Mechanisms of podocyte injury and implications for diabetic nephropathy.

Albuminuria is the hallmark of both primary and secondary proteinuric glomerulopathies, including focal segmental glomerulosclerosis (FSGS), obesity-related nephropathy, and diabetic nephropathy (DN). Moreover, albuminuria is an important feature of all chronic kidney diseases (CKDs). Podocytes play a key role in maintaining the permselectivity of the glomerular filtration barrier (GFB) and injury of the podocyte, leading to foot process (FP) effacement and podocyte loss, the unifying underlying mechanism of proteinuric glomerulopathies. The metabolic insult of hyperglycemia is of paramount importance in the pathogenesis of DN, while insults leading to podocyte damage are poorly defined in other proteinuric glomerulopathies. However, shared mechanisms of podocyte damage have been identified. Herein, we will review the role of haemodynamic and oxidative stress, inflammation, lipotoxicity, endocannabinoid (EC) hypertone, and both mitochondrial and autophagic dysfunction in the pathogenesis of the podocyte damage, focussing particularly on their role in the pathogenesis of DN. Gaining a better insight into the mechanisms of podocyte injury may provide novel targets for treatment. Moreover, novel strategies for boosting podocyte repair may open the way to podocyte regenerative medicine.

Protective Role of the M-Sec-Tunneling Nanotube System in Podocytes.

BACKGROUND: Podocyte dysfunction and loss are major determinants in the development of proteinuria. FSGS is one of the most common causes of proteinuria, but the mechanisms leading to podocyte injury or conferring protection against FSGS remain poorly understood. The cytosolic protein M-Sec has been involved in the formation of tunneling nanotubes (TNTs), membrane channels that transiently connect cells and allow intercellular organelle transfer. Whether podocytes express M-Sec is unknown and the potential relevance of the M-Sec-TNT system in FSGS has not been explored. METHODS: We studied the role of the M-Sec-TNT system in cultured podocytes exposed to Adriamycin and in BALB/c M-Sec knockout mice. We also assessed M-Sec expression in both kidney biopsies from patients with FSGS and in experimental FSGS (Adriamycin-induced nephropathy). RESULTS: Podocytes can form TNTs in a M-Sec-dependent manner. Consistent with the notion that the M-Sec-TNT system is cytoprotective, podocytes overexpressed M-Sec in both human and experimental FSGS. Moreover, M-Sec deletion resulted in podocyte injury, with mitochondrial abnormalities and development of progressive FSGS. In vitro, M-Sec deletion abolished TNT-mediated mitochondria transfer between podocytes and altered mitochondrial bioenergetics. Re-expression of M-Sec reestablishes TNT formation and mitochondria exchange, rescued mitochondrial function, and partially reverted podocyte injury. CONCLUSIONS: These findings indicate that the M-Sec-TNT system plays an important protective role in the glomeruli by rescuing podocytes via mitochondrial horizontal transfer. M-Sec may represent a promising therapeutic target in FSGS, and evidence that podocytes can be rescued via TNT-mediated horizontal transfer may open new avenues of research.

MicroRNA 146a is associated with diabetic complications in type 1 diabetic patients from the EURODIAB PCS.

BACKGROUND: MicroRNA-146a-5p (miR-146a-5p) is a key regulator of inflammatory processes. Expression of miR-146a-5p is altered in target organs of diabetic complications and deficiency of miR-146a-5p has been implicated in their pathogenesis. We investigated if serum miR-146a-5p levels were independently associated with micro/macrovascular complications of type 1 diabetes (DM1). METHODS: A nested case-control study from the EURODIAB PCS of 447 DM1 patients was performed. Cases (n = 294) had one or more complications of diabetes, whereas controls (n = 153) did not have any complication. Total RNA was isolated from all subjects and miR-146a-5p levels measured by qPCR. Both the endogenous controls U6 snRNA and the spike (Cel-miR-39) were used to normalize the results. Logistic regression analysis was carried out to investigate the association of miR-146a-5p with diabetes complications. RESULTS: MiR-146a-5p levels were significantly lower in cases [1.15 (0.32-3.34)] compared to controls [1.74 (0.44-6.74) P = 0.039]. Logistic regression analysis showed that levels of miR-146a-5p in the upper quartile were inversely associated with reduced odds ratio (OR) of all complications (OR 0.34 [95% CI 0.14-0.76]) and particularly with cardiovascular diseases (CVD) (OR 0.31 [95% CI 0.11-0.84]) and diabetic retinopathy (OR 0.40 [95% CI 0.16-0.99]), independently of age, sex, diabetes duration, A1c, hypertension, AER, eGFR, NT-proBNP, and TNF-α. CONCLUSIONS: In this large cohort of DM1 patients, we reported an inverse and independent association of miR-146a-5p with diabetes chronic complications and in particular with CVD and retinopathy, suggesting that miR-146a-5p may be a novel candidate biomarker of DM1 complications.

Thrombopoietin Contributes to Enhanced Platelet Activation in Patients with Type 1 Diabetes Mellitus.

Atherosclerotic cardiovascular disease is the major cause of morbidity and mortality in patients with type 1 diabetes mellitus (T1DM). Enhanced platelet reactivity is considered a main determinant of the increased atherothrombotic risk of diabetic patients. Thrombopoietin (THPO), a humoral growth factor able to stimulate megakaryocyte proliferation and differentiation, also modulates the response of mature platelets by enhancing both activation and binding to leukocytes in response to different agonists. Increased THPO levels have been reported in different clinical conditions characterized by a generalized pro-thrombotic state, from acute coronary syndromes to sepsis/septic shock, and associated with elevated indices of platelet activation. To investigate the potential contribution of elevated THPO levels in platelet activation in T1DM patients, we studied 28 T1DM patients and 28 healthy subjects. We measured plasma levels of THPO, as well as platelet-leukocyte binding, P-selectin, and THPO receptor (THPOR) platelet expression. The priming activity of plasma from diabetic patients or healthy subjects on platelet-leukocyte binding and the role of THPO on this effect was also studied in vitro. T1DM patients had higher circulating THPO levels and increased platelet-monocyte and platelet-granulocyte binding, as well as platelet P-selectin expression, compared to healthy subjects, whereas platelet expression of THPOR did not differ between the two groups. THPO concentrations correlated with platelet-leukocyte binding, as well as with fasting glucose and Hb1Ac. In vitro, plasma from diabetic patients, but not from healthy subjects, primed platelet-leukocyte binding and platelet P-selectin expression. Blocking THPO biological activity using a specific inhibitor prevented the priming effect induced by plasma from diabetic patients. In conclusion, augmented THPO may enhance platelet activation in patients with T1DM, potentially participating in increasing atherosclerotic risk.

Self-management education may improve blood pressure in people with type 2 diabetes. A randomized controlled clinical trial.

BACKGROUND AND AIMS: Diabetes is a suitable model to evaluate intervention programmes aimed at chronic diseases, because of its well-defined and measurable process and outcome indicators. In this study, we aimed at investigating the effects of group based self-management education on clinical and psychological variables in type 2 diabetes. METHODS AND RESULTS: Four-year randomized controlled clinical trial (ISRCTN14558376) comparing Group Care and traditional one-to-one care. Clinical and psychological variables were monitored at baseline, 2 and 4 years. Although differences between groups appear to be non-significant at univariate analysis, body weight, BMI and HbA1c, systolic and diastolic blood pressure improved in the patients followed by Group Care but not among Controls. Prescription of lipid-lowering and anti-hypertensive agents did not change among the patients on Group Care, whereas anti-hypertensives were stepped up among Controls without improving their blood pressure. Multivariable analysis suggests that blood pressure improvement among patients on Group Care was independent of BMI, duration of diabetes and antihypertensive medication, suggesting a direct effect of education, presumably by increasing adherence. The "Powerful Others" dimension of the Locus of Control worsened and fear of complications decreased among Controls. CONCLUSIONS: The results confirm that a multidisciplinary structured group educational approach improves blood pressure, presumably through better adherence to healthy lifestyle and medication, in people with type 2 diabetes. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN14558376.

SGLT2 inhibition to address the unmet needs in diabetic nephropathy.

Current treatment of diabetic nephropathy is effective; however, substantial gaps in care still remain and new therapies are urgently needed to reduce the global burden of the complication. Desirable properties of an "ideal" new drug should include primary prevention of microalbuminuria, additive/synergistic anti-proteinuric effect in combination therapy with renin angiotensin system blockers, reduction of chronic kidney disease progression to lower the risk of end-stage renal disease, and cardiovascular protection. Growing evidence suggests that sodium-glucose cotransporter 2 inhibitors (SGLT2i) may fulfil many of these criteria and represent novel tools to cover the unmet needs in diabetic nephropathy care. However, the underlying mechanisms of SGLT2i renal benefits are still poorly understood and promising results from cardiovascular outcome trials with SGLT2i need confirmation in dedicated renal outcome trials.

Nutritional behavior in Italian and immigrant children.

BACKGROUND: There are 1.2 million of immigrant children living in Italy. However, data on their nutritional habits are limited. The aim of this study was to assess the nutritional profile in a cohort of both Italian and immigrant children. METHODS: The study included 86 children aged 5-15 consecutively enrolled from January 2016 to May 2017 within a larger epidemiological study on determinants of diabetes. Immigrant state was defined on the basis of the parent origin. Data on nutritional profile, frequency of food group consumption, and eating habits were collected using the 24-hour dietary recall method and a questionnaire. Anthropometric parameters were measured. RESULTS: In the cohort of immigrant children there was a higher prevalence of both overweight (27.3 vs. 14.1%) and obesity (18.2 vs. 3.1%) subjects and a greater total calorie intake compared to Italian children, mainly due to excess simple carbohydrate intake. Immigrant children had a higher consumption of sweets, snacks, and drinks with added sugar. Moreover, unhealthy habits, such as eating alone and eating while watching TV, were more frequent among immigrant children. CONCLUSIONS: In this cohort, immigrant children had a higher prevalence of overweight/obesity possibly due to less healthy nutritional habits. Culturally-tailored nutritional interventions may help preventing the development of obesity-related diseases in this population.

The role of cannabinoid signaling in acute and chronic kidney diseases.

The endogenous cannabinoids anandamide and 2-arachidonoylglycerol bind to the cannabinoid receptors of type 1 and 2. These receptors are also the binding sites for exogenous, both natural and synthetic, cannabinoids that are used for recreation purposes. Until recently, cannabinoids and cannabinoid receptors have attracted little interest among nephrologists; however, a full endocannabinoid system (ECS) is present in the kidney and it has recently emerged as an important player in the pathogenesis of diabetic nephropathy, drug nephrotoxicity, and progressive chronic kidney disease. This newly established role of the ECS in the kidney might have therapeutic relevance, as pharmacological modulation of the ECS has renoprotective effects in experimental animals, raising hope for future potential applications in humans. In addition, over the last years, there has been a number of reported cases of acute kidney injury (AKI) associated with the use of synthetic cannabinoids that appear to have higher potency and rate of toxicity than natural Cannabis. This poorly recognized cause of renal injury should be considered in the differential diagnosis of AKI, particularly in young people. In this review we provide an overview of preclinical evidence indicating a role of the ECS in renal disease and discuss potential future therapeutic applications. Moreover, we give a critical update of synthetic cannabinoid-induced AKI.

Cannabinoid Receptors in Diabetic Kidney Disease.

PURPOSE OF REVIEW: The purpose of this review is to examine and summarize studies assessing the relevance of the endocannabinoid system (ECS) in diabetic kidney disease (DKD). RECENT FINDINGS: Endocannabinoids and endocannabinoid receptors of type 1 (CB1R) and of type 2 (CB2R) are present in the normal kidney. Expression of CB1R and CB2R is altered in experimental DKD. Studies in experimental animals and cultured kidney cells show a beneficial effect of peripheral CB1R blockade and CB2R activation in DKD and an even greater efficacy of a combined treatment. Preclinical studies confirm that both CB1R and CB2R are implicated in the pathogenesis of DKD and may represent novel targets for treatment. However, we need to gain a better understanding of the ECS prior to move to human clinical trial.

Haemoglobin A1c variability is a strong, independent predictor of all-cause mortality in patients with type 2 diabetes.

AIMS: To evaluate various measures of haemoglobin (Hb) A1c variability, compared with average HbA1c, as independent predictors of mortality. MATERIALS AND METHODS: The Renal Insufficiency And Cardiovascular Events Italian multicentre study enroled 15 733 patients with type 2 diabetes from 19 diabetes clinics during 2006-2008. A total of 3 to 5 HbA1c measures, obtained during the 2-year period before enrolment, were available from 9 centres (8290 patients) and were used to calculate average HbA1c (HbA1c -MEAN) and HbA1c variability, measured as intra-individual standard deviation (HbA1c-SD), SD adjusted for the number of HbA1c assessments (HbA1c-AdjSD) and coefficient of variation (HbA1c-CV), that is, the HbA1c-SD to HbA1c-MEAN ratio. Vital status on October 31, 2015 was retrieved for 8252 patients (99.5%). RESULTS: The measures of HbA1c variability increased according to quartiles of HbA1c-MEAN and vice versa. HbA1c-MEAN and measures of HbA1c variability were associated with all-cause mortality; however, the strength of association of HbA1c-MEAN was lower than that of HbA1c -SD, HbA1c-CV or HbA1c-AdjSD, and disappeared after adjusting for confounders and any of the measures of HbA1c variability. Mortality increased with quartiles of HbA1c-MEAN, HbA1c -SD, HbA1c-CV and HbA1c-AdjSD, but only the association with HbA1c variability measures remained after adjustment for confounders and/or each other measure. In the fully adjusted model, mortality risk was lower for HbA1c-SD below the median and higher for HbA1c-SD above the median, regardless of whether HbA1c-MEAN was below or above the median. Conclusions HbA1c variability is a strong, independent predictor of all-cause mortality in type 2 diabetes and appears to be even more powerful than average HbA1c in predicting mortality.

NTproBNP in insulin-resistance mediated conditions: overweight/obesity, metabolic syndrome and diabetes. The population-based Casale Monferrato Study.

BACKGROUND AND AIMS: NTproBNP and BNP levels are reduced in obese subjects, but population-based data comparing the pattern of this relationship in the full spectrum of insulin-resistance mediated conditions, overweight/obesity, metabolic syndrome and diabetes, are limited. METHODS: The study-base were 3244 individuals aged 45-74 years, none of whom had heart failure, 1880 without diabetes and 1364 with diabetes, identified as part of two surveys of the population-based Casale Monferrato Study. All measurements were centralized. We examined with multiple linear regression and cubic regression splines the relationship between NTproBNP and BMI, independently of known risk factors and confounders. A logistic regression analysis was also performed to assess the effect of overweight/obesity (BMI ≥ 25 kg/m2), diabetes and metabolic syndrome on NTproBNP values. RESULTS: Out of the overall cohort of 3244 people, overweight/obesity was observed in 1118 (59.4%) non-diabetic and 917 (67.2%) diabetic subjects, respectively. In logistic regression, compared to normal weight individuals, those with a BMI ≥ 25 kg/m2 had a OR of 0.70 (95% CI 0.56-0.87) of having high NTproBNP values, independently of diabetes. As interaction between diabetes and NTproBNP was evident (p < 0.001), stratified analyses were performed. Diabetes either alone or combined with overweight/obesity or metabolic syndrome enhanced fourfold and over the OR of having high NTproBNP levels, while the presence of metabolic syndrome alone had a more modest effect (OR 1.54, 1.18-2.01) even after having excluded individuals with CVD. In the non-diabetic cohort, obesity/overweight and HOMA-IR ≥ 2.0 decreased to a similar extent the ORs of high NTproBNP [0.76 (0.60-0.95) and 0.74 (0.59-0.93)], but the association between overweight/obesity and NTproBNP was no longer significant after the inclusion into the model of HOMA-IR, whereas CRP > 3 mg/dl conferred a fully adjusted OR of 0.65 (0.49-0.86). CONCLUSIONS: NT-proBNP levels are lower in overweight/obesity, even in those with diabetes. Both insulin-resistance and chronic low-grade inflammation are involved in this relationship. Further intervention studies are required to clarify the potential role of drugs affecting the natriuretic peptides system on body weight and risk of diabetes.

Dual therapy targeting the endocannabinoid system prevents experimental diabetic nephropathy.

BACKGROUND: The endocannabinoid system has been implicated in the pathogenesis of diabetic nephropathy (DN). We investigated the effect of combined therapy with AM6545, a 'peripherally' restricted cannabinoid receptor type 1 (CB1R) neutral antagonist, and AM1241, a cannabinoid receptor type 2 (CB2R) agonist, in experimental DN. METHODS: Renal function and structure, podocyte proteins and markers of both fibrosis and inflammation were studied in streptozotocin-induced diabetic mice treated for 14 weeks with vehicle, AM6545, AM1241 and AM6545-AM1241. RESULTS: Single treatment with either AM6545 or AM1241 alone reduced diabetes-induced albuminuria and prevented nephrin loss both in vivo and in vitro in podocytes exposed to glycated albumin. Dual therapy performed better than monotherapies, as it abolished albuminuria, inflammation, tubular injury and markedly reduced renal fibrosis. Converging anti-inflammatory mechanisms provide an explanation for this greater efficacy as dual therapy abolished diabetes-induced renal monocyte infiltration and M1/M2 macrophage imbalance in vivo and abrogated the profibrotic effect of M1 macrophage-conditioned media on cultured mesangial cells. CONCLUSION: 'Peripheral' CB1R blockade is beneficial in experimental DN and this effect is synergically magnified by CB2R activation.

Heat Shock Proteins in Vascular Diabetic Complications: Review and Future Perspective.

Heat shock proteins (HSPs) are a large family of proteins highly conserved throughout evolution because of their unique cytoprotective properties. Besides assisting protein refolding and regulating proteostasis under stressful conditions, HSPs also play an important role in protecting cells from oxidative stress, inflammation, and apoptosis. Therefore, HSPs are crucial in counteracting the deleterious effects of hyperglycemia in target organs of diabetes vascular complications. Changes in HSP expression have been demonstrated in diabetic complications and functionally related to hyperglycemia-induced cell injury. Moreover, associations between diabetic complications and altered circulating levels of both HSPs and anti-HSPs have been shown in clinical studies. HSPs thus represent an exciting therapeutic opportunity and might also be valuable as clinical biomarkers. However, this field of research is still in its infancy and further studies in both experimental diabetes and humans are required to gain a full understanding of HSP relevance. In this review, we summarize current knowledge and discuss future perspective.

Levels of N-terminal pro brain natriuretic peptide are enhanced in people with the uncomplicated metabolic syndrome: a case-cohort analysis of the population-based Casale Monferrato study.

BACKGROUND: Both metabolic syndrome (MetS) and N-amino terminal fragment of the prohormone B-type natriuretic peptide (NT-proBNP) confer increased risk of cardiovascular diseases (CVD). We assessed if NT-proBNP levels were greater in people with uncomplicated MetS, who had neither CVD/chronic kidney disease (CKD) nor diabetes, as compared with subjects who met none of the defining criteria of the MetS. METHODS: A case-cohort study from the non-diabetic population-based Casale Monferrato study was performed, after exclusion of all subjects with established CVD, CKD [estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m(2)], and CRP values ≥3 mg/L. Cases (n = 161) with MetS were compared with all subjects within the cohort (n = 124) who were completely free of any component of the MetS. Serum NT-proBNP was centrally measured by immunoenzymatic assay. RESULTS: NT-proBNP levels were significantly higher in cases than in control subjects [35.4 (15.5-98.2) vs 24.4 (11.7-49.6) pg/mL, p = 0.014]. In logistic regression analysis, compared with NT-proBNP values in the lower quartiles (≤49.64 pg/mL), higher values conferred odds ratio 4.17 (1.30-13.44) of having the MetS, independently of age, sex, microalbuminuria, CRP, eGFR, and central obesity. This association was evident even after the exclusion of hypertensive subjects. Further adjustment for log-HOMA and diastolic blood pressure did not modify the strength of the association, while central obesity was a negative confounder. CONCLUSIONS: Compared with people without any component of the MetS, those with uncomplicated MetS, who had neither CVD/CKD nor diabetes, had increased NT-proBNP values, even if they were normotensive and although absolute values were still in the low range. The insulin resistance state did not mediate this association, while central obesity was a negative confounder.

Deficiency of cannabinoid receptor of type 2 worsens renal functional and structural abnormalities in streptozotocin-induced diabetic mice.

A functionally active endocannabinoid system is present within the kidney. The cannabinoid receptor type 2 (CB2) is expressed by both inflammatory cells and podocytes, and its activation has beneficial effects in experimental diabetic nephropathy. To further explore the role of CB2 in diabetic nephropathy, we studied renal functional and structural abnormalities in streptozotocin-induced diabetic CB2 knockout mice. In diabetic mice, deletion of the CB2 receptor albuminuria, the downregulation of podocin and nephrin, mesangial expansion, overexpression of extracellular matrix components, monocyte infiltration, and reduced renal function were all exacerbated. To investigate the relative contributions of podocytes and monocytes to the phenotype of diabetic knockout mice, bone marrow transplantation experiments were performed. The lack of CB2 on bone marrow-derived cells was shown to be important in driving the enhanced glomerular monocyte accrual found in diabetic knockout mice. Absence of CB2 on resident glomerular cells had a major role in worsening diabetic nephropathy, both functional and structural abnormalities, likely by enhanced MCP-1 and CB1 signaling. Studies in cultured podocytes demonstrated that CB2 expression is not altered by a high glucose milieu but is downregulated by mechanical stretch, mimicking glomerular capillary hypertension. Thus, CB2 deletion worsens diabetic nephropathy, independent of bone marrow-derived cells.

Distribution of cardiovascular disease and retinopathy in patients with type 2 diabetes according to different classification systems for chronic kidney disease: a cross-sectional analysis of the renal insufficiency and cardiovascular events (RIACE) Italian multicenter study.

BACKGROUND: The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (NKF's KDOQI) staging system for chronic kidney disease (CKD) is based primarily on estimated GFR (eGFR). This study aimed at assessing whether reclassification of subjects with type 2 diabetes using two recent classifications based on both eGFR and albuminuria, the Alberta Kidney Disease Network (AKDN) and the Kidney Disease: Improving Global Outcomes (KDIGO), provides a better definition of burden from cardiovascular disease (CVD) and diabetic retinopathy (DR) than the NKF's KDOQI classification. METHODS: This is a cross-sectional analysis of patients with type 2 diabetes (n = 15,773) from the Renal Insufficiency And Cardiovascular Events Italian Multicenter Study, consecutively visiting 19 Diabetes Clinics throughout Italy in years 2007-2008. Exclusion criteria were dialysis or renal transplantation. CKD was defined based on eGFR, as calculated from serum creatinine by the simplified Modification of Diet in Renal Disease Study equation, and albuminuria, as measured by immunonephelometry or immunoturbidimetry. DR was assessed by dilated fundoscopy. Prevalent CVD, total and by vascular bed, was assessed from medical history by recording previous documented major acute events. RESULTS: Though prevalence of complications increased with increasing CKD severity with all three classifications, it differed significantly between NKF's KDOQI stages and AKDN or KDIGO risk categories. The AKDN and KDIGO systems resulted in appropriate reclassification of uncomplicated patients in the lowest risk categories and a more graded independent association with CVD and DR than the NKF's KDOQI classification. However, CVD, but not DR prevalence was higher in the lowest risk categories of the new classifications than in the lowest stages of the NKF's KDOQI, due to the inclusion of subjects with reduced eGFR without albuminuria. CVD prevalence differed also among eGFR and albuminuria categories grouped into AKDN and KDIGO risk category 1 and moderate, respectively, and to a lesser extent into higher risk categories. CONCLUSIONS: Though the new systems perform better than the NKF's KDOQI in grading complications and identifying diabetic subjects without complications, they might underestimate CVD burden in patients assigned to lower risk categories and should be tested in large prospective studies. TRIAL REGISTRATION: ClinicalTrials.gov; NCT00715481.

Early life socioeconomic indicators and risk of type 1 diabetes in children and young adults.

OBJECTIVE: To examine the potential role of 2 early-life socioeconomic indicators, parental education, and crowding index, on risk of type 1 diabetes (T1DM) in patients up to age 29 years to test heterogeneity by age at onset according to the hygiene hypothesis. STUDY DESIGN: The study base was 330 950 individuals born from 1967 to 2006 who resided in the city of Turin at any time between 1984 and 2007. Data on their early life socioeconomic position were derived from the Turin Longitudinal Study; 414 incident cases of T1DM up to age 29 years were derived from the Turin T1DM registry. RESULTS: Socioeconomic indicators had opposing effects on risk of T1DM in different age at onset subgroups. In a Poisson regression model that included both socioeconomic indicators, there was a 3-fold greater risk of T1DM (relative risk 2.91, 95% CI 0.99-8.56) in children age 0-3 years at diagnosis living in crowded houses. In the 4- to 14-year subgroup, a low parental educational level had a protective effect (relative risk 0.50, 95% CI 0.29-0.84), and the effect of crowding nearly disappeared. In the 15- to 29-year subgroup, neither crowding nor parental educational level was clearly associated with the incidence of T1DM. CONCLUSIONS: We provide evidence of heterogeneity by age at onset of the association between early-life socioeconomic indicators and the risk of T1DM. This finding is consistent with the hypothesis that infectious agents in the perinatal period may increase the risk, whereas in the following years they may become protective factors (hygiene hypothesis).

Serum MicroRNA-191-5p Levels in Vascular Complications of Type 1 Diabetes: The EURODIAB Prospective Complications Study.

CONTEXT: MicroRNA-191-5p regulates key cellular processes involved in the pathogenesis of diabetic complications such as angiogenesis, extracellular matrix deposition, and inflammation. However, no data on circulating microRNA-191-5p in the chronic complications of diabetes are available. OBJECTIVE: To assess whether serum levels of microRNA-191-5p were associated with micro- and macrovascular disease in a large cohort of subjects with type 1 diabetes mellitus (DM1) from the EURODIAB Prospective Complication Study. DESIGN AND SETTING: Levels of microRNA-191-5p were measured by quantitative PCR in 420 patients with DM1 recruited as part of the cross-sectional analysis of the EURODIAB Prospective Complication Study. Cases (n = 277) were subjects with nephropathy and/or retinopathy and/or cardiovascular disease (CVD). Controls (n = 143) were patients without complications. Logistic regression analysis was performed to evaluate the potential independent association of microRNA-191-5p levels with chronic complications of diabetes. RESULTS: Levels of microRNA-191-5p were significantly reduced (P < .001) in cases compared with controls even after adjustment for age, sex, and diabetes duration. Logistic regression analysis revealed that microRNA-191-5p was negatively associated with a 58% reduced odds ratio (OR) of chronic diabetes complications, specifically CVD, micro-macroalbuminuria, and retinopathy (OR, 0.42; 95% CI, 0.23-0.77), independent of age, sex, physical activity, educational levels, diabetes duration, glycated hemoglobin, total insulin dose, hypertension, smoking, total cholesterol, albumin excretion rate, estimated glomerular filtration rate, serum vascular cell adhesion molecule-1, and tumor necrosis factor-α. Analyses performed separately for each complication demonstrated a significant independent association with albuminuria (OR, 0.36; 95% CI, (0.18-0.75) and CVD (OR, 0.34; 95% CI, 0.16-0.70). CONCLUSIONS: In DM1 subjects, microRNA-191-5p is inversely associated with vascular chronic complications of diabetes.

Novel Insight into the Mechanisms of the Bidirectional Relationship between Diabetes and Periodontitis.

Periodontitis and diabetes are two major global health problems despite their prevalence being significantly underreported and underestimated. Both epidemiological and intervention studies show a bidirectional relationship between periodontitis and diabetes. The hypothesis of a potential causal link between the two diseases is corroborated by recent studies in experimental animals that identified mechanisms whereby periodontitis and diabetes can adversely affect each other. Herein, we will review clinical data on the existence of a two-way relationship between periodontitis and diabetes and discuss possible mechanistic interactions in both directions, focusing in particular on new data highlighting the importance of the host response. Moreover, we will address the hypothesis that trained immunity may represent the unifying mechanism explaining the intertwined association between diabetes and periodontitis. Achieving a better mechanistic insight on clustering of infectious, inflammatory, and metabolic diseases may provide new therapeutic options to reduce the risk of diabetes and diabetes-associated comorbidities.

Association of serum MicroRNA-145-5p levels with microvascular complications of type 1 Diabetes: The EURODIAB prospective complications study.

AIMS: To investigate whether serum miR-145-5p levels were associated with micro-macrovascular chronic complications in patients with type 1 diabetes (DM1). METHODS: A nested case-control study from the EURODIAB Prospective Complications Study was performed. Cases (n = 289) had one or more complications of diabetes, whereas controls (n = 153) did not have any complication. We measured miR-145-5p levels by qPCR and investigated the association with diabetes complications. RESULTS: Mean miR-145-5p levels were significantly lower in cases with microangiopathy [2.12 (0.86-4.94)] compared to controls [3.15 (1.21-7.36), P < 0.05] even after adjustment for age, gender, and diabetes duration. In logistic regression analysis, miR-145-5p levels in the lowest tertile were associated with an over three-fold increased odds ratio (OR) of albuminuria [3.22 (1.17-8.81)], independently of both demographic and diabetes-related factors. In addition, mir145-5p levels in the lowest tertile were independently and inversely associated with arterial hypertension [1.96 (1.08-3.56)] and hypertension was the mediator of the relationship between miR-145-5p and albuminuria. CONCLUSIONS: In this large cohort of DM1 patients, we found an inverse association between miR-145-5p and albuminuria that was mediated by systemic hypertension.