Novel Risk Markers for Type 2 Diabetes : Inflammation, Body Fat and Sex Hormones

_Background:_ Chronic low-grade inflammation, body fat composition and sex hormones are among the most important factors that enhance the risk of type 2 diabetes. The aim of this thesis was to further explore the role of pathways that link the above mentioned risk factors to type 2 diabetes development. _Methods:_ The studies in this thesis were performed in the Rotterdam Study, a prospective population-based cohort study. _Results:_ Chapter 2.1 studied the association of a set of inflammatory markers with progression from normoglycemia to pre-diabetes, type 2 DM and finally to insulin therapy. Our findings suggested that various inflammatory markers might be associated with progression from normoglycemia to pre-diabetes (IL13, ENRAGE, CRP), T2D (IL13, IL17, CRP) or insulin therapy start (IL13). Among them, EN-RAGE was a novel inflammatory marker for pre-diabetes, IL17 for incident T2D and IL13 for pre-diabetes, incident T2D and insulin therapy start. Chapter 2.2 investigated the role of dietary antioxidants and plasma oxidant-antioxidant status in low-grade chronic inflammation and adipocytokine levels. Our findings suggested that high overall dietary antioxidant capacity of diet and lower levels of UA were associated with lower levels of pro-inflammatory adipocytokines and higher levels of anti-inflammatory adipocytokines. In chapter 2.3, we aimed to investigate the association between serum uric acid and risk of prediabetes and type 2 diabetes mellitus. Our findings agreed with the notion that serum uric acid is more closely related to early-phase mechanisms in the development of type 2 diabetes mellitus than late-phase mechanisms. In chapter 3 we focused on the role of lipids and body fat in the risk for type 2 diabetes. Chapter 3.1 investigated the role of serum levels of various apolipoproteins on the risk for type 2 diabetes. We found that serum apoCIII levels as well as apoCIII-to-apoA1 ratio were independently associated with incident T2D. These associations were stronger than that of HDL-C levels with type 2 diabetes. Chapter 3.2 investigated the associations of several novel metabolic indices, combining anthropometric and lipid measures (VAI, LAP, TyG), and DXA measurements on body fat with i

Novel Risk Markers for Type 2 Diabetes : Inflammation, Body Fat and Sex Hormones

_Background:_ Chronic low-grade inflammation, body fat composition and sex hormones are among the most important factors that enhance the risk of type 2 diabetes. The aim of this thesis was to further explore the role of pathways that link the above mentioned risk factors to type 2 diabetes development. _Methods:_ The studies in this thesis were performed in the Rotterdam Study, a prospective population-based cohort study. _Results:_ Chapter 2.1 studied the association of a set of inflammatory markers with progression from normoglycemia to pre-diabetes, type 2 DM and finally to insulin therapy. Our findings suggested that various inflammatory markers might be associated with progression from normoglycemia to pre-diabetes (IL13, ENRAGE, CRP), T2D (IL13, IL17, CRP) or insulin therapy start (IL13). Among them, EN-RAGE was a novel inflammatory marker for pre-diabetes, IL17 for incident T2D and IL13 for pre-diabetes, incident T2D and insulin therapy start. Chapter 2.2 investigated the role of dietary antioxidants and plasma oxidant-antioxidant status in low-grade chronic inflammation and adipocytokine levels. Our findings suggested that high overall dietary antioxidant capacity of diet and lower levels of UA were associated with lower levels of pro-inflammatory adipocytokines and higher levels of anti-inflammatory adipocytokines. In chapter 2.3, we aimed to investigate the association between serum uric acid and risk of prediabetes and type 2 diabetes mellitus. Our findings agreed with the notion that serum uric acid is more closely related to early-phase mechanisms in the development of type 2 diabetes mellitus than late-phase mechanisms. In chapter 3 we focused on the role of lipids and body fat in the risk for type 2 diabetes. Chapter 3.1 investigated the role of serum levels of various apolipoproteins on the risk for type 2 diabetes. We found that serum apoCIII levels as well as apoCIII-to-apoA1 ratio were independently associated with incident T2D. These associations were stronger than that of HDL-C levels with type 2 diabetes. Chapter 3.2 investigated the associations of several novel metabolic indices, combining anthropometric and lipid measures (VAI, LAP, TyG), and DXA measurements on body fat with i

The association between serum uric acid and the incidence of prediabetes and type 2 diabetes mellitus: The Rotterdam Study

BACKGROUND: Limited evidence is available about the association between serum uric acid and sub-stages of the spectrum from normoglycaemia to type 2 diabetes mellitus. We aimed to investigate the association between serum uric acid and risk of prediabetes and type 2 diabetes mellitus. METHODS: Eligible participants of the Rotterdam Study (n = 8,367) were classified into mutually exclusive subgroups of normoglycaemia (n = 7,030) and prediabetes (n = 1,337) at baseline. These subgroups were followed up for incident prediabetes (n = 1,071) and incident type 2 diabetes mellitus (n = 407), respectively. We used Cox proportional hazard models to determine hazard ratios (HRs) for incident prediabetes among individuals with normoglycaemia and incident type 2 diabetes mellitus among individuals with prediabetes. RESULTS: The mean duration of follow-up was 7.5 years for incident prediabetes and 7.2 years for incident type 2 diabetes mellitus. A standard deviation increment in serum uric acid was significantly associated with incident prediabetes among individuals with normoglycaemia (HR 1.10, 95% confidence interval (CI) 1.01; 1.18), but not with incident type 2 diabetes mellitus among individuals with prediabetes (HR 1.07, 95% CI 0.94; 1.21). Exclusion of individuals who used diuretics or individuals with hypertension did not change our results. Serum uric acid was significantly associated with incident prediabetes among normoglycaemic women (HR 1.13, 95% CI 1.02; 1.25) but not among normoglycaemic men (HR 1.08, 95% CI 0.96; 1.21). In contrast, serum uric acid was significantly associated with incident type 2 diabetes mellitus among prediabetic men (HR 1.23, 95% CI 1.01; 1.48) but not among prediabetic women (HR 1.00, 95% CI 0.84; 1.19). CONCLUSIONS: Our findings agree with the notion that serum uric acid is more closely related to early-phase mechanisms in the development of type 2 diabetes mellitus than late-phase mechanisms

Novel inflammatory markers for incident pre-diabetes and type 2 diabetes: the Rotterdam Study

The immune response involved in each phase of type 2 diabetes (T2D) development might be different. We aimed to identify novel inflammatory markers that predict progression from normoglycemia to pre-diabetes, incident T2D and insulin therapy. We used plasma levels of 26 inflammatory markers in 971 subjects from the Rotterdam Study. Among them 17 are novel and 9 previously studied. Cox regression models were built to perform survival analysis. Main Outcome Measures: During a follow-up of up to 14.7 years (between April 1, 1997, and Jan 1, 2012) 139 cases of pre-diabetes, 110 cases of T2D and 26 cases of insulin initiation were identified. In age and sex adjusted Cox models, IL13 (HR = 0.78), EN-RAGE (1.30), CFH (1.24), IL18 (1.22) and CRP (1.32) were associated with incident pre-diabetes. IL13 (0.62), IL17 (0.75), EN-RAGE (1.25), complement 3 (1.44), IL18 (1.35), TNFRII (1.27), IL1ra (1.24) and CRP (1.64) were associated with incident T2D. In multivariate models, IL13 (0.77), EN-RAGE (1.23) and CRP (1.26) remained associated with pre-diabetes. IL13 (0.67), IL17 (0.76) and CRP (1.32) remained associated with T2D. IL13 (0.55) was the only marker associated with initiation of insulin therapy in diabetics. Various inflammatory markers are associated with progression from normoglycemia to pre-diabetes (IL13, EN-RAGE, CRP), T2D (IL13, IL17, CRP) or insulin therapy start (IL13). Among them, EN-RAGE is a novel inflammatory marker for pre-diabetes, IL17 for incident T2D and IL13 for pre-diabetes, incident T2D and insulin therapy start

Relation of antioxidant capacity of diet and markers of oxidative status with C-reactive protein and adipocytokines: a prospective study

Background The role of dietary antioxidants and plasma oxidant-antioxidant status in low-grade chronic inflammation and adipocytokine levels is not established yet. Objectives We aimed to evaluate whether total dietary antioxidant capacity (assessed by dietary ferric reducing antioxidant potential (FRAP)), serum uric acid (UA) and gamma glutamyltransferase (GGT) were associated with low-grade chronic inflammation and circulating adipocytokines. Methods Data of 4506 participants aged ≥ 55 years from the Rotterdam Study were analyzed. Baseline (1990–1993) FRAP score was assessed by a food frequency questionnaire. Baseline UA and GGT levels were assessed in non-fasting serum samples. Serum high sensitivity C-reactive protein (hs-CRP) was measured at baseline and 10 years later. Plasma leptin, adiponectin, plasminogen activator inhibitor-1 (PAI-1) and resistin levels were assessed 10 years later. Results A high FRAP score was associated with lower levels of UA and GGT. Overall, no association was found between FRAP and hs-CRP levels. FRAP score was associated with lower levels of leptin and PAI-1, higher levels of adiponectin, and no difference in resistin levels. Increased levels of UA were associated with higher levels of hs-CRP, PAI-1 and leptin; lower levels of adiponectin and no difference in resistin levels. Similarly, GGT was associated with higher levels of hs-CRP whereas no association was observed between GGT and adipocytokines. Conclusion These findings suggest that overall antioxidant capacity of diet and low levels of UA are associated with circulating adipocytokines whereas no consistent association was found with hs-CRP

Novel metabolic indices and incident type 2 diabetes among women and men: the Rotterdam Study

Aims/hypothesis: Both visceral and truncal fat have been associated with metabolic disturbances. We aimed to investigate the associations of several novel metabolic indices, combining anthropo

Plasma Metabolomics Identifies Markers of Impaired Renal Function: A Meta-analysis of 3089 Persons with Type 2 Diabetes

CONTEXT: There is a need for novel biomarkers and better understanding of the pathophysiology of diabetic kidney disease. OBJECTIVE: To investigate associations between plasma metabolites and kidney function in people with type 2 diabetes (T2D). DESIGN: 3089 samples from individuals with T2D, collected between 1999 and 2015, from 5 independent Dutch cohort studies were included. Up to 7 years follow-up was available in 1100 individuals from 2 of the cohorts. MAIN OUTCOME MEASURES: Plasma metabolites (n = 149) were measured by nuclear magnetic resonance spectroscopy. Associations between metabolites and estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), and eGFR slopes were investigated in each study followed by random effect meta-analysis. Adjustments included traditional cardiovascular risk factors and correction for multiple testing. RESULTS: In total, 125 metabolites were significantly associated (PFDR = 1.5×10-32 - 0.046; β = -11.98-2.17) with eGFR. Inverse associations with eGFR were demonstrated for branched-chain and aromatic amino acids (AAAs), glycoprotein acetyls, triglycerides (TGs), lipids in very low-density lipoproteins (VLDL) subclasses, and fatty acids (PFDR < 0.03). We observed positive associations with cholesterol and phospholipids in high-density lipoproteins (HDL) and apolipoprotein A1 (PFDR < 0.05). Albeit some metabolites were associated with UACR levels (P < 0.05), significance was lost after correction for multiple testing. Tyrosine and HDL-related metabolites were positively associated with eGFR slopes before adjustment for multiple testing (PTyr = 0.003; PHDLrelated < 0.05), but not after. CONCLUSIONS: This study identified metabolites associated with impaired kidney function in T2D, implying involvement of lipid and amino acid metabolism in the pathogenesis. Whether these processes precede or are consequences of renal impairment needs further investigation

Scuola Innovativa Secondaria di Secondo Grado “G. Baruffi”, Mondovì (CN)

Il progetto per la Scuola Innovativa Secondaria di Secondo Grado “G. Baruffi”, sita a Mondovì (CN), si è collocato al quinto posto nell’ambito del concorso di progettazione in due gradi, Missione 2 – Componente 3 – Investimento 1.1 “Costruzione di nuove scuole mediante sostituzione di edifici” del Piano nazionale di ripresa e resilienza (PNRR), finanziato dall’Unione europea – Next Generation EU (CIG 929765077F, Codice 2° grado A0VEE3MO). L’edificio di progetto ridisegna la morfologia del lotto, di particolare pregio poiché collocato all’ingresso della città alta: il terreno viene modellato seguendo l’organicità del versante in un processo di ricucitura del territorio che ha visto, negli anni, la costruzione di edifici barriera calati sulla collina. Il volume ricalca il sedime delle mura medioevali inserendosi come limitare della vecchia città e andando a ricostruirne il perimetro. La nuova scuola si innesta sul territorio e diventa parte di esso; sul lato della corte viene a determinarsi un ampio spazio adibito a parco che vive in simbiosi con la scuola: i piani raccordati del terreno penetrano l’edificio ai vari livelli permettendo agli alunni di uscire direttamente all’aperto. L’obiettivo primario della progettazione è garantire prestazioni molto elevate e, nell’ottica della transizione energetica degli edifici, questa ha garantito la riduzione del fabbisogno energetico della scuola al fine di un’elevata efficienza dei componenti architettonici oltre che generatori alimentati esclusivamente da fonti rinnovabili. La riduzione dei carichi termici minimizza la potenza dei generatori (riduzione del 55% dei fabbisogni rispetto all’edificio di riferimento) e garantisce fabbisogni globali di energia primaria inferiori a 90 kWh/(anno m2). Il consumo di energia primaria EPgl,tot è di oltre il 50% inferiore alla soglia fissata per i requisiti degli edifici nZEB mentre l’EPgl,nren è inferiore del 75%. Il fotovoltaico (circa 180 kWp) genera, su base annua, circa 200.000 kWh, riuscendo a coprire il 70% del fabbisogno elettrico richiesto dall’edificio mediante autoproduzione. A questo risultato è associato uno studio approfondito sulla contemporaneità tra produzione ed uso dell’energia che suggerisce un sistema di accumulo a batterie per i cicli di breve durata ed uno di produzione di idrogeno integrato da fuelcell/microcogenerazione per i cicli più lunghi. L’impiantistica è dunque funzionale a rendere l’edificio nZEB ed altamente efficiente, con comfort ottimale e controllo distinto per ogni singolo spazio, rispondendo ai criteri della certificazione LEED Platinum. Il controllo, tramite un BMS auto adattativo è gestibile sia dall’utenza, con limitazioni secondo i principi dell’adaptive comfort, che da remoto. Il comfort luminoso è garantito da sistemi a LED “blue-hazard-free” con controllo DALI per l’integrazione con la luce naturale. Nel progetto si pone grande attenzione al risparmio idrico: una vasca di raccolta dell’acqua meteorica interrata funziona da accumulo idrico per alimentare l’impianto di irrigazione, mentre le essenze arboree utilizzate saranno autoctone e a bassa esigenza idrica. Inoltre, il progetto persegue la sostenibilità ambientale mediante l’uso di isolante in pannelli in fibra di canapa ad elevate prestazioni termoacustiche che, con uno sfasamento termico elevato, contribuisce ad aumentare l’inerzia delle pareti, smorzando l’onda termica. La fibra di canapa possiede una bassa energia incorporata ed è completamente rinnovabile e recuperabile. Il progetto, infatti, promuove una visione di medio-lungo termine dei principali elementi costruttivi relativamente ai cicli di manutenzione e sostituzione. Una valutazione comparativa con ausilio di metodologia di Life Cycle Assessment ha permesso di individuare fra le diverse tipologie di componenti e sistemi costruttivi, quelli che presentano un minor impatto sull’ambiente

Serum dehydroepiandrosterone levels are associated with lower risk of type 2 diabetes: the Rotterdam Study

Aims/hypothesis Previous literature documents controversial results for the impact of dehydroepiandrosterone (DHEA) in glucose metabolism. We aimed to assess the associations between serum levels of DHEA and its main derivatives DHEA sulphate (DHEAS) and androstenedione, as well as the ratio of DHEAS to DHEA, and risk of type 2 diabetes. Methods We used data on serum levels of DHEA, DHEAS and androstenedione from 5189 middle-aged and elderly men and women from the prospective population-based Rotterdam Study. Type 2 diabetes was defined as a fasting blood glucose ≥7.0 mmol/l or a non-fasting blood glucose ≥11.1 mmol/l. Results During a median follow-up of 10.9 years, 643 patients with incident type 2 diabetes were identified. After adjusting for age, sex, cohort, fasting status, fasting glucose and insulin, and BMI, both serum DHEA levels (per 1 unit natural logtransformed, HR 0.76, 95% CI 0.67, 0.87) and serum DHEAS levels (per 1 unit natural log-transformed, HR 0.82, 95% CI 0.73, 0.92) were inversely associated with risk of type 2 diabetes in the total population. Further adjustment for alcohol, smoking, physical activity, prevalent cardiovascular disease, serum total cholesterol, use of lipid-lowering medications, systolic BP, treatment for hypertension, C-reactive protein, oestradiol and testosterone did not substantially affect the association between DHEA and incident type 2 diabetes (per 1 unit natural log-transformed, HR 0.80, 95% CI 0.65, 0.99), but abolished the association between DHEAS and type 2 diabetes. Androstenedione was not associated with risk of type 2 diabetes, nor was DHEAS to DHEA ratio. Conclusions/interpretation DHEA serum levels might be an independent marker of type 2 diabetes