Objectives: To examine the relationship between kidney hyperfiltration during adolescence and subsequent changes in estimated glomerular filtration rate (eGFR) and urinary albumin creatinine ratio (UACR) in a young cohort of participants with type 1 diabetes. Additionally, to explore urinary mitochondrial DNA to nuclear DNA ratio (mtDNA:nDNA) as a marker of metabolic stress and its association with early changes in kidney function. Methods: Eighty adolescents were studied at baseline (mean [SD] age 14.2 [1.5] years; mean diabetes duration 6.7 [3.0] years) and at follow-up 9.2 (1.3) years later. Blood pressure, HbA1c, lipids, eGFR, UACR, and heart rate variability were assessed at each visit. Urinary mtDNA:nDNA was measured by quantitative PCR. Results: Overall, 4.2% of participants had diabetic kidney disease at follow-up. Hyperfiltration at baseline (>135 mL/min/1.73 m2 ) was seen in 31% of adolescents and was associated with a decline in eGFR at follow-up when adjusted for sex, diabetes duration, and HbA1c (hyperfiltration -1.46 [3.07] mL/min/1.73 m2 /year vs non-hyperfiltration -0.51 [2.48] mL/min/1.73 m2 /year, P = .02). Participants with hyperfiltration also had higher odds of undergoing rapid eGFR decline (>3 mL/min/1.73 m2 /year) compared to those without hyperfiltration (odds ratio 14.11 [95% CI 2.30-86.60], P = .004). Baseline urinary mtDNA:nDNA was significantly associated with both greater annual rate of eGFR decline and rapid eGFR decline in univariable but not multivariable modeling. Conclusion: Hyperfiltration during adolescence is significantly associated with greater reduction in eGFR and higher risk of rapid eGFR decline after similar to 9 years, following transition into young adulthood in type 1 diabetes. Urinary mtDNA:nDNA measured during adolescence may be a novel predictor of early changes in kidney function

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.

Brief summary: using a murine model of diabetes and ex vivo experiments in human T-cell cultures, this study showed that short-term administration of an antagonist to the receptor for advanced glycation end products (sRAGE) modulates functional T regulatory cells (Treg) expansion and thus prevents diabetes.

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.

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.

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 (NODShiLt) 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 NODShiLt mice and NODscid 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-2Db than H-2Kb under all conditions. Moreover, more 10–12 mer peptides were isolated from H-2Db 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.

There is a paucity of data on whether Australian university students are meeting specific nutrient guidelines, and the relationship between diet and physical activity patterns with body composition and metabolic health. In this study, biomedical students from The University of Queensland were recruited (150 males and 211 females, 19–25 years), and nutritional intake (ASA24-Australia) and physical activity levels (Active Australia Survey) quantified. Body composition (height, waist circumference, body mass, BMI, and percentage body fat; BOD POD) and metabolic health (oral glucose tolerance test) were also measured. Median daily energy intake was 6760 kJ in females and 10,338 kJ in males, with more than 30% of total energy coming from energy-dense, nutrient-poor foods. Only 1 in 10 students met fruit or vegetable recommendations, with less than one third meeting recommendations for fibre, calcium, and potassium. Intakes of calcium and iron were particularly low among female students, with only 16% and 6% of students meeting the recommended dietary intake (RDI), respectively. The majority of males and almost half of all females exceeded the suggested dietary target (SDT) for sodium. Sufficient physical activity (≥150 min over ≥5 sessions per week) was met by more than 80% of students. Body composition and blood glucose concentrations were largely normal but an early sign of insulin resistance (HOMA-IR > 2.0), measured in a subset of students, was present in 21% of males and 17% of females. Modest reductions in blood glucose levels and percentage body fat were associated with increasing vigorous activity. Low intakes of fibre, calcium, and potassium could be corrected by increasing fruit, vegetable, and dairy intake, and, among females, health promotion messages focusing on iron-rich foods should be prioritised. While these nutrient deficiencies did not translate into immediate metabolic heath concerns, dietary behaviours can track into adulthood and have lasting effects on overall health.

Abstract 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.

Half of the mortality in diabetes is seen in individuals <50 years of age and commonly predicted by the early onset of kidney disease (DKD). In Type 1 diabetes, increased uACR (urinary albumin-creatinine ratio) 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 yrs; M:F-54:46, HbA1C-66.1(12.3) mmol/mol; diabetes duration-10.7±5.2 yrs; BMI-24.5(5.3) kg.m-2] and 10 year historical uACR, HbA1C and random blood glucose concentrations collected retrospectively. Glucose fluctuations in the absence of diabetes were also compared to 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 (uACRAUC0-10yrs, 29.7±8.8 vs 4.5±0.5; P<0.01 vs low risk) and early kidney dysfunction including ~8.3ml.min-1.1.73m-2 higher estimated glomerular filtration rates (eGFRSCHWARTZ; Padj <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 SGLT2 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.

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.

Summary 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.

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 (AUC0–240min) 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 AUC0–240min was only lower during IIGI compared to OGTT at the 25 g dose (p = 0.0015). sRAGE AUC0–240min was negatively correlated to AUC0–240min 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.

The AGER gene encodes for a number of RAGE isoforms, with the membrane bound signal transduction and “decoy” circulating soluble RAGE being the best characterised. Here we demonstrate a novel nuclear isoform of RAGE in mice and human kidney cortex which by cell and size fractionation we determined to be approximately 37kda. This nuclear RAGE isoform is functional and binds to DNA sequences within the upstream 5’ promoter region of its own gene, AGER . This binding was shown to be abrogated by mutating the DNA consensus binding sequences during electromobility shift assay (EMSA) and was independent of NF-□B or AP-1 binding. Cotransfection of expression constructs encoding various RAGE isoforms along with AGER gene promoter reporter-plasmids identified that the most likely source of the nuclear isoform of RAGE was a cleavage product of the nt-RAGE isoform. In obese mice with impaired kidney function, there was increased binding of nuclear RAGE within the A. Region of ager gene promoter with corresponding increases in membrane bound RAGE in renal cells. These findings were reproduced in vitro using proximal tubule cells. Hence, we postulate that RAGE expression is in part, self-regulated by the binding of a nuclear RAGE isoform to the promoter of the AGER gene (encoding RAGE) in the kidney. We also suggest that this RAGE self-regulation is altered under pathological conditions and this may have implications for chronic kidney disease.