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The Ionospheric Connection Explorer, or ICON, is a new NASA Explorer mission that will explore the boundary between Earth and space to understand the physical connection between our world and our space environment. This connection is made in the ionosphere, which has long been known to exhibit variability associated with the sun and solar wind. However, it has been recognized in the 21st century that equally significant changes in ionospheric conditions are apparently associated with energy and momentum propagating upward from our own atmosphere. ICON's goal is to weigh the competing impacts of these two drivers as they influence our space environment. Here we describe the specific science objectives that address this goal, as well as the means by which they will be achieved. The instruments selected, the overall performance requirements of the science payload and the operational requirements are also described. ICON's development began in 2013 and the mission is on track for launch in 2017. ICON is developed and managed by the Space Sciences Laboratory at the University of California, Berkeley, with key contributions from several partner institutions.

Objective: Excess accumulation of advanced glycation end products (AGEs) contributes to aging and chronic diseases. We aimed to obtain evidence that exposure to AGEs plays a role in the development of type 1 diabetes (T1D).Research Design and Methods: The effect of AGEs was examined on insulin secretion by MIN6N8 cells and mouse islets and in vivo in three separate rodent models: AGE-injected or high AGE-fed Sprague-Dawley rats and nonobese diabetic (NODLt) mice. Rodents were also treated with the AGE-lowering agent alagebrium.Results: β-Cells exposed to AGEs displayed acute glucose-stimulated insulin secretory defects, mitochondrial abnormalities including excess superoxide generation, a decline in ATP content, loss of MnSOD activity, reduced calcium flux, and increased glucose uptake, all of which were improved with alagebrium treatment or with MnSOD adenoviral overexpression. Isolated mouse islets exposed to AGEs had decreased glucose-stimulated insulin secretion, increased mitochondrial superoxide production, and depletion of ATP content, which were improved with alagebrium or with MnTBAP, an SOD mimetic. In rats, transient or chronic exposure to AGEs caused progressive insulin secretory defects, superoxide generation, and β-cell death, ameliorated with alagebrium. NODLt mice had increased circulating AGEs in association with an increase in islet mitochondrial superoxide generation, which was prevented by alagebrium, which also reduced the incidence of autoimmune diabetes. Finally, at-risk children who progressed to T1D had higher AGE concentrations than matched nonprogressors.Conclusions: These findings demonstrate that AGEs directly cause insulin secretory defects, most likely by impairing mitochondrial function, which may contribute to the development of T1D. [ABSTRACT FROM AUTHOR]

Objective: Chronic low-grade activation of the immune system (CLAIS) predicts type 2 diabetes via a decrease in insulin sensitivity. Our study investigated potential relationships between nuclear factor-kappaB (NF-kappaB) and c-Jun NH(2)-terminal kinase (JNK) pathways-two pathways proposed as the link between CLAIS and insulin resistance.Research Design and Methods: Adiposity (dual-energy X-ray absorptiometry), waist-to-hip ratio (WHR), and insulin sensitivity (M, hyperinsulinemic-euglycemic clamp) were measured in 22 healthy nondiabetic volunteers (aged 29 +/- 11 years, body fat 28 +/- 11%). NF-kappaB activity (DNA-binding assay) and JNK1/2 activity (phosphorylated JNK) were assessed in biopsies of the vastus lateralis muscle and subcutaneous adipose tissue and in peripheral blood mononuclear cell (PBMC) lysates.Results: NF-kappaB activities in PBMCs and muscle were positively associated with WHR after adjustment for age, sex, and percent body fat (both P < 0.05). NF-kappaB activity in PBMCs was inversely associated with M after adjustment for age, sex, percent body fat, and WHR (P = 0.02) and explained 16% of the variance of M. There were no significant relationships between NF-kappaB activity and M in muscle or adipose tissue (both NS). Adipose-derived JNK1/2 activity was not associated with obesity (all P> 0.1), although it was inversely related to M (r = -0.54, P < 0.05) and explained 29% of its variance. When both NF-kappaB and JNK1/2 were examined statistically, only JNK1/2 activity in adipose tissue was a significant determinant of insulin resistance (P = 0.02).Conclusions: JNK1/2 activity in adipose tissue but not NF-kappaB activity in PBMCs is an independent determinant of insulin resistance in healthy individuals. [ABSTRACT FROM AUTHOR]

The biochemical process of advanced glycation appears to play a central role in the development and progression of diabetic vascular complications. A number of strategies to influence this pathway have been designed, one of which involves the putative advanced glycation end-product (AGE) crosslink breaker, alagebrium which has been shown in in vitro studies to cleave preformed AGE crosslinks. This agent has been studied in various models of diabetic complications and has been shown to attenuate diabetic renal disease, cardiac dysfunction, and atherosclerosis. In addition to the ability of alagebrium to reduce tissue levels of AGEs, this drug appears to inhibit activation of certain protein kinase C isoforms. Planned clinical studies in diabetic subjects at risk of complications should assist in determining the role of alagebrium in the prevention, retardation, and reversal of diabetic micro- and macrovascular disease. [ABSTRACT FROM AUTHOR]

Background: As orthopedic surgery becomes increasingly competitive, orthopedic surgeons are now pursuing advanced degrees more frequently to enhance their resumes or gain additional expertise. The specific impact of this additional training and education on a surgeon's career trajectory is not well defined. The purpose of this study was to understand the impact of an advanced degree on the academic career of orthopedic shoulder and elbow surgeons., Methods: Orthopedic shoulder and elbow fellowship-trained surgeons were identified using the directory listed on the American Shoulder and Elbow Surgeons website. Demographics, education, and current professional roles were obtained. Research productivity was obtained using SCOPUS and Google Scholar. Advanced degrees were defined as those additional to the primary medical degree (Doctor of Medicine [MD] or Doctor of Osteopathic Medicine [DO]). Outcome measures collected included timing of advanced degree obtainment, current academic and leadership roles, leadership on journal editorial boards, and research productivity. Statistical analysis was performed using the chi-square test and Mann-Whitney U test to determine the association of advanced degrees on outcome measures., Results: In total, 893 orthopedic shoulder and elbow surgeons were identified, of whom 129 had advanced degrees. Most common advanced degrees included Master of Science (MS/MSc; 43%), Master of Business Administration (MBA; 23%), and Doctor of Philosophy (PhD; 13%). The most common period of degree obtainment was before medical school (35%) with the least common times being after medical school/before residency (0.9%) and between residency and fellowship training (0.9%). Surgeons who held advanced degrees demonstrated greater research productivity, with a higher h-index (p < 0.001), a greater number of citations (p < 0.001), and more publications (p < 0.001). Of the 523 shoulder and elbow surgeons who worked at an academic institution, those holding advanced degrees were more likely to serve as orthopedic department chair (p < 0.001) and serve an editorial board position (< 0.001)., Conclusion: This study found that having an advanced degree as an orthopedic shoulder and elbow surgeon was linked to higher research impact and productivity and an increased likelihood of becoming a department chair and holding an editorial position. These significant findings can help future trainees and department leadership in understanding the importance and impact of additional training on career trajectories for academic faculty., (Copyright © 2024. Published by Elsevier Inc.)

Glucagon like peptide-1 (GLP-1) is a hormone produced and released by cells of the gastrointestinal tract following meal ingestion. GLP-1 receptor agonists (GLP-1RA) exhibit kidney-protective actions through poorly understood mechanisms. Here we interrogated whether the receptor for advanced glycation end products (RAGE) plays a role in mediating the actions of GLP-1 on inflammation and diabetic kidney disease. Mice with deletion of the GLP-1 receptor displayed an abnormal kidney phenotype that was accelerated by diabetes and improved with co-deletion of RAGE in vivo. Activation of the GLP-1 receptor pathway with liraglutide, an anti-diabetic treatment, downregulated kidney RAGE, reduced the expansion of bone marrow myeloid progenitors, promoted M2-like macrophage polarization and lessened markers of kidney damage in diabetic mice. Single cell transcriptomics revealed that liraglutide induced distinct transcriptional changes in kidney endothelial, proximal tubular, podocyte and macrophage cells, which were dominated by pathways involved in nutrient transport and utilization, redox sensing and the resolution of inflammation. The kidney-protective action of liraglutide was corroborated in a non-diabetic model of chronic kidney disease, the subtotal nephrectomised rat. Thus, our findings identify a novel glucose-independent kidney-protective action of GLP-1-based therapies in diabetic kidney disease and provide a valuable resource for exploring the cell-specific kidney transcriptional response ensuing from pharmacological GLP-1R agonism., (Copyright © 2023 International Society of Nephrology. All rights reserved.)

Hypoglycemia in type 1 diabetes associates with changes in the pancreatic islet α cells, where the receptor for advanced glycation end products (RAGE) is highly expressed. This study compared islet RAGE expression in donors without diabetes, those at risk of, and those with type 1 diabetes. Laser-dissected islets were subject to RNA bioinformatics and adjacent pancreatic tissue were assessed by confocal microscopy. We found that islets from type 1 diabetes donors had differential expression of the RAGE gene (AGER) and its correlated genes, based on glucagon expression. Random forest machine learning revealed that AGER was the most important predictor for islet glucagon levels. Conversely, a generalized linear model identified that glucagon expression could be predicted by expression of RAGE signaling molecules, its ligands and enzymes that create or clear RAGE ligands. Confocal imaging co-localized RAGE, its ligands and signaling molecules to the α cells. Half of the type 1 diabetes cohort comprised of adolescents and a patient with history of hypoglycemia-all showed an inverse relationship between glucagon and RAGE. These data confirm an association between glucagon and islet RAGE, its ligands and signaling pathways in type 1 diabetes, which warrants functional investigation into a role for RAGE in hypoglycemia., (© 2023. Springer Nature Limited.)

The two-year prime mission of the NASA Ionospheric Connection Explorer (ICON) is complete. The baseline operational and scientific objectives have been met and exceeded, as detailed in this report. In October of 2019, ICON was launched into an orbit that provides its instruments the capability to deliver near-continuous measurements of the densest plasma in Earth's space environment. Through collection of a key set of in-situ and remote sensing measurements that are, by virtue of a detailed mission design, uniquely synergistic, ICON enables completely new investigations of the mechanisms that control the behavior of the ionosphere-thermosphere system under both geomagnetically quiet and active conditions. In a two-year period that included a deep solar minimum, ICON has elucidated a number of remarkable effects in the ionosphere attributable to energetic inputs from the lower and middle atmosphere, and shown how these are transmitted from the edge of space to the peak of plasma density above. The observatory operated in a period of low activity for 2 years and then for a year with increasing solar activity, observing the changing balance of the impacts of lower and upper atmospheric drivers on the ionosphere., Competing Interests: Competing InterestsThe authors have no financial interests attached to the scientific results presented in this report., (© The Author(s) 2023.)

Second harmonic generation is the lowest-order wave-wave nonlinear interaction occurring in, e.g., optical, radio, and magnetohydrodynamic systems. As a prototype behavior of waves, second harmonic generation is used broadly, e.g., for doubling Laser frequency. Second harmonic generation of Rossby waves has long been believed to be a mechanism of high-frequency Rossby wave generation via cascade from low-frequency waves. Here, we report the observation of a Rossby wave second harmonic generation event in the atmosphere. We diagnose signatures of two transient waves at periods of 16 and 8 days in the terrestrial middle atmosphere, using meteor-radar wind observations over the European and Asian sectors during winter 2018-2019. Their temporal evolution, frequency and wavenumber relations, and phase couplings revealed by bicoherence and biphase analyses demonstrate that the 16-day signature is an atmospheric manifestation of a Rossby wave normal mode, and its second harmonic generation gives rise to the 8-day signature. Our finding confirms the theoretically-anticipated Rossby wave nonlinearity., (© 2022. The Author(s).)

The receptor for advanced glycation endproducts (RAGE) is involved in multiple inflammatory processes. RAGE participates in adaptive and innate immune responses but its role in human immune cell responses has not been directly tested in vivo. We treated humanized mice (NSG) with the small molecule antagonist of RAGE, azeliragon, (AZ), and measured effects on xenogeneic (B6) skin graft rejection. AZ delayed the median time to xenograft rejection (22 vs 56 days, P = 0.0001). PD-1 expression on CD4+ and CD8+ T cells was lower following AZ therapy. Transcriptome studies showed inhibition of pathways in splenocytes with AZ including IL-23, IL-17A and IL-1β signaling. The serum levels of IL-1β and IL-17A in AZ treated mice were reduced in mice that did not reject skin grafts. The RAGE antagonist prevented xenograft rejection by human immune cells in a murine model. A RAGE antagonist may be a useful inhibitor of adaptive human immune responses., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Type 1 diabetes (T1D) is an autoimmune disease in which the β-cells of the pancreas are attacked by the host's immune system, ultimately resulting in hyperglycemia. It is a complex multifactorial disease postulated to result from a combination of genetic and environmental factors. In parallel with increasing prevalence of T1D in genetically stable populations, highlighting an environmental component, consumption of advanced glycation end products (AGEs) commonly found in in Western diets has increased significantly over the past decades. AGEs can bind to cell surface receptors including the receptor for advanced glycation end products (RAGE). RAGE has proinflammatory roles including in host-pathogen defense, thereby influencing immune cell behavior and can activate and cause proliferation of immune cells such as islet infiltrating CD8 + and CD4 + T cells and suppress the activity of T regulatory cells, contributing to β-cell injury and hyperglycemia. Insights from studies of individuals at risk of T1D have demonstrated that progression to symptomatic onset and diagnosis can vary, ranging from months to years, providing a window of opportunity for prevention strategies. Interaction between AGEs and RAGE is believed to be a major environmental risk factor for T1D and targeting the AGE-RAGE axis may act as a potential therapeutic strategy for T1D prevention.

Type 1 diabetes is an autoimmune disease with no cure, where clinical translation of promising therapeutics has been hampered by the reproducibility crisis. Here, short-term administration of an antagonist to the receptor for advanced glycation end products (sRAGE) protected against murine diabetes at two independent research centers. Treatment with sRAGE increased regulatory T cells (Tregs) within the islets, pancreatic lymph nodes, and spleen, increasing islet insulin expression and function. Diabetes protection was abrogated by Treg depletion and shown to be dependent on antagonizing RAGE with use of knockout mice. Human Tregs treated with a RAGE ligand downregulated genes for suppression, migration, and Treg homeostasis (FOXP3, IL7R, TIGIT, JAK1, STAT3, STAT5b, CCR4). Loss of suppressive function was reversed by sRAGE, where Tregs increased proliferation and suppressed conventional T-cell division, confirming that sRAGE expands functional human Tregs. These results highlight sRAGE as an attractive treatment to prevent diabetes, showing efficacy and reproducibility at multiple research centers and in human T cells., (© 2022 by the American Diabetes Association.)

Inflammasomes are multiprotein platforms responsible for the release of pro-inflammatory cytokines interleukin (IL)-1β and IL-18. Mouse studies have identified inflammasome activation within dendritic cells (DC) as pivotal for driving tubulointerstitial fibrosis and inflammation, the hallmarks of chronic kidney disease (CKD). However, translation of this work to human CKD remains limited. Here, we examined the complex tubular cell death pathways mediating inflammasome activation in human kidney DC and, thus, CKD progression. Ex vivo patient-derived proximal tubular epithelial cells (PTEC) cultured under hypoxic (1% O 2 ) conditions modelling the CKD microenvironment showed characteristics of ferroptotic cell death, including mitochondrial dysfunction, reductions in the lipid repair enzyme glutathione peroxidase 4 (GPX4) and increases in lipid peroxidation by-product 4-hydroxynonenal (4-HNE) compared with normoxic PTEC. The addition of ferroptosis inhibitor, ferrostatin-1, significantly reduced hypoxic PTEC death. Human CD1c + DC activated in the presence of hypoxic PTEC displayed significantly increased production of inflammasome-dependent cytokines IL-1β and IL-18. Treatment of co-cultures with VX-765 (caspase-1/4 inhibitor) and MCC950 (NLRP3 inflammasome inhibitor) significantly attenuated IL-1β/IL-18 levels, supporting an NLRP3 inflammasome-dependent DC response. In line with these in vitro findings, in situ immunolabelling of human fibrotic kidney tissue revealed a significant accumulation of tubulointerstitial CD1c + DC containing active inflammasome (ASC) specks adjacent to ferroptotic PTEC. These data establish ferroptosis as the primary pattern of PTEC necrosis under the hypoxic conditions of CKD. Moreover, this study identifies NLRP3 inflammasome signalling driven by complex tubulointerstitial PTEC-DC interactions as a key checkpoint for therapeutic targeting in human CKD., (© 2022. Crown.)

Since the 1980s, chronic kidney disease (CKD) affecting all ages has increased by almost 25%. This increase may be partially attributable to lifestyle changes and increased global consumption of a "western" diet, which is typically energy dense, low in fruits and vegetables, and high in animal protein and ultra-processed foods. These modern food trends have led to an increase in the consumption of advanced glycation end products (AGEs) in conjunction with increased metabolic dysfunction, obesity and diabetes, which facilitates production of endogenous AGEs within the body. When in excess, AGEs can be pathological via both receptor-mediated and non-receptor-mediated pathways. The kidney, as a major site for AGE clearance, is particularly vulnerable to AGE-mediated damage and increases in circulating AGEs align with risk of CKD and all-cause mortality. Furthermore, individuals with significant loss of renal function show increased AGE burden, particularly with uraemia, and there is some evidence that AGE lowering via diet or pharmacological inhibition may be beneficial for CKD. This review discusses the pathways that drive AGE formation and regulation within the body. This includes AGE receptor interactions and pathways of AGE-mediated pathology with a focus on the contribution of diet on endogenous AGE production and dietary AGE consumption to these processes. We then analyse the contribution of AGEs to kidney disease, the evidence for dietary AGEs and endogenously produced AGEs in driving pathogenesis in diabetic and non-diabetic kidney disease and the potential for AGE targeted therapies in kidney disease.

We present simultaneous, independent measurements of the atmospheric semidiurnal lunar tide in neutral winds and plasma velocities from NASA's Ionospheric Connection Explorer, and in atomic oxygen 135.6 nm airglow measured by the Global-scale Observations of the Limb and Disk. Westward tidal winds near 115 km at the magnetic equator occur during part of the upward phase of the in-situ plasma drift. Vertical motions associated with the field-aligned plasma velocity occur away from the magnetic equator. The morphology of the lunar tide, and the phasing between the airglow and plasma velocities are consistent with E  ×  B drift as a mechanism for linking neutral wind and plasma perturbations. This work provides the first observational quantification of global-scale E- and F-region coupling through E  ×  B and field-aligned vertical drifts., (© 2022. American Geophysical Union. All Rights Reserved.)

Background: Hyperglycaemia occurs frequently in the critically ill. Dietary intake of advanced glycation end-products (AGEs), specifically Nε-(carboxymethyl)lysine (CML), may exacerbate hyperglycaemia through perturbation of insulin sensitivity. The present study aimed to determine whether the use of nutritional formulae, with varying AGE loads, affects the amount of insulin administered and inflammation., Methods: Exclusively tube fed patients (n = 35) were randomised to receive Nutrison Protein Plus Multifibre®, Diason® or Glucerna Select®. Insulin administration was standardised according to protocol based on blood glucose (<10 mmol L -1 ). Samples were obtained at randomisation and 48 h later. AGEs in nutritional formula, plasma and urine were measured using mass spectrometry. Plasma inflammatory markers were measured using an enzyme-linked immunosorbent assay and multiplex bead-based assays., Results: AGE concentrations of CML in nutritional formulae were greatest with delivery of Nutrison Protein Plus® (mean [SD]; 6335 pmol mol -1 [2436]) compared to Diason® (4836 pmol mol -1 [1849]) and Glucerna Select® (4493 pmol mol -1 [1829 pmol mol -1 ]) despite patients receiving similar amounts of energy (median [interquartile range]; 12 MJ [8.2-13.7 MJ], 11.5 MJ [8.3-14.5 MJ], 11.5 MJ [8.3-14.5 MJ]). More insulin was administered with Nutrison Protein Plus® (2.47 units h -1 [95% confidence interval (CI) = 1.57-3.37 units h -1 ]) compared to Diason® (1.06 units h -1 [95% CI = 0.24-1.89 units h -1 ]) or Glucerna Select® (1.11 units h -1 [95% CI = 0.25-1.97 units h -1 ]; p = 0.04). Blood glucose concentrations were similar. There were associations between greater insulin administration and reductions in circulating interleukin-6 (r = -0.46, p < 0.01), tumour necrosis factor-α (r = -0.44, p < 0.05), high sensitivity C-reactive protein (r = -0.42, p < 0.05) and soluble receptor for advanced glycation end-products (r = -0.45, p < 0.01) concentrations., Conclusions: The administration of greater AGE load in nutritional formula potentially increases the amount of insulin required to maintain blood glucose within a normal range during critical illness. There was an inverse relationship between exogenous insulin and plasma inflammatory markers., (© 2021 The British Dietetic Association Ltd.)

Earth's equatorial ionosphere exhibits substantial and unpredictable day-to-day variations in density and morphology. This presents challenges in preparing for adverse impacts on geopositioning systems and radio communications even 24 hours in advance. The variability is now theoretically understood as a manifestation of thermospheric weather, where winds in the upper atmosphere respond strongly to a spectrum of atmospheric waves that propagate into space from the lower and middle atmosphere. First-principles simulations predict related, large changes in the ionosphere, primarily through modification of wind-driven electromotive forces: the wind-driven dynamo. Here we show the first direct evidence of the action of a wind dynamo in space, using the coordinated, space-based observations of winds and plasma motion made by the National Aeronautics and Space Administration Ionospheric Connection Explorer. A clear relationship is found between vertical plasma velocities measured at the magnetic equator near 600 km and the thermospheric winds much farther below. Significant correlations are found between the plasma and wind velocities during several successive precession cycles of the Ionospheric Connection Explorer's orbit. Prediction of thermospheric winds in the 100-150 km altitude range emerges as the key to improved prediction of Earth's plasma environment., Competing Interests: Competing interests The authors declare no competing interests.

A quasi-2-day wave (Q2DW) event during January-February, 2020, is investigated in terms of its propagation from 96 to 250 km as a function of latitude (10°S to 30°N), its nonlinear interactions with migrating tides to produce 16 and 9.6-h secondary waves (SWs), and the plasma drift and density perturbations that it produces in the topside F-region (590-607 km) between magnetic latitudes 18°S and 18°N. This is accomplished through analysis of coincident Ionospheric Connections Explorer (ICON) measurements of neutral winds, plasma drifts and ion densities, and wind measurements from four low-latitude (±15°) specular meteor radars (SMRs). The Q2DW westward-propagating components that existed during this period consist of zonal wavenumbers s = 2 and s = 3, that is, Q2DW+2 and Q2DW+3 (e.g., He, Chau et al., 2021, https://doi.org/10.1029/93jd00380). SWs in the ICON measurements are inferred from Q2DW+2 and Q2DW+3 characteristics derived from traditional longitude-UT fits that potentially contain aliasing contributions from SWs (" apparent " Q2DWs), from fits to space-based zonal wavenumbers that each reflect the aggregate signature of either Q2DW+2 or Q2DW+3 and its SWs combined (" effective " Q2DWs), and based on information contained in published numerical simulations. The total Q2DW ionospheric responses consists of F-region field-aligned and meridional drifts of order ±25 ms -1 and ±5-7 ms -1 , respectively, and total ion density perturbations of order (±10%-25%). It is shown that the SWs can sometimes make substantial contributions to the Q2DW winds, drifts, and plasma densities.

The kidneys balance many byproducts of the metabolism of dietary components. Previous studies examining dietary effects on kidney health are generally of short duration and manipulate a single macronutrient. Here, kidney function and structure were examined in C57BL/6J mice randomized to consume one of a spectrum of macronutrient combinations (protein [5%-60%], carbohydrate [20%-75%], and fat [20%-75%]) from weaning to late-middle age (15 months). Individual and interactive impacts of macronutrients on kidney health were modeled. Dietary protein had the greatest influence on kidney function, where chronic low protein intake decreased glomerular filtration rates and kidney mass, whereas it increased kidney immune infiltration and structural injury. Kidney outcomes did not align with cardiometabolic risk factors including glucose intolerance, overweight/obesity, dyslipidemia, and hypertension in mice with chronic low protein consumption. This study highlights that protein intake over a lifespan is an important determinant of kidney function independent of cardiometabolic changes., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)

Half of the mortality in diabetes is seen in individuals <50 years of age and commonly predicted by the early onset of diabetic kidney disease (DKD). In type 1 diabetes, increased urinary albumin-to-creatinine ratio (uACR) during adolescence defines this risk, but the pathological factors responsible remain unknown. We postulated that early in diabetes, glucose variations contribute to kidney injury molecule-1 (KIM-1) release from circulating T cells, elevating uACR and DKD risk. DKD risk was assigned in youth with type 1 diabetes ( n = 100; 20.0 ± 2.8 years; males/females, 54:46; HbA 1c 66.1 [12.3] mmol/mol; diabetes duration 10.7 ± 5.2 years; and BMI 24.5 [5.3] kg/m 2 ) and 10-year historical uACR, HbA 1c , and random blood glucose concentrations collected retrospectively. Glucose fluctuations in the absence of diabetes were also compared with streptozotocin diabetes in apolipoprotein E -/- mice. Kidney biopsies were used to examine infiltration of KIM-1-expressing T cells in DKD and compared with other chronic kidney disease. Individuals at high risk for DKD had persistent elevations in uACR defined by area under the curve (AUC; uACR AUC0-10yrs , 29.7 ± 8.8 vs. 4.5 ± 0.5; P < 0.01 vs. low risk) and early kidney dysfunction, including ∼8.3 mL/min/1.73 m 2 higher estimated glomerular filtration rates (modified Schwartz equation; P adj < 0.031 vs. low risk) and plasma KIM-1 concentrations (∼15% higher vs. low risk; P < 0.034). High-risk individuals had greater glycemic variability and increased peripheral blood T-cell KIM-1 expression, particularly on CD8 + T cells. These findings were confirmed in a murine model of glycemic variability both in the presence and absence of diabetes. KIM-1 + T cells were also infiltrating kidney biopsies from individuals with DKD. Healthy primary human proximal tubule epithelial cells exposed to plasma from high-risk youth with diabetes showed elevated collagen IV and sodium-glucose cotransporter 2 expression, alleviated with KIM-1 blockade. Taken together, these studies suggest that glycemic variations confer risk for DKD in diabetes via increased CD8 + T-cell production of KIM-1., (© 2021 by the American Diabetes Association.)

Mechanisms by which advanced glycation end products (AGEs) contribute to type 1 diabetes (T1D) pathogenesis are poorly understood. Since life-long pharmacotherapy with alagebrium chloride (ALT) slows progression to experimental T1D, we hypothesized that acute ALT therapy delivered prediabetes, may be effective. However, in female, non-obese diabetic (NOD ShiLt ) mice, ALT administered prediabetes (day 50-100) did not protect against experimental T1D. ALT did not decrease circulating AGEs or their precursors. Despite this, pancreatic β-cell function was improved, and insulitis and pancreatic CD45.1 + cell infiltration was reduced. Lymphoid tissues were unaffected. ALT pre-treatment, prior to transfer of primed GC98 CD8 + T cell receptor transgenic T cells, reduced blood glucose concentrations and delayed diabetes, suggesting islet effects rather than immune modulation by ALT. Indeed, ALT did not reduce interferon-γ production by leukocytes from ovalbumin-pre-immunised NOD ShiLt mice and NOD scid recipients given diabetogenic ALT treated NOD splenocytes were not protected against T1D. To elucidate β-cell effects, NOD-derived MIN6N8 β-cell major histocompatibility complex (MHC) Class Ia surface antigens were examined using immunopeptidomics. Overall, no major changes in the immunopeptidome were observed during the various treatments with all peptides exhibiting allele specific consensus binding motifs. As expected, longer MHC Class Ia peptides were captured bound to H-2D b than H-2K b under all conditions. Moreover, more 10-12 mer peptides were isolated from H-2D b after AGE modified bovine serum albumin (AGE-BSA) treatment, compared with bovine serum albumin (BSA) or AGE-BSA+ALT treatment. Proteomics of MIN6N8 cells showed enrichment of processes associated with catabolism, the immune system, cell cycling and presynaptic endocytosis with AGE-BSA compared with BSA treatments. These data show that short-term ALT intervention, given prediabetes, does not arrest experimental T1D but transiently impacts β-cell function.

Aims: The accumulation of advanced glycation end products is implicated in the development and progression of diabetic kidney disease. No study has examined whether stimulating advanced glycation clearance via receptor manipulation is reno-protective in diabetes. Podocytes, which are early contributors to diabetic kidney disease and could be a target for reno-protection., Materials and Methods: To examine the effects of increased podocyte oligosaccharyltransferase-48 on kidney function, glomerular sclerosis, tubulointerstitial fibrosis and proteome (PXD011434), we generated a mouse with increased oligosaccharyltransferase-48kDa subunit abundance in podocytes driven by the podocin promoter., Results: Despite increased urinary clearance of advanced glycation end products, we observed a decline in renal function, significant glomerular damage including glomerulosclerosis, collagen IV deposition, glomerular basement membrane thickening and foot process effacement and tubulointerstitial fibrosis. Analysis of isolated glomeruli identified enrichment in proteins associated with collagen deposition, endoplasmic reticulum stress and oxidative stress. Ultra-resolution microscopy of podocytes revealed denudation of foot processes where there was co-localization of oligosaccharyltransferase-48kDa subunit and advanced glycation end-products., Conclusions: These studies indicate that increased podocyte expression of oligosaccharyltransferase-48 kDa subunit results in glomerular endoplasmic reticulum stress and a decline in kidney function., Competing Interests: J.M.F. is supported by a Senior Research Fellowship (APP1004503;1102935) from the National Health and Medical Research Council of Australia (NHMRC). B.L.S. is supported by a Career Development Fellowship (APP1087975) from the NHMRC. A.Z. received a scholarship from Kidney Health Australia (SCH17; 141516) and the Mater Research Foundation. M.T.C. is supported by a Career Development Fellowship from the Australian Type 1 Diabetes Clinical Research Network, a special initiative of the Australian Research Council. This research was supported by the NHMRC, Kidney Health Australia and the Mater Foundation, which had no role in the study design, data collection and analysis, decision to publish, or preparation or the manuscript., (© 2021 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.)

Reduced protein intake, through dilution with carbohydrate, extends lifespan and improves mid-life metabolic health in animal models. However, with transition to industrialised food systems, reduced dietary protein is associated with poor health outcomes in humans. Here we systematically interrogate the impact of carbohydrate quality in diets with varying carbohydrate and protein content. Studying 700 male mice on 33 isocaloric diets, we find that the type of carbohydrate and its digestibility profoundly shape the behavioural and physiological responses to protein dilution, modulate nutrient processing in the liver and alter the gut microbiota. Low (10%)-protein, high (70%)-carbohydrate diets promote the healthiest metabolic outcomes when carbohydrate comprises resistant starch (RS), yet the worst outcomes were with a 50:50 mixture of monosaccharides fructose and glucose. Our findings could explain the disparity between healthy, high-carbohydrate diets and the obesogenic impact of protein dilution by glucose-fructose mixtures associated with highly processed diets.

Coincident Ionospheric Connections Explorer (ICON) measurements of neutral winds, plasma drifts and total ion densities (:=Ne, electron density) are analyzed during January 1-21, 2020 to reveal the relationship between neutral winds and ionospheric variability on a day-to-day basis. Atmosphere-ionosphere (A-I) connectivity inevitably involves a spectrum of planetary waves (PWs), tides and secondary waves due to wave-wave nonlinear interactions. To provide a definitive attribution of dynamical origins, the current study focuses on a time interval when the longitudinal wave-4 component of the E-region winds is dominated by the eastward-propagating diurnal tide with zonal wavenumber s = -3 (DE3). DE3 is identified in winds and ionospheric parameters through its characteristic dependence on local solar time and longitude as ICON's orbit precesses. Superimposed on this trend are large variations in low-latitude DE3 wave-4 zonal winds (±40 ms -1 ) and topside F-region equatorial vertical drifts at periods consistent with 2-days and 6-days PWs, and a ~3-day ultra-fast Kelvin wave (UFKW), coexisting during this time interval; the DE3 winds, dynamo electric fields, and drifts are modulated by these waves. Wave-4 variability in Ne is of order 25%-35%, but the origins are more complex, likely additionally reflecting transport by ~20-25 ms -1 wave-4 in-situ winds containing strong signatures of DE3 interactions with ambient diurnal Sun-synchronous winds and ion drag. These results are the first to show a direct link between day-to-day wave-4 variability in contemporaneously measured E-region neutral winds and F-region ionospheric drifts and electron densities.

To examine if skin autofluorescence (sAF) differed in early adulthood between individuals with type 1 diabetes and age-matched controls and to ascertain if sAF aligned with risk for kidney disease. Young adults with type 1 diabetes (N = 100; 20.0 ± 2.8 years; M:F 54:46; FBG-11.6 ± 4.9 mmol/mol; diabetes duration 10.7 ± 5.2 years; BMI 24.5(5.3) kg/m 2 ) and healthy controls (N = 299; 20.3 ± 1.8 years; M:F-83:116; FBG 5.2 ± 0.8 mmol/L; BMI 22.5(3.3) kg/m 2 ) were recruited. Skin autofluorescence (sAF) and circulating AGEs were measured. In a subset of both groups, kidney function was estimated by GFR CKD-EPI CysC and uACR, and DKD risk defined by uACR tertiles. Youth with type 1 diabetes had higher sAF and BMI, and were taller than controls. For sAF, 13.6% of variance was explained by diabetes duration, height and BMI (P model  = 1.5 × 10 -12 ). In the sub-set examining kidney function, eGFR and sAF were higher in type 1 diabetes versus controls. eGFR and sAF predicted 24.5% of variance in DKD risk (P model  = 2.2 × 10 -9 ), which increased with diabetes duration (51%; P model  < 2.2 × 10 -16 ) and random blood glucose concentrations (56%; P model  < 2.2 × 10 -16 ). HbA 1C and circulating fructosamine albumin were higher in individuals with type 1 diabetes at high versus low DKD risk. eGFR was independently associated with DKD risk in all models. Higher eGFR and longer diabetes duration are associated with DKD risk in youth with type 1 diabetes. sAF, circulating AGEs, and urinary AGEs were not independent predictors of DKD risk. Changes in eGFR should be monitored early, in addition to uACR, for determining DKD risk in type 1 diabetes.

Scope: This study evaluates the effects of a chronic high protein diet (HPD) on kidney injury, intestinal permeability and gut microbiota perturbations in a mouse model., Method and Results: Mice are fed a diet containing either 20% or 52% energy from protein for 24 weeks; protein displaced an equivalent amount of wheat starch. The HPD does not alter glycemic control or body weight. The HPD induces kidney injury as evidenced by increase in albuminuria, urinary kidney injury molecule-1, blood urea nitrogen, urinary isoprostanes and renal cortical NF-κB p65 gene expression. HPD decreases intestinal occludin gene expression, increases plasma endotoxin and plasma monocyte chemoattractant protein-1, indicating intestinal leakiness and systemic inflammation. Cecal microbial analysis reveals that HPD feeding does not alter alpha diversity; however, it does alter beta diversity, indicating an altered microbial community structure with HPD feeding. Predicted metagenome pathway analysis demonstrates a reduction in branched-chain amino acid synthesis and an increase of the urea cycle with consumption of a HPD., Conclusion: These results demonstrate that long term HPD consumption in mice causes albuminuria, systemic inflammation, increase in gastrointestinal permeability and is associated with gut microbiome remodeling with an increase in the urea cycle pathway, which may contribute to renal injury., (© 2021 Wiley-VCH GmbH.)

Intake of processed foods has increased markedly over the past decades, coinciding with increased microvascular diseases such as chronic kidney disease (CKD) and diabetes. Here, we show in rodent models that long-term consumption of a processed diet drives intestinal barrier permeability and an increased risk of CKD. Inhibition of the advanced glycation pathway, which generates Maillard reaction products within foods upon thermal processing, reversed kidney injury. Consequently, a processed diet leads to innate immune complement activation and local kidney inflammation and injury via the potent proinflammatory effector molecule complement 5a (C5a). In a mouse model of diabetes, a high resistant starch fiber diet maintained gut barrier integrity and decreased severity of kidney injury via suppression of complement. These results demonstrate mechanisms by which processed foods cause inflammation that leads to chronic disease., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Longitudinal structures in the Martian thermosphere and topside ionosphere between 150 and 200 km altitudes are studied using in situ electron and neutral measurements from the NASA Mars Atmosphere and Volatile EvolutioN (MAVEN) mission. Four time intervals are selected for comparison, during which MAVEN sampled similar local time (9.3-10.3 h) and latitude (near 20°S) regions but at different solar longitude positions (two near northern summer solstice, one each at northern vernal and autumnal equinoxes). Persistent and pronounced tidal oscillations characterize the ionosphere and thermosphere, whose longitudinal variations in density are generally in-phase with each other. Our analysis of simultaneous and collocated neutral and electron data provides direct observational evidence for thermosphere-ionosphere coupling through atmospheric tides. We conclude that the ionosphere is subject to modulation by upward-propagating thermal tides, via both tide-induced vertical displacement and photochemical reactions. Atmospheric tides constitute a ubiquitous and significant perturbation source to the ionospheric electron density, up to ~15% near 200 km.

Postprandial glucose excursions are postulated to increase the risk for diabetes complications via the production of advanced glycation end products (AGEs). The soluble receptor of AGEs (sRAGE) likely acts as a decoy receptor, mopping up AGEs, diminishing their capacity for pro-inflammatory and pro-apoptotic signaling. Recent evidence suggests that AGEs and soluble receptor for AGEs (sRAGE) may be altered under postprandial and fasting conditions. Here, we investigated the effects of increasing oral glucose loads during oral glucose tolerance tests (OGTT) and matched isoglycaemic intravenous (i.v.) glucose infusions (IIGI) on circulating concentrations of sRAGE. Samples from eight individuals with type 2 diabetes and eight age-, gender-, and body mass index (BMI)-matched controls, all of whom underwent three differently dosed OGTTs (25 g, 75 g, and 125 g), and three matched IIGIs were utilised (NCT00529048). Serum concentrations of sRAGE were measured over 240 min during each test. For individuals with diabetes, sRAGE area under the curve (AUC 0-240 min ) declined with increasing i.v. glucose dosages ( p < 0.0001 for trend) and was lower during IIGI compared to OGTT at the 125 g dosage ( p = 0.004). In control subjects, sRAGE AUC 0-240 min was only lower during IIGI compared to OGTT at the 25 g dose ( p = 0.0015). sRAGE AUC 0-240 min was negatively correlated to AUC 0-240 min for the incretin hormone glucagon-like peptide -1 (GLP-1) during the 75 g OGTT and matched IIGI, but only in individuals with type 2 diabetes. These data suggest that gastrointestinal factors may play a role in regulating sRAGE concentrations during postprandial glucose excursions, thus warranting further investigation.

Rationale: Treatment efficacy for diabetes mellitus is largely determined by assessment of HbA1c (glycated hemoglobin A1c) levels, which poorly reflects direct glucose variation. People with prediabetes and diabetes mellitus spend >50% of their time outside the optimal glucose range. These glucose variations, termed transient intermittent hyperglycemia (TIH), appear to be an independent risk factor for cardiovascular disease, but the pathological basis for this association is unclear., Objective: To determine whether TIH per se promotes myelopoiesis to produce more monocytes and consequently adversely affects atherosclerosis., Methods and Results: To create a mouse model of TIH, we administered 4 bolus doses of glucose at 2-hour intervals intraperitoneally once to WT (wild type) or once weekly to atherosclerotic prone mice. TIH accelerated atherogenesis without an increase in plasma cholesterol, seen in traditional models of diabetes mellitus. TIH promoted myelopoiesis in the bone marrow, resulting in increased circulating monocytes, particularly the inflammatory Ly6-C hi subset, and neutrophils. Hematopoietic-restricted deletion of S100a9 , S100a8 , or its cognate receptor Rage prevented monocytosis. Mechanistically, glucose uptake via GLUT (glucose transporter)-1 and enhanced glycolysis in neutrophils promoted the production of S100A8/A9. Myeloid-restricted deletion of Slc2a1 (GLUT-1) or pharmacological inhibition of S100A8/A9 reduced TIH-induced myelopoiesis and atherosclerosis., Conclusions: Together, these data provide a mechanism as to how TIH, prevalent in people with impaired glucose metabolism, contributes to cardiovascular disease. These findings provide a rationale for continual glucose control in these patients and may also suggest that strategies aimed at targeting the S100A8/A9-RAGE (receptor for advanced glycation end products) axis could represent a viable approach to protect the vulnerable blood vessels in diabetes mellitus. Graphic Abstract: A graphic abstract is available for this article.

Type 1 diabetes (T1D) is one of the most common chronic diseases manifesting in early life, with the prevalence increasing worldwide at a rate of approximately 3% per annum. The prolonged hyperglycaemia characteristic of T1D upregulates the receptor for advanced glycation end products (RAGE) and accelerates the formation of RAGE ligands, including advanced glycation end products, high-mobility group protein B1, S100 calcium-binding proteins, and amyloid-beta. Interestingly, changes in the expression of RAGE and these ligands are evident in patients before the onset of T1D. RAGE signals via various proinflammatory cascades, resulting in the production of reactive oxygen species and cytokines. A large number of proinflammatory ligands that can signal via RAGE have been implicated in several chronic diseases, including T1D. Therefore, it is unsurprising that RAGE has become a potential therapeutic target for the treatment and prevention of disease. In this review, we will explore how RAGE might be targeted to prevent the development of T1D., (© 2019 Wiley Periodicals, Inc.)

Diabetes affects oxygen availability in the kidney, forcing the renal environment to rapidly and sustainably adapt. Physiological adaptations including activation of hypoxia inducible factor-1α and metabolic reprogramming toward pathways requiring less oxygen to maintain adenosine triphosphate production such as anaerobic glycolysis are impaired in the diabetic kidney. However, this study by Hasegawa et al. demonstrates renoprotection in diabetic kidney disease via the use of the hypoxia inducible factor-1α stabilizer enarodustat, opening a new therapeutic avenue to tackle these metabolic abnormalities., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

High stage and recurrent ovarian clear cell carcinoma (OCC) are associated with poor prognosis and resistance to chemotherapy. A distinguishing histological feature of OCC is abundant cytoplasmic stores of glucose, in the form of glycogen, that can be mobilized for cellular metabolism. Here, we report the effect on preclinical models of OCC of disrupting glycogen utilization using the glucose analogue 2-deoxy-D-glucose (2DG). At concentrations significantly lower than previously reported for other cancers, 2DG markedly improves the efficacy in vitro of carboplatin chemotherapy against chemo-sensitive TOV21G and chemo-resistant OVTOKO OCC cell lines, and this is accompanied by the depletion of glycogen. Of note, 2DG doses-of more than 10-fold lower than previously reported for other cancers-significantly improve the efficacy of carboplatin against cell line and patient-derived xenograft models in mice that mimic the chemo-responsiveness of OCC. These findings are encouraging, in that 2DG doses, which are substantially lower than previously reported to cause adverse events in cancer patients, can safely and significantly improve the efficacy of carboplatin against OCC. Our results thus justify clinical trials to evaluate whether low dose 2DG improves the efficacy of carboplatin in OCC patients.

Mitochondrial stress has been widely observed in diabetic kidney disease (DKD). Cyclophilin D (CypD) is a functional component of the mitochondrial permeability transition pore (mPTP) which allows the exchange of ions and solutes between the mitochondrial matrix to induce mitochondrial swelling and activation of cell death pathways. CypD has been successfully targeted in other disease contexts to improve mitochondrial function and reduced pathology. Two approaches were used to elucidate the role of CypD and the mPTP in DKD. Firstly, mice with a deletion of the gene encoding CypD (Ppif-/-) were rendered diabetic with streptozotocin (STZ) and followed for 24 weeks. Secondly, Alisporivir, a CypD inhibitor was administered to the db/db mouse model (5 mg/kg/day oral gavage for 16 weeks). Ppif-/- mice were not protected against diabetes-induced albuminuria and had greater glomerulosclerosis than their WT diabetic littermates. Renal hyperfiltration was lower in diabetic Ppif-/- as compared with WT mice. Similarly, Alisporivir did not improve renal function nor pathology in db/db mice as assessed by no change in albuminuria, KIM-1 excretion and glomerulosclerosis. Db/db mice exhibited changes in mitochondrial function, including elevated respiratory control ratio (RCR), reduced mitochondrial H2O2 generation and increased proximal tubular mitochondrial volume, but these were unaffected by Alisporivir treatment. Taken together, these studies indicate that CypD has a complex role in DKD and direct targeting of this component of the mPTP will likely not improve renal outcomes., (© 2020 The Author(s).)

Retrieval of the properties of the middle and upper atmosphere can be performed using several different interferometric and photometric methods. The emission-shape and Doppler shift of both atomic and molecular emissions can be observed from the ground and space to provide temperature and bulk velocity. These instantaneous measurements can be combined over successive times/locations along an orbit track, or successive universal/local times from a ground station to quantify the motion and temperature of the atmosphere needed to identify atmospheric tides. In this report, we explore how different combinations of space-based wind and temperature measurements affect the retrieval of atmospheric tides, a ubiquitous property of planetary atmospheres. We explore several scenarios informed by the use of a tidally forced atmospheric circulation model, an empirically based emissions reference, and a low-earth orbit satellite observation geometry based on the ICON mission design. This capability provides a necessary tool for design of an optimal mission concept for retrieval of atmospheric tides from ICON remote-sensing observations. Here it is used to investigate scenarios of limited data availability and the effects of rapid changes in the total wave spectrum on the retrieval of the correct tidal spectrum. An approach such as that described here could be used in the design of future missions, such as the NASA DYNAMIC mission (National Research Council, Solar and space physics: a science for a technological society, 2013)., Competing Interests: Competing interestsThe authors declare that they have no competing interest., (© The Author(s) 2020.)

The sequelae of diabetes include microvascular complications such as diabetic kidney disease (DKD), which involves glucose-mediated renal injury associated with a disruption in mitochondrial metabolic agility, inflammation, and fibrosis. We explored the role of the innate immune complement component C5a, a potent mediator of inflammation, in the pathogenesis of DKD in clinical and experimental diabetes. Marked systemic elevation in C5a activity was demonstrated in patients with diabetes; conventional renoprotective agents did not therapeutically target this elevation. C5a and its receptor (C5aR1) were upregulated early in the disease process and prior to manifest kidney injury in several diverse rodent models of diabetes. Genetic deletion of C5aR1 in mice conferred protection against diabetes-induced renal injury. Transcriptomic profiling of kidney revealed diabetes-induced downregulation of pathways involved in mitochondrial fatty acid metabolism. Interrogation of the lipidomics signature revealed abnormal cardiolipin remodeling in diabetic kidneys, a cardinal sign of disrupted mitochondrial architecture and bioenergetics. In vivo delivery of an orally active inhibitor of C5aR1 (PMX53) reversed the phenotypic changes and normalized the renal mitochondrial fatty acid profile, cardiolipin remodeling, and citric acid cycle intermediates. In vitro exposure of human renal proximal tubular epithelial cells to C5a led to altered mitochondrial respiratory function and reactive oxygen species generation. These experiments provide evidence for a pivotal role of the C5a/C5aR1 axis in propagating renal injury in the development of DKD by disrupting mitochondrial agility, thereby establishing a new immunometabolic signaling pathway in DKD., (© 2019 by the American Diabetes Association.)

Non-alcoholic fatty liver disease (NAFLD) affects up to 30% of the adult population and is now a major cause of liver disease-related premature illness and deaths in the world. Treatment is largely based on lifestyle modification, which is difficult to achieve in most patients. Progression of simple fatty liver or steatosis to its severe form non-alcoholic steatohepatitis (NASH) and liver fibrosis has been explained by a 'two-hit hypothesis'. Whilst simple steatosis is considered the first hit, its transformation to NASH may be driven by a second hit. Of several factors that constitute the second hit, advanced glycation end products (AGEs), which are formed when reducing-sugars react with proteins or lipids, have been implicated as major candidates that drive steatosis to NASH via the receptor for AGEs (RAGE). Both endogenous and processed food-derived (exogenous) AGEs can activate RAGE, mainly present on Kupffer cells and hepatic stellate cells, thus propagating NAFLD progression. This review focuses on the pathophysiology of NAFLD with special emphasis on the role of food-derived AGEs in NAFLD progression to NASH and liver fibrosis. Moreover, the effect of dietary manipulation to reduce AGE content in food or the therapies targeting AGE/RAGE pathway on disease progression is also discussed.

Genetic factors influence susceptibility to diabetic kidney disease. Here we mapped genes mediating renal hypertrophic changes in response to diabetes. A survey of 15 mouse strains identified variation in diabetic kidney hypertrophy. Strains with greater (FVB/N(FVB)) and lesser (C57BL/6 (B6)) responses were crossed and diabetic F2 progeny were characterized. Kidney weights of diabetic F2 mice were broadly distributed. Quantitative trait locus analyses revealed diabetic mice with kidney weights in the upper quartile shared alleles on chromosomes (chr) 6 and 12; these loci were designated as Diabetic kidney hypertrophy (Dkh)-1 and -2. To confirm these loci, reciprocal congenic mice were generated with defined FVB chromosome segments on the B6 strain background (B6.Dkh1/2f) or vice versa (FVB.Dkh1/2b). Diabetic mice of the B6.Dkh1/2f congenic strain developed diabetic kidney hypertrophy, while the reciprocal FVB.Dkh1/2b congenic strain was protected. The chr6 locus contained the candidate gene; Ark1b3, coding aldose reductase; the FVB allele has a missense mutation in this gene. Microarray analysis identified differentially expressed genes between diabetic B6 and FVB mice. Thus, since the two loci identified by quantitative trait locus mapping are syntenic with regions identified for human diabetic kidney disease, the congenic strains we describe provide a valuable new resource to study diabetic kidney disease and test agents that may prevent it., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

The accumulation of advanced glycation end products (AGEs) have been implicated in the development and progression of diabetic kidney disease (DKD). There has been interest in investigating the potential of AGE clearance receptors, such as oligosaccharyltransferase-48 kDa subunit (OST48) to prevent the detrimental effects of excess AGE accumulation seen in the diabetic kidney. Here the objective of the study was to increase the expression of OST48 to examine if this slowed the development of DKD by facilitating the clearance of AGEs. Groups of 8-week-old heterozygous knock-in male mice (n = 9-12/group) over-expressing the gene encoding for OST48, dolichyl-diphosphooligosaccharide-protein glycosyltransferase (DDOST+/-) and litter mate controls were randomised to either (i) no diabetes or (ii) diabetes induced via multiple low-dose streptozotocin and followed for 24 weeks. By the study end, global over expression of OST48 increased glomerular OST48. This facilitated greater renal excretion of AGEs but did not affect circulating or renal AGE concentrations. Diabetes resulted in kidney damage including lower glomerular filtration rate, albuminuria, glomerulosclerosis and tubulointerstitial fibrosis. In diabetic mice, tubulointerstitial fibrosis was further exacerbated by global increases in OST48. There was significantly insulin effectiveness, increased acute insulin secretion, fasting insulin concentrations and AUC insulin observed during glucose tolerance testing in diabetic mice with global elevations in OST48 when compared to diabetic wild-type littermates. Overall, this study suggested that despite facilitating urinary-renal AGE clearance, there were no benefits observed on kidney functional and structural parameters in diabetes afforded by globally increasing OST48 expression. However, the improvements in insulin secretion seen in diabetic mice with global over-expression of OST48 and their dissociation from effects on kidney function warrant future investigation.

Glucose metabolism in the kidney is currently foremost in the minds of nephrologists, diabetologists and researchers globally, as a result of the outstanding success of SGLT2 inhibitors in reducing renal and cardiovascular disease in individuals with diabetes. However, these exciting data have come with the puzzling but fascinating paradigm that many of the beneficial effects on the kidney and cardiovascular system seem to be independent of the systemic glucose lowering actions of these agents. This manuscript places into context an area of research highly relevant to renal glucose metabolism, that of glycogen accumulation and metabolism in the diabetic kidney. Whether the glycogen that abnormally accumulates is pathological (the villain), is somehow protective (the hero) or is inconsequential (the bystander) is a research question that may provide insight into the link between diabetes and diabetic kidney disease., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Extremes of dysglycaemia as well as glycaemic variability are associated with excess mortality in critically ill patients. Glycaemic variability is an increasingly important measure of glucose control in the intensive care unit (ICU) due to this association; however, there is limited data pertaining to the relationship between exogenous glucose from nutrition and glycaemic variability and clinical outcomes. The primary aim of this study was to determine if glycaemic variability is associated with an increase in mortality. Secondary objectives were to investigate any factors affecting glycaemic variability, and to characterise the role nutrition, particularly carbohydrate, plays as a contributing factor to glycaemic variability and other clinical outcomes (duration of ventilation and ICU length of stay)., Methods: Data on patients in a combined medical/surgical tertiary Australian Intensive Care Unit (ICU), ventilated for >24 h and exclusively fed by artificial nutrition support was extracted from a clinical database of prospectively collected information over an 18 month period. Glycaemic variability was defined as the coefficient of variation (GV; standard deviation/mean of blood glucose levels x 100). Statistical analysis was performed using logistic regression, zero-truncated negative binomial and linear regression as appropriate to the distribution of the outcome variable using R software., Results: Data on up to 759 subjects was available. The average age of the study cohort was 56.9 years with a mean (standard deviation) APACHE III score of 72 (28). 66% of the study subjects were male. Glycaemic variability was associated with an increase in mortality (odds ratio 1.02; 95% CI: 1.00-1.04, p = 0.03). Factors associated with glycaemic variability included Acute Physiology and Chronic Health Evaluation III score (0.09, 0.06-0.11, p < 0.001), being male (-1.67, -2.97 to -0.38), p = 0.01) and mean units of insulin per day (0.08, 0.06-0.09, p < 0.001). There was no effect of any nutritional factor on glycaemic variability. Further exploratory analyses though showed that for those patients who required insulin during ICU admission, increased insulin dose was associated with increasing carbohydrate (incidence rate ratio (IRR) 1.003, 1.001-1.005, p = 0.001). Mean daily carbohydrate provision (grams) was associated with an increase in ventilation hours (IRR, 95% CI: 1.009, 1.008-1.009, p < 0.001) and length of intensive care unit stay (IRR, 95% CI: 1.007, 1.006-1.008, p < 0.001)., Conclusion: This study confirms that GV was associated with excess mortality. Furthermore, administration of increasing doses of insulin was associated with increased GV. Increased carbohydrate intake was associated with an increased insulin requirement, as well as increased duration of mechanical ventilation and ICU length of stay. These findings provide important context for further prospective trials investigating the effect of carbohydrate provision in mechanically ventilated critically ill patients requiring artificial nutritional support., (Copyright © 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)