Nasir Ludin

Goethe University Frankfurt

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Johannes Pantel

Goethe University Frankfurt

Silke Matura

Goethe University Frankfurt

Ulrich Pilatus

Goethe University Frankfurt

Lena Wachter

University of Giessen

Gunter P. Eckert

University of Giessen

Elke Hattingen

Goethe University Frankfurt

Ong Moua

University of Colorado Anschutz Medical Campus

Stefan A. Wudy

University of Giessen

Richard K.P. Benninger

University of Colorado Anschutz Medical Campus

Werner Blum

University of Kassel

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University of Giessen

University of Colorado Anschutz Medical Campus

Goethe University Frankfurt

University of Colorado System

University of Colorado Denver

The Medical Center of Aurora

University Hospital Frankfurt

Centro Universitario de Araras Dr Edmunso Ulson

Diabetes Australia

Giessen School of Theology

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GeroScience (2023)

Carmina V. Silaidos Martina Reutzel Lena Wachter Fabian Dieter Nasir Ludin

Abstract Mitochondrial dysfunction is a hallmark of cellular senescence and many age-related neurodegenerative diseases. We therefore investigated the relationship between mitochondrial function in peripheral blood cells and cerebral energy metabolites in young and older sex-matched, physically and mentally healthy volunteers. Cross-sectional observational study involving 65 young (26.0 ± 0.49 years) and 65 older (71.7 ± 0.71 years) women and men recruited. Cognitive health was evaluated using established psychometric methods (MMSE, CERAD). Blood samples were collected and analyzed, and fresh peripheral blood mononuclear cells (PBMCs) were isolated. Mitochondrial respiratory complex activity was measured using a Clarke electrode. Adenosine triphosphate (ATP) and citrate synthase activity (CS) were determined by bioluminescence and photometrically. N-aspartyl-aspartate (tNAA), ATP, creatine (Cr), and phosphocreatine (PCr) were quantified in brains using 1 H- and 31 P-magnetic resonance spectroscopic imaging (MRSI). Levels of insulin-like growth factor 1 (IGF-1) were determined using a radio-immune assay (RIA). Complex IV activity (CIV) (− 15%) and ATP levels (− 11%) were reduced in PBMCs isolated from older participants. Serum levels of IGF-1 were significantly reduced (− 34%) in older participants. Genes involved in mitochondrial activity, antioxidant mechanisms, and autophagy were unaffected by age. tNAA levels were reduced (− 5%), Cr (+ 11%), and PCr (+ 14%) levels were increased, and ATP levels were unchanged in the brains of older participants. Markers of energy metabolism in blood cells did not significantly correlate with energy metabolites in the brain. Age-related bioenergetic changes were detected in peripheral blood cells and the brains of healthy older people. However, mitochondrial function in peripheral blood cells does not reflect energy related metabolites in the brain. While ATP levels in PBMCs may be be a valid marker for age-related mitochondrial dysfunction in humans, cerebral ATP remained constant.

Bioenergetics

Adenosine triphosphate

Senescence

10.1007/s11357-023-00810-9

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How heterogeneity in glucokinase and gap junction coupling determines the islet electrical response

bioRxiv (Cold Spring Harbor Laboratory) (2019)

JaeAnn M. Dwulet Nasir Ludin Robert A. Piscopio Wolfgang E. Schleicher Ong Moua

ABSTRACT Understanding how cell sub-populations in a tissue impact the function of the overall system is often challenging. There is extensive heterogeneity among insulin-secreting β-cells within islets of Langerhans, including their insulin secretory response and gene expression profile; and this heterogeneity can be altered in diabetes. Several studies have identified variations in nutrient sensing between β-cells, including glucokinase (GK) levels, mitochondrial function or expression of genes important for glucose metabolism. Sub-populations of β-cells with defined electrical properties can disproportionately influence islet-wide free-calcium activity ([Ca 2+ ]) and insulin secretion, via gap junction electrical coupling. However, it is poorly understood how sub-populations of β-cells with altered glucose metabolism may impact islet function. To address this, we utilized a multicellular computational model of the islet in which a population of cells deficient in GK activity and glucose metabolism was imposed on the islet, or where β-cells were heterogeneous in glucose metabolism and GK kinetics were altered. This included simulating Glucokinase gene ( GCK ) mutations that cause monogenic diabetes. We combined these approaches with experimental models in which gck was genetically deleted in a population of cells or GK was pharmacologically inhibited. In each case we modulated gap junction electrical coupling. Both the simulated islet and the experimental system required 30-50% of the cells to have near-normal glucose metabolism. Below this number, the islet lacked any glucose-stimulated [Ca 2+ ] elevations. In the absence of electrical coupling the change in [Ca 2+ ] was more gradual. As such, given heterogeneity in glucose metabolism, electrical coupling allows a large minority of cells with normal glucose metabolism to promote glucose-stimulated [Ca 2+ ]. If insufficient numbers of cells are present, which we predict can be caused by a subset of GCK mutations that cause monogenic diabetes, electrical coupling exacerbates [Ca 2+ ] suppression. This demonstrates precisely how heterogeneous β-cell populations interact to impact islet function. SIGNIFICANCE Biological tissues contain heterogeneous populations of cells. Insulin-secreting β-cells within the islets of Langerhans are critical for regulating blood glucose homeostasis. β-cells are heterogeneous but it is unclear how the islet response is impacted by different cell populations and their interactions. We use a multicellular computational model and experimental systems to predict and quantify how cellular populations defined by varied glucose metabolism interact via electrical communication to impact islet function. When glucose metabolism is heterogeneous, electrical coupling is critical to promote electrical activity. However, when cells deficient in glucose metabolism are in the majority, electrical activity is completely suppressed. Thus modulating electrical communication can promotes islet electrical activity, following dysfunction caused by gene mutations that impact glucose metabolism.

Glucokinase

Carbohydrate Metabolism

10.1101/696096

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MRSI DETECTABLE CHOLINE METABOLISM AS MARKER FOR GENDER DIFFERENCES IN AGING

Proceedings on CD-ROM - International Society for Magnetic Resonance in Medicine. Scientific Meeting and Exhibition/Proceedings of the International Society for Magnetic Resonance in Medicine, Scientific Meeting and Exhibition (2023)

Ulrich Pilatus Gunter P. Eckert Nasir Ludin Silke Matura Johannes Pantel

Combining quantitative (mmol/l) 1 H MRSI and 31 P MRSI data from the brain of healthy volunteers revealed a choline component (rCho=tCho-(PCho+GPC)) which is visible with 1 H MRSI but missing in 31 P MRSI. This component, which may account for a fraction of mobile phospholipids, is reduced in young female (mean age 26) subjects. Lower levels would indicate a higher integrity of the membrane phospholipids in the brain of young women. A possible reason is the higher estrogen levels in this group.

Choline

10.58530/2022/1636

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