Impact of Incretin-Based Therapies on Adipokines and Adiponectin

Adipokines are a family of hormones and cytokines with both pro- and anti-inflammatory effects released into the circulation to exert their hormonal effects. Adipokines are closely involved in most metabolic pathways and play an important modulatory role in lipid and carbohydrate homeostasis as they are involved in the pathophysiology of most metabolic disorders. Incretin-based therapy is a newly introduced class of antidiabetic drugs that restores euglycemia through several cellular processes; however, its effect on adipokines expression/secretion is not fully understood. In this review, we propose that incretin-based therapy may function through adipokine modulation that may result in pharmacologic properties beyond their direct antidiabetic effects, resulting in better management of diabetes and diabetes-related complications.

Isoprenoid Derivatives of Lysophosphatidylcholines Enhance Insulin and GLP-1 Secretion through Lipid-Binding GPCRs

Insulin plays a significant role in carbohydrate homeostasis as the blood glucose lowering hormone. Glucose-induced insulin secretion (GSIS) is augmented by glucagon-like peptide (GLP-1), a gastrointestinal peptide released in response to ingesting nutriments. The secretion of insulin and GLP-1 is mediated by the binding of nutrients to G protein-coupled receptors (GPCRs) expressed by pancreatic β-cells and enteroendocrine cells, respectively. Therefore, insulin secretagogues and incretin mimetics currently serve as antidiabetic treatments. This study demonstrates the potency of synthetic isoprenoid derivatives of lysophosphatidylcholines (LPCs) to stimulate GSIS and GLP-1 release. Murine insulinoma cell line (MIN6) and enteroendocrinal L cells (GLUTag) were incubated with LPCs bearing geranic acid (1-GA-LPC), citronellic acid (1-CA-LPC), 3,7-dimethyl-3-vinyloct-6-enoic acid (GERA-LPC), and (E)-3,7,11-trimethyl- 3-vinyldodeca-6,10-dienoic acid (1-FARA-LPC). Respective free terpene acids were also tested for comparison. Besides their insulin- and GLP-1-secreting capabilities, we also investigated the cytotoxicity of tested compounds, the ability to intracellular calcium ion mobilization, and targeted GPCRs involved in maintaining lipid and carbohydrate homeostasis. We observed the high cytotoxicity of 1-GERA-LPC and 1-FARA-LPC in contrast 1-CA-LPC and 1-GA-LPC. Moreover, 1-CA-LPC and 1-GA-LPC demonstrated the stimulatory effect on GSIS and 1-CA-LPC augmented GLP-1 secretion. Insulin and GLP-1 release appeared to be GPR40-, GPR55-, GPR119- and GPR120-dependent.

Grapevine Red Blotch Disease Affects Carbohydrate Homeostasis and Cell Call Characteristics in Vitis Vinifera L.

BackgroundGrapevines are commonly infected with one or more viruses causing a significant threat to the sustainability of quality wine grape production worldwide. The recently identified Grapevine red blotch disease (GRBD) significantly affects the yield and quality of wine grapes. It is largely unknown how the red blotch disease affects carbohydrate homeostasis and regulate the source-to-sink relationship in grapevines. We took an integrative approach to determine the consequences of viral infection in commercially grown, two popular wine grape cultivars from distinct locations in the eastern Washington.ResultsThe deep sequencing approach revealed that Grapevine red blotch virus (GRBV) was found in all symptomatic vines, while asymptomatic vines were free of this virus. Analysis of mature berries at commercial harvest in virus-infected vines indicated significant changes in the soluble sugar accumulation along with the increase in leaf sucrose and starch content. To follow up with the altered carbohydrate homeostasis, we analyzed cell wall components in winter canes of virus-infected vines and compared them to their virus-free counterparts. Major cell wall monosaccharide contents and total lignin content was not affected due to red blotch disease in either cultivar. However, high-resolution glycome profiling revealed consistent changes in loosely bound cell wall pectin matrices and tightly bound non-fucosylated xyloglucans in virus-infected vines. Furthermore, in cv. Syrah, co-infection with other viruses leads to additional cell wall compositional variations.ConclusionsThese changes highlighted that virus infection in woody perennial leads to detrimental adjustments in the soluble and storage carbohydrates, and in the cell wall layers that could be attributed to lower vine performance or vine decline in a relatively short time. The information gained from such qualitative cell wall structural fine-tuning could be used in assessing how viruses or other pathogenic agents affect perennial longevity.

The Drosophila melanogaster Neprilysin Nepl15 is involved in lipid and carbohydrate storage

The prototypical M13 peptidase, human Neprilysin, functions as a transmembrane “ectoenzyme” that cleaves neuropeptides that regulate e.g. glucose metabolism, and has been linked to type 2 diabetes. The M13 family has undergone a remarkable, and conserved, expansion in the Drosophila genus. Here, we describe the function of Drosophila melanogaster Neprilysin-like 15 (Nepl15). Nepl15 is likely to be a secreted protein, rather than a transmembrane protein. Nepl15 has changes in critical catalytic residues that are conserved across the Drosophila genus and likely renders the Nepl15 protein catalytically inactive. Nevertheless, a knockout of the Nepl15 gene reveals a reduction in triglyceride and glycogen storage, with the effects likely occurring during the larval feeding period. Conversely, flies overexpressing Nepl15 store more triglycerides and glycogen. Protein modeling suggests that Nepl15 is able to bind and sequester peptide targets of catalytically active Drosophila M13 family members, peptides that are conserved in humans and Drosophila, potentially providing a novel mechanism for regulating the activity of neuropeptides in the context of lipid and carbohydrate homeostasis.

Discriminatory alteration of carbohydrate homeostasis by gold nanoparticles ingestion in Drosophila

With the extensive usage of gold nanoparticles (AuNPs) in various industrial sectors and biomedical applications, evaluation of their possible effects on human health becomes imperative. Therefore, the present study was aimed toward assessing the dose-dependent impact of AuNPs ingestion on metabolic homeostasis using Drosophila melanogaster as a model system. We found that larval ingestion of higher dose of AuNPs significantly reduced body weight. Further analysis of the crucial energy reservoir showed selective alteration in carbohydrate levels without any change in the lipid and protein levels. Transcriptional downregulation of glycogen synthase further supported impaired glycogen metabolism in flies supplemented with higher dose of AuNPs. Additionally, ingestion of higher dose of AuNPs in larvae results in significantly increased levels of reactive oxygen species (ROS) in the peripheral tissues, suggestive of stress condition. Our findings clearly imply that supplementing higher doses of AuNPs at an early developmental stage can potentially cause weight loss, impair glycogen metabolism, and elevate ROS production. Therefore, determination of a biologically effective dose is critical for the safety of mankind and vulnerable populations at the workplace.

Genetic associations for two biological age measures point to distinct aging phenotypes

Biological age measures outperform chronological age in predicting various aging outcomes, yet little is known regarding genetic predisposition. We performed genome-wide association scans of two age-adjusted biological age measures (PhenoAgeAcceleration and BioAgeAcceleration), estimated from clinical biochemistry markers1,2 in European-descent participants from UK Biobank. The strongest signals were found in the APOE gene, tagged by the two major protein-coding SNPs, PhenoAgeAccel-rs429358 (APOE e4 determinant) (p=1.50 × 10-72); BioAgeAccel-rs7412 (APOE e2 determinant) (p=3.16 × 10-60). Interestingly, we observed inverse APOE e2 and e4 associations and unique pathway enrichments when comparing the two biological age measures. Genes associated with BioAgeAccel were enriched in lipid related pathways, while genes associated with PhenoAgeAccel showed enrichment for immune system, cell function, and carbohydrate homeostasis pathways, suggesting the two measures capture different aging domains. Our study reaffirms that aging patterns are heterogenous across individuals, and the manner in which a person ages may be partly attributed to genetic predisposition.

Elevated temperatures impose transcriptional constraints on coffee genotypes and elicit intraspecific differences in thermoregulation

ABSTRACTThe projected impact of global warming on coffee production may require the heat-adapted genotypes in the next decades. To identify thermotolerance cellular strategies, we compared the effect of elevated temperature on two commercial Coffea arabica L. genotypes exploring leaf physiology, transcriptome and carbohydrate/protein composition. Growth temperatures were 23/19°C (day/night), as optimal condition (OpT), and 30/26°C (day/night) as a possible warmer scenario (WaT). The cv. Acauã showed lower levels of leaf temperature under both conditions compared to cv. Catuaí, whereas slightly or no differences for other leaf physiological parameters. Therefore, to explore thermoregulatory pathways the leaf transcriptome was examined using RNAseq. Genotypes showed a marked number of differentially-expressed genes (DEGs) under OpT, however DEGs strongly decrease in both at WaT condition indicating a transcriptional constraint. DEGs responsive to WaT revealed shared and genotype-specific genes mostly related to carbohydrate metabolism. Under OpT, leaf starch content was greater in cv. Acauã although the levels of leaf starch, sucrose, and leaf protein decreased in both genotypes as WaT was imposed. These findings indicate that genotypes with a greater capacity to maintain carbohydrate homeostasis under temperature fluctuations could be more thermotolerant and which may be useful in breeding for a changing climate.HIGHLIGHTIn response to warming, transcriptional differences decrease in coffee genotypes hampering breeding programs. Differences in gene expression and sugar levels confirm intraspecific variation associating thermotolerance to maintenance of energetic homeostasis.

Hypoglycemia in neonates: a review of the literature and a case report

Hypoglycemia in the neonatal period is one of the urgent problems of pediatric endocrinology. The main factors that lead to disruption of carbohydrate homeostasis are generally known, but the issues of neonatal hypoglycemia continue to be actively studied. In the last few years, the effect of low blood glucose on brain neurons has been studied, the issues of glycemia monitoring in the first days of life have been outlined, and strategies for managing newborns with hypoglycemic syndrome are being discussed.

Perspectives of application of intranasally administered insulin for correction of metabolic and hormonal disorders in diabetes mellitus and metabolic syndrome

In recent years, the possibility of using intranasally administered insulin to treat Alzheimers disease and other cognitive disorders has been widely studied. At the same time, the possibility of its use in the treatment of diabetes mellitus is practically not investigated, which is due to the insufficient study of the molecular mechanisms of its action on the hormonal and metabolic status of the organism. The review discusses literature data and the results of our own research on the role of insulin in the central regulation of energy homeostasis, as well as on the experience of using intranasally administered insulin to correct eating disorders and metabolic and hormonal dysfunctions developing under conditions of experimental diabetes mellitus and metabolic syndrome. In studies involving healthy volunteers, various effects of intranasally administered insulin were shown, including effects on cognitive function, eating behavior and weight loss, and the gender specificity of its action was found. In the course of numerous studies of intranasally administered insulin in animal models of diabetes mellitus, not only stabilization of carbohydrate homeostasis was shown, but also a positive effect in the form of restoration of the functional activity of insulin signaling pathways in the hypothalamus and other parts of the brain. We have presented and analyzed data on the systemic effects of intranasally administered insulin in rodents with experimental models of diabetes mellitus, as well as in healthy individuals.