Search

The recently identified glycerol-3-phosphate (Gro3P) phosphatase (G3PP) in mammalian cells, encoded by thePGPgene, was shown to regulate intermediary metabolism by hydrolyzing Gro3P and to control glucose-stimulated insulin secretion (GSIS) in β-cells,in vitro. We now examined in inducible β-cell specific G3PP-KO (BKO) mice, the role of G3PP in the control of insulin secretionin vivo, β-cell function and glucotoxicity. BKO mice, compared toMCrecontrols, showed increased body weight, adiposity, fed insulinemia, GSIS, reduced plasma triglycerides and mildly altered glucose tolerance. Isolated BKO mouse islets at high (16.7 mM) but not low or intermediate glucose (3-8 mM) showed elevated GSIS, Gro3P, metabolites reflecting β-cell activation, O2consumption, ATP production and reduced glycerol release. BKO islets chronically exposed to elevated glucose showed increased apoptosis, reduced insulin content and expression ofPdx-1, MafAandIns-2genes. As G3PP channels glucose carbons towards glycerol formation and release, the results demonstrate that β-cell are endowed with a “glycerol shunt” acting as a glucose excess security valve. We propose that the glycerol shunt plays a role in glucodetoxification, the prevention of insulin hypersecretion, acts as a defense against excess body weight gain and contributes to β-cell mass preservation in the face of hyperglycemia.

Cardiometabolic diseases, including type 2 diabetes, obesity and non-alcoholic fatty liver disease, have enormous impact on modern societies worldwide. Excess nutritional burden and nutri-stress together with sedentary lifestyles lead to these diseases. Deranged glucose, fat, and energy metabolism is at the center of nutri-stress, and glycolysis-derived glycerol-3-phosphate (Gro3P) is at the crossroads of these metabolic pathways. Cellular levels of Gro3P can be controlled by its synthesis, utilization or hydrolysis. The belief that mammalian cells do not possess an enzyme that hydrolyzes Gro3P, as in lower organisms and plants, is challenged by our recent work showing the presence of a Gro3P phosphatase (G3PP) in mammalian cells. A previously described phosphoglycolate phosphatase (PGP) in mammalian cells, with no established physiological function, has been shown to actually function as G3PP, under physiological conditions, particularly at elevated glucose levels. In the present review, we summarize evidence that supports the view that G3PP plays an important role in the regulation of gluconeogenesis and fat storage in hepatocytes, glucose stimulated insulin secretion and nutri-stress in β-cells, and lipogenesis in adipocytes. We provide a balanced perspective on the pathophysiological significance of G3PP in mammals with specific reference to cardiometabolic diseases.

Simple Summary A number of diseases, including cancers, can be diagnosed with “biomarkers”, such as specific proteins, hormones, or mutations in some genes. These molecules reflect abnormal processes in the affected organs, and are useful for diagnosis and disease treatment options. The need exists to have reliable markers for various types of cancers such as prostate cancer (PC). Many cancers show high utilization of glucose for their growth; we recently identified an enzyme, glycerol 3-phosphate phosphatase (G3PP), that can modulate glucose utilization by cells. Our work revealed a high expression of G3PP in prostate cancer cells in patients with aggressive tumors. With further validation, G3PP expression in prostate cancer tumors may become a useful prognostic biomarker and aid in the management of patients with PC. Abstract The limitations of the biomarker prostate-specific antigen (PSA) necessitate the pursuit of biomarkers capable of better identifying high-risk prostate cancer (PC) patients in order to improve their therapeutic management and outcomes. Aggressive prostate tumors characteristically exhibit high rates of glycolysis and lipogenesis. Glycerol 3-phosphate phosphatase (G3PP), also known as phosphoglycolate phosphatase (PGP), is a recently identified mammalian enzyme, shown to play a role in the regulation of glucose metabolism, lipogenesis, lipolysis, and cellular nutrient-excess detoxification. We hypothesized that G3PP may relieve metabolic stress in cancer cells and assessed the association of its expression with PC patient prognosis. Using immunohistochemical staining, we assessed the epithelial expression of G3PP in two different radical prostatectomy (RP) cohorts with a total of 1797 patients, for whom information on biochemical recurrence (BCR), metastasis, and mortality was available. The association between biomarker expression, biochemical recurrence (BCR), bone metastasis, and prostate cancer-specific survival was established using log-rank and multivariable Cox regression analyses. High expression of G3PP in PC epithelial cells is associated with an increased risk of BCR, bone metastasis, and PC-specific mortality. Multivariate analysis revealed high G3PP expression in tumors as an independent predictor of BCR and bone metastasis development. High G3PP expression in tumors from patients eligible for prostatectomies is a new and independent prognostic biomarker of poor prognosis and aggressive PC for recurrence, bone metastasis, and mortality.

Metabolic stress due to nutrient excess and lipid accumulation is at the root of many age-associated disorders and the identification of therapeutic targets that mimic the beneficial effects of calorie restriction has clinical importance. Here, using C. elegans as a model organism, we study the roles of a recently discovered enzyme at the heart of metabolism in mammalian cells, glycerol-3-phosphate phosphatase (G3PP) (gene name Pgp) that hydrolyzes glucose-derived glycerol-3-phosphate to glycerol. We identify three Pgp homologues in C. elegans (pgph) and demonstrate in vivo that their protein products have G3PP activity, essential for glycerol synthesis. We demonstrate that PGPH/G3PP regulates the adaptation to various stresses, in particular hyperosmolarity and glucotoxicity. Enhanced G3PP activity reduces fat accumulation, promotes healthy aging and acts as a calorie restriction mimetic at normal food intake without altering fertility. Thus, PGP/G3PP can be considered as a target for age-related metabolic disorders., Glycerol-3-phosphate phosphatase is a recently discovered enzyme at the heart of metabolism. Here, the authors used C. elegans and showed that its activation promotes stress resistance, healthy aging and acts as a calorie restriction mimetic at normal food intake without altering fertility.

Enhanced energy expenditure in brown (BAT) and white adipose tissues (WAT) can be therapeutic against metabolic diseases. We examined the thermogenic role of adipose α/β-hydrolase domain 6 (ABHD6), which hydrolyzes monoacylglycerol (MAG), by employing adipose-specific ABHD6-KO mice. Control and KO mice showed similar phenotypes at room temperature and thermoneutral conditions. However, KO mice were resistant to hypothermia, which can be accounted for by the simultaneously increased lipolysis and lipogenesis of the thermogenic glycerolipid/free fatty acid (GL/FFA) cycle in visceral fat, despite unaltered uncoupling protein 1 expression. Upon cold stress, nuclear 2-MAG levels increased in visceral WAT of the KO mice. Evidence is provided that 2-MAG causes activation of PPARα in white adipocytes, leading to elevated expression and activity of GL/FFA cycle enzymes. In the ABHD6-ablated BAT, glucose and oxidative metabolism were elevated upon cold induction, without changes in GL/FFA cycle and lipid turnover. Moreover, response to in vivo β3-adrenergic stimulation was comparable between KO and control mice. Our data reveal a MAG/PPARα/GL/FFA cycling metabolic signaling network in visceral adipose tissue, which contributes to cold tolerance, and that adipose ABHD6 is a negative modulator of adaptive thermogenesis., Visceral adipose adipose α/β-hydrolase domain 6 regulates cold adaptation and acts as a brake for heat production via the regulation of thermogenic glycerolipid/free fatty acid cycling.

BackgroundThis study aimed to find prevalence of use of smart devices in children aged five years or less and associated factors in KuwaitMethodsA cross-sectional study of 964 parents conducted by distributing a questionnaire. Following the American Academy of Pediatrics (AAP) recommendations for the smart devices use in children, our population was divided into two groups (less than 2 years old and 2-5 years old).Results Reported prevalence of use was 53.2% in children less than 2 years old and 86.3% in 2-5 years old. A significantly higher mean age of fathers was seen in children who used smart devices compared to those who did not in both age groups. The use of smart devices in children less than 2 years was significantly associated with Kuwaiti nationality, family income and governorate. In addition, the higher the family income, the more the use of smart devices. The highest use of smart devices was seen in Capital (60%) and Ahmadi (58.3%). While the lowest was seen in Jahra (30%). In both age groups, most of the parents who reported the smart devices use in their children knew that its use at early age might harm their child. ConclusionYoung children use of smart devices is prevalent in Kuwait. Campaigns need to be carried out to increase parents’ knowledge about the potential risks of smart devices on children’s brains and development.

Background Children and adolescents are becoming the most prolific users of smart technology (ST) devices due to the numerous advantages presented by these devices. However, the overuse of ST devices can have detrimental impacts on health. Therefore, the aim of this study was to investigate the pattern of ST device use among school students in Kuwait and the possible associated health problems. Methods This cross-sectional survey used a pretested questionnaire to collect data from students of different educational levels within the governmental sector: primary, secondary and high school. Chi-square tests were applied to find associations or significant differences between the categorical variables, in which p Results This study included 3015 students, of whom 53.6% were female. The sample had an equal distribution of primary (33.8%), secondary (32.4%) and high school students (33.8%). Almost all of the participants (99.7%) owned a ST device, chiefly smartphones (87.7%). Most of the students used ST devices for > 4 total hours per day on average, which is categorised as “overuse”. Among those overusing ST devices, the symptoms most commonly experienced included headaches (35.0%), sleep disturbances (36.6%) and neck/shoulder pain (37.7%). Students who used ST devices for Conclusion The overuse of ST devices per day and per session by school-aged children has the potential to have a detrimental impact on their health, as has been noticed among students in Kuwait. Healthcare professionals, school authorities and parents could use these results to plan strategies to change ST device use behaviours among schoolchildren.

Additional file 1. A questionnaire-English version.

[Purpose] Over the years physiotherapy has been recognized as a popular mode of treatment that decreases the disability and dependency rate of patients. However, there is still a need for its recognition in multidisciplinary health care structures. If a physician were well aware of how a physical therapist could help with treatment if patients and prevent complications, hospital patient load could be decreased to a greater extent. The aim of this study was to study the awareness, perception and beliefs of physicians working in Saudi Arabia about physiotherapy. [Subjects and Methods] Three hundred fifteen members of the Saudi Commission for Health Specialties (SCFHS) with different specialties, nationalities, designation, and work experience, working in various hospitals in 5 regions of Saudi Arabia were invited to participate in this study. A 22-item questionnaire was used for data collection including sections on physicians' demographics, educational levels and knowledge about physiotherapy. [Results] After applying the inclusion and exclusion criteria, data from 280 respondents was used for analysis. Seventy-five percent of respondents reported to having some knowledge of physiotherapy, and 11% of them referred patients to physiotherapy departments regularly, while 14% referred patients occasionally. To the best of our knowledge, this is first study performed in Saudi Arabia to evaluate awareness of physicians about the physiotherapy profession. [Conclusion] The results of this study highlight the need to organize various workshops and lectures about the effectiveness of physiotherapy in various diseases for physicians, on a regular basis, to update them with evidence-based treatment. It is the responsibility of physical therapists to raise the perceptions of other healthcare professionals about their profession.

Glucose metabolism promotes insulin secretion in β-cells via metabolic coupling factors that are incompletely defined. Moreover, chronically elevated glucose causes β-cell dysfunction, but little is known about how cells handle excess fuels to avoid toxicity. Here we sought to determine which among the candidate pathways and coupling factors best correlates with glucose-stimulated insulin secretion (GSIS), define the fate of glucose in the β-cell, and identify pathways possibly involved in excess-fuel detoxification. We exposed isolated rat islets for 1 h to increasing glucose concentrations and measured various pathways and metabolites. Glucose oxidation, oxygen consumption, and ATP production correlated well with GSIS and saturated at 16 mm glucose. However, glucose utilization, glycerol release, triglyceride and glycogen contents, free fatty acid (FFA) content and release, and cholesterol and cholesterol esters increased linearly up to 25 mm glucose. Besides being oxidized, glucose was mainly metabolized via glycerol production and release and lipid synthesis (particularly FFA, triglycerides, and cholesterol), whereas glycogen production was comparatively low. Using targeted metabolomics in INS-1(832/13) cells, we found that several metabolites correlated well with GSIS, in particular some Krebs cycle intermediates, malonyl-CoA, and lower ADP levels. Glucose dose-dependently increased the dihydroxyacetone phosphate/glycerol 3-phosphate ratio in INS-1(832/13) cells, indicating a more oxidized state of NAD in the cytosol upon glucose stimulation. Overall, the data support a role for accelerated oxidative mitochondrial metabolism, anaplerosis, and malonyl-CoA/lipid signaling in β-cell metabolic signaling and suggest that a decrease in ADP levels is important in GSIS. The results also suggest that excess-fuel detoxification pathways in β-cells possibly comprise glycerol and FFA formation and release extracellularly and the diversion of glucose carbons to triglycerides and cholesterol esters.

Obesity, and the associated disturbed glycerolipid/fatty acid (GL/FA) cycle, contribute to insulin resistance, islet β-cell failure, and type 2 diabetes. Flux through the GL/FA cycle is regulated by the availability of glycerol-3-phosphate (Gro3P) and fatty acyl-CoA. We describe here a mammalian Gro3P phosphatase (G3PP), which was not known to exist in mammalian cells, that can directly hydrolyze Gro3P to glycerol. We identified that mammalian phosphoglycolate phosphatase, with an uncertain function, acts in fact as a G3PP. We found that G3PP, by controlling Gro3P levels, regulates glycolysis and glucose oxidation, cellular redox and ATP production, gluconeogenesis, glycerolipid synthesis, and fatty acid oxidation in pancreatic islet β-cells and hepatocytes, and that glucose stimulated insulin secretion and the response to metabolic stress, e.g., glucolipotoxicity, in β-cells. In vivo overexpression of G3PP in rat liver lowers body weight gain and hepatic glucose production from glycerol and elevates plasma HDL levels. G3PP is expressed at various levels in different tissues, and its expression varies according to the nutritional state in some tissues. As Gro3P lies at the crossroads of glucose, lipid, and energy metabolism, control of its availability by G3PP adds a key level of metabolic regulation in mammalian cells, and G3PP offers a potential target for type 2 diabetes and cardiometabolic disorders.

Diet induced obese (DIO) mice can be stratified according to their weight gain in response to high fat diet as low responders (LDR) and high responders (HDR). This allows the study of β-cell failure and the transitions to prediabetes (LDR) and early diabetes (HDR). C57BL/6N mice were fed for 8 weeks with a normal chow diet (ND) or a high fat diet and stratified as LDR and HDR. Freshly isolated islets from ND, LDR and HDR mice were studied ex-vivo for mitochondrial metabolism, AMPK activity and signalling, the expression and activity of key enzymes of energy metabolism, cholesterol synthesis, and mRNA profiling. Severely compromised glucose-induced insulin secretion in HDR islets, as compared to ND and LDR islets, was associated with suppressed AMP-kinase activity. HDR islets also showed reduced acetyl-CoA carboxylase activity and enhanced activity of 3-hydroxy-3-methylglutaryl-CoA reductase, which led respectively to elevated fatty acid oxidation and increased cholesterol biosynthesis. HDR islets also displayed mitochondrial membrane hyperpolarization and reduced ATP turnover in the presence of elevated glucose. Expression of protein kinase Cε, which reduces both lipolysis and production of signals for insulin secretion, was elevated in DIO islets. Genes whose expression increased or decreased by more than 1.2-fold were minor between LDR and ND islets (17 differentially expressed), but were prominent between HDR and ND islets (1508 differentially expressed). In HDR islets, particularly affected genes were related to cell cycle and proliferation, AMPK signaling, mitochondrial metabolism and cholesterol metabolism. In conclusion, chronically reduced AMPK activity, mitochondrial dysfunction, elevated cholesterol biosynthesis in islets, and substantial alterations in gene expression accompany β-cell failure in HDR islets. The β-cell compensation process in the prediabetic state (LDR) is largely independent of transcriptional adaptive changes, whereas the transition to early diabetes (HDR) is associated with major alterations in gene expression.

Mutations in ADP-ribosylation factor guanine nucleotide-exchange factor 2 (ARFGEF2) lead to autosomal recessive periventricular heterotopia (PH). To date, 11 mutations, (six missense mutations, one splicing mutation, one small deletion, two small insertions, and one small deletion/insertion) have been reported. Assessing ARFGEF2 mutations will provide a holistic overview of PH. This retrospective study was conducted in 2016 at King Faisal Specialist Hospital and Research Center. For the index patient, magnetic resonance imaging studies revealed a symmetrical focal hyperintensity involving the putamen bilaterally and the inner aspect of the globus pallidus. After family members were genotyped, an autozygosity analysis was performed, followed by exome sequencing of the index patient; A comprehensive filtering approach based on the loss of heterozygosity (LOH) was used to identify variants in phenotypically relevant genes. We report a consanguineous family with two affected individuals, a boy and a girl, with a history of microcephaly, global developmental delay, intellectual disability, myoclonic seizure, and dystonia. The patients carried a novel nonsense mutation (c.3974G>A, p. Trp1325*) in the Armadillo-type fold domain of ARFGEF2. These findings extend our understanding of the phenotype–genotype correlations for ARFGEF2 mutations.