AimTo investigate the association of plasma metabolites with incident and prevalent chronic kidney disease (CKD) in people with type 2 diabetes and establish whether this association is causal... Show moreAimTo investigate the association of plasma metabolites with incident and prevalent chronic kidney disease (CKD) in people with type 2 diabetes and establish whether this association is causal.Materials and MethodsThe Hoorn Diabetes Care System cohort is a large prospective cohort consisting of individuals with type 2 diabetes from the northwest part of the Netherlands. In this cohort we assessed the association of baseline plasma levels of 172 metabolites with incident (Ntotal = 462/Ncase = 81) and prevalent (Ntotal = 1247/Ncase = 120) CKD using logistic regression. Additionally, replication in the UK Biobank, body mass index (BMI) mediation and causality of the association with Mendelian randomization was performed.ResultsElevated levels of total and individual branched-chain amino acids (BCAAs)-valine, leucine and isoleucine-were associated with an increased risk of incident CKD, but with reduced odds of prevalent CKD, where BMI was identified as an effect modifier. The observed inverse effects were replicated in the UK Biobank. Mendelian randomization analysis did not provide evidence for a causal relationship between BCAAs and prevalent CKD.ConclusionsOur study shows the intricate relationship between plasma BCAA levels and CKD in individuals with type 2 diabetes. While an association exists, its manifestation varies based on disease status and BMI, with no definitive evidence supporting a causal link between BCAAs and prevalent CKD. Show less
Yuan, L.S.; Verhoeven, A.; Blomberg, N.; Eyk, H.J. van; Bizino, M.B.; Rensen, P.C.N.; ... ; Berg, B.M. van den 2024
Type 2 diabetes mellitus (T2DM) poses a higher risk for complications in South Asian individuals compared to other ethnic groups. To shed light on potential mediating factors, we investigated... Show moreType 2 diabetes mellitus (T2DM) poses a higher risk for complications in South Asian individuals compared to other ethnic groups. To shed light on potential mediating factors, we investigated lipidomic changes in plasma of Dutch South Asians (DSA) and Dutch white Caucasians (DwC) with and without T2DM and explore their associations with clinical features. Using a targeted quantitative lipidomics platform, monitoring over 1000 lipids across 17 classes, along with 1H NMR based lipoprotein analysis, we studied 51 healthy participants (21 DSA, 30 DwC) and 92 T2DM patients (47 DSA, 45 DwC) from the MAGNetic resonance Assessment of VICTOza efficacy in the Regression of cardiovascular dysfunction in type 2 dIAbetes mellitus (MAGNA VICTORIA) study. This comprehensive mapping of the circulating lipidome allowed us to identify relevant lipid modules through unbiased weighted correlation network analysis, as well as disease and ethnicity related key mediatory lipids. Significant differences in lipidomic profiles, encompassing various lipid classes and species, were observed between T2DM patients and healthy controls in both the DSA and DwC populations. Our analyses revealed that healthy DSA, but not DwC, controls already exhibited a lipid profile prone to develop T2DM. Particularly, in DSA-T2DM patients, specific lipid changes correlated with clinical features, particularly diacylglycerols (DGs), showing significant associations with glycemic control and renal function. Our findings highlight an ethnic distinction in lipid modules influencing clinical outcomes in renal health. We discover distinctive ethnic disparities of the circulating lipidome and identify ethnicity-specific lipid markers. Jointly, our discoveries show great potential as personalized biomarkers for the assessment of glycemic control and renal function in DSA-T2DM individuals. Show less
Background. Previous clinical studies have shown that various measures of glucose metabolism are associated with a risk of chronic kidney disease in different populations, but results were not... Show moreBackground. Previous clinical studies have shown that various measures of glucose metabolism are associated with a risk of chronic kidney disease in different populations, but results were not consistent. In this study we assessed measures of glucose metabolism and their association with kidney function in a population-based study.Methods. The Netherlands Epidemiology of Obesity study is a population-based cohort study of middle-aged men and women. We categorized the study population according to glycaemic levels into normoglycaemia (reference group), pre-diabetes mellitus (pre-DM), known DM and newly diagnosed DM. Outcome variables were serum creatinine, estimated glomerular filtration rate (eGFR), glomerular hyperfiltration (defined as an eGFR >90th percentile; >102mL/min/1.73m(2)) and micro-albuminuria. We examined the association between measures of glucose metabolism [fasting glucose, haemoglobin A1c (HbA1c), fasting insulin, glucose area under the curve (AUC), insulin AUC, Homoeostatic Model Assessment of Insulin Resistance (HOMA-IR), HOMA of beta-cell function (HOMA-B) and disposition index] and measures of kidney function.Results. Of the total population (N=6338), 55% of participants were classified as normoglycaemic (reference), 35% as pre-DM, 7% as DM and 4% as newly diagnosed DM. Compared with the reference group, diagnosed and newly diagnosed DMs were associated with a slightly higher trend in eGFR {+2.1mL/min/1.73m(2) [95% confidence interval (CI) -0.2-4.4] and +2.7mL/min/1.73m(2) [95% CI -0.3-5.7], respectively}. A 1% higher HbA1c was associated with increased odds of hyperfiltration [odds ratio (OR) 1.41 (95% CI 1.06-1.88)]. Higher levels of fasting plasma glucose, AUC glucose and HOMA-B were associated with hyperfiltration. Fasting insulin, AUC insulin and HOMA-IR were not associated with hyperfiltration. The OR of microalbuminuria was 1.21 (95% CI 1.04-1.42) per mmol/L higher fasting glucose concentrations.Conclusions. Both fasting and post-prandial glucose and HOMA-B, but not measures of insulin resistance, were associated with glomerular hyperfiltration, while fasting glucose was also associated with microalbuminuria. Show less
Leptin is a hormone which functions in the regulation of energy homeostasis via suppression of appetite. In zebrafish, there are two paralogous genes encoding leptin, called lepa and lepb. In a... Show moreLeptin is a hormone which functions in the regulation of energy homeostasis via suppression of appetite. In zebrafish, there are two paralogous genes encoding leptin, called lepa and lepb. In a gene expression study, we found that the lepb gene, not the lepa gene, was significantly downregulated under the state of insulin-resistance in zebrafish larvae, suggesting that the lepb plays a role in glucose homeostasis. In the current study, we characterised lepb-deficient (lepb(-/)(-)) adult zebrafish generated via a CRISPR-CAS9 gene editing approach by investigating whether the disruption of the lepb gene would result in the development of type 2 diabetes mellitus (T2DM) and diabetic complications. We observed that lepb(-)(/-)adult zebrafish had an increase in body weight, length and visceral fat accumulation, compared to age-matched control zebrafish. In addition, lepb(-/-) zebrafish had significantly higher blood glucose levels compared to control zebrafish. These data collectively indicate that lepb(-/-)adult zebrafish display the features of T2DM. Furthermore, we showed that lepb(-/-) adult zebrafish had glomerular hypertrophy and thickening of the glomerular basement membrane, compared to control zebrafish, suggesting that lepb(-/-) adult zebrafish develop early signs of diabetic nephropathy. In conclusion, our results demonstrate that lepb regulates glucose homeostasis and adiposity in zebrafish, and suggest that lepb(-/-) mutant zebrafish are a promising model to investigate the role of leptin in the development of T2DM and are an attractive model to perform mechanistic and therapeutic research in T2DM and its complications. Show less
Uil, M.; Hau, C.M.; Ahdi, M.; Mills, J.D.; Kers, J.; Saleem, M.A.; ... ; Roelofs, J.J.T.H. 2021
Background. Diabetic nephropathy (DN) is a major complication of diabetes and the main cause of end-stage renal disease. Extracellular vesicles (EVs) are small cell-derived vesicles that can alter... Show moreBackground. Diabetic nephropathy (DN) is a major complication of diabetes and the main cause of end-stage renal disease. Extracellular vesicles (EVs) are small cell-derived vesicles that can alter disease progression by microRNA (miRNA) transfer.Methods. In this study, we aimed to characterize the cellular origin and miRNA content of EVs in plasma samples of type 2 diabetes patients at various stages of DN. Type 2 diabetes patients were classified in three groups: normoalbuminuria, microalbuminuria and macroalbuminuria. The concentration and cellular origin of plasma EVs were measured by flow cytometry. A total of 752 EV miRNAs were profiled in 18 subjects and differentially expressed miRNAs were validated.Results. Diabetic patients with microalbuminuria and/or macroalbuminuria showed elevated concentrations of total EVs and EVs from endothelial cells, platelets, leucocytes and erythrocytes compared with diabetic controls. miR-99a-5p was upregulated in macroalbuminuric patients compared with normoalbuminuric and microalbuminuric patients. Transfection of miR-99a-5p in cultured human podocytes downregulated mammalian target of rapamycin (mTOR) protein expression and downregulated the podocyte injury marker vimentin.Conclusions. Type 2 diabetes patients with microalbuminuria and macroalbuminuria display differential EV profiles. miR-99a-5p expression is elevated in EVs from macroalbuminuria and mTOR is its validated mRNA target. Show less
Gerrits, T.; Zandbergen, M.; Wolterbeek, R.; Bruijn, J.A.; Baelde, H.J.; Scharpfenecker, M. 2020
Diabetic nephropathy (DN) is a complication of diabetes mellitus that can lead to proteinuria and a progressive decline in renal function. Endoglin, a co-receptor of TGF-beta, is known primarily... Show moreDiabetic nephropathy (DN) is a complication of diabetes mellitus that can lead to proteinuria and a progressive decline in renal function. Endoglin, a co-receptor of TGF-beta, is known primarily for regulating endothelial cell function; however, endoglin is also associated with hepatic, cardiac, and intestinal fibrosis. This study investigates whether endoglin contributes to the development of interstitial fibrosis in DN. Kidney autopsy material from 80 diabetic patients was stained for endoglin and Sirius Red and scored semi-quantitatively. Interstitial endoglin expression was increased in samples with DN and was correlated with Sirius Red staining (p < 0.001). Endoglin expression was also correlated with reduced eGFR (p = 0.001), increased creatinine (p < 0.01), increased systolic blood pressure (p < 0.05), hypertension (p < 0.05), and higher IFTA scores (p < 0.001). Biopsy samples from DN patients were also co-immunostained for endoglin together with CD31, CD68, vimentin, or alpha-SMA Endoglin co-localized with both the endothelial marker CD31 and the myofibroblast marker alpha-SMA. Finally, we used shRNA to knockdown endoglin expression in a human kidney fibroblast cell line. We found that TGF-beta 1 stimulation upregulated SERPINE1, CTGF, and ACTA2 mRNA and alpha-SMA protein, and that these effects were significantly reduced in fibroblasts after endoglin knockdown. Taken together, these data suggest that endoglin plays a role in the pathogenesis of interstitial fibrosis in DN. Show less
Everaert, I.; He, J.L.; Hanssens, M.; Stautemas, J.; Bakker, K.; Albrecht, T.; ... ; Derave, W. 2020
doi:10.1152/ajprenal.00329.2019. Manipulation of circulating histidine-containing dipeptides (HCD) has been shown to affect the development of diabetes and early-stage diabetic nephropathy (DN).... Show moredoi:10.1152/ajprenal.00329.2019. Manipulation of circulating histidine-containing dipeptides (HCD) has been shown to affect the development of diabetes and early-stage diabetic nephropathy (DN). The aim of the present study was to investigate whether such interventions, which potentially alter levels of circulating HCD, also affect the development of advanced -stage DN. 'Iwo interventions, aerobic exercise training and overexpression of the human carnosinase-1 (hCNI) enzyme, were tested. BTBR ob/ob mice were either subjected to aerobic exercise training (20 wk) or genetically manipulated to overexpress hCNi, and different diabetes- and DNrelated markers were compared with control ob/ob and healthy (wild type) mice. An acute exercise study was performed to elucidate the effect of obesity, acute running, and hCNI overexpression on plasma HCD levels. Chronic aerobic exercise training did not affect the development of diabetes or DN, but hCNI overexpression accelerated hyperlipidemia and aggravated the development of alburninuria, mesangial matrix expansion, and glomerular hypertrophy- of ob/ob mice. In line, plasma, kidney, and muscle 11CD were markedly lower in oh/oh versus wild -type mice, and plasma and kidney HCD in particular were lower in ob/ob hCNI versus ob/ob mice but were unaffected by aerobic exercise. In conclusion, advanced glomerular damage is accelerated in mice overexpressing the hCNI enzyme but not protected by chronic exercise training. Interestingly, we showed, for the first time, that the development of DN is closely linked to renal HCD availability. Further research will have to elucidate whether the stimulation of renal HCD levels can he a therapeutic strategy to reduce the risk for developing DN. Show less
Bus, P.; Chua, J.S.; Klessens, C.Q.F.; Zandbergen, M.; Wolterbeek, R.; Kooten, C. van; ... ; Baelde, H.J. 2018
