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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.

Background Successfully recruiting male participants to complete a healthcare related study is important for healthcare study completion and to advance our clinical knowledgebase. To date, most research studies have examined the barriers and facilitators of female participants in longitudinal healthcare-related studies with limited information available about the needs of males in longitudinal research. This systematic review examines the unique barriers and facilitators to male recruitment across longitudinal healthcare-related research studies. Methods Following PRIMSA guidelines, MEDLINE, Embase, CINAHL and Web of Science databases were systematically searched using the terms recruitment and/or retention, facilitators and/or barriers and longitudinal studies from 1900 to 2023 which contained separate data on males aged 17–59 years. Health studies or interventions were defined longitudinal if they were greater than or equal to 12 weeks in duration with 3 separate data collection visits. Results Twenty-four articles published from 1976–2023 met the criteria. One-third of the studies had a predominantly male sample and four studies recruited only male participants. Males appear disinterested towards participation in health research, however this lack of enthusiasm can be overcome by clear, non-directive communication, and studies that support the participants interests. Facilitating factors are diverse and may require substantial time from research teams. Conclusions Future research should focus on the specific impact of these factors across the spectrum of longitudinal health-related studies. Based on the findings of this systematic review, researchers from longitudinal health-related clinical trials are encouraged to consider male-specific recruitment strategies to ensure successful recruitment and retention in their studies. Registration This systemic review is registered with the PROSPERO database (CRD42021254696).

Blood glucose control is the primary strategy to prevent complications in diabetes. At the onset of kidney disease, therapies that inhibit components of the renin angiotensin system (RAS) are also indicated, but these approaches are not wholly effective. Here, we show that once daily administration of the novel glucose lowering agent, empagliflozin, an SGLT2 inhibitor which targets the kidney to block glucose reabsorption, has the potential to improve kidney disease in type 2 diabetes. In male db / db mice, a 10-week treatment with empagliflozin attenuated the diabetes-induced upregulation of profibrotic gene markers, fibronectin and transforming-growth-factor-beta. Other molecular (collagen IV and connective tissue growth factor) and histological (tubulointerstitial total collagen and glomerular collagen IV accumulation) benefits were seen upon dual therapy with metformin. Albuminuria, urinary markers of tubule damage (kidney injury molecule-1, KIM-1 and neutrophil gelatinase-associated lipocalin, NGAL), kidney growth, and glomerulosclerosis, however, were not improved with empagliflozin or metformin, and plasma and intra-renal renin activity was enhanced with empagliflozin. In this model, blood glucose lowering with empagliflozin attenuated some molecular and histological markers of fibrosis but, as per treatment with metformin, did not provide complete renoprotection. Further research to refine the treatment regimen in type 2 diabetes and nephropathy is warranted.

Metabolic dysfunction-associated steatohepatitis (MASH) is the most prevalent cause of liver disease worldwide, with a single approved therapeutic. Previous research has shown that interleukin-22 (IL-22) can suppress β-cell stress, reduce local islet inflammation, restore appropriate insulin production, reverse hyperglycemia, and ameliorate insulin resistance in preclinical models of diabetes. In clinical trials long-acting forms of IL-22 have led to increased proliferation in the skin and intestine, where the IL-22RA1 receptor is highly expressed. To maximise beneficial effects whilst reducing the risk of epithelial proliferation and cancer, we designed short-acting IL-22-bispecific biologic drugs that successfully targeted the liver and pancreas. Here we show 10-fold lower doses of these bispecific biologics exceed the beneficial effects of native IL-22 in multiple preclinical models of MASH, without off-target effects. Treatment restores glycemic control, markedly reduces hepatic steatosis, inflammation, and fibrogenesis. These short-acting IL-22-bispecific targeted biologics are a promising new therapeutic approach for MASH. Novel short-acting IL-22 bispecific biologics offer new hope for treating metabolic dysfunction-associated steatohepatitis (MASH), a global health concern with few treatment options. Here, the authors show these drugs significantly improve blood sugar control, liver fat, inflammation, and scarring.

Advanced glycation end products (AGEs) are the final products of the Maillard reaction, a complex process that has been studied by food chemists for a century. Over the past 30 years, the biological significance of advanced glycation has also been discovered. There is mounting evidence that advanced glycation plays a homeostatic role within the body and that food-related Maillard products, intermediates such as reactive α-dicarbonyl compounds and AGEs, may influence this process. It remains to be understood, at what point AGEs and their intermediates become pathogenic and contribute to the pathogenesis of chronic diseases that inflict current society. Diabetes and its complications have been a major focus of AGE biology due to the abundance of excess sugar and α-dicarbonyls in this family of diseases. While further temporal information is required, a number of pharmacological agents that inhibit components of the advanced glycation pathway have already showed promising results in preclinical models. These therapies appear to have a wide range of mechanistic actions to reduce AGE load. Some of these agents including Alagebrium, have translated successfully to clinical trials, while others such as aminoguanidine, have had undesirable side-effect profiles. This review will discuss different pharmacological agents that have been used to reduce AGE burden in preclinical models of disease with a focus on diabetes and its complications, compare outcomes of those therapies that have reached clinical trials, and provide further rationale for the use of inhibitors of the glycation pathway in chronic diseases.

Aims/hypothesis Islet transplantation is used therapeutically in a minority of patients with type 1 diabetes. Successful outcomes are hampered by early islet beta cell loss. The adjuvant co-transplantation of mesenchymal stromal cells (MSCs) has the promise to improve islet transplant outcome. Methods We used a syngeneic marginal islet mass transplantation model in a mouse model of diabetes. Mice received islets or islets plus 250,000 MSCs. Kidney subcapsule, intra-hepatic and intra-ocular islet transplantation sites were used. Apoptosis, vascularisation, beta cell proliferation, MSC differentiation and laminin levels were determined by immunohistochemical analysis and image quantification post-transplant. Results Glucose homeostasis after the transplantation of syngeneic islets was improved by the co-transplantation of MSCs together with islets under the kidney capsule ( p  = 0.01) and by intravenous infusion of MSCs after intra-hepatic islet transplantation ( p  = 0.05). MSC co-transplantation resulted in reduced islet apoptosis, with reduced numbers of islet cells positive for cleaved caspase 3 being observed 14 days post-transplant. In kidney subcapsule, but not in intra-ocular islet transplant models, we observed increased re-vascularisation rates, but not increased blood vessel density in and around islets co-transplanted with MSCs compared with islets that were transplanted alone. Co-transplantation of MSCs did not increase beta cell proliferation, extracellular matrix protein laminin production or alpha cell numbers, and there was negligible MSC transdifferentiation into beta cells. Conclusions/interpretation Co-transplantation of MSCs may lead to improved islet function and survival in the early post-transplantation period in humans receiving islet transplantation.

A new study reveals the identity of proinflammatory and anti-inflammatory cytokines that influence beta cell stress and thus glucose tolerance. In type 2 diabetes, hyperglycemia is present when an increased demand for insulin, typically due to insulin resistance, is not met as a result of progressive pancreatic beta cell dysfunction. This defect in beta cell activity is typically characterized by impaired insulin biosynthesis and secretion, usually accompanied by oxidative and endoplasmic reticulum (ER) stress. We demonstrate that multiple inflammatory cytokines elevated in diabetic pancreatic islets induce beta cell oxidative and ER stress, with interleukin-23 (IL-23), IL-24 and IL-33 being the most potent. Conversely, we show that islet-endogenous and exogenous IL-22, by regulating oxidative stress pathways, suppresses oxidative and ER stress caused by cytokines or glucolipotoxicity in mouse and human beta cells. In obese mice, antibody neutralization of IL-23 or IL-24 partially reduced beta cell ER stress and improved glucose tolerance, whereas IL-22 administration modulated oxidative stress regulatory genes in islets, suppressed ER stress and inflammation, promoted secretion of high-quality efficacious insulin and fully restored glucose homeostasis followed by restitution of insulin sensitivity. Thus, therapeutic manipulation of immune regulators of beta cell stress reverses the hyperglycemia central to diabetes pathology.

In high‐income nations, multiple micronutrient (MMN) supplementation during pregnancy is a common practice. We aimed to describe maternal characteristics associated with supplement use and daily dose of supplemental nutrients consumed in pregnancy, and whether guideline alignment and nutrient status are related to supplement use. The Queensland Family Cohort is a prospective, Australian observational longitudinal study. Maternal characteristics, nutrient intake from food and supplements, and biochemical nutrient status were assessed in the second trimester (n = 127). Supplement use was reported by 89% of participants, of whom 91% reported taking an MMN supplement. Participants who received private obstetric care, had private health insurance and had greater alignment to meat/vegetarian alternatives recommendations were more likely to report MMN supplement use. Private obstetric care and general practitioner shared care were associated with higher daily dose of supplemental nutrients consumed compared with midwifery group practice. There was high reliance on supplements to meet nutrient reference values for folate, iodine and iron, but only plasma folate concentrations were higher in MMN supplement versus nonsupplement users. Exceeding the upper level of intake for folic acid and iron was more likely among combined MMN and individual supplement/s users, and associated with higher plasma concentrations of the respective nutrients. Given the low alignment with food group recommendations and potential risks associated with high MMN supplement use, whole food diets should be emphasized. This study confirms the need to define effective strategies for optimizing nutrient intake in pregnancy, especially among those most vulnerable where MMN supplement use may be appropriate. Multiple micronutrient (MMN) supplementation in the second trimester is prevalent, associated with private obstetric care, private health insurance and consuming more meat/vegetarian alternatives. There is high reliance on supplements to meet intake guidelines for folate, iodine and iron, which also raises concern for excess nutrient intake and associated risks. Key messages Multiple micronutrient (MMN) supplementation during pregnancy is a common practice in high‐income countries. Participants who received private obstetric care, had private health insurance and had greater alignment to meat/vegetarian alternatives recommendations were more likely to report MMN supplement use. There was high reliance on supplements to meet intake guidelines for folate, iodine and iron, which also raised concern for excess nutrient intake. This study confirms the need to define effective strategies for optimizing nutrient intake in pregnancy, including the promotion of whole food diets and appropriate use of MMN supplements.

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.

The placenta is a temporary organ present during pregnancy that is responsible for coordinating all aspects of pregnancy between the mother and fetus. It has a distinct epigenetic, transcriptomic, and mutational landscape with low levels of methylation, high numbers of transcribed loci, and a high mutational burden relative to somatic tissues. We present this landscape through the application of nanopore sequencing technology to provide a more comprehensive picture of female placental genomics and methylomics along with integrated haplotype-resolved transcriptomic analyses across eight trios. Whole genome sequencing of trios allows robust phasing, permitting comprehensive genome-wide investigation of parent-of-origin methylation and transcription. This enhanced view facilitates identifications of many differentially methylated regions (DMRs), both conserved and differing between individuals, as well as previously unreported imprinted genes including ILDR2 and RASA1 which are potentially important for healthy placental and fetal development. The placenta is a crucial organ required for human pregnancy which has a unique epigenetic and gene expression landscape. Here, the authors have applied nanopore whole genome sequencing technology to provide a comprehensive map of the placental methylome focused on allele-specific effects.