of exercise-induced stimulation of pAKT, pTBC1D1 and phospho-p38 kinase signaling, (ii) loss of GAS muscle mass, (iii) extensive formation of tubular aggregates (TA), (iv) disorganized cristae architecture in mitochondria, (v) increased expression of the inflammatory cytokines Tnfα, Il6 and Ifnɣ, and fibrosis. The impaired maximum running speed and endurance in the treadmill exercise in Chga-KO mice correlated with decreased glucose uptake and glycolysis, defects in glucose oxidation and decreased mitochondrial cytochrome C oxidase activity. The lack of adaptation to endurance training correlated with the lack of stimulation of p38MAPK that is known to mediate the response to tissue damage. Since CgA sorts proteins to the regulated secretory pathway, we speculate that lack of CgA could cause misfolding of membrane proteins inducing aggregation of sarcoplasmic reticulum (SR) membranes and formation of tubular aggregates that is observed in Chga-KO mice. In conclusion, CgA deficiency renders the muscle energy deficient, impairs performance in treadmill exercise and prevents regeneration after exercise-induced tissue damage

Catestatin Inhibits Obesity-Induced Macrophage Infiltration and Inflammation in the Liver and Suppresses Hepatic Glucose Production Leading to Improved Insulin Sensitivity

The activation of Kupffer cells (KCs) and monocyte (Mc)-derived recruited macrophages (McMΦs) in the liver contributes to obesity-induced insulin resistance and type 2 diabetes. Diet-induced obese (DIO) mice treated with Chromogranin A (CgA) peptide catestatin (CST) showed several positive results. These included decreased hepatic/plasma lipids and plasma insulin, diminished expression of gluconeogenic genes, attenuated expression of pro-inflammatory genes, increased expression of anti-inflammatory genes in McMΦs, and inhibition of the infiltration of McMΦs resulting in improvement of insulin sensitivity. Systemic CST knockout (CST-KO) mice on normal chow diet (NCD) ate more food, gained weight, and displayed elevated blood glucose and insulin levels. Supplementation of CST normalized glucose and insulin levels. To verify that the CST deficiency caused macrophages to be very pro-inflammatory in CST-KO-NCD mice and produced glucose intolerance, we tested the effects of FACS-sorted F4/80+Ly6C- cells (representing KCs) and F4/80-Ly6C+ cells (representing McMΦs) on hepatic glucose production (HGP). Both basal and glucagon-induced HGP was markedly increased in hepatocytes co-cultured with KCs and McMΦs from NCD-fed CST-KO mice, and the effect was abrogated upon pre-treatment of CST-KO-MΦs with CST. Thus, we provide a novel mechanism of HGP suppression through CST-mediated inhibition of macrophage infiltration and function

Analysis of Stability and G × E Interaction of Rice Genotypes across Saline and Alkaline Environments in India

Genotype × environment (G × E) interaction effects are of special interest for identifying the most suitable genotypes with respect to target environments, representative locations and other specific stresses. Twenty-two advanced breeding lines contributed by the national partners of the Salinity Tolerance Breeding Network (STBN) along with four checks were evaluated across 12 different salt affected sites comprising five coastal saline and seven alkaline environments in India. The study was conducted to assess the G × E interaction and stability of advanced breeding lines for yield and yield components using additive main effects and multiplicative interaction (AMMI) model. In the AMMI1 biplot, there were two mega-environments (ME) includes ME-A as CARI, KARAIKAL, TRICHY and NDUAT with winning genotype CSR 2K 262; and ME-B as KARSO, LUCKN, KARSA, GOA, CRRI, DRR, BIHAR and PANVE with winning genotypes CSR 36. Genotypes CSR 2K 262, CSR 27, NDRK 11-4, NDRK 11-3, NDRK 11-2, CSR 2K 255 and PNL 1-1-1-6-7-1 were identified as specifically adapted to favorable locations. The stability and adaptability of AMMI indicated that the best yielding genotypes were CSR 2K 262 for both coastal saline and alkaline environments and CSR 36 for alkaline environment. CARI and PANVEL were found as the most discernible environments for genotypic performance because of the greatest GE interaction. The genotype CSR 36 is specifically adapted to coastal saline environments GOA, KARSO, DRR, CRRI and BIHAR and while genotype CSR 2K 262 adapted to alkaline environments LUCKN, NDUAT, TRICH and KARAI. Use of most adapted lines could be used directly as varieties. Using them as donors for wide or specific adaptability with selection in the target environment offers the best opportunity for widening the genetic base of coastal salinity and alkalinity stress tolerance and development of adapted genotypes. Highly stable genotypes can improve the rice productivity in salt-affected areas and ensure livelihood of the resource poor farming communities

Catestatin Inhibits Obesity-Induced Macrophage Infiltration and Inflammation in the Liver and Suppresses Hepatic Glucose Production Leading to Improved Insulin Sensitivity

The activation of Kupffer cells (KCs) and monocyte (Mc)-derived recruited macrophages (McMΦs) in the liver contributes to obesity-induced insulin resistance and type 2 diabetes. Diet-induced obese (DIO) mice treated with Chromogranin A (CgA) peptide catestatin (CST) showed several positive results. These included decreased hepatic/plasma lipids and plasma insulin, diminished expression of gluconeogenic genes, attenuated expression of pro-inflammatory genes, increased expression of anti-inflammatory genes in McMΦs, and inhibition of the infiltration of McMΦs resulting in improvement of insulin sensitivity. Systemic CST knockout (CST-KO) mice on normal chow diet (NCD) ate more food, gained weight, and displayed elevated blood glucose and insulin levels. Supplementation of CST normalized glucose and insulin levels. To verify that the CST deficiency caused macrophages to be very pro-inflammatory in CST-KO-NCD mice and produced glucose intolerance, we tested the effects of FACS-sorted F4/80+Ly6C- cells (representing KCs) and F4/80-Ly6C+ cells (representing McMΦs) on hepatic glucose production (HGP). Both basal and glucagon-induced HGP was markedly increased in hepatocytes co-cultured with KCs and McMΦs from NCD-fed CST-KO mice, and the effect was abrogated upon pre-treatment of CST-KO-MΦs with CST. Thus, we provide a novel mechanism of HGP suppression through CST-mediated inhibition of macrophage infiltration and function

Impact of CP phases on neutrinoless double beta decay

We highlight in a model independent way the dependence of the effective Majorana mass parameter, relevant for neutrinoless double beta decay, on the CP phases of the PMNS matrix, using the most recent neutrino data including the cosmological WMAP measurement. We perform our analysis with three active neutrino flavours in the context of three kinds of mass spectra: quasi-degenerate, normal hierarchical and inverted hierarchical. If a neutrinoless double beta decay experiment records a positive signal, then assuming that Majorana masses of light neutrinos are responsible for it, we show how it might be possible to discriminate between the three kinds of spectra.Comment: 10 pages, latex, 9 eps figs, version to appear in Phys Rev